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The training in specific communication skills during medical school is based on the notion that independent of the physician's medical knowledge, the practice of communication skills will have a significant impact upon the character and quality of the consultation. The reason for consulting the doctor may be concerns about more than symptom-related distress . In some studies, successful levels of communication skills have been linked to students' diagnostic efficiency, patient stress, patient compliance, medical errors, general outcome, outcome in chronic disorders, and patient and physician satisfaction . However, the intermediate variable between communication skills and such outcome measures, the content of a consultation in a general practice setting, has still not been sufficiently explored. One way to explore these issues is to observe students or physicians in their interaction with patients in a clinical setting. In this regard, one basic methodological problem should be addressed. Should one employ a standardized patient (i.e. an actor in a constructed but typical patient setting) or many different patients? This study design has adopted the first option so all interviewers attending the study could be compared in their skills, but the generalization of the findings may be limited to the specific case being played by the actor, even if the case in its relative complexity is fairly representative of patients in general practice. Findings indicate that a significant case-by-student interaction between communication skills and decision making exists and that individuals' communication skills vary systematically with specific cases . The length of the test being observed may also influence the results. A 15-minute consultation, ordinary in a general practice setting and part of the present study design, has been found to be too short to assess generalizable interviewing skills . Concerning background variables, we would presume that female and older students will develop communication skills promoting psychosocial issues more easily and more effectively than males and younger students. The sample has to be viewed as an "availability" sample, and we cannot know for sure how representative the attendees were of the national student population. The data from our survey sample showed that the gender proportion among the final-year students in spring 2004 (N = 320) was 65% females (N = 208, ratio 0.65, CI 95% 0.60 – 0.70); in the observational sample (N = 111 of the same 320), the gender proportion of females was 70% (N = 78, ratio 0.70, CI 95% 0.61 – 0.78). Mean age among the 320 was 27,3 (CI 95% 26,9 – 27,7) years, among the 111 27,8 (CI 95% 27,2 – 28,4). When we compared the scores on a self-report questionnaire assessing their self evaluation of communication skills (Oslo Inventory of Self-reported Communication Skills – OSISCS), the participants in the survey study yielded approximately the same mean score (3,75 +0 .46 on a 1–5 scale) one year earlier (when they were in their 5 th year of medical school; medical school in Norway lasts for six years) as the 111 attendees (3,51 +0 .34) with minor variance between genders . With overlapping confidence intervals regarding gender and age and close to similar scores on self-reported skills, none of these differences should be viewed as significant. Thus we presume that we have achieved a fairly representative sample. Since the construction of the content scale was not based upon psychometric properties, we found it most reasonable to look at the face validity. The 15 consultation content items (Table 1 ) were divided into three Content indices: The Somatic Index comprising the two diagnostic items (myomas and anemia) together with the five illness items (numbers 3 – 7). Due to very low internal consistency (Cronbach's α = 0.26), the two diagnostic items were excluded and with the five illness items left constituting the Illness index (1), alpha increased to 0.44. The Concern Index (2) comprised two items related to the patient's concern about possible cancer (numbers 8 – 9, α = 0.53), and the Psychosocial Index (3) comprised the six psychosocial items (numbers 10 – 15, α = 0.46). We also constructed a fourth index called The Informing/planning Index (4) by combining two items (item 6 – treatment planning and item 9 – information, α = 0.72) from the Maastricht History and Advice Checklist (MAAS) . This index covered the action taken by the student at the end of the consultation. MAAS items were scored on a 0–5 scale, yielding a median of 3,0. A cut off >3 was used to demonstrate presence of the item during the consultation. Inter-rater reliability between the MAAS raters was (ICC(1.1)) = 0.69. The Arizona Communication Interview Rating Scale (ACIR) consists of 14 items (Table 2 ) all with a scale from 1 (least) to 5 (best) . Three trained raters scored the videotapes and one separate rater scored 2/3 of them in order to check the inter-rater reliability (not the same as above). The Intra-class correlation coefficient between raters was similar to that between the MAAS raters ICC(1.1) = 0.69. The overall ACIR mean was 3,10 (0.69). The psychometric properties of ACIR have been found satisfactory in an earlier study . A Principal Component Analysis with a Varimax rotation yielded a typical one-factor solution, so the overall mean was used in all analyses. The internal consistency of ACIR in our sample was 0.91 (Cronbach's α). As one way of validating ACIR, we correlated ACIR-mean against the MAAS-mean (without the two items constituting the Informing/planning index being used as a content index) giving a value of Pearson's r = 0.61. The question of tautology may be raised as the rating of the ACIR items could be influenced by how the content items were rated and vice versa, even if separate raters were used. We, therefore, wished to control for this possibility using a special procedure. When carefully scrutinizing the ACIR items one by one, we categorized them as content-related and non-content-related. Items number 3, 4, 5, 6, 8, 10 and 11 were considered non-content-related. This categorization, which of course may be disputed, is highly consonant with the separation of ACIR items performed in a previous study by Aspegren et al. . This group of items (numbers 5, 6, 8, 10, and 11, Cronbach's α = 0.86) was viewed as more typical for civil social conversation, i.e. not strictly related to a specific medical context. The mean of these non-content related items could be used as a substitute for the ordinary overall ACIR-mean in the multiple analyses to test for possible differences in association with our outcome variables (Content indices). In four linear regression analyses, the four consultation Content indices (Illness, Psychosocial, Concern, and Informing/planning) were used as dependent variables and the overall ACIR-mean as the independent variable with gender and age as control variables. The level of communication skills had a significant impact upon the Psychosocial, the Concern and the Informing/planning indices, controlled for gender and age, yielding standardized Beta-values of 0.45 for the concern index (explaining 19% of the variance), .34 for the Informing/planning index (11%), and 0.29 for the psychosocial index (8%). The Illness index had no significant relationship to level of communication skills (Table 5 ). When substituting the overall ACIR-mean with the ACIR non-content-related mean, no deviating associations were detected (Beta-values deviating at a maximum of 0.02). When exploring characteristics for the eight sub-groups derived from combinations of the dichotomized Illness, Psychological/concerns, and the Informing/planning part-counts, overall ACIR-mean was significantly higher in those with high score (above median) on all three indices (Illness, Psychosocial/concern, and Informing/planning) compared with those having low score on all three or high on the Illness but low on the two others (F = 4,60, p = 0.001). Gender and age did not vary between the eight sub-groups. One of the main findings in this study is that the level of communication skills was significantly related to the total content index, especially to the Psychosocial, the Concerns, and the Informing/planning indices, but not to the Illness index, controlled for gender and age. As shown in Table 5 , the strongest relationship was with the Concern index, while the Informing/planning and Psychosocial indices yielded somewhat weaker relationships. This implies that the higher the level of communication skills, the more adequately addressed was the content of the consultation related to the patient's possible stressors; i.e. her fear of having the cancer from which her mother may have died 10 years earlier, responsibility for her children, the divorce she had been through, and the burden of moving to a new place, a.o. The students with the higher level of communication skills were also more able to perform adequate informing/planning procedures at the end of the consultation. These results were supported by the fact that students scoring high on all three dichotomized indices (the Illness, the Psychosocial/Concerns, and Informing/planning) had significantly higher levels of communication skills than those scoring low on all three indices, as well as those with high score on the Illness, but low scores on the other two indices. No variation in gender and age characterized these sub groups, showing that it was the level of communication skills that mattered. The risk of tautology when exploring associations between phenomena with instruments possibly covering some of the same issues has been considered and attended to by testing any possible difference when using the overall mean in contrast to the no-content-related mean of ACIR. When no such difference existed, it is reasonable to presume that the relationship we have found between communication skills and the content indices in this specific consultation was real and not confounded by lack of construct validity for the two instruments. The finding that there was no significant relationship between a high level of communication skills and a high count on the Illness index is important. This may be due to a low variance in the Illness index, but this does not coincide with Table 3 . Another interpretation of this finding, therefore, may be that the somatic content of this particular consultation (the diagnoses of possible myomas and anemia as well as the subjective complaints) depends more on biomedical knowledge than the communication skills themselves and that the presence of these symptoms was not related to psychosocial aspects. Along the same line, we found that those who scored high on the Illness index but low on the Psychosocial and Informing/planning indices had a significantly lower level of communication skills compared with those with high scores on all three indices. This supports the view that graduate students who are very competent in evaluating somatic complaints nevertheless may fail to identify important psychosocial stressors and concerns, in this case due to the lack of communication skills. We know that these issues are important both for patient compliance and satisfaction as well as for the further course and outcome of many somatic disorders . In order to obtain valuable information on the emotional burdens of patients who may be less willing than the "patient" in this study to disclose such issues, the need for specific communication skills is obvious. In a study by Pfeiffer et al. , a decrease in students' communication skills was found through the last part of medical school, after an initial increase, especially their skills in obtaining an adequate social history. One interpretation offered was that this can be due to a medical culture which de-emphasizes communication skills in favor of somatic knowledge. This can also be a possible explanation of our findings. Therefore it is important to identify factors that may enhance as well as hamper the development of communication skills among medical students. This study has shown that the level of communication skills and the content of the consultation with regard to psychosocial issues, patient concerns and the informing and planning procedures (with a representative patient in a general practice setting) among graduate medical students are significantly correlated. On the other hand, no such relationship between communication skills and the somatic/illness content of the consultation was detected. Even if the students attending this study had good biomedical knowledge on this specific case, they may have overlooked important psychosocial stressors as well as the patient's concerns, and may have lacked the necessary skills to conclude this single patient consultation in a fruitful way. In this light, medical schools and researchers, utilizing a broader spectrum of patient stories, should continue to identify factors that promote as well as inhibit medical students' learning of communication skills.
|
Other
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biomedical
|
en
| 0.999996
|
18298853
|
Oral lesions are well-documented clinical features in patients with Crohn's disease (CD) . The spectrum of these lesions described so far in the medical and dental literature is quite large and includes oral ulceration, labial, buccal and gingival swelling, buccal abscesses, mucosal inflammatory hyperplasia, mucosal tags and fissuring, gingivitis, granulomatous inflammation of minor salivary glands, granulomatous cheilitis , candidiasis, angular cheilitis, lichen planus, pyostomatitis vegetans, lymphadenopathy, perioral erythema, orofacial granulomatosis, midline lip fissuring, cobblestone appearance of the mucosa, and dental caries. The prevalence of oral lesions in newly diagnosed patients has been estimated to be up to 48% . The patient was a man aged 25. He was a smoker (20 cigarettes per day) since the age of 19. His symptoms started on June 1998 at the age of 24, with chronic diarrhea not accompanied by mucus or blood in the stools, abdominal pain, fever, or loss of weight. Two years previously on June 1996, he had noticed a slight swelling of the lower lip which contrasted with the previously normal appearance of his mouth . He consulted a specialist in oral medicine, who performed a lip biopsy. The histology of the specimen (13 × 7 × 7 mm) showed a multilayer squamous epithelium covering the tissue specimen, scattered clusters of lymphocytes and histiocytes resembling non-caseating granulomas, as well as infiltration of the small vessel walls of the underlying connective tissue by monocytes . The diagnosis was compatible with granulomatous cheilitis. Colonoscopy performed in 1998 revealed large ulcers in the terminal ileum and caecum. Enteroclysis confirmed the involvement of the terminal ileum in a total length of 50 cm. Administration of methylprednisolone, mesalazine and cholestyramine, resulted in prompt improvement of clinical symptoms and laboratory abnormalities. Orofacial granulomatosis is a term generally used to describe swelling of the orofacial area, mainly the lips, secondary to an underlying granulomatous inflammatory process. It is a heterogeneous clinical condition that presents with chronic swelling of the oral or facial tissues due to granulomatous inflammation. Granulomatous cheilitis is a very rare disorder of unknown etiology, characterised by recurrent swelling of the labial tissues. The typical histological picture is the formation of scattered aggregates of non-caseating granulomas and epithelioid histiocytes. Melkersson-Rosenthal syndrome (a triad of orofacial swelling, facial paralysis and a fissured tongue) is one manifestation of orofacial granulomatosis, which more commonly presents as granulomatous cheilitis alone . Most reported cases of orofacial granulomatosis have been in adults and some in adolescents. Orofacial granulomatosis in the paediatric population may be an initial manifestation of CD. The interesting points regarding the clinical manifestations and the course of our patient were the fact that granulomatous cheilitis preceded the diagnosis of CD by two years, the fact that the enlargement of the lower lip occurred in parallel with the clinical exacerbations of CD and that the administration of corticosteroids resulted not only in improvement of bowel symptoms but also in diminishment of the size of the lip swelling. Another point of interest was the fact that granulomatous cheilitis was the only extraintestinal manifestation in our patient, a fact not mentioned in other descriptions. The etiology of this lesion is unknown although various factors including levels of vitamins and trace elements, other nutritional components, and certainly the underlying inflammatory bowel disease could be involved. Mycobacterium paratuberculosis has not been found to be implicated in the pathogenesis of orofacial granulomatosis or oral CD as was suggested previously. In the absence of mechanical irritation or other mucosal disease, the oral lesions in CD could be attributed to the inflammatory bowel disease itself. It is of interest that patients with oral lesions have a significantly higher proportion of involvement of the upper gastrointestinal tract (esophagus) with CD . This case emphasizes the fact that orofacial granulomatosis may be misdiagnosed since its clinical manifestations may be independent of or even precede the appearance of CD. Thus, patients with possible granulomatus cheilitis should be carefully asked about the presence of gastrointestinal symptoms. Those with suspicious symptoms should have a careful gastrointestinal evaluation, including enteroclysis or imaging capsule as well as complete gastrointestinal endoscopic examination. Once granulomatus cheilitis is diagnosed the patient should be followed up carefully and investigated for CD when gastrointestinal symptoms develop . However, not all authors agree completely with this assumption. Van der Waal et al found a low chance of developing CD in their patients with granulomatus cheilitis and thus they suggest that patients with a negative history of gastrointestinal complaints should not be exposed to routine investigations of the gastrointestinal tract .
|
Review
|
biomedical
|
en
| 0.999997
|
18718001
|
A forty five year old lady presented with chronic dull aching pain with gradually increasing lump in the epigastric and pelvic region since 3 years. A well defined, firm mass of about 20 × 20 centimeters was palpable in epigastrium extending more on right hypochondrium, probably arising from left lobe of liver. A similar mass was palpable in the hypogastrium while multiple small nodular masses palpable in the right iliac fossa and lumbar region. Detailed inquest revealed a 5 year old incidence of blunt abdominal trauma, while working in her farm. The ultrasonography and CT scan showed multiple thin walled cysts of varying size involving left lobe of liver, peritoneal cavity, omentum and mesentery. Cysts showing internal septae and peripheral tiny calcific foci were also seen extending into pelvis around uterus, adnexae and retro-uterine cervical region, markedly compressing distal descending colon, sigmoid colon and rectum. Ileal loops were compressed and displaced superiorly. Serology for hydatid cyst disease was positive with ELISA test. Two courses of 4 weeks of Albendazole (15 mg/kg/day) were given with the interval of 1 month. The follow up after 1 month did not show any decrease in the size of the cysts and decision of laparotomy was taken. Peritoneal cavity was crammed with cysts ranging from 1 to 12 centimeters . Omentum was studded with cysts which was incised and cysts were picked up . A superficial cyst found in the left lobe of liver was opened with small incision and the hydatid fluid and daughter cysts were drained. After the excision of germinal membrane the cavity was masupialized. Later, the pelvic cavity was exposed and cysts adherent to adnexa, uterus, broad ligament, urinary bladder and rectum were removed. More than 250 cysts of different sizes were removed from the abdomen . Patient died of anaphylactic shock within few hours of operation.
|
Clinical case
|
clinical
|
en
| 0.999996
|
18822182
|
Diseases of the heart valves cut across all age groups, race and geographic locations to form a significant cause of morbidity and mortality. These deformities may be congenital or acquired, as a result of developmental, post-inflammatory and degenerative changes. In our country, owing to high prevalence of rheumatic heart disease , the etiology in most valvular dysfunctions (stenosis and/or regurgitation) is attributed to rheumatic heart disease, unless proved otherwise. This is largely true in most instances, but there do exist occasions, where a "rheumatic "assumption is erroneous. We present a rare case of inflammatory pseudotumor, manifesting as a granulomatous valvulitis, producing chronic mitral and aortic regurgitation in a 62 years old lady. A 62-year-old woman presented to our Cardiovascular & Thoracic Center with complaints of breathlessness and palpitation. The dyspnea (grade II), present for the past eight years, had progressed in six months to grades III/IV. She had had past hospital admissions for similar complaints. A secundum atrial septal defect had been closed in the year 1990. She was advised valve replacement for rheumatic valvular heart disease. Routine hematological and biochemical investigations had been normal. Two-dimensional echocardiography showed severe mitral and moderate aortic, regurgitation. The pulmonary arterial pressure was 80 mm Hg. She was taken up for mitral and aortic valve replacements. The anterior mitral leaflet was thick and fleshy while the posterior leaflet was thin. There was no significant sub-valvular pathology. The anterior leaflet and the medial scallop of the posterior leaflet were excised and the valve was replaced by Carbomedics mechanical valve (27 mm). The right and non-coronary cusps of the aortic valve showed similar thickening. The cusps were excised and the valve replaced by a St. Jude's mechanical valve (19 mm). During surgery, there was inadvertent tear of the superior caval vein, which was sutured and the patient was put on ventilator support. She expired eight hours after surgery. On gross examination, the anterior leaflet , at its basal, commissural aspects was nodular and firm. The remaining leaflet was mildly thickened with rolling of the free margin. The tendinous chords were discrete, but moderately thickened. The right and non-coronary cusps were markedly thickened and firm; the left cusp looked normal . The thickened portions of both valves had a homogeneous, creamy cut surface. No thrombi were identified on gross. On histology, these valves revealed extensive polymorphic inflammatory infiltrate in their entire thickness with associated vascularization and minimal collagenization. There were plasma cells, lymphocytes, histiocytes and clusters of multinucleated giant cells , with few eosinophils and neutrophils. Interestingly, there were total seven foci of central ill-defined necroses, accompanied by nuclear debris and neutrophils ; these were surrounded by a vague palisade of histiocytes and giant cells. Stains for microorganisms, including fungi and acid fast bacilli, were negative. Since no obvious vegetations were formed, we entertained a possibility of Q fever endocarditis, but the organism ( Coxiella burnetii ) could not be demonstrated on immunohistochemistry or in-situ hydridization. We designated this lesion initially as idiopathic granulomatous valvulitis, but on the basis of exclusion, a diagnosis of valvular inflammatory pseudotumor was finally made. Immunohistochemistry confirmed the polyclonality of the inflammatory cells; myofibroblastic cells were not identified. In the partial chest autopsy that was subsequently performed, similar inflammatory cells were identified at the anterior mitral annulus and in the walls of the right and non-coronary sinuses of Valsalva. There was no involvement of the preserved posterior mitral leaflet or the ascending aorta. Our patient, a woman in her early sixties, had long-standing mitral and aortic regurgitation. She had had secundum atrial septal defect, patched at the age of 45 years. This type of defect is known to coexist with mitral valvular disease, especially rheumatic . However, review of the valvular morphology at operation and the subsequent valvectomy, did not suggest a rheumatic etiology. More interesting was the presence of inflammation that produced a tumorous expansion of the leaflet/cusps or an "inflammatory pseudotumor". Such inflammatory pseudotumors (IPT) or inflammatory myofibroblastic tumors (IMT), apart from the lungs, are also described in other organs, but occurrence in the heart is rare. Since its first description in 1975 , fewer than 30 cases of cardiac IMT have been described . By and large, the tumors have manifested mainly in children as inflow or outflow obstructions due to a propensity to involve the chambers . The present case is the eleventh case to be reported in adults . Apart from cardiac symptoms, our patient did not have any other constitutional symptoms, seen with IPTs . The IMT are considered as quasineoplastic lesions composed of inflammatory cells and myofibroblasts. In one subset of IMT, there is a profusion of inflammatory cells, secondary to infective or non-infective immune reactions, while the other group (considered neoplastic) is composed of myofibroblastic proliferation . We saw a predominance of inflammatory cells, including multinucleated giant cells in the excised mitral and aortic valves; the entire tissue had been processed. Hence we have preferred to use the term IPT. So far only nine patients have had involvement of the atrioventricular or the arterial valves with or without concomitant chamber involvement . It is interesting to note that lesions which tended to infiltrate the entire thickness of the valve leaflet/cusp were predominantly inflammatory while those having a polypoidal configuration were rich in spindled cells . No organisms were identified by special stains performed for bacteria, Mycobacteria and fungi. Assuming that there was a subtle underlying mitral valvulopathy due to the defect in the inter-atrial septum, we thought that a strong contender for producing valvulitis is chronic Q fever, where endocarditis accounts for 60 to 70% of the cases . The patients are often afebrile, and interestingly, vegetations are absent or small . However, Coxiella burnetii was not detected. One must also bear in mind other rarer causes of granulomatous valvulitis such as rheumatoid arthritis , Wegener's granulomatosis , and large vessel vasculitides . Our patient did not have any manifestations, suggestive of the aforementioned diseases.
|
Clinical case
|
biomedical
|
en
| 0.999995
|
19523243
|
Malignant transformation of mature cystic teratoma (MCT) is a rare complication occurring in approximately 1–3% of patients who have mature cystic teratoma . Although any of the constituent tissues of a teratoma has the potential to undergo malignant transformation, squamous cell carcinoma is the most commonly associated malignancy . Other reported malignancies arising in MCT include carcinoid tumor, adenocarcinoma, basal cell carcinoma, adenosquamous carcinoma, thyroid carcinoma, sebaceous carcinoma, malignant melanoma, sarcoma and neuroectodermal tumor . Primary renal carcinoid tumor is a low grade malignancy with neuroendocrine differentiation, and was first described by Resnick et al in 1966 . Since then less than 100 cases of primary renal carcinoid tumor have appeared in the international medical literature, and are often associated with horseshoe kidney (18–26%), renal teratoma (15%) and polycystic kidney disease (2%) . Primary carcinoid tumor arising within mature cystic teratoma of the kidney is rare. Only seven cases of primary carcinoid tumor arising in mature cystic teratoma of the kidney have been reported in the world medical literature to date , since the association was first described in 1976 by Kojiro et al . The simultaneous occurrence of mature cystic teratoma and adenocarcinoma in the kidney is also rare . To the best of our knowledge, the synchronous presentation in the same kidney of mature cystic teratoma, carcinoid tumor and adenocarcinoma has never been reported in the world medical literature. We present a unique and first case of a 50-year-old female with both primary carcinoid tumor and primary moderately differentiated adenocarcinoma simultaneously arising within mature cystic teratoma of horseshoe kidney. Additionally, we review the world medical literature and discuss the extreme rarity of this combination of primary tumors in the kidney and the probable common histogenesis of these synchronous neoplasms in horseshoe kidney. The patient was a 50-year-old female who presented with a 3-months history of progressive chronic low back and right hip pain. She had no symptoms of carcinoid syndrome. She had no previous history of malignancy, chemotherapy or radiotherapy. General physical exam was unremarkable. Chest radiographs and electrocardiogram were within normal limits. Her routine hemogram, urine and blood biochemical analyses were within normal ranges. A lumbar spine X-ray, done to workup her complaint of low back pain, accidentally found a large (1.9 cm) calcification overlying the lower pole of the right kidney . Subsequent computed tomography (CT) and magnetic resonance imaging (MRI) scans of abdomen and pelvis revealed horseshoe shaped kidney and a large (10.5 × 7.8 cm) multiseptated cystic lesion immediately anterior to the right renal pelvis with central calcification (1.9 cm) and peripheral enhancement , which was interpreted radiologically as a Bosniak category IV renal lesion with a 90% chance of malignancy. No additional lesions were identified in the brain, gastrointestinal tract, liver, spleen, pancreas, bladder, uterus, ovaries and bones on additional MRI scans of the abdomen, brain, chest and pelvis, and positron emission tomography (PET) scan. This excluded the possibility of other primary malignancies metastatic to the right kidney. Her serum levels of alpha-fetoprotein (α-FP), beta-subunit of human chorionic gonadotropin (β-hCG), carbohydrate antigen (CA) 19-9, CA72-4, CA125, carcinoembryonic antigen (CEA), chromogranin and serotonin were within normal ranges. Her urinary 5-hydroxyindoleacetic acid (5-HIAA) level was also within normal range. In view of the high concern for primary malignancy in this Bosniak category IV right renal lesion, the patient elected to undergo right partial nephrectomy for definitive surgical treatment. After the peritoneal cavity was surgically opened, a thorough inspection and palpation of the peritoneal cavity was performed which revealed no ascitic fluid, adhesions, or other evidence of metastatic disease or non-renal primary malignancy. The entire right renal tumor was surgically resected with an excellent margin of 0.5 cm of normal parenchyma surrounding the entire cyst wall, and the tumor was entirely confined to the kidney. No other lesions were present in the adjacent renal parenchyma. The postoperative period was uneventful and the patient was discharged four days after surgery. Additional sections were used to perform immunohistochemical studies using an avidin-biotin peroxidase technique with hematoxylin counterstain. The antibodies used in this study included the following; alpha-methylacyl-coenzyme A-racemase (AMACR/P504S) [1:100, Ventana Medical Systems Inc, Tucson, Arizona], calretinin (1:100, Becton Dickinson, San Jose, California, USA), carbonic anhydrase IX (CA-IX, 1:200, DakoCytomation, Carpinteria, California, USA), CD10 (1:200, Ventana), CD56 (1:200, DakoCytomation), CD99 (1:100, Ventana), CDX2 (1:100, Ventana), chromogranin (1:200, Signet Pathology Systems Inc, Dedham, Massachusetts, USA), cytokeratin 7 (CK7, 1:200, Ventana), cytokeratin 20 (CK20, 1:200, DakoCytomation), pancytokeratin cocktail (AE1-AE3, 1:500, DakoCytomation; CAM 5.2, 1:50, Becton Dickinson; MNF116, 1:50, DakoCytomation; and UCD/PR-10.11, 1:25, Zymed, San Francisco, California), smooth muscle actin (SMA, 1:200, DakoCytomation), synaptophysin (1:100, DakoCytomation), and thyroid transcription factor-1 (TTF-1, 1:250, Ventana). Appropriate tissue sections that had been shown to be positive or negative for each marker were used as controls. Slides stained omitting the primary antibody were also used as negative controls. We analyzed the intensity and immunoreactivity of the immunostained sections. The intensity was graded qualitatively as weak, moderate, or strong on the basis of the brown color produced by the 3, 3'-diaminobenzidine chromogen. Diffuse and intense brown staining of the cytoplasmic or nuclear surfaces, as appropriate for each stain, was interpreted as strong staining intensity. Moderate intensity staining was characterized as non-diffuse but intense staining pattern, whereas weak intensity had a non-diffuse and non-intense staining pattern. Immunoreactivity was quantitatively estimated by the percentage of positive cells per representative section. Immunoreactivity was graded as 1+, 2+, and 3+, corresponding to less than 25%, between 25% and 50%, and greater than 50% of neoplastic cells showing positive staining per representative section, respectively. Grossly, the partial nephrectomy specimen revealed an encapsulated multiloculated gray-tan tumor (9.7 × 7.4 × 7.8 cm). The interface between tumor and uninvolved kidney was sharp. Sectioning of the tumor revealed circumscribed complex solid and multiloculated cystic lesion with large area of calcification (1.7 cm). The largest cyst measured up to 1.4 cm, and the cysts were filled with yellow-tan gelatinous material. The wall of the cysts showed focal thickened firm and hard calcified areas. The tumor was confined to the kidney and was at least 0.5 cm from the nearest stapled resection margin. There was no gross evidence of extension of the tumor into the renal pelvis, renal vein, renal artery, ureter, renal sinus, renal capsule, or perinephric adipose tissue. The entire tumor was submitted for histological examination. The histological examination revealed three components. The first component was multilocular cystic spaces lined by mucinous columnar enteric-type or colonic-like epithelium and ciliated epithelium , and containing fragments of smooth muscle in the wall. These findings in the first component represent a mature cystic teratoma . The predominant teratomatous element in the first component was mucinous columnar enteric-type or colonic-like epithelium , followed by ciliated epithelium , and smooth muscle . The second and third components of the tumor make up the solid parts of the tumor. The second component of the tumor showed tightly-packed back-to-back highly atypical infiltrating glands composed of cohesive pleomorphic epithelioid cells with adjacent necrosis . The tumor cells were large with abundant eosinophilic cytoplasm, enlarged nuclei with contour irregularities, and occasional prominent nucleoli . Mitotic figures were readily identified. There was no evidence of lymphovascular invasion. These features of the second component represent an invasive moderately differentiated adenocarcinoma . The carcinoid tumor and adenocarcinoma components were found adjacent and closely apposed to each other, with or without a clear transition zone. The third component showed proliferating trabecular and anastomosing ribbon-like nests of monotonous small round cells with fine granular "salt-and-pepper" chromatin pattern , and peripheral palisading . Mitotic figures were not identified. There was no evidence of lymphovascular invasion. These features of the third component represent a carcinoid tumor . The carcinoid tumor and adenocarcinoma components were found underneath and closely apposed to the epithelial lining of the teratomatous cysts, and focally invading teratomatous smooth muscle wall . All surgical resection margins were free of the three components of the tumor. Alpha-methylacyl-coenzyme A-racemase (AMACR/P504S), calretinin, CD10 and thyroid transcription factor-1 (TTF-1) did not stain any of the three components of the tumor. The teratomatous cysts were lined by ciliated epithelium (strong and diffuse cytoplasmic labeling for cytokeratin 7 and pancytokeratin) and mucinous columnar enteric-type or colonic-like epithelium , but were negative for calretinin (a mesothelial marker). Additionally, the teratomatous cyst wall was strongly and diffusely immunoreactive (3+, cytoplasmic staining) for smooth muscle actin ; and weakly and focally immunoreactive (1+, cytoplasmic staining) for carbonic anhydrase IX (CA-IX), CD99, chromogranin and synaptophysin. The carcinoid tumor and adenocarcinoma components were found adjacent and closely apposed to each other , with the adenocarcinoma component in right upper part of figure being strongly and diffusely immunoreactive (3+, cytoplasmic staining) for CK7 whilst the carcinoid tumor component in left lower part of figure being negative for CK7 . The adenocarcinoma component was strongly and diffusely immunoreactive (3+, cytoplasmic staining) for CK7 and pancytokeratin; weakly and focally immunoreactive (1+, cytoplasmic staining) for CD56 and synaptophysin; and negative for CA-IX, CD99, CDX2, chromogranin, CK20 and SMA. The carcinoid tumor component was strongly and diffusely immunoreactive (3+, cytoplasmic staining) for CD56 , chromogranin and synaptophysin ; weakly and focally immunoreactive (1+, cytoplasmic staining) for pancytokeratin ; and negative for CA-IX, CD99, CDX2, CK7, CK20 and SMA. On the basis of the above histopathological and immunohistochemical features, a definitive diagnosis of synchronous primary carcinoid tumor and primary moderately differentiated adenocarcinoma arising within mature cystic teratoma of horseshoe kidney was rendered. This tumor could not be staged since no relevant staging system exists for synchronous primary carcinoid tumor and primary moderately differentiated adenocarcinoma of kidney. Her postsurgery serum levels of alpha-fetoprotein (α-FP), beta-subunit of human chorionic gonadotropin (β-hCG), carbohydrate antigen (CA) 19-9, CA 72-4, CA 125, carcinoembryonic antigen (CEA), chromogranin and serotonin continued to remain within normal ranges. Her postsurgery urinary 5-HIAA level also continued to remain within normal range. Additionally, postsurgery whole body somatostatin receptor scintigraphy with octreotide performed was negative, hence confirming the carcinoid tumor as originating primarily in the resected renal tumor (rather than elsewhere with metastasis to the kidney) and the absence of metastases from the resected renal carcinoid tumor. Hence, the partial nephrectomy with complete resection of the tumor was considered adequate conservative clinical management. She received no adjuvant therapy. Two follow-up CT and MRI scans of the brain, abdomen, chest and pelvis, and PET scans performed at 3-month intervals after surgery revealed no lesions. The patient herein presented is alive with no evidence of local recurrence or metastatic disease, six months postoperatively, and regular periodic follow-up with interval CT, MRI and PET imaging studies, and octreotide scintigraphy is planned. Mature cystic teratomas may consist of a wide variety of ectodermal, mesodermal, and endodermal tissues, and hence the possibility of additional neoplasms occurring in teratomas, though rare, can at least be anticipated. It is not surprising that squamous cell carcinoma leads the list of secondary neoplasms arising in teratomas, because many mature cystic teratomas contain large amounts of squamous epithelium . In second place among secondary neoplasms in mature cystic teratomas, carcinoid tumor and adenocarcinoma are said to be of equal frequency, but the former is reported to be increasing in frequency . Hence, adenocarcinoma or carcinoid tumor arising from mature cystic teratoma of kidney is an uncommon occurrence . The simultaneous occurrence of mature cystic teratoma and adenocarcinoma in the same kidney is rare , and so is the simultaneous occurrence of mature cystic teratoma and carcinoid tumor in the same kidney . Similarly, the simultaneous occurrence of carcinoid tumor and adenocarcinoma in the same kidney is rare. To the best of our knowledge, the synchronous presentation in the same kidney of these three neoplasms (mature cystic teratoma, carcinoid tumor and adenocarcinoma) has never been reported in the world medical literature. We have presented a unique and first case of a 50-year-old female with both carcinoid tumor and adenocarcinoma simultaneously arising within mature cystic teratoma of horseshoe kidney. We discuss below the extreme rarity of this combination of three primary tumors in the kidney and the probable common histogenesis of these three synchronous neoplasms in horseshoe kidney. Carcinoid tumors are characteristically low grade malignant tumors with neuroendocrine differentiation that have been described in several locations, including the gastrointestinal, respiratory, hepatobiliary, and genitourinary systems. Carcinoid tumors most commonly occur in the gastrointestinal tract (74%) and bronchial system of the lungs (25%) . In less than 1% of cases these tumors have been reported in the genitourinary system. Carcinoid tumors arising in the genitourinary system are rare, but have been reported in the ovary, testes, kidney and prostate . Primary renal carcinoid tumor is the second most prevalent genitourinary carcinoid tumor in each sex, following testicular carcinoids in males and ovarian carcinoids in females . Primary renal carcinoid tumors are among the most unusual of all renal neoplasms, since neuroendocrine cells are not found within normal renal parenchyma. Primary renal carcinoid tumors have been reported in the literature primarily as case reports (as in the case herein presented), with the three largest series to date consisting of 5 , 6 , and 21 patients. Primary carcinoid tumor of the kidney was first described by Resnick et al. in 1966 , and since then fewer than 100 cases of primary renal carcinoid tumor have appeared in the international medical literature . Primary renal carcinoid tumors have been reported to arise most commonly in the setting of acquired and congenital renal abnormalities (as in the case herein presented), such as horseshoe kidney (18–26%) , renal teratoma or teratoid malformation (15%) , and polycystic kidney disease (2%) . The age range for reported cases of primary renal carcinoid tumor is 12 to 78 years, but most patients present in the fourth to seventh decades of life and there is no gender predilection . A recent review of 56 primary renal carcinoid tumors reported in the literature up to December 2005 by Romero et al. observed that the median patient age was 49 years. Romero et al. further reported that horseshoe kidneys were present in 17.8% of patients (as in the case herein presented), incidental diagnosis was made in 28.6% of patients (as in the case herein presented), and metastases were present in 45.6% of patients at initial diagnosis. They also observed that the significant adverse prognostic factors include age greater than 40 years, tumor size greater than 4 cm, purely solid tumors on cut surface, mitotic rate higher than 1 per 10 high power fields, metastasis at initial diagnosis and tumors extending through the renal capsule . The largest series of primary renal carcinoid tumors reported to date consisting of 21 patients by Hansel et al. observed that the mean patient age was 52 years. As in the case herein presented, Hansel et al. further reported that horseshoe kidneys were present in 19% of patients, and calcifications were present in 23.8% of cases of primary renal carcinoid tumor. They concluded that primary renal carcinoid tumor was morphologically and immunohistochemically similar to carcinoid tumors present at other anatomic sites, and that patients frequently presented with regional lymph node metastases and may progress to distant organ metastases, but usually have a prolonged clinical course despite widely metastatic disease . Complete surgical resection is the main treatment modality for primary renal carcinoid tumors and can be curative for localized disease (as in the case herein presented), and long-term follow-up of patients is recommended since metastases have occurred as late as seven years after the primary diagnosis . Primary carcinoid tumors of the kidney are rare , and primary carcinoid tumor arising within horseshoe kidneys and mature teratomas of the kidney are even rarer. Less than 100 cases of carcinoid tumor of the kidney have been reported in the international medical literature , including 18 cases arising in horseshoe kidneys and seven cases arising within mature cystic teratomas . A recent review by Armah and Parwani identified that only seven cases of primary carcinoid tumor arising in mature cystic teratoma of kidney have been reported in the world medical literature to date , since the association was first described in 1976 by Kojiro et al . Primary carcinoid tumor arising in a mature teratoma of the kidney is over-represented in patients with congenital developmental renal defects such as horseshoe kidney, with one out of the seven cases (15%) of primary carcinoid tumor arising in mature cystic teratoma occurring in a horseshoe kidney . Epidemiologically, primary carcinoid tumor arising within mature cystic teratoma of the kidney occurred predominantly in the fourth to seventh decades of life (mean age of 41.4 years), except one case occurring at age 23, and showed no sex predilection . An incidental diagnosis was made in 28.6% of cases, and clinically apparent carcinoid syndrome was absent in all the seven reviewed cases of primary carcinoid tumor arising within mature cystic teratoma of the kidney (as in the case herein presented), likely reflecting their hindgut origin and the breakdown of their secreted biologically active hormones in the liver before reaching the systemic arterial circulation. Armah and Parwani further observed that primary carcinoid tumor arising within mature cystic teratoma of the kidney were morphologically similar to carcinoid tumors present in normal kidneys and at other anatomic sites, and that surgery was curative with no additional treatment required, and no local recurrences and metastases occurred in all seven cases reviewed , as in the case herein presented. Immunohistochemically, synaptophysin, chromogranin and neuron specific enolase were the most valuable markers for the diagnosis of primary carcinoid tumor arising within mature teratoma of the kidney , as in the case herein presented. Despite the absence of long term follow-up data for some of the seven cases reviewed, the biologic behavior and prognosis of primary carcinoid tumor arising within mature teratoma of the kidney appeared excellent , as in the case herein presented. Recent studies comparing the prognosis of carcinoid tumors arising within teratomatous and normal kidneys have reported contradictory findings . Four studies have reported better prognosis for carcinoid tumor arising within teratomatous kidneys compared to those arising within normal kidneys . However, a recent review of renal carcinoid tumors revealed that neither renal teratoma nor horseshoe kidneys derived carcinoid tumors were associated with a better prognosis than carcinoid tumors originating in normal kidneys . Hence, although definitive conclusions cannot be drawn from such a small set of studies and patients without systematic long term 5-year follow-up, the ultimate biologic behavior of primary carcinoid tumor arising within mature teratoma of the kidney and horseshoe kidneys may be excellent, and may be better than that for carcinoid tumors arising in normal kidneys and non-renal locations . We were not able to find any reported case of simultaneous occurrence of mature cystic teratoma, carcinoid tumor and adenocarcinoma in the same kidney, in our literature search. We have herein described a case of coexistent mature cystic teratoma, carcinoid tumor and adenocarcinoma in a horseshoe kidney in a 50-year-old female. The age of the case herein presented is close to the mean and/or median age of both previously reported patients with carcinoid tumor arising within normal kidneys (49–52 years) and carcinoid tumor arising within teratomatous kidneys (41.4 years) . The strong expression of three neuroendocrine markers (CD56, chromogranin and synaptophysin) and the absence of expression of two epithelial markers (CK7 and CK20), exclude the possibility of invasive urothelial carcinoma arising from the renal pelvis in the case herein presented. Most urothelial carcinomas have the immunoprofile of CK7+/CK20+ or CK7+/CK20- . In contrast, most carcinoid tumors arising from the digestive tract or of hindgut origin have the pattern CK7-/CK20- , as in the case herein presented. Therefore, it is most likely that the carcinoid tumor in the present case arose outside the urothelial epithelium of the renal pelvis. Carcinoid tumors are thought to arise from enterochromaffin cells or amine precursor uptake and decarboxylation (APUD) cells, and are widely distributed throughout the body. In the urogenital tract, APUD cells have been described in the urinary bladder (especially in the neck and trigone), the urethra, the prostate, and the renal pelvis, but not in the renal parenchyma . In contrast, paraganglionic tissue is present in fetal or adult renal hilum . Although primary renal carcinoid tumors, as in the case herein presented, exhibit morphologic and immunohistochemical features consistent with a hindgut neuroendocrine phenotype , the precise histogenesis of renal carcinoid tumors is uncertain and is a matter for continuing speculation. Multiple published reports support the notion that renal carcinoid tumors are derived from interspersed neuroendocrine cells associated with acquired and congenital renal abnormalities such as teratomas and horseshoe kidneys . Carcinoid tumors occurring in renal teratomas are thought to be derived from neuroendocrine cells of the gastrointestinal and respiratory epithelium, which are components of these teratomatous lesions . Two main hypotheses have been proposed for the coexistence of congenital and acquired renal abnormalities (such as horseshoe kidney and mature cystic teratoma) and secondary malignancies (such as carcinoid tumor and adenocarcinoma in the case herein presented) in the kidney. The most popular hypothesis, the totipotent cell hypothesis, states that primary renal carcinoid tumor arise from totipotential primitive stem cells capable of neuroendocrine, mesenchymal and epithelial differentiation . Although conclusive evidence for this theory is lacking at present, one renal carcinoid tumor has been shown to share some genetic aberrations with renal cell carcinomas, indicating a common genetic event in the tumorigenesis for these two entities . Furthermore, this hypothesis of derivation from a multipotent stem cell is most consistent with the occurrence of neuroendocrine tumor in conjunction with epithelial malignancies, which might express markers of both components, as in the case herein presented. The less popular hypothesis states that the coexistence of carcinoid tumors (and other secondary malignancies such as adenocarcinoma in the case herein presented) with congenital and acquired renal abnormalities (such as horseshoe kidney and mature cystic teratoma) are due to hyperplasia of interspersed neuroendocrine cells within metaplastic or teratomatous epithelium in horseshoe kidneys; or nests of misplaced progenitor cells developing into teratomatous intestinal or respiratory epithelia in renal teratomas, might serve as a nidus for renal carcinoid tumors and adenocarcinoma. Cases of renal carcinoid tumor arising in association with renal teratoma and/or horseshoe kidneys lend weight to this hypothesis . The relative risk of renal carcinoid tumors in patients with horseshoe kidneys has been calculated at between 62 and 85 . Horseshoe kidneys have been proposed to be the result of teratogenic factors, which may also account for the increased risk of malignant tumors in horseshoe kidneys . The high association of carcinoid tumors with horseshoe kidneys is likely due to predisposing embryological factors or teratogenic events involving the abnormal migration of posterior nephrogenic cells in utero , which coalesce to form the isthmus of horseshoe kidneys . Additionally, this hypothesis is supported by the common occurrence of renal carcinoid tumors in the isthmus of teratomatous and horseshoe kidneys , as in the case herein presented with an additional adenocarcinoma. Applying this hypothesis to the case herein presented, the carcinoid tumor and adenocarcinoma would represent secondary tumors derived from foci of neuroendocrine and epithelial differentiation in the mature cystic teratoma of the horseshoe kidney. This hypothesis suggests that renal carcinoid tumors bearing no relationship to congenital and acquired renal abnormalities might arise directly from neuroendocrine cells situated in the renal pelvic urothelium . From the above discussion, the direct supporting experimental and clinical evidence for these two hypotheses of histogenesis for multiple malignancies arising within teratomatous and horseshoe kidneys is inconclusive, and the exact mechanism is not well understood. As with all malignancies, the pathway for carcinogenesis is likely to be complex and multifactorial. Further studies would be required in order to elucidate the precise histogenesis for multiple secondary neoplasms arising within teratomatous and horseshoe kidneys. Synchronous primary carcinoid tumor and primary adenocarcinoma arising within mature teratoma of horseshoe kidney is a unique occurrence. This is the first reported case to our knowledge of mature cystic teratoma coexisting with carcinoid tumor and adenocarinoma in the same kidney. This unique case report emphasizes the need for thorough sectioning and entire submission for histologic evaluation of mature cystic teratomas since multiple additional histogenetically distinct small neoplasms occurring in a mature cystic teratoma could easily be missed through incomplete sectioning and histologic evaluation, potentially compromising patient care. Although longterm follow-up was lacking in the case herein presented, this unique occurrence of three neoplasms in horseshoe kidney was not associated with local recurrence and metastasis, was surgically curable, and had a rather favorable prognosis.
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19918501
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Autoimmune hemolytic anemia is occasionally reported in patients with other autoimmune illnesses, most commonly systemic lupus erythematosis, rheumatoid arthritis, scleroderma, and ulcerative colitis . There are at least 10 case reports of autoimmune hemolytic anemia associated with hyperthyroidism , and 1 report of autoimmune hemolytic anemia associated with reactive arthritis . However, a Medline search reveals no previous reports of concurrent reactive arthritis, hyperthyroidism, and autoimmune hemolytic anemia. We report the case of a 40-year-old man who developed severe warm autoimmune hemolytic anemia while under treatment for both Graves’ disease and reactive arthritis. Our subject’s mother and possibly his maternal grandmother also had autoimmune hemolytic anemia, which raises the possibility of hereditary autoimmune hemolytic anemia, a rarely reported condition . A 40-year-old Caucasian American man with reactive arthritis, Graves’ disease, type 2 diabetes mellitus, mitral valve prolapse, and Gilbert’s disease was admitted with one month of progressive jaundice, fatigue, lightheadedness, and exertional dyspnea. He also described dark urine (“the color of raspberry iced tea”) and dark brown to black stools. He denied fevers or chills, but gave a long history of night sweats and occasional diarrhea, which he ascribed to his medications. He had no history of blood transfusions, prior hepatitis, alcohol use, intravenous drug use, or tattoos, and he did not use herbal medications or supplements. He had recently come to Cleveland to help care for his father, who had stage IV colon cancer. His mother had been diagnosed with autoimmune hemolytic anemia at the age of 40; she was treated with corticosteroids and eventually required splenectomy. His maternal grandmother also had anemia and jaundice, although the patient was not aware of the cause. His medications were etanercept, metformin, pioglitazone, methimazole, niacin, and aspirin. He had stopped the pioglitazone and metformin more than one month prior to admission (before the onset of jaundice) on the advice of an endocrinologist. He had been diagnosed with reactive arthritis about 10 years before admission, and had been treated with etanercept for the previous 8 years. His Graves’ disease had been diagnosed 18 months before admission, and treated over that time with methimazole. Physical examination revealed a calm, well-nourished man with scleral icterus and generalized jaundice. Blood pressure was 130/76, heart rate 102/min., respiratory rate 16/min, temperature 97.7F. There was no cervical, supraclavicular, epitrochlear, axillary, or inguinal lymphadenopathy. The thyroid gland was not enlarged or tender, and there was no proptosis, lid-lag, or tremor. The lungs were clear and the heart rhythm was regular without murmur, click, or gallop. The abdomen was soft and non-tender, with the liver edge palpable 2 cm below the right costal margin; the spleen was not palpable. A vesiculobullous rash was seen on the plantar aspect of the right foot. Laboratory tests were significant for hemoglobin 5.8 g/dL, hematocrit 18.7%, MCV 107.5, platelet count 231,000, WBC count 9,800, reticulocyte count 23.4%, Bilirubin 13.6 (direct 0.6), LDH 369, and haptoglobin <6. Hepatitis A, B, and C serologies, antinuclear antibody, antimicrosomal antibody, D-dimer, cold agglutinins, cryoglobulins, and HIV test were negative. The fibrinogen was normal at 342. The INR was 0.8 and the partial thromboplastin time was 26.4. The peripheral smear showed spherocytes and bite cells, with no schistocytes, helmet cells, spur cells, sickle cells, or teardrop cells. The differential was 54.1% neutrophils, 35.6% lymphocytes, 8.3% monocytes, 1.7% eosinophils, and 0.3% basophils. Direct antiglobulin test (DAT) was + for anti IgG and negative for anti-C3. The indirect antiglobulin test was negative. The G6PD level was normal. TSH was 1.067. In this case, the elevated LDH and indirect bilirubin, low haptoglobin, and high reticulocyte count all were consistent with hemolysis. There was no fever, leukocytosis, or pertinent travel history to suggest malaria or babesiosis, and there was no evidence of spider or insect bites. The patient did not have a history of chronic anemia, which was against the diagnosis of hereditary spherocytosis. The normal fibrinogen, negative D-dimer, and absence of schistocytes on peripheral smear ruled out a microangiopathic process. A normal G6PD level, obtained after the acute phase of the illness, eliminated G6PD deficiency as a possibility. The DAT revealed an anti-IgG antibody on the RBC’s, consistent with either a warm autoimmune hemolytic anemia (WAIHA) or a drug-induced hemolytic anemia (DIHA). There are 4 case reports of metformin-induced hemolytic anemia , but our patient had stopped metformin at least a month before his symptoms developed, so this was very unlikely. There is one reported case of a patient with rheumatoid arthritis who developed cold agglutinin disease during etanercept treatment , but cold agglutinin disease is associated with IgM antibodies and typically causes only mild hemolysis. Our patient’s cold agglutinin screen was negative. None of his other medications have been reported to cause hemolytic anemia. The leading diagnosis was therefore WAIHA. Most cases of WAIHA are idiopathic, but secondary causes can include viral infections, autoimmune disorders (particularly SLE, RA, UC, and scleroderma), immune system malignancies (most commonly CLL), AIDS and other immunodeficiency disorders, and various non-lymphoid neoplasms. The work-up for secondary causes was negative with the exception of the CT scan findings of thymus enlargement, mild splenomegaly, and multiple sub-centimeter (ranging 5 to 9 mm) hypodensities in the liver and kidney of uncertain significance. WAIHA often precedes the development of lymphoid malignancies, sometimes by several months; a repeat CT scan is planned in 2-3 months to reassess the abnormalities. Graves’ disease is associated in some patients with autoimmune dysfunction of multiple organs, including pernicious anemia, type 1 diabetes mellitus, autoimmune adrenal insufficiency, vitiligo, systemic sclerosis, myasthenia gravis, Sjogren’s syndrome, systemic lupus erythematosis, and rheumatoid arthritis. Multiple cases of autoimmune hemolytic anemia associated with hyperthyroidism have been reported. In Graves’ disease, IgG type autoantibodies bind to the thyroid cell and activate the thyroid stimulating hormone receptor, which increases thyroid metabolic activity. In one case of hyperthyroidism with AIHA, treatment of hyperthyroidism with propylthiouracil not only restored euthyroidism but ameliorated the hemolytic anemia as well, without use of corticosteroids or blood transfusions . The authors speculate that the hyperdynamic circulatory state in hyperthyroidism might accelerate hemolysis in antibody-coated red blood cells. Thomson et al. describe a patient who developed Graves’ disease during long-term immunosuppressive therapy for acquired autoimmune hemolytic anemia . Thomson’s conclusion was that the IgG type immunoglobulins that cause Graves’ disease can develop even in the setting of long-term immunosuppressive treatment. At the time he developed WAIHA, our patient was clinically and chemically euthyroid after 18 months of propylthiouracil treatment. He had also been on immunosuppressive treatment with the tumor necrosis factor-inhibitor etanercept for several years, with good control of his reactive arthritis symptoms. The WAIHA seems not to have developed in response to a flare-up of either condition. Reactive arthritis occurs after primary extraarticular infections, either enteric or sexually transmitted, and is characterized by the presence of bacterial antigen and/or viable but non-culturable bacteria that persist within the joint. HLA-B27 is present in 70-80% of patients with reactive arthritis, and HLA-B27 increases the risk of reactive arthritis by 25-fold. Although there are a number of known bacterial triggers for development of reactive arthritis, the precise mechanism of the pathologic host response is unknown. Possibilities include an HLA-B27 autoantigen, cellular uptake of causative organisms, toll-like receptors, and chemokine involvement . Graves’ disease has been associated with a variety of infectious agents, including Yersinia enterocolitica , which is also one of the bacteria known to cause reactive arthritis . Yersinia enterocolitica has not, however, been reported as a cause of WAIHA. We were unable to find any prior case reports of concurrent reactive arthritis and Graves disease. There is one report of a 30-year-old man in Papua New Guinea who developed severe hemolytic anemia (Hb 2.8) in the setting of reactive arthritis with urethritis, conjunctivitis, and keratoderma blenorrhagica . Although a DAT was not reported, the author argued that the hemolysis was autoimmune because malaria and hypersplenism were excluded, and the anemia resolved with methotrexate and prednisolone treatment. There are only a few case reports of hereditary autoimmune hemolytic anemia . The paucity of reports and the sporadic pattern of involvement suggests that familial occurrence of AIHA is likely to be coincidental, although the sharing of HLA antigens 1 and 8 in a report of two affected sisters might argue for a genetic susceptibility in some cases . It has been postulated that autoimmune diseases are a “mosaic” of genetic, immune, hormonal, and environmental factors. Genetic causes may include human leukocyte antigen (HLA) genes, non-HLA immune-regulatory or tissue-specific genes, and genetically-determined selective IgA deficiency . Environmental factors may include infection, with Yersinia as a possibility, or the use of medications including long-term cytokine suppression with etanercept. A combination of genetic and environmental factors might have contributed to this patient’s development of multiple autoimmune diseases. We report the first case of concurrent reactive arthritis, Graves’ disease, and autoimmune hemolytic anemia. Yersinia enterocolitica infection could theoretically cause both reactive arthritis and Graves’ disease, although we cannot prove this connection in our patient’s case. It is not clear whether the autoimmune hemolysis was coincidental or related to an underlying condition that predisposed this patient to multiple autoimmune diseases. The family history of autoimmune hemolysis suggests the possibility of an inherited predisposition.
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20454696
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Achromatopsia is a congenital autosomal recessive cone disorder with a prevalence of 1 in 30,000 individuals . The clinical features include low visual acuity, nystagmus, photophobia, severe color vision defects, and no recordable or only residual cone function on electroretinography (ERG) with normal rod functions. Fundoscopy is usually normal, although macular pigmentary changes and atrophy have been described in the literature . ACHM is characterized by progressive cone loss, which has been described in a large proportion of patients in terms of the worsening of the macular appearance and deterioration of the central vision irrespective of the genetic cause . It has been reported that the use of red contact lenses or red tinted glasses can alleviate photophobia in patients with ACHM or cone dystrophy . To date, ACHM has been described as being caused by mutations in four genes: cyclic nucleotide-gated channel alpha-3 ( CNGA3), cyclic nucleotide-gated channel beta-3 (CNGB3), guanine nucleotide-binding protein, alpha-transducing activity polypeptide 2 (GNAT2), and phosphodiesterase 6C ( PDE6C) . The proteins encoded by these four genes are specifically expressed in cone photoreceptor cells, where they have been shown to be involved in the cone phototransduction cascade. CNGA3 encodes the α-subunit and CNGB3 the β-subunit of the cyclic nucleotide-gated (CNG) channel that has a central function in signal transduction of the visual pathway . 25% of all ACHM patients carry mutations in CNGA3 , and 45%–50% carry CNGB3 mutations, whereas only a few families have been reported to have GNAT2 or PDE6C mutations . Mutations in CNGA3 , CNGB3, and PDE6C have also been associated with cone dystrophy in a small proportion of patients . For family RP26, blood samples were collected from 16 individuals (four affected and 12 healthy individuals) from a six generation pedigree . For family RP44, blood samples were collected from eight individuals (two affected and six normal individuals) from a four-generation pedigree . DNA isolation was performed as described previously . All the affected members of family RP26 (IV-1, V-2, V-3, VI-2), and seven individuals of family RP44 (healthy individuals III-2, IV-2, IV-4, IV-6, IV-7 and affected individuals IV-1 and IV-3) were genotyped using the Affymetrix 10K single nucleotide polymorphism (SNP) array containing 10,204 SNPs (Affymetrix, Santa Clara, CA). Multipoint parametric linkage analysis of the SNP array data of both families was performed using the GeneHunter program in the EasyLinkage software package (version 5.02) . Fine-mapping of the region on chromosome 2q11.2 with the highest logarithm (base 10) of odds (LOD) score in family RP26 was conducted using microsatellite markers that were amplified by the polymerase chain reaction (PCR) under standard conditions. Haplotypes were constructed based upon the size of the alleles of the microsatellites. The positions of the microsatellite markers were derived from the Marshfield map. Two-point parametric LOD scores for the microsatellite markers were calculated using the SuperLink program (version 1.6) in the EasyLinkage software package . The sequencing primers for the candidate genes CNGA3 and CNGB3 have been described before . For family RP26, the seven coding exons of the CNGA3 gene were sequenced in one affected individual (V-2) along with a control sample, and for family RP44, all 18 coding exons of the CNGB3 gene were sequenced in individual IV-1 as well as a control sample. The amplified PCR products were separated on agarose gel and purified with a Nucleospin DNA extraction kit (Nucleospin Extract II, Macherey-Nagel GmbH and Co, Germany). Purified products were directly sequenced using the corresponding primers and dye-termination chemistry . Segregation of the CNGA3 mutation in family RP26, and analysis of the mutation in 22 unrelated probands with autosomal recessive retinal dystrophies and 150 ethnically-matched control individuals, was performed via allele-specific PCR . For this purpose, three primers were designed; a forward wild type (5′-AAA GGT GGG CAC AAA CTA CCC AGA AGT GAG G-3′), forward mutant (5′-AAA GGT GGG CAC AAA CTA CCC AGA AGT GAG T-3′) and a common reverse primer (5′-AAT GGC AAA GTA GAT GCA GGC ATT CCA GTG G-3′). DNA was amplified using 0.5 mM dNTPs, 1.5 mM MgCl 2 , 0.3 μM of each forward and reverse primer, and 2.5 U Taq polymerase. The thermal cycling conditions were as follows: initial denaturation at 95 °C for 5 min, followed by 35 cycles at 95 °C for 30 s, 60 °C for 30 s, and 72 °C for 30 s, with a final extension cycle at 72 °C for 6 min. Due to the specific genetic defect that was identified, the affected members of family RP26 were clinically revisited and a detailed clinical examination was performed to confirm the status of the disease in the family. Fundoscopy and electroretinogram (ERG) data were obtained for both families. Visual acuity tests were performed for the affected individuals (IV-1, V-2, and VI-2) of family RP26, and they were also subjected to color differentiation tests using the standard Ishihara plates. Family RP44 could not be revisited for the visual acuity test, but a detailed clinical history was documented from the proband (IV-1) of the family. The affected members of family RP26 were also given pink glasses to use for the alleviation of photophobia. In family RP26, whole-genome SNP array analysis revealed a homozygous interval of 9.1 Mb at 2q11.2 between SNP rs718159 and rs1375002 in all the affected members, with a multi-point LOD score of 3.81 at theta 0. Confirmation and refinement of this region was performed by analyzing microsatellite markers between flanking SNPs rs718159 and rs1375002 . As a result, the critical region for the underlying defect was refined from the initial 9.1 Mb to 7.2 Mb, flanked by markers rs718159 and D2S2229 . This region contains the CNGA3 gene, which has previously been implicated in ACHM and cone dystrophy . In family RP44, homozygosity was observed at nine different chromosomal regions in both affected members (IV-1, IV-3), with a LOD score of 1.22 at theta 0, whereas the unaffected individuals III-2, IV-2, IV-4, IV-6, and IV-7 were heterozygous in these regions. The CNGB3 gene, which has also previously been shown to be involved in ACHM and cone dystrophy, resides in one of these regions on chromosome 8q21.3 . Sequencing of all the coding exons of the CNGB3 gene in the proband of family RP44 resulted in the identification of a novel mutation, a one nucleotide deletion at position 1825 in exon 16 of the gene c.1825delG; Figure 3A ), which results in a frameshift and premature termination of the protein (p.V609WfsX9). Segregation analysis in the family revealed that the two affected individuals, IV-1 and IV-3, are homozygous for the mutation, while four healthy persons (III-2, IV-2, IV-4, IV-7) are heterozygous carriers, and two healthy persons (IV-5, IV-6) are homozygous for the wild type allele . The c.1825delG mutation was not identified in 44 probands with retinal dystrophies. As it has previously been reported that mutations in CNGA3 and CNGB3 are associated with cone dysfunction , the clinical status of the affected individuals from both families was re-evaluated. The affected individuals of family RP26 (IV-1 and VI-2), who were aged 35 and 11 years, respectively, at the time of fundoscopy, showed a normal macular region. However, one affected individual from each family (RP26_V-2 [age 14 years] and RP44_IV-1 [age 19 years]) showed the beginning of a Bull’s eye maculopathy , and revealed some residual cone responses on the photopic ERG on the 30 Hz flicker stimulation , showing that the disease is progressive in these patients. The affected individuals from family RP26 had congenital nystagmus, photophobia and were color blind. In addition, the affected individuals (IV-1, V-2, and VI-2) had low visual acuity of 20/200, 20/400, and 20/200, respectively. Members of family RP44 could not be revisited for the visual acuity test because they live in a very remote rural area. In this family, a detailed telephone interview with both affected members IV-1 and IV-3 revealed that they also had congenital nystagmus. In addition, they had photophobia along with low visual acuity and were found to be color blind, thereby confirming the molecular diagnosis of ACHM. There are six cyclic nucleotide gated (CNG) channels present in mammals, and these are divided in two subfamilies, the A subunits (CNGA1–4) and the B subunits (CNGB1 and CNGB3). The CNGA3 and CNGB3 channels play a critical role in cone-mediated vision, which is required for central and color vision, as well as visual acuity. CNGA3 and CNGB3 encode the cone CNG channel subunits that are able to form heterotetramers , although CNGA3 subunits may also form homotetramers . Mutations in these two genes have been shown to result in different forms of ACHM and cone dystrophy . In CNGA3 , the p.R274S mutation is located in a conserved region , which is part of the fourth transmembrane helix (S4) . The arginine residue at this position is conserved among the CNG alpha subunits of rods (CNGA1) and olfactory neurons (CNGA2), Shaker K + channels and HCN channels . Mutations in the S4 domain have been shown to cause failure in cellular channel processing. Mutant channel proteins are not glycosylated, and do not reach the surface plasma membrane; they remain trapped in the endoplasmic reticulum, and are most likely misfolded . The c.1825delG mutation in exon 16 of CNGB3 should in theory give rise to nonsense-mediated decay of the mutant RNA, and can, therefore, be considered a loss-of-function mutation. In case there is residual CNGB3 mRNA, the predicted truncated protein (p.V609WfsX9) lacks the conserved cyclic nucleotide-monophosphate (cNMP) domain. The cNMP domain is the binding site for cyclic nucleotides, and is involved in the cyclic nucleotide mediated activation of the protein. It is hypothesized that both putative effects of this variant will lead to the loss-of-function of CNGB3. Identification of causative mutations aided in the correct diagnosis of ACHM in these two Pakistani families, which had previously been diagnosed to suffer from retinal dystrophy. After the correct re-diagnosis of the disease, the use of pink glasses reduced the photophobia to some extent in the affected individuals of family RP26. Due to the use of these dark colored pink glasses, the light exposure was reduced, resulting in increased scotopic vision that helped the patients to see objects at a distance, even during the day time. In this study, we report the first genetic screening and use of dark glasses as supportive therapy for ACHM in Pakistan, a disease that is often misdiagnosed.
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Review
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biomedical
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en
| 0.999996
|
20602800
|
Her initial set of cardiac enzymes, complete blood count (CBC), basic metabolic panel (BMP) and urine analysis were normal. She was admitted with diagnosis of unstable angina. Treatment with heparin, eptifibatide and nitroglycerine was begun. Her repeat EKG on 09/07/09 showed ST depressions in the inferior leads, repeat cardiac enzymes were normal, however her chest pain continued to persist. 2D Echocardiogram (ECHO) on 09/07/09 revealed ejection fraction (EF) of 65%, without any pericardial effusion. Chest pain continued to persist, became hypotensive and oliguric, blood pressure medications were with held. Repeat CBC and BMP revealed elevated WBC 15,800/μl and hemoglobin of 9.4 gm/dl. Serum creatinine changed from 1.13 to 3.01 and blood urea nitrogen increased from 29 to 53. Urine analysis revealed 15-20 white blood cells per high power field (HPF), positive leukocyte esterase and nitrite, 5-10 red blood cells per HPF. In view of leucocytosis, increased renal parameters and pyuria septic shock secondary to urinary tract infection was considered and transferred to Intensive care unit (ICU). After fluid resuscitation, broad spectrum antibiotics were intiated. On 09/09/09 in ICU the patient was in distress and continued to have chest pain. Vital signs were significant for pulse rate 90/min, regular, BP 70 mmHg, RR of 22/min, SpO2 95%. Auscultation of heart and lungs was unremarkable. Central venous pressure was 15 cm of water. Intravenous vasopressor therapy was intiated. As her chest pain continued to persist, a non-contrast computerized tomography (CT) of the chest was done which revealed hemorrhagic pericardial effusion with lead perforation of the right atrium which was subsequently confirmed by 2D ECHO Imaging studies including chest x-rays, 2D/3D ECHO and CT scan have been utilized to diagnose the atrial perforation. The superiority of the either CT scan or ECHO has to be further studied . In this case the suspicious chest x-ray after the placement of the central line lead to the further investigations. Persisting chest pain without elevation of troponins and hemodynamic instability with elevated JVD raised the suspicion pericardial tamponade. CT scan of the chest confirmed the hemorrhagic pericardial effusion along with the exact position of the right atrial lead. 2D ECHO with multiple projections further confirmed the effusion. During the surgery the lead was noted to perforate the right atrium and it was retrieved and the perforated atrial wall was repaired.
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Other
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biomedical
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en
| 0.999996
|
20704700
|
Ticlopidine is a thienopyridine derivative with platelet inhibitor capability. It acts by inhibiting the platelet aggregation induced by adenosine diphosphate and by blocking the membrane receptors of fibrinogen. It is used to prevent thrombosis in patients with cerebrovascular or coronary artery disease. Two randomized clinical studies proved the drug's efficacy versus placebo and aspirin in reducing the risk of transient ischemic attack and stroke in patients with a history of cerebrovascular events. Because of its adverse effects, the use of this drug is reserved for patients in whom aspirin is contraindicated, not tolerated, or when treatment with aspirin fails. The most common side effects are mild and transitory: diarrhea, dyspepsia, nausea and rashes. More serious, but less frequent, adverse effects are hematological dyscrasia (particularly agranulocytosis, aplastic anemia, neutropenia, pancytopenia, thrombocytopenia and thrombotic thrombocytopenia purpura) and cholestatic hepatitis. However, to our knowledge, there are only a few published reports of the simultaneous occurrence of hematological and hepatic toxicity induced by ticlopidine. We report a case of agranulocytosis associated with cholestatic hepatitis related to the use of ticlopidine. A 70-year-old Caucasian woman was admitted to our Rehabilitation Ward (San Paolo Hospital, Milan) because of gait ataxia after right bulbar stroke, which occurred 10 days previously. Her medical history pointed out hypertension and hypercholesterolemia. She had no prior history with regard to hematological or liver diseases, alcohol abuse or blood transfusion. Her habitual medications were aspirin 100 mg/day, atorvastatin 20 mg/day and amlodipine 5 mg/day. Immediately after her stroke, she discontinued aspirin and started therapy with ticlopidine 250 mg twice daily. Upon admission, her blood tests were normal. About four weeks later, she developed agranulocytosis. Her white blood count was 2600 cells/μL , neutrophil count was 100 cells/μL , and liver function tests revealed a mixed cholestasis and hepatocellular injury. She had no fever and she was asymptomatic. She had elevated levels of alanine aminotransferase (560 U/L, reference range 5 to 41 U/L), of aspartate aminotransferase (551 U/L, reference range 5 to 41 U/L), of γ-glutamyl transpeptidase (449 U/L, reference range 11 to 50 U/L), of alkaline phosphatase (821 U/L, reference range 98 to 279 U/L). Total and direct bilirubin and the coagulation tests were normal.
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Review
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biomedical
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en
| 0.999996
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20860812
|
She was comatose and had a fever (39.1°C). The Glasgow coma score (GCS) was 7: eye opening, verbal response and motor response were 1, 2 and 4, respectively. Meningismus was present. Her eyeballs deviated to the left; the pupils were equal and normally reactive to light. The deep tendon reflexes were normal, with no pathological reflex. As she had frequently experienced generalized seizures with hypoventilation, the patient received mechanical ventilation. Intravenous sedation (midazolam) was started. The white cell count was 18200/μL and the C-reactive protein concentration was elevated (13.5 mg/dL). Other blood cell counts and the results of routine biochemical analysis were normal. Cranial T2-weighted magnetic resonance imaging showed bilateral regions of increased signal intensity in the hippocampus and amygdaloid body, the insular, medial temporal and medial frontal lobes . A lumbar puncture on day one showed 321 white cells/mm 3 (93% lymphocytes, 7% polyneutrophils), 1 red cell/mm 3 , a protein concentration of 66 mg/dL and a glucose concentration of 74 mg/dL. Real-time PCR amplification of HSV-1 in cerebrospinal fluid (CSF) was positive (38,000 copies/mL). HSV-1 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies were not detected in the CSF. In the serum, HSV-1 IgM antibodies were absent and the HSV-1 IgG antibody titer was 26.3. HSVE was diagnosed. Cranial computed tomography (CT) performed on day five showed hemorrhagic foci in the left amygdaloid body and low-intensity bilateral lesions in the frontal and temporal lobes. We performed repeated lumbar punctures in order to evaluate the disease severity and the responses to these treatments because a reduced consciousness level and cranial neuroimaging abnormalities persisted. CSF analysis performed on day seven showed 188 lymphocytes/mm 3 , 38 red cells/mm 3 , a glucose concentration of 72 mg/dL and increased titers of HSV-1 IgM and IgG antibodies (3.08 and 6.17, respectively). During her hospitalization, she did not experience any intermittent or persistent hypertension. Intravenous heparin (12,000 U/day) was started and the dose was adjusted according to the activated partial thromboplastin time for about a month (maximal dose of heparin, 20,400 U/day). CSF analysis on day 39 showed 6 lymphocytes/mm 3 , 52 red cells/mm 3 and a glucose concentration of 78 mg/dL; the titers of HSV-1 IgM and IgG antibodies were 1.34 and greater than 12.8, respectively. Cranial CT on day 54 showed that the subarachnoid and intracranial bleeding had disappeared. Enhanced CT angiography demonstrated an avascular area in the left temporal lobe but no other arterial or venous abnormalities, such as aneurysm formation or irregular vascular distribution, were evident (data not shown). PCR has become the standard diagnostic test for HSVE. However, intrathecal antibody measurements are still of value, with an estimated specificity of 80% or 95% . Real-time PCR is a recent modification of conventional PCR for HSV. The relation between the results of PCR and intrathecal antibody levels remains poorly understood. This issue has been addressed by one study but real-time PCR and measurement of antibody titers were performed in many patients at different times . Intrathecal viral genomes on PCR and increased intrathecal HSV antibodies have been detected within five days and after seven days from the onset of neurologic symptoms, respectively. Our study found that the results of real-time HSV PCR were positive three days after the onset of central nervous symptoms, without intrathecally synthesized specific HSV antibodies. Intracerebral hematoma is rarely associated with HSVE and only 14 cases have so far been reported. To the best of our knowledge, this is the first report to document a case of HSVE associated with subarachnoid bleeding. Obvious abnormalities of major cerebral vascular arteries, such as aneurysm formation and an irregular distribution of the anterior, middle and posterior cerebral arteries, were not evident which suggests that the subarachnoid bleeding was directly attributed to HSVE. HSV causes a necrotizing vasculopathy ascribed to cortical and subcortical intense hemorrhagic necrosis and perivascular cuffing in the medial temporal and orbitofrontal regions and CSF analysis often demonstrates the presence of red cells. In gyri located near the CSF, diffuse necrotizing angiitis of venules and capillaries induced by intense inflammatory necrotizing vasculopathy can cause vessel wall necrosis and subsequent bleeding, leading to hematogenous spread into the CSF space. Subarachnoid bleeding in our patient may have been caused by red-cell diapedesis from the hemorrhagic necrotizing amygdaloid body into the adjacent CSF spaces, resulting in 'subarachnoid bleeding with intraventricular extension'. Coagulopathy or hepatocellular damage with a consequent insufficient production of clotting factors can complicate severe HSV infections and may potentially cause bleeding.
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Clinical case
|
biomedical
|
en
| 0.999998
|
21113305
|
The surgical management of GORD sometimes fails,whether performed as an open procedure or laparoscopically, and may require a reoperation for optimal results . Amongst the various mechanisms of failure, migration of the stomach into potential spaces such as in paraoesophageal herniation is a serious and important complication as the diagnosis may be significantly delayed resulting in an increase in morbidity and mortality of the affected patients [ 5 – 7 ]. In this report, we describe a case of migration of the stomach into a congenital postdiaphragmatic space following laparoscopic Nissen Fundoplication. She then continued to be hypoxic and hypotensive and a chest X-ray revealed a right sided pneumothorax which was managed with a right chest drain. Serial arterial blood gas samples did not reveal any acid-base disturbances at this stage. A gastrografin swallow ruled out any perforation in the oesophagus and was otherwise nonspecific. After a short period of noninvasive ventilation, she remained hypoxic and was consequently intubated. A second chest drain was inserted on the left side due to worsening bilateral pleural effusions on a subsequent chest X-ray. A repeat OGD revealed a normal GOJ with a rotated and distended stomach but there was no evidence of gastric outlet obstruction. As the patient continued to deteriorate, a computerised tomography (CT) scan was done which confirmed herniation of the stomach into a congenital postdiaphragmatic space. At exploratory laparotomy, the anterior wall of the stomach was noted to be herniating into a congenital space behind the diaphragm pushing the liver and the inferior vena cava anteriorly. There was no evidence of a gastric volvulus. Following the retrieval of the herniating segment, the wrap was noted to be congested with an area of ischaemia which recovered promptly following reduction and no resection was necessary. The wrap was undone revealing a defect in the anterior wall of the stomach. The margins of the defect, which were of doubtful viability, were trimmed and the defect was closed with nonabsorbable sutures and covered with omentum. The stomach was then fixed to the anterior abdominal wall with nonabsorbable sutures. No defect was noted in the diaphragm where three hiatal interrupted nonabsorbable sutures, which were placed during the previous fundoplication and were noted with a normal length of abdominal oesophagus. Although migration of Nissen fundoplication wraps has been previously described [ 5 – 7 ], there are no reports of migration into congenital spaces including congenital post diaphragmatic spaces in the literature. It is timely to raise awareness of this potentially serious complication and carefully present the associated clinical features . In our case, it is possible that the creation of pneumoperitoneum resulted in a residual pocket of gas within the space exposing it as a potential herniating space postoperatively. A further possibility is that a tight GOJ after fundoplication might have induced acute gastric dilatation and herniation. It is notable that the patient did not have specific symptoms apart from reflux to account for the presence of this congenital space. As described earlier, our patient presented with nonspecific clinical signs including hypoxia, hypotension, pyrexia, vomiting, a unilateral pneumothorax, and bilateral pleural effusions. Some of her nonspecific symptoms could be explained in the context of systemic inflammatory response syndrome. Worsening of her clinical condition despite aggressive conservative treatment in ICU was a prompt for further investigations and subsequent surgical intervention. Anterior gastropexy was considered to be the most appropriate surgical intervention in the context of the life-threatening clinical presentation. The retention of an adequate length of abdominal oesophagus with an intact oesophageal hiatus repaired by three nonabsorbable sutures could explain the resolution of reflux symptoms after a long period of followup.
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Review
|
biomedical
|
en
| 0.999997
|
21734923
|
Les tumeurs neuro-ectodermiques primitives appartiennent à la famille des tumeurs sarcomateuses d’Ewing qui dérivent toutes de la même cellule souches . Les cellules de la crête neurale sont soupconnées d’être à l’origine de ces tumeurs. Les sites de prédilections de ces sarcomes sont: la région paravertébrale, la paroi thoracique et les extrémités distales. Plus rarement, ils se développent aux dépens du poumon, de l’utérus, des ovaires, des voies urinaires, du myocarde, de la glande parotide et du rein . Le diagnostic positif des tumeurs neuro-ectodermiques primitives nécessite la contribution de l’histopathologie, de l’immunohistochimie et de la cytogénétique. Il s’agit d’un homme de 30 ans, sans antécédents particuliers, se plaignant de douleurs épigastriques évoluant depuis un mois dans un contexte d’apyrexie et de conservation de l’état général, sans vomissement ni hémorragie digestive extériorisée. L’examen clinique a objectivé une masse épigastrique de 9 cm de grand axe fixée au plan profond mobile par rapport au plan superficiel et indolore. La fibroscopie oesogastroduodénale a révélé la présence d’une ulcération antropylorique de la face antérieure de 2 cm de grand axe. L’échographie abdominale a montré l’existence d’une masse tissulaire de 10 cm de grand axe, présentant des végétations endokystiques et se développant au dépend de l’estomac sans ascite et sans image de métastase hépatique. La Tomodensitométrie (TDM) abdominale a confirmé ces données, et a visualisé la tumeur kystique avec sa composante tissulaire périphérique rehaussée par le produit de contraste . Le rétablissement de la continuité a été réalisé au moyen d’une anastomose oeso-jéjunale sur anse en Y. Les suites opératoires ont été simples avec reprise de l’alimentation au 5 ème jour. L’examen anatomopathologique de la tumeur trouvait des massifs de petites cellules contenant des tâches noirâtres, des nucléoles arrondis et ovales, un cytoplasme éosinophile et des mitoses fréquentes. Ces cellules présentaient une discrète différentiation en rosette et un stroma de nature desmoplastique. Les ganglions n’étaient pas envahis. L’immunomarquage par les anticorps anticytokératine, antichromagranine, antidésmine et antisynaptophysine était négatif. En revanche, celui par l’anticorps anti-CD99 (Mic2) était fortement positif. Il s’agissait donc, d’une localisation gastrique d’une tumeur neuroectodérmique primitive périphérique. Le geste chirurgical étant jugé curatif, le complément chimiothérapique n’a pas été indiqué. Au recul de six mois, le contrôbiologique et scanographique n’a pas objectivé de récidive. En janvier 2000, l’OMS a classé Les pPNET comme appartenant au groupe des tumeurs neuroépithéliales embryonnaires c’est-à-dire développées à partir de cellules germinales du tube neural . Ces tumeurs représentent moins de 1 % de tous les sarcomes. Elles prédominent avant l’âge de 35 ans (75 % des cas) avec un pic de fréquence entre 15 et 20 ans. Neuf cas sur dix sont de race blanche avec une légère prédominance masculine, mais aucun facteur favorisant n’est retrouvé . La localisation thoracique est la plus fréquente (44%) suivie des pPNET abdominopelviens (26%) puis des extrémités (20 %) et enfin de la tête (6 %) . A notre connaissance, notre cas serait le 3ème cas de pPNET gastrique décrit chez l’adulte . Les signes cliniques manquent de spécificité. La douleur abdominale ainsi que la présence d’une masse abdominale et d’une fièvre sont les symptô les plus fréquents. La biologie est également non spécifique. Les examens radiologiques explorent la tumeur et recherchent les métastases, localisées par ordre de fréquence aux poumons (50 %), os (25 %), moelle (20 %), foie et cerveau , jugeant ainsi de la résécabilité de la tumeur primitive. D’un point de vue anatomopathologie, la tumeur est multilobulaire, molle, friable. Elle est en général blanchâtre avec de larges plages de nécroses, des formations kystiques et des hémorragies intratumorales . D’un point de vue microscopique, les cellules tumorales sont rondes, avec un noyau arrondi. La membrane nucléaire est bien distincte, avec une chromatine fine et parfois un ou deux petits nucléoles. Les mitoses sont plus ou moins fréquentes. En général on note la présence de grains de glycogène intracytoplasmiques. La présence de rosettes ou pseudo-rosettes caractérise plus précisément les PNET. La plupart du temps, ces tumeurs surexpriment un antigène déterminé par le gène MIC2 désigné sous le nom de CD99. Elles surexpriment d’autre part une autre protéine appelée FLI1 issue de la translocation entre le chromosome 22 et le chromosome 11.
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Study
|
biomedical
|
fr
| 0.999998
|
21849070
|
Pancoast syndrome is most commonly associated with a primary lung carcinoma and rarely with metastatic malignancies and certain infections, including mucormycosis. It is characterized by Horner syndrome, shoulder pain radiating down the arm, compression of the brachial blood vessels, and, in long-standing cases, atrophy of the arm and hand muscles. Pulmonary mucormycosis usually occurs in the setting of hematological malignancies. The typical presentation is a patient with neutropenic fever, pulmonary infiltrates, and a clinical course that worsens despite antibiotics. We present a case of pulmonary mucormycosis associated with postchemotherapy neutropenia in a patient with acute myeloid leukemia. His course was fulminating, leading to chest wall invasion, brachial plexopathy, and Horner syndrome. A 51-year-old Caucasian man was hospitalized for the management of a relapse of acute myeloid leukemia. He had hyperleukocytosis and complained of mild shortness of breath and generalized weakness. He denied cough, fevers or chills, hemoptysis, or orthopnea. He had smoked 39 pack years. His significant medical history began six months prior to admission, when his condition was diagnosed as acute myelomonocytic leukemia. He had been treated with cytarabine and daunorubicin followed by high-dose cytarabine. Shortly after admission, he required urgent leukopheresis because of worsening hyperleukocytosis and acute respiratory failure. He recovered and had further chemotherapy with clofarabine and cytarabine. Eighteen days after admission, he was neutropenic and febrile. He developed left axillary burning pain, which evolved in a matter of hours to numbness of his arm. Soon afterward, weakness started in his hand and later moved proximally up his arm. At that time, he had a temperature of 38°C, a respiratory rate of 20 breaths per minute, a heart rate of 133 beats per minute, blood pressure of 117/77 mm Hg, and an oxygen saturation of 94% on 50% venturi mask. He was dyspneic and a chest examination revealed signs of lung consolidation in the left upper and left lower lobes. A chest radiograph revealed elevation of the left hemidiaphragm, alveolar and interstitial opacities of the left upper lobe and lower lobe with air bronchograms, and blunting of the costophrenic angle. He was started on broad-spectrum antibiotics and voriconazole prophylaxis. A physical examination revealed edema of the skin over the anterior left chest wall but no erythema, scaling, or discrete skin lesions. In a matter of hours, the numbness spread from a T1 distribution to a C8 distribution. The following day, his left arm was plegic with the exception of trace movement of the deltoid muscle. He was anesthetic to all sensory modalities in the left arm as well as areflexic. He also developed a left Horner syndrome. Further swelling developed in his left arm and anterosuperior chest with fullness in the supraclavicular fossa. Doppler ultrasound showed occlusion of his left distal subclavian, axillary, and brachial arteries and deep vein thrombosis of his left internal jugular, subclavian, and axillary veins. Heparin was started for his thrombosis, but soon after he had mild hemoptysis. A chest computed tomography scan showed extensive edematous changes of the left chest wall and axilla along with left pleural effusion and pulmonary parenchymal consolidation. A bronchoscopy that revealed a blood clot in the left upper lobe bronchus without endobronchial lesions was performed. Six days after the onset of numbness, a palpable purpuric plaque developed over his left chest and progressed to a 2 cm black eschar. A punch biopsy of the plaque was performed. With failure to respond with broad spectrum antibiotics (which included vancomycin, imipenem, voriconazole and acyclovir), liposomal amphotericin B 5 mg/kg per day was added empirically to his regimen. A histological evaluation of skin biopsy showed abundant angiocentric and angioinvasive ribbon-like hyphae with irregular nonparallel contours, occasional right-angle branching, and rare septae . Cultures from both skin and bronchoalveolar lavage confirmed a diagnosis of mucormycosis by a Rhizopus species. Twenty-four hours later, he developed respiratory distress, shock, and multiorgan failure resulting in death. An autopsy was declined by his next of kin. Pulmonary mucormycosis occurs with inhalation of spores into the bronchioles and alveoli, usually resulting in a rapidly progressive pneumonia or endobronchial disease. Symptoms are typically nonspecific and may include fever, dyspnea, cough, and chest pain . The infection can spread to contiguous organs or disseminate hematogenously. Of particular interest to our case is the overwhelming speed with which the process extended from the lung parenchyma to the surrounding structures (tissue, nerves, vessels, and skin). The progression of symptoms suggests that the lower brachial plexus trunk became ischemic initially and that the rest of the plexus followed as the lesion extended from the lung to the surrounding tissues. Mucor is known to locally invade nerves, most often in rhinocerebral disease. Common clinical findings include rhinitis, periorbital and facial swelling, mucosal necrosis, ophthalmoplegia, multiple cranial nerve palsies, facial pain, and headache . Whereas stroke from rhinocerebral mucormycosis causing occlusion of the cavernous portion of the internal carotid is well documented , involvement of the brachial vascular and nervous plexus is a very unusual presentation. Three reports document mucormycosis presenting as a Pancoast syndrome . Notably, two had diabetes (both survived) as their only risk factor and one had acute lymphoblastic leukemia (died). Pancoast syndrome is characterized by Horner syndrome (ptosis, miosis, hemianhidrosis, and enophthalmos), shoulder pain radiating toward the axilla or ulnar aspect of the arm, compression of the brachial blood vessels, and atrophy of the arm and hand muscles. This syndrome is most commonly caused by a bronchogenic carcinoma in the superior sulcus of the lung with destructive lesions of the thoracic inlet and invasion of the brachial plexus and cervicothoracic sympathetic chain. Other causes include metastatic neoplasms and infections. In a recent review of 31 patients with infectious causes of Pancoast syndrome, five were immunocompromised (acute myelogenous leukemia, acute lymphoblastic leukemia, and postchemotherapy), and all had opportunistic organisms ( Aspergillus spp., mucor, nocardia, and Pseudoallescheria boydii ) . In contrast, only one of the 26 immunocompetent patients had an opportunistic organism. In immunocompromised patients, it can be challenging to distinguish pulmonary disease caused by mucormycosis from that caused by aspergillosis. The concomitant presence of sinusitis or a history of voriconazole prophylaxis may suggest mucormycosis . Of note, our patient received voriconazole prophylaxis. The radiographic presentation of pulmonary mucormycosis can be diverse, and there are no pathognomonic radiographic features. In a review of imaging findings in 32 cases of mucormycosis, two thirds of the patients had consolidation as a main finding . Other radiographic manifestations include cavitation, mass-like lesions, widened mediastinum, an "air crescent sign", "halo sign", pleural effusion, and fistula to the chest wall . Chamilos and colleagues , in a retrospective chart review, found that multiple nodules (at least 10) and the presence of pleural effusion were more often found in mucormycosis than in aspergillosis. Definitive diagnosis of mucormycosis often evades initial noninvasive techniques such as sputum and blood cultures. The organism may be recovered by bronchoscopy with bronchoalveolar lavage or transbronchial lung biopsy. However, because of the focal distribution of the disease, transthoracic computed tomography-guided needle biopsy or open lung biopsy may be required to make the diagnosis in pulmonary disease . Histology is characterized by infarction and necrosis of tissue which results from an invasion of the vasculature by hyphae. The fungus can also be associated with neural, vascular, and cutaneous invasion, as in our patient. The fungus is usually recognized by broad, irregular, nonseptate, right-angled, branching hyphae and is demonstrated by hematoxylin and eosin and specialized fungal stains. In contrast, Aspergillus hyphae are narrow with septate branches at 45° angles. As with other fungal diseases, mucorales rarely grow by culture.
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Clinical case
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biomedical
|
en
| 0.999996
|
22242023
|
Venous thromboembolism (VTE) remains one of the main direct causes of maternal mortality in developed countries [ 1 – 4 ], largely due to pulmonary thromboembolism (PE) [ 5 – 7 ] which is responsible for around 20% of maternal deaths . Epidemiologic studies estimate the annual frequency of deep venous thrombosis (DVT) in the general population to be from 0.16‰ to 1‰ , of which 2% are pregnancy related . There is an increased risk of thromboembolic event, either DVT or PE, during pregnancy and puerperium , and it has been estimated that the risk of VTE is 10-fold higher [ 11 – 15 ], reaching up to 2‰ . Established risk factors for VTE during pregnancy include maternal age , obesity (body mass index (BMI) >30) , preeclampsia/hypertension, parity ≥3 , previous VTE or congenital or acquired thrombophilia , smoking, diabetes , multiple gestation , black race , and anaemia. During the labour there are other factors : type of delivery (with 3–6-fold higher risk for cesarean versus vaginal delivery, higher for emergency cesarean , and mid-cavity instrumental delivery) , prolonged labour >12 hours , immobility; major abdominal surgery for >30 minutes during pregnancy or puerperium , preterm delivery , excessive blood loss (>1 litre), or blood transfusion. In the postpartum period, other factors may be added as dehydration, immobility, and anaemia . Table 2 shows the characteristics of the deliveries and the associated thromboembolism risk factors. Cesareans were almost always at term, with only 12.7% preterm, while 73.6% were emergency cesareans, an added thrombosis risk factor. The most frequent anesthesia was locoregional (88.3%). Other potential thrombosis factors (due to the possible underlying disease) were placental abruption (2.2%) and intrauterine growth retardation (IUGR) (8.5%). In the present study, only placental abruption and gestational age (preterm) were significantly related to PE ( P < 0.005). There was only one PE case. This case was in a 25-year-old nulliparous woman assigned to group B with a BMI of 29.5 and no family history of thrombosis; her smoking habit of <10 cigarettes/day was the only risk factor during pregnancy. She was hospitalized in week 32 with placental abruption symptoms and underwent emergency cesarean with locoregional anesthesia. At this time two other risk factors were added up: emergency cesarean section and vaginal bleeding. The fetus was delivered alive with appropriate weight for gestational age. The mother presented with moderate anemia that required intravenous iron treatment. On the first postoperative day, before beginning the thrombophylaxis with bemiparin, she reported difficulty in breathing and pain in right costodiaphragmatic recess. PE was diagnosed after clinical examination, elevated D-dimer, and complementary tests: perfusion lung scintigraphy (PE in lateral and medial segments of medial lobe of right lung) and bilateral lower limb Doppler's ultrasound examination (normal). Consequently, a therapeutic LMWH regimen was started instead of the thromboprophylaxis regimen and was subsequently replaced with oral anticoagulant therapy. A hypercoagulation test at 6 months ruled out thrombophilias. Some authors have recommended the postcesarean use of LMWH only when there is an additional risk factor or in cases of emergency cesarean . However, we agree with the recommendations of several clinical practice guidelines , which have recommended that the threshold for prescribing thromboprophylaxis should be lower in the postnatal period than that in the antenatal period since the risk of developing VTE per day is higher and the duration of exposure shorter. Even some of them recommend that all women, who have had an emergency caesarean section or an elective cesarean section and have one or more additional risk factors for VTE, should receive thromboprophylaxis with LMWH for seven days. We agree with the recommendations of recent clinical practice guidelines ; and although, a cost-effectiveness analysis was not completed specifically for this population subgroup, the cost-effectiveness model for medical patients indicates that prophylaxis with LMWH is cost effective for patients at increased risk. In our investigation, bemiparin 3500 once daily during five days has been sufficient to prevent thromboembolic events, so health costs are lower (two days less than recommended in the clinical practice guideline) , although clotting factors may take a few more days to normalize.
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Study
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biomedical
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en
| 0.999996
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22335966
|
Cluster headache (CH) is defined as a paroxysmal, strictly unilateral and very severe headache . It is seen very rarely with a prevalence of less than 0.1% . Ptosis, miosis, lacrimation, conjunctival injection, rhinorrhea and nasal congestion are autonomic symptoms, which usually accompany retro-orbital pain. CH can be categorized into episodic and chronic forms. Various treatment modalities have been tried in both the prevention and treatment of CH . The intranasal application of 10% lidocaine to the nasal mucosa corresponding to the sphenopalatine fossa has proved effective . However, the mechanism of lidocaine in treating the headache is unknown. Here, we report a male patient suffering from CH and severe ptosis that immediately resolved with intranasal lidocaine application and discuss the possible mechanism of lidocaine in treating CH. A 22-year-old Turkish man presented with a five-year history of intermittent daily headache centered on the left retro-orbital and orbital side. The pain was unilateral with a side shift only within the same bout. He experienced four to twenty attacks a week from the beginning of the bout, which resulted in severe social agitation. The attacks started abruptly and usually peaked within five minutes, without any aura or precipitating factors, and lasted 30 minutes to 120 minutes. He suffered from rhinorrhea, lacrimation and ptosis during the headaches, without any noted nausea, vomiting or photophobia. He had previously used several daily medications unsuccessfully, such as verapamil 160 mg thrice daily, naproxen 500 mg thrice daily, ibuprofen 600 mg thrice daily, dexketoprofen trometamol 25 mg twice daily, indomethacin 25 mg thrice daily, loratadine 5 mg daily and prednisolone 60 mg daily. Both general and neurological examinations between attacks and hematological-biochemical screenings were normal. He had neither significant past medical history nor family history of headache. On the day of a severe headache, an ophthalmological examination of our patient revealed lacrimation, conjunctival injection and ptosis without miosis. We measured both his pupils as 3.5 mm, with normal pupillary reactions to both light and near stimulation. As attacks occurred without significant periods of remission, we diagnosed our patient with chronic CH. We applied a cotton tip with 2 mL of lidocaine hydrochloride and epinephrine (Jetocaine, 20 mg lidocaine/0.025 mg epinephrine) into the left nostril for 10 minutes. The ptosis responded to the treatment and the intensity of his headache decreased. The magnetic resonance (MR) images of his brain and orbit and MR angiography of his brain and carotid artery were within normal limits. In 12 months of follow-up, he had six to ten attacks a week accompanied by autonomic symptoms, which resolved with intranasal lidocaine application. CH is a type of primary headache characterized by severe, unilateral trigeminal pain with cranial parasympathetic autonomic symptoms involving oculocephalic functions . The estimated prevalence is less than one in 1,000 in the general population and the disease affects men with a sex ratio between two point five and seven point five to one . The diagnostic criteria of the International Headache Society allow for the distinction of two main CH subtypes, namely an episodic form and a chronic form . In the episodic form, attacks occur daily for some weeks followed by a period of remission. In the chronic form, attacks occur without significant periods of remission. Practitioners have used lidocaine as an acute treatment option for many types of headache by suppository, intramuscular, intravenous and nasal routes. Lidocaine 4% application in the sphenopalatine fossa may offer the fastest relief of any known agent . The sphenopalatine ganglion (SPG) resides just posterior to and immediately above the posterior tip of the middle turbinate, beneath the nasal mucosa at a depth of 1 mm to 9 mm. Intranasal lidocaine is administered with the patient supine, with the tip of the nose pointed vertically, and the head turned slightly toward the side of the block. A cotton-tipped applicator saturated with 4% lidocaine is inserted intranasally and applied to the lateral posterior wall of the nasal cavity. The application of lidocaine to the area corresponding to the sphenopalatine fossa has been shown to be effective at extinguishing pain attacks in patients with CH. Robbins reported the clinical features and results of the treatment of 30 patients with CH who had tried 4% lidocaine solution as a nasal spray to abort the attacks. Of these 30 patients, 27% of the patients reported moderate relief, 27% obtained mild relief and 46% found no relief from the lidocaine. Costa et al . conducted a placebo-controlled study in nine CH patients on the effect of a 1 mL solution of 10% lidocaine applied during nitroglycerine-precipitated CH attacks, applying a cotton swab intranasally on both sides in the area of the sphenopalatine fossa under anterior rhinoscopy. In all treated patients, the pain disappeared on average within 37 minutes of lidocaine application. It has been demonstrated that nasal congestion, rhinorrhea, lacrimation and photophobia generally disappear with pain, while conjunctival injection, miosis and ptosis are resolved later . In our case, following intranasal lidocaine application, pain ceased first and then ptosis resolved, as described in the literature. We encountered no complications in our case and, to date, there is no reported toxicity in the literature. The mechanism for lidocaine in treating CH is unknown. Lidocaine provides its anesthetic effect as a sodium pump inhibitor. It is hypothesized that lidocaine provides local anesthesia, blocking neural transmission of the SPG, which may be important in CH pathophysiology . The SPG is a complex region, including sensory fibers that contribute to the trigeminal nerve, as well as both parasympathetic and sympathetic fibers. Therefore, intranasal lidocaine may produce both sensory and parasympathetic nerve blockade. However, the mechanisms by which these blockages occur are not clear.
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Clinical case
|
biomedical
|
en
| 0.999997
|
22802895
|
Glomus tumor (GT), also termed tumor of Popoff, or Barre-Masson syndrome, is an extremely rare benign lesion composed of rounded uniform cells often arranged in a brick-work-like manner. They are intimately associated with the vascular structures . At one time, this tumor was considered to derive from the neuromyoarterial glomus, a neurovascular structure . At present, however, it is believed that the tumor arises from the modified smooth muscle cell. Outside the bone, the glomus tumors with cellular atypia (so-called symplastic glomus tumors) and malignant glomus tumors have been described both of which are exceedingly rare . In 1812, Wood made the first clinical description of a GT; he described it as a “painful cutaneous tubercle” . In 1924, Masson published its first comprehensive pathologic description . These tumors typically present as a painful, firm, purplish, solitary, subcutaneous nodule. Tumor size is generally reported to be small, rarely bigger than 1 cm . When the tumors are located at the lower extremity, the average tumor size is more than 2 cm, in contrast to those tumors located in typical locations (fingers). Symptoms include intense burning pain at the tumor size, which occurs spontaneously or is precipitated by temperature changes or touch. A fear of using the lower extremity may cause severe limb atrophy, extremity vasomotor disturbances or flexion restrictions .
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Clinical case
|
clinical
|
en
| 0.999998
|
22937298
|
Calcium is not only an important component of bone, it also plays a key role in generating action potentials. As a result, hypocalcaemia increases excitability of nerve and muscle cells, leading to cramps and, in severe cases, tetany. Serum calcium levels are hormonally controlled, mainly by parathyroid hormone and vitamin D. The latter is to a small extent attained from food, but the majority is formed in sun-exposed skin. The risk for deficiency is increased in dark-skinned people living at higher latitudes. We describe a case of a dark-skinned patient with extreme hypocalcaemia, caused by an unusual disorder in calcium metabolism. An 18-year-old negroid woman presented at the emergency department with progressive cramps in both hands for two days. She was born in Jamaica and had moved to The Netherlands eight months prior to presentation. She had no relevant medical history and did not use any medication. On physical examination, we found her fingers to be cramped with Trousseau's sign positive. No other abnormalities were observed. Laboratory analysis showed severe hypocalcaemia (1.17 mmol/L; reference value 2.10–2.50) and hyperphosphataemia (2.0 mmol/L; 0.7–1.4) with normal blood levels of albumin (36 g/L; 35–50), creatinin (61 μ mol/L; 50–90), and alkaline phosphatase (96 U/L; 0–120). Magnesium was slightly decreased (0.6 mmol/L; 0.7–1.0). Electrocardiography showed normal QTc time, but flattened ST segments, consistent with hypocalcaemia. As could be expected in a dark-skinned person in Dutch autumn, the 25OHD level was low (31 nmol/L; 50–280). However, this minor deficiency was an unlikely explanation for the severe calcium depletion. 1,25-(OH) 2 -vitamin D was low normal (69 pmol/L; 48–161). Instead, the combination of hypocalcaemia and hyperphosphataemia was considered more consistent with hypoparathyroidism, a diagnosis supported by urine analysis, showing a low excretion of both calcium (0.8 mmol/day; 2.5–7.5) and phosphate (5 mmol/day; 10–50). Unexpectedly, parathyroid hormone (PTH) was increased (22.1 pmol/L; 1.3–6.9), rendering the possibility of pseudohypoparathyroidism (PHP). To confirm this diagnosis, an Ellsworth-Howard test was performed, measuring urinary phosphate excretion after administration of a high dose of synthetic PTH. In our patient, phosphate excretion only increased fivefold, where a 100-fold increase is regarded as normal, supporting the diagnosis PHP. No other hormonal imbalances were found. Although the normal alkaline phosphatase level suggested no PTH-induced increase in bone resorption, densitometry was performed to assess bone mineral density, revealing normal values of the lumbar spine ( T = +0.2) and hips ( T = +1.4). Different types of PHP, each with specific features, have been described ( Table 1 ). The best known type of PHP is type 1a, where biochemical disruptions are combined with a phenotype called Albright's hereditary osteodystrophy (AHO), including short stature, round face, brachymetacarpia, and subcutaneous ossifications . The origin of PTH resistance accounts for the differences between the types. The GNAS1 gene, encoding the PTH receptor, can either be mutated (PHP type 1a and pseudo-PHP) or its methylation can be altered (PHP type 1b). In most target tissues both maternal and paternal alleles are transcriptionally active. However, in the proximal tubulus only the maternal allele is read. Thus, changes in the paternal GNAS1 allele do not lead to electrolyte imbalances . In our patient, who presented with biochemical abnormalities and a normal phenotype, the most likely diagnosis is PHP type 1b, a methylation defect of the maternal GNAS1 gene. This is supported by the fact that a mutation in GNAS1 could not be demonstrated. However, type 2 PHP, where the problem originates from the signaling cascade of PTH, cannot be ruled out. Since all types of PHP are congenital and the patient did not experience any symptoms during the first 18 years of her life, we believe moving to The Netherlands aggravated her hypocalcaemia. Possibly, the lack of sunshine in Dutch winter resulted in decreased vitamin D levels, lowering calcium levels even further. Strangely, even with low 25OHD levels and a PTH resistant kidney, calcitriol levels were within the normal range. Adaptation might have occurred by augmenting the normal activation of 25OHD in other tissues. We assume that vitamin D levels were significantly higher when living in a sunnier climate.
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Clinical case
|
biomedical
|
en
| 0.999998
|
23243539
|
Hemangiomas are benign vascular lesions that are most common in infancy and childhood. The tumor occurs frequently in head and neck. One third of these lesions will present at birth. Besides, 20% of hemangiomas are multiple. Hemangiomas of the tympanic membrane and/or external auditory canal are rare entities, with 16 previous case reports in the literature. It is a benign vascular tumor. It generally occurs in males in the sixth decade of life. It appears as a small vascular lesion interesting the deep posterior bony external auditory canal and/or the posterior superior tympanic membrane. The first two cases of hemangioma of the tympanic membrane and posterior external ear canal were reported by Freedman et al. in 1972 . Balkany et al. in 1978 reported the first case of capillary hemangioma exclusively envolving the tympanic membrane . In 1982, there was proposed a hemangiomas classification that divides these lesions in two histological categories: cavernous and capillary. The cavernous hemangioma is characterized by large cavernous vascular space lined by endothelium. Capillary hemangioma is made up of small vessel of capillary caliber. It is lobulated and lacks a capsule. In 1990, one case of mixed hemangioma (cavernous/capillary) has been described . Pathologic examination revealed a well-defined proliferation of dilated tortuous vascular structures, closely adhering to each other, filled by erythrocytes in the lumen. They varied in size and were delimited by a single layer of flat endothelial cells. Superficially, the lesion was lined by hyperkeratotic squamous epithelium. These features were consistent with a cavernous hemangioma . The postoperative course was uneventful, and conductive hearing loss disappeared. There has been no recurrence for 1 year postoperatively. All authors, except Magliulo, exclude the involvement of middle ear or mastoid. In fact, in no case histological examination after the surgical procedure showed involvement of the middle ear and/or mastoid. Even in the case described by Magliulo, hemangioma interested in full-thickness the tympanic membrane in correspondence of the handle of the hammer but without signs of erosion or pathology of the same . In the light of the lack of aggressiveness of the disease, while in the past it tended to increase the area of excision and then use a myringoplasty, if not even to a exploratory mastoidectomy, the most recent reports indicate the simple excision technique of choice with respect to medial layers of the tympanic membrane. Recurrence of hemangioma has been reported only in one case and was related to inadequate surgical excision .
|
Review
|
biomedical
|
en
| 0.999998
|
23710383
|
Drug-induced immune hemolytic anemia (DIIHA) is a serious condition that can be a rare side effect of commonly used over-the-counter medications. The incidence of DIIHA is estimated to be 1 per million of the population. While no explicit data exist regarding the incidence of ibuprofen induced hemolysis, various case series have found that NSAIDs compromise less than 15% of cases; the majority of cases are caused by beta-lactamase antibiotics (e.g., cephalosporins and penicillins). Timely recognition of this condition along with discontinuation of the offending agent is paramount in treating its potentially fatal complications [ 1 – 3 ]. A 36-year-old healthy caucasian female presented to the emergency department complaining of 1-day duration of shortness of breath. The only medication that she was taking was ibuprofen, which she started to take twice daily one week before presentation for tension headaches. The patient was found to have regular sinus tachycardia of 127 beats per minute. Subsequent physical examination revealed jugular venous distention and pale mucous membranes with no jaundice, lymphadenopathy, or organomegaly. No obvious source of bleeding was identified. Upon initial workup, she was found to be severely anemic with a hemoglobin of 4.9 (normal range 12–15 g/dL), hematocrit of 14.2 (normal range 36%–47%), MCV 98.8 (normal range 80–100 fL), and RDW of 24.6 (normal range 11%–14.5%). Anemia workup was initiated and was significant for an elevated lactate dehydrogenase (LDH) 435 (normal range 135–214 IU/L), reticulocytosis 23.2 (normal range 0.5%–2.8%), and decreased haptoglobin <6 (normal range 36–195 mg/dL). Stool test for occult blood was negative. Type and screen were positive for antibodies and Direct Antiglobulin Test (DAT) was reactive with anti-IgG and anti-C3 antibodies. Coombs test elution was also found to be positive. Biochemical tests except for bilirubin 2.7 (normal range 0.0–1.0 mg/dL) were unremarkable. The patient's peripheral blood smear demonstrated an abundance of spherocytes and polychromasia . No abnormalities were noted among white blood cells and platelets. Antinuclear antibodies (dsDNA, Chromatin, Ribosomal P, SS/A, SS/B, Sm, SmRNP, RNP, Scl 70, Jo 1, and Centromere B), rheumatoid factor (RF) and CT scan of chest, abdomen, and pelvis were all negative as part of the workup for autoimmune hemolytic anemia. Drug-induced immune hemolytic anemia (DIIHA) is a rare condition, affecting approximately 1 per million of the population. As a comparison, drug-induced thrombocytopenia and neutropenia have an incidence of 10–18 cases per million and 2–15 cases per million, respectively . DIIHA can be further classified by dividing the drug into whether or not antibodies to the drug are present: drug dependent (DDAB) and drug independent (DIAB). DDAB shows activity only in the presence of the drug; DIAB has activity in the absence of drug . Most cases of DIIHA are caused by DDABs. Usually direct antigen testing (DAT), which is also known as the direct Coombs test, is used to diagnose DIIHA . In this test washed RBCs are mixed with antiserum or monoclonal antibodies prepared against IgG and a third component of complement C3d . It is positive almost in all cases of DIIHA, although some rare cases of negative DAT can be occasionally seen . If DAT is positive, then elution test should be performed to characterize antibodies. In case of DDAB elution test is negative since drug is not present in vitro testing. DIIHA is less frequently mediated by DIAB which is almost identical to warm autoimmune hemolytic anemia (WAIHA). In this case both DAT and elution are positive. The only way to differentiate between DIAB and WAIHA is to stop the causative agent and observe the hematologic response . Usually it takes a few weeks to reach hematological remission, meanwhile serological remission (when Combs test becomes negative) might take a few months . Treatment of DDAB is discontinuation of an offending drug. In the case of DIAB, steroids should be also added besides culprit drug discontinuation . The main diagnostic entities to be considered in the differential diagnosis of drug-induced immune hemolytic anemia (DIIHA) include different causes of warm autoimmune hemolytic anemia (WAIHA), since they are characterized by IgG antibodies that react with red blood cell antigens at body temperatures. The main causes of WAIHA are idiopathic WAIHA, autoimmune and connective tissue diseases (especially systemic lupus erythematosus, scleroderma, dermatomyositis, ulcerative colitis, and rheumatoid arthritis), lymphoma, chronic lymphocytic leukemia, and prior organ transplantation [ 8 – 13 ]. DIIHA is most commonly confused with idiopathic WAIHA, which is more common . An elution test can be useful in differentiating DIIHA from WAIHA. In the case of WAIHA, both DAT and elution tests are positive. In rare cases of DDAB and in almost all cases of DIAB, the elution test can be positive too. In this scenario the only way to confirm the diagnosis of DIIHA is documentation of complete hematologic and serologic recovery after discontinuing the offending medicine .
|
Review
|
biomedical
|
en
| 0.999997
|
24711821
|
Basal cell adenoma (BCA) is a benign salivary gland tumor that most frequently arises in the parotid gland and is characterized by the basaloid appearance of the tumor cells and the absence of the myxochondroid stromal component present in pleomorphic adenoma. BCA accounts for 1–3% of all salivary gland tumors and is included as a separate salivary gland tumor in the 1991 World Health Organization classification . Of 13749 primary epithelial salivary gland tumors, 160 cases of BCA were registered at the Armed Forces Institute of Pathology (AFIP) in 1991. The main locations are the parotid gland (75%) and the minor salivary glands of the upper lip (20%) . Here, we report a rare case of BCA arising in the minor salivary gland of the upper lip. The patient was a 59-year-old Japanese man who visited the Division of Oral and Maxillofacial Surgery, Ebina General Hospital, in December 2012, with a chief complaint of a mass in the upper lip, which had increased in size over several years. A mobile, elastic, and relatively soft mass without tenderness was palpable in the upper lip. The mucosa in the upper lip covering the mass was normal. The patient had no relevant medical history. The mass in the upper lip region measured 1.0 × 1.0 cm . The clinical diagnosis was suspected to be pleomorphic adenoma arising in the minor salivary gland of the upper lip. Histopathologically, the tumor was encapsulated by fibrous connective tissue and demarcated from the surrounding tissues ( Figure 3(a) ). It consisted of monomorphic epithelial cells with a trabecular or tubular pattern (Figures 3(b) and 3(c) ). The solid nests were composed of almost uniform epithelial cells that were columnar or cuboidal in shape with scanty eosinophilic cytoplasm and round to ovoid nuclei. The stroma surrounding the epithelial tumor nests was composed of thin fibrous tissue and was well demarcated from the solid nests (Figures 3(a) and 3(b) ). Further analysis showed a glandular structure containing a mucinous substance that was positive in Periodic Acid-Schiff (PAS) staining ( Figure 4(a) ) and deposition of abundant PAS-positive basal lamina material within and around the tumor nests ( Figure 4(b) ). The incidence of BCA is low, accounting for 1 to 3% of all salivary gland tumors, with a peak in the seventh decade of life . The main locations are the parotid gland (75%) and the minor salivary glands of the upper lip (20%) . Fantasia and Neville have reported 50 cases of BCA arising in the upper lip in the minor salivary gland . Mucoceles most commonly involve the lower lips of young patients (second and third decades), whereas the BCA typically occurs in older patients (mean age: 61 years) and usually involves the upper lip . Histopathologically, BCAs are benign tumors composed of relatively isomorphic basaloid cells, a conspicuous basal cell layer, and distinctive basement membrane-like material. Most are well circumscribed and encapsulated, although a multinodular microscopic pattern may be found in any of the subtypes. BCAs lack the characteristic myxochondroid matrix found in pleomorphic adenoma . BCAs are classified based on their morphologic pattern into four subtypes: solid, trabecular, tubular, and membranous , with the solid variant being the most common. The tumor in our case had a predominant tubular-trabecular pattern composed of islands of tumor cells with a hyperchromatic, palisaded, and peripheral layer of cells . The initial clinical diagnosis was suspected to be pleomorphic adenoma in the minor salivary gland in the upper lip. In such cases, immunohistochemistry is needed for differential diagnosis to exclude mucocele, malignant lymphoma, lymphangioma, hemangioma, adenocystic carcinoma (ACC), and basal cell adenocarcinoma (BCAC). Hiranuma et al. also suggested that a mixed tumor should be considered in differential diagnosis for BCA. Important distinguishing features of BCAs include an absence of histologically recognizable myoepithelial cells and a sharp demarcation between the epithelium and stroma. The stroma in a BCA tends to be scanty and thereis an absence of the myxoid or chondroids elements that are present in pleomorphic adenoma. BCA has sometimes been mistaken for ACC. Jung et al. reported that, compared to BCA without capsular invasion, the BCACs and BCAs with capsular invasion were more likely to be larger and have solid or cribriform patterns and most BCACs and BCAs exhibited nuclear beta-catenin expression, and beta-catenin, CK5/6, CD117, and S-100 protein were helpful for differentiating basal cell neoplasms from ACC. BCAs with capsular invasion shared several pathological features with BCACs, including a large size and frequent cribriform patterns but the malignant potential of these tumors seems highly limited and should be reexamined. Jung et al. also reported that beta-catenin immunostaining may aid the differential diagnosis between basal cell neoplasms and ACCs. Final diagnosis is difficult based on imaging and clinical findings alone. Thus, total excision and immunohistochemistry including Ki-67 labeling and beta-catenin should be performed to make a definite diagnosis. The recurrence rate is 25% for the membranous variant of BCA and malignant transformation of BCA has been reported . Therefore, it is necessary to perform complete tumor excision. This approach was used in our case and the postoperative course was uneventful 12 months after surgery with no recurrence.
|
Clinical case
|
biomedical
|
en
| 0.999995
|
24716095
|
Deep venous thromboses (DVTs) and pulmonary embolisms (PEs), commonly described together as venous thromboembolisms (VTEs), are important complications in hospitalized patients. DVTs commonly occur in the deep veins of the lower leg or the proximal veins of the iliofemoral segment and rarely occur in the inferior vena cava (IVC) [ 2 – 5 ]. Some case reports and reviews of IVC thrombosis currently exist; however, little information has been published regarding its morphology. We present three cases of IVC thrombosis, with each showing a different morphology. A 60-year-old man underwent surgical resection for cholangiocarcinoma and was referred to our department because of an IVC thrombus detected on contrast-enhanced abdominal computed tomography (CT), four days later. The patient did not have a family history of VTEs or sudden and/or premature deaths. Prior to his diagnosis, he had not complained of chest pain, dyspnea, or lower back pain. His physical examination showed a regular pulse rate of 96 beats/min, a blood pressure of 106/69 mmHg, and a low-grade temperature of 37.8°C. Auscultation failed to detect any obvious murmur or rales, and peripheral leg edema was not observed. Laboratory tests revealed an increased D-dimer concentration (12.8 μ g/mL) and a slightly decreased concentration of antithrombin (55%) and protein C (62%). The patient was also negative for the presence of antinuclear antibody, lupus anticoagulant, and cardiolipin antibody; his protein S concentration was normal. Contrast-enhanced abdominal CT demonstrated the presence of a mural thrombus adhered to the vessel wall in the infrarenal IVC ( Figure 1(a) ); interruption or hypoplasia of the IVC was not observed. We initially administered anticoagulant therapy with unfractionated heparin and antithrombin to minimize the possibility of bleeding complications. However, the IVC thrombus was found to increase in size, five days later ( Figure 1(b) ). Thus, we switched to an anticoagulant therapy involving warfarin and fondaparinux sodium, and the IVC thrombosis shrank significantly during the following month of treatment ( Figure 1(c) ); the patient was then discharged. A 40-year-old woman presented with a uterine cervical adenocarcinoma with metastasis to the liver, right kidney, pelvis, and sacral bone. She was referred to our department because an IVC thrombus was detected on contrast-enhanced abdominal CT. The patient's family history was unremarkable, but she did present with lower back pain and severe, bilateral leg edema. A physical examination showed a regular pulse rate of 91 beats/min, blood pressure of 132/90 mmHg, and a normal temperature of 35.9°C. Upon auscultation, the patient did not demonstrate any obvious murmur or rales. Her laboratory tests revealed severe anemia (hemoglobin level, 6.8 g/dL) and an increased D-dimer concentration (32.4 μ g/mL). Contrast-enhanced CT demonstrated a massive, floating thrombus, approximately 18 × 20 mm in size, extending from the right common iliac vein to the infrarenal IVC (Figures 2(a) and 2(b) ); an intra-arterial thrombus occluding a right lower lobe pulmonary artery was also noted ( Figure 2(c) ). We considered the patient to have a high risk of recurrent PE, but administration of an effective and safe anticoagulant therapy was difficult due to her severe anemia. Thus, an IVC filter was implanted. Although PEs were successfully prevented, she succumbed to the uterine cervical adenocarcinoma approximately 1 month later. A 37-year-old man with a liver abscess was referred to our department for management after the implantation of an IVC filter. The patient's family history was unremarkable, and the patient had not complained of chest pain, dyspnea, or lower back pain. His physical examination showed a regular pulse rate of 80 beats/min, blood pressure of 90/50 mmHg, and a normal temperature of 36.8°C. The patient did not demonstrate any obvious murmur or rales, but his laboratory tests revealed an increased D-dimer concentration (3.6 μ g/mL); the patient did not show any findings suggestive of congenital thrombotic disease. Contrast-enhanced CT and catheter-based venography demonstrated a small, polyp-like thrombus at the site of the infrarenal IVC , in absence of any IVC malformation. The patient was administered an anticoagulant therapy involving unfractionated heparin, and the IVC thrombus was completely resolved approximately 2 weeks later. He was discharged after removal of the filter. IVC thrombosis is a rare but significant complication in hospitalized patients. According to a report from the United States, DVTs occur in 0.85% of hospitalized patients and 1.25% of these patients have IVC thrombosis. PEs occurred in 12% of the patients with IVC thrombosis, in the absence of DVTs at other sites . However, relevant information regarding IVC thrombosis, especially about its morphology, remains scarce. In this report, our findings indicate that IVC thromboses can show at least three morphologies, that is, mural, floating, and small, polyp-like thromboses; this has not been reported previously. The clinical significance of the morphological characteristics of IVC thrombi could not be clarified based on the reported cases. However, we speculate that the floating and polyp-like thrombi may be more likely to cause PEs than the mural type because the risk of PE has been reported to be also higher in patients with free-floating thrombi in the lower-extremity deep veins . Further studies in more patients are required to verify or refute this suggestion. The classical physical signs of IVC thrombosis include bilateral leg swelling and dilated superficial abdominal wall collateral veins ; another sign preceding the development of these signs is lower back pain . However, two of the present cases did not have significant clinical signs or symptoms, and the IVC thromboses were only incidentally diagnosed when the patients underwent contrast-enhanced CT. The etiology of DVTs includes long-haul flights, pregnancy, prolonged immobility, cancer, obesity, oral contraceptive use, thrombophilia, a history of VTE, and the presence of varicose veins . IVC thromboses have also been reported to be frequently associated with cancer . Furthermore, extensive venous thromboses are frequently seen in postmortem liver abscesses , and IVC thromboses have been occasionally reported in patients with liver abscesses . Thus, physicians should keep in mind that such patients may have IVC thromboses as well as lower-extremity vein thromboses, even if they are asymptomatic.
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Study
|
biomedical
|
en
| 0.999996
|
24891960
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Vascular tumors in the oral region have been traditionally described as hamartomas or malformations rather than as true neoplasms. Stout stated that a vascular tumor, in contrast to a hamartoma, contained more endothelial cells than was necessary to line the lumina. Clinically, vascular lesions have a tumor-like appearance, due to endothelial proliferation in vessels and enlargement of vessels with secondary reactive change . Intravascular papillary endothelial hyperplasia (IPEH) is a benign, nonspecific, vascular lesion consisting of reactive proliferation of the endothelial cells that arise in organizing thrombus . It comprises approximately 2% of the vascular tumors of the skin and subcutaneous tissue . A 40-year-old female patient reported with a complaint of pain and increased swelling on the right side of the face of 1-week duration. The swelling was first noticed by the patient on the right cheek region 4 years back and was not associated with any trauma or chronic irritation. The swelling had gradually increased in size and was asymptomatic until a week before reporting to us during which the patient claimed that the swelling exhibited rapid increase in size and was associated with continuous moderate pain which aggravated on manipulation. No meal time variation in size of swelling was noted and patient did not give history of dryness of mouth. The patient's medical history was otherwise noncontributory. Clinical examination revealed a solitary diffuse extraoral swelling on the right cheek, measuring about 2 × 2 cm. The skin overlying the swelling was normal with no secondary changes. On palpation, the swelling was tender, with no local rise in temperature, soft to firm in consistency, and lobulated with a smaller hard nodule palpable at the inferior portion of the swelling . The swelling was nonfluctuant, nonreducible, noncompressible, and nonpulsatile. The swelling was not fixed to any underlying or overlying structures and was freely mobile. There were no signs of altered sensations in the area involved. Intraorally a mild fullness of the right buccal mucosa was noted with no secondary changes with similar palpatory findings as performed extraorally . Right submandibular incision measuring about 6 cm in length was marked to gain access to the masseteric area. Local anesthesia with adrenaline was infiltrated at the incision site. After the initial skin incision, parotidomasseteric fascia was then incised to gain access to the lesion within masseter muscle; care was taken not to involve any branches of facial nerve and blunt dissection was used. Once the masseter muscle was accessed, it was explored using blunt dissection and the masses of the lesion were localized. The lesion was found to have feeding blood vessels which were ligated before excision. The surgical site was checked for any residual bleeding keeping in mind the suspected nature of lesion. Upon achieving hemostasis, the surgical site was irrigated with povidone iodine solution and saline; suturing was done in layers using 3-0 vicryl and 4-0 prolene sutures . In 1922, Ewing described a rare and obscure intravascular endothelioma in the corpus cavernosum. He also described some cases of encapsulated, slow growing, subcutaneous tumors with abundant endothelial cells occurring in dilated varicose veins with previously obstructed circulation. These tumors grew in broad papillary masses formed by enlarged cells with hyperchromatic nuclei. In 1923, Pierre Masson first described an intravascular papillary proliferation formed within the lumen of inflamed hemorrhoidal plexus in a man which he believed was a neoplastic lesion and which he called Hémangioendothéliome végétant intravasculaire. Henschen described similar changes in nasal and laryngeal vessels which he considered to be a reactive phenomenon . Various terminologies have been put forth by different authors for this lesion including papillary fibroendothelioma and intravascular endothelioma, papillary proliferation of the endothelium, papillary endothelioma, Hémangioendothéliome végétant intravasculaire, L'endovasculite proliférante trombopoiétique, intravenous atypical vascular proliferation, intravascular angiomatosis, intravascular papillary endothelial hyperplasia, Masson's vegetant intravascular hemangioendothelioma, Masson's pseudoangiosarcoma, intravascular endothelial hyperplasia, Masson's lesion, and papillary endothelial hyperplasia . The most accepted term being intravascular papillary endothelial hyperplasia (IPEH) was first used by Clearkin and Enzinger as quoted by Johraku et al. . The pathogenesis of IPEH is poorly understood. One possible mechanism is a benign neoplastic process involving endothelial cell proliferation and papillary formation in the vascular lumen that undergoes degeneration and necrosis in the manner of a red infract. Alternative mechanisms include a benign endothelial proliferation arising from a thrombus as a variant of angiolymphoid hyperplasia with eosinophilia, a reactive process of endothelial cells induced by blood stasis and perivascular inflammation, and a pseudotumoral lesion caused by endothelial proliferation with papillary formation proceeded by an accumulation of thrombotic material, which serves to facilitate development of the lesion . IPEH can have varied appearance on imaging studies depending on the degree of thrombosis. In our patient, concentric calicifications were noted initially on conventional and digital radiographs. Performing an ultrasonographic study elucidated a well-defined cyst-like lesion located within the masseter. Color Doppler sonography revealed that the lesion lacked any obvious vascularity. Advanced imaging like CT and MRI enabled us to further identify the exact plane in which the lesion and associated calcific foci were located. The Hounsfield value of 100 HU and the isointense appearance on T2-weighted MRI indicated that the lesion was solid and not cystic. The lesion was also shown to have continuation with the right masseter muscle on CT and fatty infiltration of masseter on MRI which explains the difficulty in resecting the tumor mass alone. Areas of microcalcification have been noted in IPEH lesions. The presence of calcification is said to be typical in IPEH and the involved vessels may either be occluded or patent . Phleboliths, however, are also common in patients with hemangiomas. Likewise, calcification can occur in hematomas and tumors, and they can follow necrosis of soft tissues. Moreover, on angiography, IPEH can manifest as either a vascular or avascular mass. MRI is usually superior as the initial diagnostic test for vascular malformations, and further investigations are usually not necessary in low-flow lesions. The CT, MRI, and angiographic patterns of IPEH can all simulate other benign (e.g., hemangioma) and malignant (e.g., angiosarcoma) conditions. Histopathologically, in cases of IPEH associated with thrombi, an organizing thrombus is observed in an expanded blood vessel. The endothelial cells proliferated in a papillary pattern towards the lumen of the enlarged blood vessel from the area of the organizing thrombus. The structure of papillary proliferation was covered with no more than 2 layers of endothelial cells, and no atypia or mitotic activity was seen around the cores of fibrous connective tissue, which were frequently hyalinized and hypocellular . Histological differential diagnosis of IPEH includes angiosarcoma, hemangioma, mucocele, intravenous, pyogenic granuloma, Kaposi sarcoma, spindle cell hemangioendothelioma, malignant endovascular papillary angioendothelioma or Dabska's tumor, and intravascular endothelioma . Salyer and Salyer as referred by Robertson and Hernández, described the features which distinguish this lesion from angiosarcoma. (1) The lesions are well circumscribed and have a predominately intra- vascular location. (2) Extravascular lesions are associated with hematomas. (3) Rare but normal mitotic figures occur. (4) There is a lack of cellular atypia. (5) There are no necrotic areas. (6) Cells do not invade the perivascular space. (7) Solid areas exist with or without vascular differentiation. (8) Papillary fronds are one or two cells thick. (9) Papillary structures are mainly supported by a core of thrombotic material . Constantino et al. as alluded by Robertson and Hernández hypothesized the stages through which the lesion progresses into 4 stages: the process probably starts with a recently formed thrombus and early endothelial proliferation occurs. Later, papillary projections develop when endothelial cells cover the irregular surface of the thrombus. In the more advanced stage, thrombotic material is slowly resorbed and papillary projections become smaller. At an end stage, the thrombotic material is completely resorbed and only a nodule composed of endothelial cells remains . Sarode et al. cited various treatment modalities, most cases are cured by simple total excision with healthy margins. Cohen et al. used sclerotherapy (intralesional injection of a sclerosing agent “sodium tetradecyl sulfate”, causing compression and fibrosis of the blood vessels) followed by surgery with good esthetic results and minimal intra-operative bleeding. Endoscopic surgery has been used to treat an extensive IPEH of the sinonasal cavity. Noninvasively IPEH has been successfully treated by the beta-adrenergic antagonist nebivolol .
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Review
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biomedical
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en
| 0.999997
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24895698
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In 2009, a new strain of swine-originated influenza A (H1N1) caused the first pandemic of the 21st century. 1 Clinical manifestations of influenza A (H1N1) pdm09 infection ranged from mild symptoms to severe illness and death. Most patients with severe or fatal disease were reported to have underlying medical conditions, including chronic lung disease, diabetes, cardiovascular disease, neurological disease, and pregnancy; 2 – 4 nevertheless, some individuals developed neurological complications without having underlying comorbidity. In fact, neurological complications associated with either vaccination or infection events are well described in influenza. 5 – 7 We conducted systematic searches in Ovid, Medline, EMBASE, and PubMed databases using the keywords “neurological complications of Influenza AH1N1” or “post-vaccine Influenza AH1N1” to identify published papers on this topic. Two clinical neurologists (C.G. and D.-A.A.) performed a full-text review of the papers and extracted all relevant data. Inclusion criteria for this review included studies reporting basic clinical data on influenza-related neurologically defined events, laboratory data confirming influenza A (H1N1) pdm09 infection and at least age-group information (adults versus pediatrics), because in most cases, a precise age was missing. In those cases reporting the age, pediatric patients were considered as <16 years old, both for infection and post-vaccine events. Only papers written in English, Spanish, German, French, Portuguese, and Italian were included. Those papers written in other languages or poorly written because of lacking relevant clinical and epidemiological data were excluded. Additionally, two adult patients with acute disseminated encephalomyelitis (ADEM) post-influenza A H1N1 vaccination studied at a Mexican neurological care center are reported. Post-vaccine-related neurological complications were observed in 287 patients. From these, 54 were male and 14 female, and there was no information on gender for the remaining patients (219). Mean age was 30·16 ± 25 years. Neurological complications consisted mainly of Guillain-Barré syndrome (GBS) or, polyneuropathy (125), seizures (23), acute disseminated encephalomyelitis (ADEM) (20), encephalopathy-encephalitis (41), stroke (7), transverse myelitis (3), and others (68). All patients survived and permanent sequelae were reported in 2 (0·69%). CSF-cytochemical characteristics showed 23·55 ± 31·8 cell/μl, 88 ± 28·8 mg/dl of glucose, and 45·97 ± 23·7 mg/dl of protein. While few reports and series provided a neuroimaging pattern, demyelinating lesions were predominant in this group. Infection-related neurological complications were observed in 1349 patients. Mean age was 12·75 ± 14·6 years. Two hundred and ninety-four were male and 196 female; there was no gender information on the 855 remaining patients. One-thousand two hundred and fifty-six patients (93%) were pediatric and 93 were adults. Forty-nine patients showed previous co-morbidity, mostly previous neurologic disease such as anoxo-ischemic cerebral sequelae, febrile seizures, and myasthenia. In this group, 60 patients (4·7%) died and 52 (30·1%) developed permanent sequelae. CSF-cytochemical characteristics were 67·99 ± 253·5-cells/μl, 63·62 ± 27·5 mg/dl of glucose, and 118·75 ± 381·3 mg/dl of proteins. In 49 patients, previous co-morbidity factors such as obesity, asthma, or other chronic diseases were present. A wide spectrum of neurological complications was observed: encephalopathy-encephalitis (464), seizures or epileptic status (369), stroke (12), ADEM (8), transverse myelitis (4), and others (469). Some important clinical features registered in both groups were pregnancy, obesity, asthma, and other chronic diseases in 170 patients. Adults were more frequently affected in the post-vaccine group, 250 (72·9%), while children predominated in the infection group, 1256 (97·1%), chi-square value = 914, P = 0·0001. Clinical outcome was less severe in the post-vaccine group than in the infectious group, where more cases of permanent sequels and deadly events were recorded. GBS was prevalent in the post-vaccine group (64·1% versus 35·9%) chi-square value = 328, P = 0·0001), whereas the encephalopathy-encephalitis spectrum predominated in the infection group (92% versus 8%) chi-square value = 45·8, P = 0·0001). It is important to note that deaths were recorded in the viral infection group only, most of them in pediatric age band, 50 of 60 (83·3%). Neuroimaging analysis revealed two main patterns: demyelinating and vascular. The main differences between both groups are summarized in Table 1 . A 27-year-old woman with a history of atopic dermatitis received monovalent inactivated influenza A (H1N1) vaccination on December 2009; 4 weeks later, she presented cephalgia, generalized weakness, progressive left-sided hemiparesis, and hypersomnia. She was evaluated at another institution. CT scan revealed brain edema. CSF-cytochemical analysis showed 81 mg/dl of glucose and 31 mg/dl of proteins without cells. Bacterial and tuberculosis cultures were negative. Serological test against Coxsackie virus, CMV, and cysticerci, as well as CSF-PCR for herpesvirus, were negative. Acute phase reactants were normal. She was treated with acyclovir and corticosteroids for 21 days, with some clinical improvement. Four weeks later, she showed abrupt changes in social behavior and dromomania (an uncontrollable psychological urge to wander). Clinical deterioration progressed with disarthria, paresthesias, and consciousness impairment. Upon admission to our Institution, neurological examination revealed stupor, left-central facial paralysis, hypertonic reflexes, grasp reflexes, persistent postures, generalized rigidity, and a left Babinski sign, making up a catatonic syndrome. MRI scan showed demyelinating lesions involving bilateral basal ganglia and brainstem . A new evaluation with cultures and serological tests was not contributory. The patient received corticosteroids, olanzapine, and lorazepam, with slow improvement. She was discharged 3 weeks later. As an outpatient, complex neuropsychiatric symptoms appeared with hyperorality, hypermetamorphosis (an irresistible impulse to notice and react to everything within sight), and hypersexuality, also known as Klüver-Bucy syndrome. A control MRI scan performed 15 months later showed radiological improvement . During a 27-month follow-up, the patient required multiple hospitalizations at a psychiatric ward for depression and impulsivity with suicidal ideation. She is still under antipsychotic treatment and requires continuous supervision by relatives. A 64-year-old woman was referred with a 2-month history of treated arterial hypertension and vitiligo, diagnosed 6 months before. She received trivalent inactivated A (H1N1) influenza vaccination on November 2011. One month later, she developed irritability, semantic paraphasias, and memory impairment. Upon neurological examination she was alert, oriented with euthymic mood, low fluent spontaneous speech, and increased latency of verbal responses. She was unable to keep or focus attention; constructional praxis and calculation-abstraction were seriously affected. Clinical findings were consistent with a frontal lobe syndrome. Electroencephalogram showed mild generalized dysfunction. CSF-cytochemical analysis rendered 82 mg/dl of glucose and 26 mg/dl of proteins without cells. PCR-viral panel for herpesvirus family was negative, as well as VDRL, cryptococcal antigen, bacterial, fungal, and mycobacterial cultures. Other evaluations, including HIV serology, IgM serology for EBV, CMV, antinuclear antibodies, and antineuronal antibodies, were all negative. A first MRI scan taken 1 month after the initial symptoms showed diffuse cortico-subcortical white matter involvement and edema . Patient was treated with intravenous methylprednisolone for 3 days, followed by oral tapering corticosteroids. On a control MRI scan, 4 months after the symptoms onset , a significant reduction in white matter abnormalities was seen. Neurological improvement has been progressive, and at 6 months of follow-up, the patient still receives rehabilitation and psychotherapy). Although influenza virus A (H1N1) pdm09 has become a public health threat of global concern, 109 , 110 there are no accurate data regarding the worldwide frequency of neurological complications related to this disease. Here, we reviewed the reported neurological complications from this disease from pandemic onset until December 2012; we found more reports of neurological complications due to the infection itself than to vaccination. The Vaccine Adverse Event Reporting System estimated that from October 2009 through January 2010, 82·4 million doses of 2009 H1N1 vaccine were administered; death, GBS, and anaphylaxis reports after 2009-H1N1 vaccination were rare (<2 per million doses administered, each). 111 On the other hand, WHO aimed to provide access to A (H1N1) pdm09 vaccine for all countries as soon as the vaccine was available and approved. Each recipient country established its vaccination programs, with some degree of variation depending on national priorities. Some chose to vaccinate only specific priority groups, including at least some children and younger adults (including pregnant women), and healthcare workers. 112 – 118 According to our review, fatal cases and permanent neurological sequelae were reported in about 11% of patients with influenza-related neurological complications. With respect to vaccination, aging appears to be related to a higher risk of having neurological sequelae, as in our two reported cases. The clinical outcome was generally more favorable in post-vaccine neurological complications. In fact, no fatalities occurred in this group, but permanent sequelae were observed in 2/287 patients, our two ADEM post-vaccine cases, patients were female and developed severe and complex neuropsychiatric sequelae. Most patients with neurological complications related to influenza A H1N1 infection developed necrotizing or non-necrotizing encephalopathy; an antecedent of chronic diseases was found in some of these patients. 8 , 9 , 14 , 23 , 31 , 37 , 47 , 48 , 50 , 62 , 64 A number of individual factors such as the patient's age may be involved; children and elderly are the groups with the highest risk of having neurological complications, but also are those suffering underlying immune disorders, chronic diseases, or obesity. 119 , 120 In our review, most neurological complications occurred in the population younger than 16 years Graph. 1 . This result, along with the pivotal role of the young in spreading the infection, highlights the relevance of enforcing vaccination in this population group, where severe post-vaccination complications are infrequent. There are insufficient details in the published reports about neurological complications related to influenza A (H1N1) infection or vaccination to reveal other individual and circumstantial factors that may participate in the susceptibility or development of such complications, and their optimal management is unknown. With respect to pathogenesis, while influenza viruses do not seem to show a direct tropism to the nervous system, virus detection within both retina and the olfactory bulb has been described in animal models. 121 , 122 Influenza virus has been also detected by isolation or nested RT-PCR in human cerebrospinal fluid 59 , 74 , 123 , 124 on brain tissue in neuropil, ependyma, Purkinje cells, and other neurons. 125 Although in most influenza cases, no virus has been detected in CSF, the reported information stresses the relevance of searching for the virus in the central nervous system in different infection stages, particularly when neurological symptoms are present. On the other hand, other pathogenesis factors may be linked with neurological disorders related to influenza vaccination. As it is reported, the vaccine itself may promote an exacerbated peripheral inflammatory response, 126 the extension of which may be modulated by individual biological factors, that is, age, sex, and genetic background. Furthermore, an increased systemic or peripheral inflammatory response may promote neuroinflammation, which may underlie the neurological symptoms observed in the two cases reported herein, and in those published elsewhere. 127 In this regard, the severity of brain dysfunction even in cases with non-clinical neurological findings may be correlated with high levels of pro-inflammatory cytokines in blood and CSF (cytokine storm). 128 However, in some cases of CNS involvement, no cytokine storm or tissue inflammatory infiltrate has been found. 63 , 129 It is also possible that both the viral infection and the vaccination promote blood–brain barrier (BBB) dysfunction, 130 producing neuroinflammation and neurological disorders. With respect to neurological diseases related to the infection, it is important to consider the higher prevalence of encephalopathy or encephalitis in the pediatric population. The size of the influenza viral particle may prevent it from crossing the barrier in adults, but an immature BBB may be prone to virus invasion. 103 Even though our analyses show clear limitations due to the incomplete information in most of the case reports retrieved from medical literature, and also to their descriptive nature, the information reviewed in this article highlights the relevance of an accurate neurological evaluation in all suspicious cases and of an appropriate long-term clinical and imaging follow-up of infection and post-vaccination events related to influenza A (H1N1)pdm09, to clearly estimate the magnitude of neurological complications that could lead to permanent disability.
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Study
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biomedical
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en
| 0.999998
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24938492
|
Whilst self-management support is widely advocated it is clear that existing strategies are of limited benefit because they fail to take account of everyday circumstances of patients and the range of work required to manage their health within the context of their daily lives . Self-management support is frequently disconnected from the realities of social deprivation and the mundane everyday demands of living life with a long-term condition (LTC) are overlooked as are the capacity and personal support needed to balance everyday life practicalities with the additional work required to manage a LTC . Furthermore, the focus of self-management support for LTC management tends to be on moments of crisis or the temporary and transient, and lack engagement with a wider set of resources and networks . As part of a Randomised Controlled Trial aimed at managing chronic kidney disease in primary care, a needs-led intervention to improve networks of support for people with long-term health problems, Patient-Led Assessment for Network Support (PLANS) was developed . PLANS was designed to address the problem of engagement with and the mobilisation of community resources to support people with generic long-term health problems and can be used to prioritise people’s own health and social needs in a way which tailors access to local community services . Delivery of PLANS for the BRIGHT trial and Summary of the PLANS support calls conducted for the BRIGHT trial sections elucidate how PLANS was delivered in the trial. While PLANS was developed with the underlying assumption that chronic illness management and broader well-being are closely intertwined in people’s everyday lives, it was also assumed that sustainable behaviour change and engagement with available resources could only be feasible by putting the emphasis on what is acceptable to people. The BRIGHT trial led to significant improvement in health outcomes. These results will be reported in more detail elsewhere. Therefore this qualitative study was designed to understand the active ingredients of the intervention to aid generalizability and facilitate translation into everyday practice by a) understanding the ‘work’ required of participants and telephone support workers and the skills required to effectively deliver and engage with PLANS; b) understanding who it works for and why and what contexts make successful implementation more likely; c) exploring the experience of PLANS and the processes of delivery and engagement from the perspectives of participants and the telephone support workers who delivered it; and d) to gain insight into the perceived relevance of PLANS to patients who received it and determine how patient-directed resources are implemented in people’s everyday lives. Chronic kidney disease (CKD) is a developing area of research . CKD is growing in prevalence and can lead to cardiovascular morbidity and mortality which has led to clinical guidance highlighting the importance of early identification and active management of CKD to maintain vascular health in primary care . CKD is categorised into five stages with stage 5 indicating renal failure. Stages 1 to 3 are managed in primary care and are common with around 5% of the population having early stage kidney disease. There is little or no specific support or information for CKD stage 3 but there is great potential for avoiding future health problems if managed more effectively. Chronic kidney disease often exists with other conditions such as hypertension, diabetes and ischaemic heart disease and is associated with low socioeconomic status . The methods of recruitment to the BRIGHT trial are described in Blickem et al . 20 patients in the intervention arm of the BRIGHT trial were interviewed and their telephone support calls were recorded. These included 15 women and 5 men. At the baseline assessment, participants in the intervention arm of the trial were invited to take part in the current study which involved the audio recording of the telephone support calls (baseline and follow up) and a qualitative interview. Following the delivery of the telephone support call, a convenience sample of participants who consented to be contacted for this qualitative study were contacted by a researcher to arrange an interview within two weeks of delivery of the telephone support call. At the interview informed consent was obtained to conduct and audio record the interview. The length of interviews varied from approximately 40 to 90 minutes. Normalisation Process Theory (NPT) was used as a sensitising tool to explore the processes of delivery and engagement . We considered that Normalization Process Theory would be a useful analytical tool because NPT is a robust theory of implementation that helps provide awareness of the work involved in embedding and sustaining practices associated with an intervention, and thus aids understanding of what becomes normalized into everyday settings. NPT was developed to understand the embedding of new technologies into health systems PLANS is such a technology and our focus was on the work that patients and support workers needed to do to ensure the effectiveness of PLANS in accessing better support. NPT is divided into four constructs which were used to evaluate: the relevance of PLANS to patients who received it (coherence); the processes of engagement and buy-in (cognitive participation); the work done to enable PLANS to happen and who this implicates (collective action); the perceived benefits and costs of PLANS (reflexive monitoring) . All authors contributed to the analysis. A coding framework was developed by CB and AK which was informed by NPT (Additional file 3 ) and a first round of analysis was conducted using this framework. It was agreed that the analysis should also be inductive and to examine data that did not appear to ‘fit’ with the chosen theoretical framework so that important concepts or themes were not missed. All transcripts were each analysed and coded by both the first author and one of the other authors. After this round of analysis all authors attended two meetings to discuss and reach consensus about the consistency of the coding and share emergent themes from the analysis. After consensus was agreed on themes and codes a second round of analysis was conducted. CB with AK wrote the first draft of the paper and co-authors provided feedback on iterations. The invisibility or lack of awareness of CKD could be a hindrance to engagement with PLANS because some participants could not see the relevance of doing so and in some cases participants were upset because of the introduction of a new diagnosis. Therefore PLANS or any self-management resource is likely to struggle for relevance where there is an unclear health rationale for action. These findings suggest the need for greater consistency in the management of CKD within primary care for self-management support to be effective. It is reasonable to imagine that PLANS might have been more relevant or useful if delivered to a population with more ‘visible’ long-term health problems such as arthritis, heart disease or diabetes. However the ‘invisibility’ of CKD exposed some of the problems of delivering self-management support to people who do not prioritise their health in the context of other everyday life priorities and so demonstrates the value of an intervention like PLANS which operates at different levels, e.g. offering the opportunity to reflect on practical, personal or health-related problems which make life difficult but which have become normative. NPT was an appropriate heuristic device with which to analyse this data as each of the four constructs relate well to the processes of engagement and the implementation of PLANS as experienced by participants in the study. Although we looked for data that fell outside of our coding framework, we were in fact able to code all relevant data with reference to one of the NPT constructs. However, whilst NPT is presented as a temporal process, this analysis showed that many participants experience the constructs of NPT simultaneously. For example, the work of sense-making necessarily involves an appraisal of the cost-benefits of PLANS for participants. Correspondingly, the work of engagement or ‘buy-in’ was influenced by these processes. This suggests that NPT is a useful way of understanding the experience of the PLANS intervention but best understood as a non-linear progression towards successful (or not) implementation. Improving awareness of and access to local resources offers a complementary approach to traditional individually-focused models of self-management which aim to increase the capacity and resources available to people with LTCs. Appreciation of the complex challenges faced by people in socially and economically deprived circumstances draws attention towards potentially valuable ways of supporting these groups. Whilst this study provides evidence for self-care strategies which consider the everyday life contexts in which health management takes place in order to tailor support, how it works in practice raises the relevance of how novel interventions based on this more social model lead to tensions both with the norms of practice operating in primary care (e.g. the non-disclosure of a diagnosis) and of people who have accommodated to a way of life in which isolation or the burden of competing activities has become normalised, as well as the dominance of a healthcare model where there is an underlying assumption (among both patients and professionals) that there is a sharp divide between illness management support and one’s broader well-being. Hence, the design and delivery of social interventions like PLANS need to take account of personal circumstances and commitments as a key priority, but it may need to also address issues of legitimacy, which may in turn require a closer and sustainable over time involvement by health professionals in the process of its delivery. This study aimed to create understanding about pushing the boundaries of support that can be offered to people with LTCs to facilitate the adoption of this innovative and effective approach. Shifting the emphasis of self-management towards personal and community resources allows for building strategies which brings into the frame the utilisation of existing community, voluntary and third sector resources to support people with long-term health problems within socially disadvantaged communities. However, focussing on the everyday life contexts of health management raises debate about the need to address social and structural factors such as access to resources, available support, and home and work environment – but also suggests that the notion of engagement needs to be seen in the broader context of other agencies norms of practice and existing patient expectation.
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Review
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biomedical
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en
| 0.999997
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25161799
|
Acute peritonitis may be classified as primary (spontaneous), where an infection has been raised de novo within the peritoneum, or secondary, where the inflammation involving the peritoneum is the result of an identifiable primary process. Secondary peritonitis is one of the most common indications for urgent abdominal surgery. Despite great advancements in diagnostic tools, surgical equipment, and technique, management of patients with severe secondary peritonitis remains a surgical challenge, with major morbidity and a mortality rate over 50% in most series . In comparison with its levels one hour before anesthesia, plasma levels of TNF- α decreased insignificantly during surgery until immediately after the abdominal wall closure. Median values were 10.4 and 9.1 pg/mL ( P = 0.273), respectively. At 48 hours after abdominal wall closure, a mild increase in TNF- α levels was noticed, with a median value of 14.2 pg/mL ( P = 0.225) . In contrast, IL-6 increased during surgery from 362 pg/mL to 540 pg/mL ( P = 0.5), ending with 400 pg/mL 48 hours after abdominal wall closure ( P = 0.686) . The patterns of values distribution concerning TNF- α and IL-6 were not statistically different ( P = 0.449 and P = 0.375, resp.). The suggested mechanism of morbidity and mortality due to secondary peritonitis is a vicious circle, started by intraperitoneal inflammatory and toxic mediators. These induce vasodilatation and enhance the permeability of the visceral and parietal capillary vessels, thus facilitating the translocation of microorganisms, their toxic products, or cytokines from the peritoneal cavity to the circulation of the blood. This leads to a cascade of events: the onset is the systemic inflammatory response syndrome (SIRS), leading to the multiple organ failure syndrome (MOFS) and often ending with death. Analysis of our data showed no significant changes in the levels of plasma inflammatory mediators during surgical laparotomy, except for platelet count. Despite the decreasing trend of WBC, CRP, and TNF- α levels, they were statistically insignificant ( P = 0.438, P = 0.262, and P = 0.449, resp.). On the other hand, the IL-6 levels showed an increasing trend during surgery but still without statistical significance ( P = 0.375). The only significant change in the systemic inflammatory response identified in our study was attributed to the PLT count, which decreased during surgery ( P = 0.001).
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Review
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biomedical
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en
| 0.999995
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25386373
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Uterine leiomyosarcomas (LMSs) constitute 1% of all uterine malignancies and approximately 25% of uterine sarcomas, that are rare tumors that account for only 3% to 7% of all uterine cancers . They demonstrate an aggressive growth pattern with a high rate of recurrence with hematologic dissemination; the most common sites are lung, liver, and peritoneal cavity . Head and neck district is rarely interested, and only other four cases of metastasis in the oral cavity have been previously described . In particular, we illustrate the second case of metastasis in the upper buccal gingiva in a 63-year-old woman in which lung metastasis was also present. A 63-year-old woman with a history of advanced uterine LMS presented to our center with a painful, ulcerated swelling on the right upper buccal gingiva . She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy for a diagnosis of LMS staged as pT2bN0 fourteen months previously. Eight months after primary treatment she developed two bilateral lung masses (SUV max: 7.8 at (18)F-fluoride PET/CT); histological examination of the 11 mm lung mass in the right chest revealed a metastasis of LMS. An adjunctive lung mass was present in the left chest. Chemotherapy was administered, initially with isofosfamide-epidoxorubicin, with scarce tolerance (grade 3-4 neuthropenia) so that it was decided to administer taxotere. During this treatment she developed a rapidly growing mass in the right upper buccal gingiva. She was referred to her dentistry that performed an excisional biopsy under local anesthesia suspecting a “haemorragic epulis.” Histological examination was compatible with metastasis of leiomyosarcoma, incompletely excised. A CT scan performed about 1 month after resection revealed an osteolytic lesion of 30 × 35 mm of the upper maxilla ; MRI was not performed because the patient was claustrophobic. Because of the rapid growth observed just in 40 days, it was decided according to oncologist to perform a partial maxillectomy and contemporary reconstruction with temporalis muscle pedicled flap even if a lung metastasis was present. Histological examination confirmed the presence of a 6 cm spindle cells LMS, entirely excised. Immunohistochemical analysis against monoclonal antibodies for a-smooth muscle actin (a-SMA), desmin, HHF-35, caldesmon, and vimentin was positive; mitotic index (Ki67) was of 90% . Considering the radical excision, no “adjuvant” radiotherapy on the oral cavity was administered. In order to control lung metastasis and considering the aggressiveness of the disease, it was decided to perform two other cycles of chemotherapy with ifofosfamide-epidoxorubicin. A partial regression of the lung metastasis was obtained, but again it was impossible to continue treatment because of high toxicity. A PET-CT performed 3 months after surgery revealed a right femur metastasis, so that radiotherapy was performed. Two months later, after an episode of epistaxis, head and neck CT scan with contrast revealed a relapse in the masticatory space and rinopharynx: the patient was referred to palliative radiotherapy. LMSs usually arise in anatomical sites with abundant smooth muscle, such as gastrointestinal tract, retroperitoneum, and uterus; nevertheless, uterine LMSs constitute only 1% of all uterine malignancies . Despite variable results, patients with uterine LMS have an overall poor prognosis with a long-term 5-year survival and risk of recurrence ranging from 25% to 75%, even if these tumors are usually confined to the uterus at the time of diagnosis . The majority of patients who recur do so within 2 years of initial diagnosis, and up to 90% of patients who fail show distant metastases either alone or concurrent with pelvic recurrence. In our case, the tumor was confined to the uterus at the time of diagnosis, and distant metastases to the lung were detected eight months after primary treatment. The most common sites of recurrence are peritoneal cavity (30–50% of cases), lung (30–40%), and liver (about 10%); only rarely do they involve the brain and skull (<1%) owing to pulmonary arterial circulation . Metastatic uterine LMS to the oral cavity are extremely rare, and only four other cases have been previously described . Also considering LMSs originated from other primary sites, only other three cases with metastasis to oral cavity can be found . The rarity of buccal mucosa involvement can be due to the fact that in the oral cavity smooth muscle is very scarce, being present in the blood vessel walls and the circumvallate papillae of the tongue. Kim et al. hypothesize that “the metastatic mass must be related to the blood vessels in the buccal cheek, and the maxillary gingivae with haematogenous spread from the uterus via lung to the oral cavity” . In our case oral metastasis to the upper gingival developed after lung metastases. They also found that metastatic tissue was different from tissue from primary site, being more vascularized and composed by cells more spindle-shaped moderately positive to the a-SMA antibody . In our case it was impossible to compare the two specimens, because the patient underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy at another center. The treatment of choice of uterine LMS is surgery and the use of adjuvant treatment has limited impact on clinical outcome, and radiotherapy seems only to improve local control, because most recurrences develop at distant sites . The most common chemotherapic agent used for LMSs is doxorubicin, usually associated with ifofosfamide . In this case no adjuvant radiotherapy was administered after total abdominal hysterectomy with bilateral salpingo-oophorectomy, and chemotherapy was started after the detection of lung metastases. In case of metastatic disease, factors that would contribute to the decision of operability would include extent of tumor (TNM), number and type of metastases, disease free interval from the initial diagnosis to the time of metastases, and expected life span . In our case, the decision to proceed with surgical removal of the upper gingiva mass, even in presence of advanced disease, was taken in order to improve quality of life, being chemotherapy and radiotherapy inadequate to control the oral recurrence. Obviously, reconstruction has been achieved using the “simplest” methods, using temporalis muscle flaps, even if a free flap reconstruction is the treatment of choice in order to reconstruct both bone and soft tissue . Bone grafts were not use in order to avoid complication in case of irradiation . Adjuvant radiotherapy was not considered because of resection in free margins with no suspect of residual disease. Nevertheless, local recurrence was observed 5 months after surgical removal so that patient was referred to palliative radiotherapy. In conclusion, even if head and neck metastases from uterine leiomyosarcoma are rare, they have to be suspected in case of rapidly growing haemorrhagic mass. Due to the aggressive growth pattern of the tumor, wide surgical excision in free margins of metastatic lesions could not be sufficient, so that in selected cases, in order to improve local control, the use of adjuvant radiotherapy can be considered. Obviously, this can lead to improving quality of life not influencing clinical outcome.
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Clinical case
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biomedical
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en
| 0.999998
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25431599
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Mastocytosis is a clonal myeloproliferative disorder characterized by dysregulation of various organs infiltrated with abnormal mast cells and by symptoms attributed to histamine release. According to the location of mast cell proliferation it is classified into cutaneous mastocytosis (CM), affecting solely the skin, and to systemic mastocytosis (SM), involving at least one extracutaneous organ with more severe clinical manifestations. SM is further divided to six subtypes, according to the recent World Health Organization (WHO) classification, reflecting progressive mast cell clonal expansion and severity of symptoms . In up to 40% of cases, SM is accompanied by a nonmast cell hematologic disorder (SM-AHNMD) , resulting in a combination of symptoms, related to each separate component . A form of reactive mast cell hyperplasia, which is observed in other hematologic neoplasms, such as lymphoplasmacytic lymphoma and hairy cell leukemia (HCL) must be excluded . A predominance of associated myeloid disorders, especially chronic myelomonocytic leukemia (CMML) is reported in SM-AHNMD . Lymphoproliferative neoplasms are much less commonly implicated , referring to 10 reported cases of non-Hodgkin lymphomas (NHL), 3 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 1 case of HCL, 6 cases of multiple myeloma (MM), and 1 case of Hodgkin lymphoma (HL). SM associated with adult acute lymphoblastic leukemia (ALL) has been documented in the case of a patient with SM associated with B-ALL carrying the (13;13) (q12;q22) translocation . Two other cases concerning adults with concurrent CM and ALL have also been reported . Among children with ALL, six cases of concomitant CM have been described [ 8 – 11 ]. A 40-year-old Caucasian female was admitted displaying symptoms of weakness and fatigue, being febrile (37.9°C) with moderate pallor. Her liver was palpable, as well as a slightly enlarged left inguinal lymph node. She also manifested diffuse cutaneous brown macular lesions on her trunk. Her complete blood count (CBC) revealed normocytic normochromic anemia with a normal leukocyte count and moderate thrombocytopenia. Bone marrow (BM) trephine biopsy and immunophenotype showed extensive infiltration from B-ALL expressing the surface markers CD10, CD19, CD22, CD79a, CD34, CD123, CD38, and Tdt, with an aberrant coexpression of the myeloid markers CD13, CD33. Eosinophilia was noted and spindle-shaped mast cells were present, scattered or in small aggregates, being positive in c-kit and negative in CD2 staining . Polymerase chain reaction (PCR) for KITD816V mutation, fibroblast growth factor receptor 1 and platelet derived growth factor receptor (FGFR1, PDGFR) rearrangements, and breakpoint cluster region/Abelson tyrosine kinase (BCR/ABL) fusion gene was negative. Conventional cytogenetics was normal in all studied metaphases. The patient received induction therapy for B-ALL, consisting of dexamethasone, vincristine, idarubicin, cyclophosphamide, cytarabine, and thioguanine, along with intrathecal methotrexate. During induction, she developed severe low respiratory tract infections. BM immunophenotyping and trephine biopsy following induction revealed residual leukemic disease consisting of 10% lymphoblasts and an extensive mast cell infiltration exceeding 50% of nucleated BM cells . The majority of mast cells (>25%) were spindle-shaped, distributed either in a diffuse pattern or forming dense aggregates of more than 15 cells, synchronously expressing the surface markers c-kit (CD117) and CD2. Serum tryptase levels were normal. Thus, the major criterion and two out of the four minor recent diagnostic WHO criteria for SM were fulfilled, unequivocally establishing the diagnosis of SM-AHNMD, in terms of the preexisting B-lymphoid neoplasm . A subsequent skin biopsy revealed only sparse mast cells in the dermis. SM-AHNMD is a distinct form of SM characterized by synchronous evolution of two separate clonal populations, one consisting of mast cells and one as a second hematologic malignancy. CMML is the most prevalent concomitant hematologic disorder, followed by other myelodysplastic/myeloproliferative syndromes (MPN/MPDs), MPNs, MDS, and acute myeloid leukemia (AML) . Lymphoproliferative neoplasms are much less frequently found in this setting with reported cases of CLL/SLL, HCL, plasma cell dyscrasias, and lymphomas [ 3 – 5 ]. Among the latter, HL, splenic marginal zone lymphoma, diffuse large B-cell lymphoma, hepatosplenic T-cell γ / δ lymphoma, and cutaneous B-cell lymphoma have rarely been described. We are currently aware of a sole published case of an adult with KITD816V mutated SM associated with B-ALL carrying a (13;13) (q12;q22) translocation . The authors reported that B-ALL was cured by alloHSCT, while SM persisted for more than a decade. The other two reported adult patients suffered from concomitant ALL with cutaneous forms of mastocytosis . The combined nature of SM-AHNMD underlies the need to confront each malignant entity separately but simultaneously. Both its clinical course and prognosis strongly correlate with those of the associated nonmast cell neoplasm and standard regimens are required for the latter. Management of histamine related symptoms, such as anaphylaxis, pruritus, flashing, or malabsorption, lies on relevant pharmaceutical agents. Interferon- α , corticosteroids, and cytoreductive therapies, mostly cladribine, have been used to treat the SM component, with minor responses . Data on the beneficial role of allo-HSCT are scarce and conflicting, due to the rarity of relevant cases . In addition, leukemias arising in the context of SM are considered of poor risk . This was also the case for our patient, who was primarily refractory to all treatment modalities. The duration of response is a prerequisite for its estimation according to the recent International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus criteria, taking into account ascites and pleural effusions, spleen size, liver function, serum tryptase, albumin and CBC values, and mast cell infiltrates in tissue biopsy sections . Prior to duration of response, assessing organ damage is the most crucial parameter in order to apply the previously mentioned criteria in SM-AHNMD cases and may prove difficult due to shared clinicopathological features between the two components of the disease . In our case, response to IM administration could not be assessed because of chemotherapy-related toxicity. Eligible organ damage mostly consisted of transfusion dependent anemia and thrombocytopenia, due to BM infiltration from both diseases. Infiltration from the ALL clone in the performed BM biopsy was around 10% and, thus, not compatible with the severity and duration of cytopenias. Liver biopsy was not carried out due to the patient's poor performance status. As anticipated, the clinical course and prognosis of our patient were principally determined by her poor response to all applied antileukemic treatment modalities, failing to achieve CR. We should acknowledge that the concurrent SM complicated the chemotherapy related marrow and liver toxicities. IM administration enhanced transient hematologic improvement and permitted the administration of subsequent chemotherapeutic agents for ALL. In conclusion, the diagnosis of SM-AHNMD requires careful consideration of both clinical and laboratory findings. The choice of treatment depends on the nature and clinical behaviour of both disorders .
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Review
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biomedical
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en
| 0.999998
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25505998
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FGFR3 encodes a transmembrane tyrosine-protein kinase receptor that acts as cell-surface receptor for fibroblast growth factors. It has an essential role in the regulation of chondrocyte differentiation, proliferation, and apoptosis and is required for the normal skeletal development . Activating FGFR3 mutations will exacerbate the growth-inhibitory action on chondrocytes, resulting in varying degrees of severity of skeletal dysplasia as per mutation type. FGFR3 germline mutations cause skeletal disorders, while its somatic mutations have been identified in benign skin lesions and epithelial neoplasms. The mutagenic effect of FGFR3 receptors may result in various skin disorders and cancer including epidermal nevi, seborrheic keratosis, and acanthosis nigricans (AN) . Cell-specific pathways may modulate the effect of activating FGFR3 mutations in each cell type. He had normal renal and hepatic function tests and negative celiac antibody screening. His insulin growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) were normal for age. Growth hormone (GH) levels on insulin and clonidine provocation tests were normal. His hormonal assessment showed normal thyroid stimulating hormone (TSH), free thyroxine (T4), adrenocorticotrophic hormone (ACTH), and cortisol. Bone age was appropriate for chronological age. The radiological study of the skeleton was concordant with the diagnosis of hypochondroplasia. It showed mild thickening of skull calvarium, mild midfacial hypoplasia, rhizomelic shortening of humeri, femurs, and tibias bilaterally. It also demonstrated normal bilateral radii, ulnae, hands and feet. The spinal X-ray showed short pedicles with mild posterior scalloping of the upper lumbar vertebrae and lack of interpedicular distances on the AP view of the lumbar spine . Based on his initial clinical assessment and investigations, he was diagnosed with hypochondroplasia. During his follow-up clinic visits, he was noticed to have suboptimal growth velocity, and his height deviated from his genetic height potential. At the age of seven years, his height was 98 cm (−4.6 SDS) and his growth velocity was 3 cm/year. In view of his short stature, persistent low growth velocity, he was started on recombinant human growth hormone treatment with a dose of 0.03 mg/kg/day which was later adjusted to 0.05 mg/kg/day during follow-up clinic visits. His growth velocity improved to 5 cm per year; however, his height remained below SDS −3.0 . At the age of 9 years and 10 months, after almost 3 years of growth hormone treatment, he developed normoinsulinemic acanthosis nigricans around his neck . His weight was 31.1 kg (50th percentile), height was 117.2 cm (−3.3 SDS), and body mass index (BMI) was 22.6 kg/m 2 (+1.6 SDS). A 1.75 g/kg oral glucose tolerance test (OGTT) showed normal serum glucose, fasting and two hours after ingestion of a glucose load. His glycosylated hemoglobin (HBA1C) was normal 5.6% with normal fasting serum insulin 43.2 pmol/L (normal range 17.8–173 pmol/L). At the age of 13 years, his anthropometric measurements were as follows: weight 45.6 kg (50th percentile), height 130.5 cm (SDS −3.3), and BMI 26.8 kg/m 2 (+1.9 SDS). His investigations were repeated, HBA1C was 5.5%, fasting blood glucose 5.2 mmol/L, but his fasting serum insulin was higher 111.0 pmol/L (15.8 μ U/L). The homeostasis assessment index for insulin resistance (HOMA-IR) was 3.69 (normal range 0.36–2.41) indicating insulin resistance. His bone age was corresponding to 13.0 years. FGFR3 gene mutation was suspected. Genomic DNA was extracted from peripheral blood leucocytes (Qiagen Inc., Chatsworth, CA), followed by PCR and direct sequencing. A heterozygous c.1620C>A transversion was identified resulting in asparagine to lysine (p.N540K) substitution in tyrosine kinase domain of the FGFR3 . Testing of parents DNA was negative suggesting a de novo mutation. Fibroblast growth factor receptor 3 (FGFR3) is a member of a family that comprises four related receptors (FGFR1-4). FGFR3 mutations may lead to a wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia), benign skin tumors (epidermal nevi, seborrheic keratosis, and acanthosis nigricans), and epithelial malignancies (multiple myeloma, prostate and bladder carcinoma, and seminoma) . FGFR3 germline mutations cause autosomal dominant skeletal disorders, while its somatic mutations have been identified in benign skin lesions and epithelial neoplasms. Germline mutations of FGFR3 cause severe skeletal dysplasia syndromes. R248C, S249C, G372C, S373C, and K652E germline mutations are linked to thanatophoric dysplasia, and affected individuals usually die as neonates. Two other germ line FGFR3 mutations cause Crouzon (A393E) and severe achondroplasia with developmental delay and acanthosis nigricans (K652M) “SADDAN syndrome.” In both syndromes, the patients develop normoinsulinemic acanthosis nigricans . By contrast, p.Lys650Asn and p.Lys650Gln mutations that activate the FGFR3 to a lesser degree are associated with milder forms of skeletal dysplasia, such as hypochondroplasia. FGFR3 is a physiological negative regulator of skeletal growth, which restricts the length of long bones via inhibition of chondrocyte proliferation. Based on that, the profound dwarfing phenotypes in individuals carrying gain-of-function mutations in FGFR3 are not due to novel FGFR3 functions in cartilage but rather resemble an exaggeration of its physiological roles. The occurrence of somatic FGFR3 mutations in benign skin tumors and epithelial malignancies is caused by excessive cell proliferation and suggests a promitogenic FGFR3 effect on keratinocytes, melanocytes, and epithelial cells. Because the growth-inhibitory action of FGF signaling is specific to chondrocytes, whereas mitogenic for other cell types such as cells in the bladder epithelium or keratinocytes, this explains the fact that only severe forms of skeletal dysplasias had been associated with AN. Acanthosis nigricans is a velvety and papillomatous pigmented hyperkeratosis of the skin, which appears mainly on the flexures and neck. It is commonly observed in conditions associated with reduced insulin sensitivity such as obesity, lipodystrophy, and acromegaly and it is a criterion for identifying children at risk of type 2 diabetes mellitus . It results from the stimulation of keratinocytes and skin fibroblasts by the activation of growth factor receptors, such as epidermal growth factors, insulin-like growth factors (IGF1), and fibroblast growth factors . Somatic FGFR3 mutations have been detected in 40% of seborrheic keratoses (SKs) of the hyperkeratotic and acanthotic subtypes, which are very common benign skin tumors. The mechanism for the high rate of somatic FGFR3 mutations in these benign skin tumors remains elusive, but UV light exposure may play a potential role. Previous case reports described the association of normoinsulinemic acanthosis nigricans with achondroplasia and hypochondroplasia [ 9 – 13 ]. One of the early reports described a mutation in codon 650 of FGFR3 in a patient with mild form of osteochondrodysplasia and AN (p.K650Q) . Berk et al. described four relatives who had familial AN without skeletal abnormalities and were found to have FGFR3 mutation (p.K650T) . Castro-Feijóo et al. reported ten affected family members with HCH and AN due to p.K650T mutation. Four of them aged 16–46 years had normal oral glucose tolerance, while the other five had normal fasting glucose and insulin level and one patient was diagnosed with adult onset diabetes mellitus . Their finding demonstrates the coexistence of both conditions due to the same mutation which might represent a true complex. There were isolated case reports of ACH with AN developed either during treatment with growth hormone or without previous history of treatment . In a recent case series of five male patients with AN in ACH and HCH due to FGFR3 mutations, it was found that all of them had normal insulin sensitivity compared with puberty-matched controls . There was a single case report of a ten-year-old boy with ACH who developed AN during treatment with GH . On the other hand, another study of 35 children with ACH who received GH for five years did not show any evidence of increased insulin resistance or development of AN during the study period . A single case report by Blomberg et al. described a 14-year-old girl with mild hypochondroplasia due to K650Q mutation in the FGFR3 gene, who developed acanthosis nigricans and hyperinsulinemia . He concluded that FGFR3 mutation analysis should be considered in case of the coexistence of acanthosis nigricans and a skeletal dysplasia and advised testing for hyperinsulinemia, especially if FGFR3 gene mutation is confirmed. Given the complexity of FGFR3 downstream signaling, the mechanism involved in the development of AN in HCH patients is still unclear. Our findings suggest that it might be due to insulin insensitivity either related to skeletal dysplasia itself or secondary to treatment with recombinant human GH or may represent a new association that should be established by further studies. Hyperinsulinism found in our patient could be merely a possible chance; however, testing for hyperinsulinemia in hypochondroplasia patients is otherwise advised. Long-term follow-up for HCH patients is needed to clarify the risk of long-term metabolic complications.
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Review
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biomedical
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en
| 0.999998
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25574174
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First described in Japan in 1972 , Kikuchi-Fujimoto disease (KFD), or histiocytic necrotising lymphadenitis, is a relatively benign and self-limited disease that classically presents with lymphadenopathy and fever. Its aetiology is poorly understood, and it is sufficiently rare that, to our knowledge, its incidence rates have not been reported, although it is known to be much more prevalent in Asian populations . Indeed, a comprehensive literature review of KFD cases in 2003 described it as being “scarcely known in the western hemisphere” . KFD patients are typically young, with a mean age of diagnosis of 21 years . He gave a two-week history of fever, night sweats, painful knee joint, and mild shortness of breath. He had no significant past medical history. He was febrile, with a temperature of 38.2°C, and tachycardic at 105 beats/min. Blood pressure was 142/84 mm Hg, and oxygen saturation was 98% on room air. He had bilateral submandibular and cervical lymphadenopathy and bilateral parotid swelling. The lymph nodes were nontender and rubbery. Examination of his pharynx was normal, as were cardiovascular, respiratory, and abdominal examinations. Results of investigations undertaken on admission were normal full blood and differential white-cell count but elevated inflammatory markers (C-reactive protein: 49 mg/L (reference range RR < 10 mg/L); erythrocyte sedimentation rate: 70 mm/h (RR < 18 mm/h)). Renal and liver function tests were normal. Serum lactate dehydrogenase (LDH) was elevated at 721 U/L (RR < 280 U/L). Three separate blood samples were negative for a rapid malarial parasite test, and no malaria parasites were seen on blood film examination. Chest radiograph, urinalysis, and electrocardiograph were unremarkable. The initial impression was of either mumps or a travel-related tropical disease. He was treated as having sepsis of unknown origin with broad-spectrum intravenous antibiotics whilst further investigations were carried out. Two salivary samples taken one week apart were negative for mumps immunoglobulin M. Multiple blood and urine cultures were sterile. Viral serology for HIV and hepatitis A, B, and C and for cytomegalovirus was negative. Syphilis and dengue fever serology were negative. Three early-morning urine samples for acid-alcohol fast bacilli were negative. A “Monospot” test for infectious mononucleosis was negative. Serum immunoglobulin values were normal, and anti-nuclear antibody screening was negative. Over the next two weeks, episodic fever continued. Antibiotics were stopped after one week as they had conferred no symptomatic benefit or improvement in blood inflammatory markers. Paracetamol and nonsteroidal anti-inflammatory agents were given for symptomatic relief. His cervical lymphadenopathy persisted. Ultrasound scanning revealed several prominent hypoechoic lymph nodes throughout the neck and prominent lymph nodes in the groin. Supported by the elevated LDH value, the clinical impression at this point was that of lymphoma. Computer tomographic imaging of the neck, chest abdomen, and pelvis revealed bilateral enlarged cervical lymph nodes but no other significant abnormality. KFD was discovered in 1972 in Japan, when it was reported independently by two separate groups . Its exact incidence is unknown, but it is more prevalent in East Asia and the Far East . Traditionally, it was felt to have a strong female preponderance (male : female ratio of 1 : 4), but recent reports have challenged this opinion and suggest that the actual ratio is closer to 1 : 1 . KFD is often thought of as a disease of the young, with a mean age of diagnosis of 25 reported in an analysis of 244 cases . However, it has also been reported in patients ranging from 6 to 80 years old, most of whom were previously well [ 8 – 10 ]. The aetiology of KFD remains unknown. The geographic predominance in Asian countries may be related to the presence of the HLA class II alleles, HLA-DPA1 and HLA-DPB1 , which are prevalent in Asian KFD patients but extremely rare among Caucasians , an observation perhaps reflective of a genetic predisposition to the disease. An infectious cause, or at least trigger, to KFD has been postulated. Organisms such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, human herpes virus-6, human immunodeficiency virus, Yersinia enterocolitica , and Toxoplasma gondii have been implicated, but no convincing causal relationship has been identified . Some authors have hypothesised that KFD is a self-limited autoimmune condition triggered by virus-infected transformed lymphocytes . This theory is based on the histopathological features of the disease, which are similar to those seen in viral infections . However, serological testing and histological staining for viruses have been consistently unhelpful in supporting this theory. In many reported cases, KFD has coincided with, preceded, or followed a diagnosis of systemic lupus erythematosus (SLE); 32 of 244 KFD patients in one series also had SLE. Although SLE may be more prevalent in KFD patients, a clearly defined relationship between the two conditions has not been identified. Care should be taken in making the diagnosis of concomitant SLE in the patient with KFD as the two diseases share some clinical features (lymphadenopathy, rash, pyrexia of unknown origin, and arthralgia). Other autoimmune diseases such as Still's disease, Sjögren's syndrome, polymyositis, and rheumatoid arthritis also have been reported as occurring in conjunction with KFD, albeit with less frequency than SLE . KFD typically is a self-limited condition, with duration of 1 to 4 months, although a recurrence rate of 3-4% has been reported . The most common presenting signs are cervical lymphadenopathy (70–80%) and fever (30–50%) . Other less frequently reported symptoms are fatigue, arthralgia, rash, and weight loss. Affected lymph nodes are typically painless, solid, and mobile . Although cervical nodes are most often affected, nodes in other regions, including the axilla and groin, can be involved. Hepatomegaly and splenomegaly have been reported in isolated cases, 3% and 2%, respectively, in an analysis of 244 cases in 2007 . Routine laboratory indices are typically unhelpful in establishing a diagnosis of KFD. Reported haematological findings are leukopenia, neutropenia, lymphocytosis, thrombocytopenia, or anaemia . Notably, our patient displayed none of the above abnormalities. Biochemical abnormalities reported in other cases are elevated inflammatory markers (C-reactive protein and erythrocyte sedimentation rate), elevated liver transaminases, increased LDH, antinuclear antibody positivity, and reduced complement 3 values . Our patient had raised inflammatory markers and LDH only, findings which may be present in many infectious or malignant processes. The list of differential diagnoses for our patient, and for KFD in general, is long and includes any potential cause of lymphadenopathy and fever. Infectious causes are likely to be considered first, particularly as in our patient who had recently travelled to India. We considered tuberculosis, toxoplasmosis, human immunodeficiency virus, Epstein-Barr virus, herpes simplex, dengue fever, and mumps. As discussed above, autoimmune conditions such as SLE can cause a presentation similar to KFD and are therefore high in the differential diagnosis. Finally, malignancy (both haematological and solid-organ) is undoubtedly the most important diagnosis to exclude in a patient presenting with features of KFD. The high LDH levels and lymphadenopathy in our patient made us highly suspicious of lymphoma, and the excisional lymph node biopsy was carried out to exclude or confirm that diagnosis. The definitive diagnosis of KFD can be made only through lymph node biopsy and histological examination . Even with adequate tissue the lymph node appearances can be mistaken for malignant lymphoma; in one study, 30% of lymph node biopsies in KFD were initially misdiagnosed as lymphoma . The histopathological features of KFD have been classified into three stages: (1) proliferative stage, with expression of histiocytes, plasmacytoid monocytes, and lymphoid cells containing karyorrhectic nuclear fragments and eosinophilic apoptotic debris; (2) necrotising stage, with a degree of coagulative necrosis; and (3) xanthomatous stage, with foamy histiocytes predominating . A histological analysis in 2004 disputed this theory slightly, suggesting that the xanthomatous stage is not the resolving stage of KFD but is a histological variant of KFD in its own right . A characteristic and useful diagnostic feature is the absence of granulocytes in the “necrotising stage”, which is helpful in distinguishing KFD from SLE and drug induced lymphadenopathy. One analysis of 244 cases of KFD reported an overall mortality rate of 2.1%, which contradicts the widely held belief that the disease is generally benign and nonfatal. A female patient died of heart failure, in the context of other haematological autoimmune complications including haemolytic anaemia. Another patient died of pulmonary haemorrhage and a 24-week pregnant woman died from multiorgan failure after developing KFD-triggered hemophagocytic syndrome. Three patients developed KFD after organ transplantation and died of respiratory failure. These patients were immunosuppressed and there were probably other factors than KFD involved in their illness . This case describes an unusual and unexpected cause of fever and lymphadenopathy in a returning traveller. We believe that the initial focus on infectious causes was the correct approach in this patient, but the case illustrates that a history of foreign travel can sometimes be coincidental rather than directly implicated in such a presentation. It should also be remembered that the approach to the febrile traveller should not simply focus on potential exposure to infectious diseases, but also on the ethnicity of the patient, which can make the patient more or less predisposed to certain conditions. Kikuchi-Fujimoto disease is rare and relatively benign, but its clinical features can easily be mistaken for more sinister diseases. Establishing the diagnosis can therefore prevent further expensive and invasive investigations, as well as potentially harmful treatments and psychological stress to the patient.
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Review
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biomedical
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en
| 0.999994
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25667708
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Les gènes impliqués dans la mutation codent pour des sous unités des canaux ioniques responsables de l'activité électrique du cœur . Son incidence est estimée à 1/2000, selon certaines études . Il existe actuellement quatre phénotypes cliniques . Le diagnostic repose sur l’électrocardiogramme de surface qui montre un allongement de l'espace QT supérieur à 440 ms associé à des anomalies de morphologiques de l'onde T, et parfois une bradycardie. Chez le sujet sain, l'espace QT est de 440 ms, cet espace est influencée par la fréquence cardiaque et le tonus neuro-végétatif, d'où la notion de l'intervalle QT corrigé adapté au rythme cardiaque. Selon la formule de Barzett, l'intervalle QT corrigé est égal au rapport entre l'intervalle QT en milliseconde divisé par la racine carrée de l'intervalle RR du battement précédent. Un espace QT corrigé supérieure à 440 ms serait associé à une forte probabilité de syndrome du QT long . Au cours d'une étude, il a été démontré que 12% de patients génétiquement atteints avaient un QTC normal, inférieur à 440 ms . En effet, Il existe un chevauchement important des courbes de distribution des espaces QT chez les sujets sains et chez les sujets atteints . D'autres critères comme l'analyse de la morphologie de l'onde T ont été pris en considération par l’équipe de cardiologie de l'hôpital Lariboisière à l'Assistance Publique de Paris. L'analyse morphologique de l'onde T de sujets génétiquement identifiés montre des aspects spécifiques de chacun des trois locus les plus fréquemment impliqués dans la maladie. Dans la forme LQT3 l'intervalle QTc est très allongé avec une onde T tardive et de grande amplitude . Dans la forme LQT1, la morphologie de l'onde T est monophasique avec une base élargie . Dans 33% des cas, l'ECG ne permet pas une orientation différentielle entre KCNQ1 (LQT1) et SCN5A (LQT3) et dans 7% des cas de mutations dans KCNH2 (LQT2), l'ECG n'est pas spécifique . Dans la forme LQT2, on retrouve un aspect de l'onde T en double bosse Compte tenu de la variation nycthémérale de l'espace QT, un holter 24h peux être réalisé dans les cas douteux. Le test d′effort peut être utile afin de documenter la non adaptation de l′intervalle QT aux variations de fréquence cardiaque . L'enquête familiale s'avère utile pour la recherche d'une histoire de mort subite du nourrisson, d'accident de noyade, de syncope ou d’épilepsie. Le bilan réalisé à son admission aux urgences montre à l’électrocardiogramme un rythme sinusal régulier, à 105/min, on note une onde T asymétrique, l'espace QT corrigé est de 450 millisecondes . Le bilan réalisé en cours d'hospitalisation est tout a fait rassurant et montre un ionogramme normal, l'absence de germes au niveau du sédiment urinaire, il n'y a pas de foyer pulmonaire a la radiographie du thorax, la tomodensitométrie cérébrale est normale, l’électroencéphalogramme ne montre pas de foyer comitial. L’échographie cardiaque est normale. On note une excellente évolution durant l'hospitalisation, le nourrisson ne présente pas de séquelles neurologiques, ni de récidive d'arythmies.
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Other
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biomedical
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fr
| 0.999996
|
26435908
|
It has been noted that a urinary diversion may sometimes be the cause of non-hepatic hyperammonemic encephalopathy . However, the frequency of this complication is not known and considered to be extremely rare. Some cases have been reported in patients who underwent a urinary diversion due to bladder or prostate cancer . To the best of our knowledge, only one case with rectal cancer was previously reported in the Japanese literature, in which the patient suffered from a rectovesical fistula and liver dysfunction due to multiple liver metastases . Concerning the surgical procedures, we could not divide the cystic bladder from rectum because of the invasive growth of the tumor. We performed surgical management only for bowel obstruction, ileal disconnection with ileocecal bypass, and sigmoidostomy. Therefore, the serum ammonia value was kept slightly high around 80~120 μg/dl after surgery, and bladder catheter was needed during the post operative period. Consequently, these comprehensive treatments were considered to be effective to prevent the repeated hyperammonemic encephalopathy.
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Other
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biomedical
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en
| 0.999996
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26831562
|
17-b-hydroxysteroid dehydrogenase type 3 (17b-HSD3) deficiency , also previously described as 17-ketosteroid reductase deficiency, is a rare autosomal recessive form of a 46,XY disorder of sex development (DSD) and is the most common testosterone biosynthesis defect ( 1 ). The 17b-HSD3 enzyme is found mainly in the testes and is involved in the conversion of Δ4-androstenedione, which is a weak androgen, to testosterone, which is biologically more active. The 17b-HSD3 enzyme family includes at least 14 isoenzymes identified thus far and these isoenzymes contribute to reproductive organ development by playing a role in the final steps of androgen and estrogen syntheses ( 2 ). 46,XX individuals with a deficiency of this enzyme are asymptomatic and difficult to diagnose since they have normal female genitalia and normal gender roles as well as uninhibited fertility (4,5). On the other hand, 46,XY individuals may present a wide clinical spectrum from completely female appearing external genitalia (Sinnecker type 5) to slightly androgenized (Sinnecker type 4), frankly ambiguous genitalia (Sinnecker type 3) and to predominantly male genitalia with micropenis or hypospadias (Sinnecker type 2) ( 3 , 6 , 7 , 8 , 9 ). Since the clinical findings of 17b-HSD3 deficiency are similar to other 46,XY DSD forms, it may be difficult at times to establish the actual diagnosis and some of the 17b-HSD3 deficiency patients may be inadvertently diagnosed with androgen resistance (androgen insensitivity syndrome) or 5-α-reductase 2 deficiency. 17b-HSD3 deficiency is diagnosed via hormonal evaluation and the diagnosis is confirmed by molecular genetic testing. Herein, we report the case of a child who presented with bilateral palpable gonads in the inguinal region during infancy and female appearing external genitalia. A 46,XY karyotype was found and, subsequently, the child was diagnosed with 17b-HSD3 deficiency after detecting a lower T/Δ4 ratio in the stimulation test with human chorionic gonadotropin (hCG) and confirmed by molecular genetic analysis of the HSD17B3 gene. This report is presented since 17b-HSD3 deficiency is a rare form of 46,XY DSD and the mutation identified in our case has not been reported so far. A one-year-old girl was referred with the complaint of swelling in the right inguinal area. There was consanguinity in the family and the parents were first cousins. Physical examination revealed bilateral palpable gonads in the inguinal region. She had a female appearing genital status. A slight clitoral enlargement to 1.5 cm was observed although the vaginal and urethral orifices were separate. On ultrasonography, no Mullerian structures could be seen and the gonads were in the inguinal canal. The karyotype was determined as 46,XY. A hCG stimulation test was performed and following injection of 1500 U/m2 hCG for 3 days, serum androgen concentrations were measured ( Table 1 ). The test results showed that there was impairment in testosterone biosynthesis. Testosterone/dihydrotestosterone ratio was 3.6, i.e. normal value. Testosterone/androstenedione ratio was found to be 0.107 (N>0.8), suggesting 17b-HSD3 deficiency. Genetic analysis was made in order to confirm the diagnosis and molecular analysis of the HSD17B3 gene showed a homozygous mutation c.761_762delAG corresponding to p.E254VfsX10 in the patient; both parents were heterozygous. This deleterious mutation has likely caused a 17b-HSD3 deficiency in our patient, although this is a new mutation that has not been identified before, to the best of our knowledge. The parents did not accept sex reassignment into male and bilateral gonadectomy was performed. The histopathology of the gonads were consistent with testis and spermatic cord and no malignancy was seen. The most frequent presentation of 17b-HSD3 deficiency is a 46,XY case with female appearing external genitalia, labial fusion and a blind-ending vagina, with or without clitoromegaly ( 3 ). Most cases are not diagnosed at birth since they have female appearing external genitalia and are raised as female and the diagnosis of such cases is delayed until adolescence ( 9 , 10 , 11 , 12 ). In pubertal years, these individuals who have been raised as female and have not undergone gonadectomy are only diagnosed when they present with primary amenorrhea or virilization of various degrees such as increased body hair growth, thickened vocal cords, male type of body development and an enlarged clitoris. Sometimes, as is in the current case, individuals present with inguinal hernia and palpable testes in the inguinal canal or in the labiosacrotal folds and are diagnosed during childhood ( 3 , 9 , 11 ). Less often, individuals with micropenis or hypospadias are considered to be male at birth and raised accordingly ( 4 ). The extent of virilizativon of the individuals varies by the partial residual activity of the 17b-HSD3 isoenzyme in the testes and the conversion of androstenedione to testosterone by other isoenzymes found in the extratesticular tissues, such as the 17b-HSD5 isoenzyme ( 9 , 11 , 13 , 14 , 15 ). Virilization occurs also in puberty because of increased Δ4-androstenedione due to gonadotropin surge and increased conversion of androstenedione to testosterone in the extratesticular tissues ( 12 , 14 ). Patients may also suffer pubertal gynecomastia resulting from the conversion of androstenedione to estrogen through the activities of aromatase and other 17b-HSD isoenzymes ( 16 ). As in the current case, urethral and vaginal openings are separated in most of the patients with female external genitalia; however, only a short urogenital sinus has been reported in some individuals ( 11 , 17 , 18 ). The clinical findings of 17b-HSD3 deficiency are similar to androgen resistance or 5α reductase 2 deficiency and it is clinically difficult to differentiate between these conditions. 17b-HSD3 deficiency is diagnosed via hormonal evaluation and the diagnosis should be confirmed by molecular genetic testing. Typical hormonal finding of 17b-HSD3 deficiency include an increased Δ4 androstenedione and reduced testosterone concentration. Patients can be diagnosed via basal hormone levels in adulthood and in mini puberty during infancy (in infants aged below six months); however, the diagnosis may be missed unless hCG stimulation test is performed outside of these age periods. Our patient had a T/Δ4 ratio <0.8 after hCG stimulation, which strongly suggests a 17b-HSD3 deficiency. However, it should not be forgotten that this ratio may be low in other conditions related to testosterone synthesis such as dysgenetic testes ( 11 , 19 ). Displaying the absence of Mullerian structures and the presence of Wolffian structures using imaging methods is helpful in the diagnosis but remains insufficient since these can be seen in 5α reductase 2 deficiency and androgen receptor mutations as well as 17b-HSD3 deficiency. Histological examination of the specimens from the gonad shows normal testicular structures and thereby, other causes involved in the etiology of 46,XY DSD, such as testicular dysgenesis, are excluded. The definitive diagnosis of 17b-HSD3 deficiency is established through genetic testing. The HSD17B3 gene is located on chromosome 9q22 and homozygous or compound heterozygous mutations in this gene cause 17b-HSD3 deficiency ( 8 ). As far as we know, there are 29 mutations identified in this gene at this time. These mutations include intronic splice sites, exonic deletions, missense and non-sense mutations ( 20 , 21 ). A great majority of these mutations have been identified in the Arab population living in the Gaza strip. The most common mutation identified in the Arab population is the p.Arg80Gln mutation, which is a point mutation in exon 3, codon 80 and 1The mutations previously identified in the Turkish population are c655-1;G-A, p.Ala188Val and c.777-783del_GATAACC mutations ( 3 , 22 ). Among these, c655-1;G-A is a splice junction mutation and disrupts splice acceptance site; p.Ala188Val is a missense mutation and inactivates the enzyme; and c.777-783del_GATAACC causes a 7 base pair deletion and frame shift and subsequently a truncated protein ( 23 ). The mutation identified in the current patient is a new mutation that has not been previously reported. In our case, a homozygous mutation c.761_762delAG corresponding to p.E254VfsX10 was identified in the HSD17B3 gene. A deletion of two nucleotides in exon 10 was found, which leads to a frame shift and subsequently to premature termination within the protein. Another important point of 17b-HSD3 deficiency is the lack of a phenotype-genotype correlation; different phenotypes have been reported in different individuals with the same genotype within the same family. Although the same homozygous mutation is seen in different individuals of the same pedigree, different T/Δ 4 ratios have been reported after hCG stimulation ( 18 ). Sex assignment is a difficult and important decision in individuals with 17b-HSD3 deficiency, as is in other DSD cases. Transition to the male gender role is observed in a considerable amount (39-64%) of the individuals who have been raised as female, have not undergone gonadectomy and have experienced virilization in puberty ( 1 , 4 , 11 , 15 , 20 , 24 , 25 ). There are no reports of gender changes in cases raised as males ( 25 ). It has been observed that individuals who have been raised as females and have undergone gonadectomy during childhood are often satisfied with the female gender role and a very few of these individuals desire gender reassignment in the future ( 1 , 3 , 23 ). There is no association between the severity of the enzymatic defect and the adult social gender role and some cases are believed to have gender change possibly with the effect of social and cultural influences ( 1 ). Some authors suggest that sex assignment and corrective surgeries at younger ages is more favorable for the child and the family to gain the gender role behavior, whereas some authors argue that it would be more favorable if the surgery is performed only after the child reaches an age to give his/her own consent and after obtaining his/her full consent ( 26 , 27 ). What is important here is that a delay is possible until the child reaches an age to disclose his/her choice and to assist the family and the doctors in making the right decision. The 2006 Chicago Consensus Meeting indicates that male gender assignment should be determined in individuals with 17b-HSD3 deficiency, but there is no spermatogenesis in individuals raised as male, even though early orchidopexy is performed and such individuals are infertile and have a risk of 28% for developing germ cell malignancy, so it should not be forgotten to closely monitor such individuals in this regard ( 28 , 29 ). Sex assignment should be determined in consideration of the social and cultural expectations of the society in which the family lives and religious convictions. If the male gender is assigned to the severely undervirilized individuals, such as the patient presented in this report, genital reconstruction may be difficult ( 30 ). There are also some opinions suggesting that the response of external genitalia to testosterone should be evaluated via testosterone injection before sex assignment and it would be appropriate to raise such individuals as male if there is an adequate response ( 30 ).
|
Study
|
biomedical
|
en
| 0.999997
|
27239267
|
Herein we report a case of a 35-year-old male from Nawalparasi, Nepal, who had undergone a craniotomy and evacuation of acute subdural hematoma following an automobile accident 2 months before admission to our institution. He presented with complaints of an abnormal gait, with a tendency to fall backwards and also with features of frontal lobe-related incontinence. There were no significant past medical illnesses. He was taking Sodium Valproate (300 mg oral three times daily) as seizure prophylaxis following the traumatic head injury and surgical intervention for the same 2 months previously. Fundus examination revealed the presence of papilledema. A head computerized tomography (CT) scan revealed the presence of evolving hydrocephalus. To rule out hydrocephalus ex vacuo due to volume loss and changes in CSF dynamics subsequent to the previous accident, external ventricular drainage (EVD) was placed which revealed egress of CSF under pressure. The reasons for opting to choose EVD prior to VP shunting are threefold. Firstly, we had to rule out post traumatic hydrocephalus ex vacuo by measuring the opening pressure of the CSF egress and looking for the neurological improvement in the patient following CSF diversion. Secondly, since we not have the programmable VP shunting available, we need to appropriately choose the Chabra shunt depending on the opening pressure so as to prevent either over drainage or under drainage of CSF. Lastly, since it was a post traumatic case, we need to measure the CSF protein (as it may be increased from the lysed traumatic subarachnoid blood) and also we need to rule out subclinical meningitis. Both these may be the reasons for shunt failure. Following EVD, the patient showed gross improvement in his previous deficits. CSF sugar and protein was within range. Gram stain was negative for any bacteria. Repeat CT scan post EVD did not reveal any pneumocephalus. Thereafter he was scheduled for insertion of a VP shunt. EVD was clamped for 6 hours prior to the procedure to facilitate the ventricular tap. During insertion of the VP shunt, there was dry tap during an attempt of ventriculostomy from the Kocher’s point. We made two further attempts to ensure the correct trajectory of the shunt end and also to reflush the shunt end to prevent blockage due to blood clots and cell debris. We placed the shunt tip in the presumed location of the foramen of Monro of the frontal horn of ipsilateral lateral ventricle. We did not remove the EVD, hoping that it would act as a safety channel for CSF bypass had we missed the correct trajectory for the VP shunt. A postoperative scan revealed the presence of tension pneumocephalus and pneumoventriculi . The patient was managed with 100% oxygen for 3 days and was continued on antiepileptic medications at the same dose intravenously. Stringent neurological monitoring was undertaken to evaluate early neurological deterioration due to tension pneumocephalus. Pupils were routinely assessed to look for hippus (a clinical marker of epilepsy). Patient was extubated the following morning. A repeat CT scan on the 6 th day post-operation showed that the proximal shunt was in the third ventricle and there was complete resolution of the condition. The EVD was subsequently removed with no neurological deterioration of the patient on 7 th day after operation. The patient then started to walk with support from the 8 th day post-operation, and he slowly improved in gait. Patient went home walking with minimal support on the 14 th day post-operation. Patient had also regained his bladder control within that time. Patient returned, walking on his own 1 month later for his follow up in the outpatient department His gait was normal with no features of retropulsion. The shunt chamber was functioning well and his bowel habits were normal. Compliance in continuation of Sodium valproate therapy (at the aforementioned dose) was also ensured. Pneumocephalus usually occurs after head trauma, skull base fractures, and associated CSF fistulas 1 . The incidence of this entity was reported to be as high as 100% following supratentorial craniotomies 6 . On the other hand, tension pneumocephalus is a neurosurgical emergency that requires rapid surgical intervention. Pneumocephalus as a complication of CSF diversion procedures is rare 5 . Diagnosis is mainly based on clinical examination and computerized tomography (CT) scan 4 . Two CT findings that characterise the condition – the ‘Mount Fuji’ sign and the ‘air bubble’ sign - have been described by Ishiwata et al. 7 .
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Clinical case
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clinical
|
en
| 0.999997
|
27642398
|
Le pneumothorax est un épanchement gazeux entre la plèvre viscérale et la plèvre pariétale. Le pneumothorax spontané est exceptionnellement bilatéral d'où la particularité de cette observation. Il s'agit d'un patient âgé de 47 ans, fumeur à 35 paquet/année, bronchitique chronique depuis 8 ans, admis aux urgences dans un tableau de douleur thoracique diffuse, polypnée, tirage intercostal et sus sternal, et cyanose des extrémités. Les diagnostics les plus probables étaient: une exacérbation de BPCO, une embolie pulmonaire ou un pneumothorax. L'examen pleuro pulmonaire trouve un syndrome d’épanchement aérique bilatéral. La radiographie thoracique montre une hyperclareté avasculaire bilatérale accentuée à gauche. Le scanner thoracique révèle un pneumothorax bilatéral plus important à gauche, sur poumon multibulleux. Le patient a bénéficié de la mise en place d'un drain pleural sous aspiration douce (-20 cmH2O) du côté gauche le plus décollé et une exsuflation du côté controlatéral, ainsi qu'un traitement symptomatique à base de corticothérapie par voie veineuse (Solumedrol) et nébulisation de salbutamol, couverture antibiotique et repos strict au lit. L’évolution a été marquée par le retour total du poumon à la paroi des 2 côtés.
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Clinical case
|
clinical
|
fr
| 0.999998
|
27909860
|
Tibial hemimelia presents with a wide range of pathology, ranging from a hypoplastic tibia to complete absence of the tibia. The fibula is always present and may be normally formed or dysplastic and, in some cases, duplicate. The quadriceps muscle may be normally formed, distally deficient or absent, and the patella may be normally formed, dysplastic or absent. Similarly, the cruciate and collateral ligaments may be present or absent. The knee may fully extend or have a flexion contracture or dislocation. The foot may be normally formed, deficient or duplicated. The ankle may range from normal motion to fixed equino-varus. Tibial hemimelia can be unilateral or bilateral, with an estimated 30% of cases being bilateral . Spiegel noted that 72% of unilateral cases reported in the literature affected the right side . The degree of dysplasia and type may vary significantly between sides. Unilateral cases have a leg length discrepancy. Tibial hemimelia is associated with congenital anomalies affecting the ipsilateral limb either as suppressive or duplicated [ 3 – 7 ]. Associated anomalies include radial dysplasia, lobster claw deformity, hand syndactyly, polydactyly, triphalagism, missing fingers or toes, hip dysplasia, hip dislocation, coxa valga, hemivertebrae and myelomeningocele [ 8 – 11 ]. Other associated congenital anomalies include deafness, cleft palate, pseudo-hermaphroditism, cryptorchidism and hypospadias . Schoenecker et al. reported on 57 patients with tibial hemimelia of whom 34 (60%) had other associated congenital anomalies . Launois and Kuss found that 24 of 41 (59%) patients with tibial hemimelia had other congenital associated anomalies . The incidence of tibial hemimelia is reported to be one per million live births . Parent to child transmission as well as families with multiple siblings affected have been described. Clark , and Lenz suggested that tibial hemimelia was an autosomal dominant disorder, while autosomal recessive inheritance was described by Fried , Mahjlondji and McKay . In a breeding trial of Galloway cattle with tibial hemimelia, Ojo et al. implicated homozygosity of a single autosomal recessive gene with variable expressivity and pleiotropic effects on various body systems . Tibial hemimelia is associated with several syndromes. Werner’s syndrome is an autosomal dominant disorder that is currently thought to be a variant of triphalangeal thumb-polysyndactyly syndrome (TPTPS). Both diseases have been mapped to chromosome 7q . A deletion on chromosome 8q, contiguous with Langer–Giedion syndrome, or type II tricho–rhino–phalangeal syndrome (TRPS II) may also be responsible for tibial hemimelia . CHARGE syndrome, which is a pattern of congenital anomalies, including eye, nose, ear, heart, and genital defects, as well as tibial hemimelia is a mutation of the CHD7 gene (chromodomain helicase DNA-binding protein 7), located on chromosome 8q. CHD7 is known to be expressed by the developing limb bud mesenchyme . Tibial hemimelia is also linked to tibial hemimelia–diplopodia syndrome , tibial hemimelia–split hand and foot syndrome and tibial hemimelia–micromelia–trigonal brachycephaly syndrome . The Gollop–Wolfgang complex is a very rare malformation characterized by ectrodactyly of the hand, ipsilateral bifurcation of the femur and tibial hemimelia ; both autosomal dominant and recessive inheritance have been reported for this malformation . The pathoanatomy of limbs affected by tibial hemimelia has been examined. Evans and Smith found either an absence or duplication of some muscles, with some muscles being functionless and attached to only one bone. Based on their results, these authors postulated a mesoblast disorder. Hovelacque and Noel suggested the same in their study of mouse embryos in 1909 . Turker et al. dissected limbs with complete tibial aplasia and consistently observed that the affected leg had a dimple where the skin was tethered over fibula. The saphenous and lesser saphenous veins and sural and superficial and deep peroneal nerves were all intact. The posterior tibial neurovascular bundle was found to be short and acting as a tether. The lateral and superficial posterior compartment muscles were intact with normal insertions. The anterior and deep posterior compartments did not have a discrete boundary and their tendons had anomalous courses and sometimes split. There were no identifiable posterior tibial or anterior tibial muscle bellies, but all specimens had a tendon inserting medially on the midfoot that tethered the foot in supination while three specimens had an anomalous tendon inserting onto the neck of the talus. All specimens had a flat tendon-like structure on the anterior border of the fibula that wrapped around and inserted on the posterior capsule of the ankle. The abductor hallucis muscle was always present, even in feet without medial rays. No discrete plantar fascia was found. All specimens had subtalar coalitions, and some had midfoot coalitions and the talus articulated with the distal medial fibula on its posterolateral side. The Jones classification , published in 1978 and based on plain radiography findings, divides tibial hemimelia into four types, ranging from the most deficient to the least deficient. Jones type I is distinguished by the absence of a visible tibia and is subclassified into two groups: the Ia group, with a hypoplastic distal femoral epiphysis, and the Ib group, with normal ossification of the distal femoral epiphysis that suggests the presence of an unossified proximal tibial epiphysis. Jones type II condition is characterized by the presence of an ossified proximal tibia but with a distal tibia deficiency; Jones type III, by an ossified distal tibia, with a proximal tibia deficiency; Jones type IV, by a shortened tibia with distal tibio-fibular diastasis . Fig. 1 Jones classification. Reproduced with permission by the Paley Foundation Weber introduced a new classification which takes into account the cartilaginous anlage, if it is present. His classification distinguishes 7 types with 12 subtypes, including the addition of a few types of tibial hemimelia which were unclassifiable by the Jones classification . Opposite to the Jones, the Weber classification is in order of increasing deficiency, with subgroups based on whether the cartilage anlage is present (a) or not (b). Weber type I is characterized by tibial hypoplasia but with intact joints proximally and distally; Weber type II, by distal diastasis of the tibia and fibula; Weber type III, by distal tibial aplasia; Weber type IV, by proximal tibial aplasia; Weber type V, by bifocal tibial aplasia proximally and distally; Weber type VI, by complete tibial agenesis with double fibulae; Weber type VII, by complete tibial agenesis with a single fibula. The Weber classification also assigns a score to determine the functional ability of the limb, taking into consideration the tibia (0–22 points), presence of an anlage (0–10 points), presence of patella (0–3 points), rest of limb (0–2 points, includes hip joint, distal femur, fibula, foot, and muscle function of hip, knee, and ankle). Higher scores indicate less impairment of the limb. Five classes are defined based on the score, indicating the degree of deficiency and difficulty of reconstruction. Fig. 2 Weber classification. Reproduced with permission by the Paley Foundation Paley, Packer and Burghardt recently classified 113 tibial hemimelia limbs treated earlier by the author. These authors reported 47 Jones type Ia, five Jones type 1b, 18 Jones type II, two Jones type III and 10 Jones type IV cases; 31 cases in this series were ‘unclassifiable’ (27.4%). The same series was classified by the Weber classification. There were 18 Weber type I, 11 Weber type II, three Weber type IVa, 17 Weber type IIIb, zero Weber type IVa, two Weber type IVb, five Weber type Va, zero Weber type Vb, zero Weber type VIa, zero Weber type VIb, four Weber type VIIa and 47 Weber type VIIb cases; there were also six ‘unclassifiable’ cases using the Weber classification (5.3%). When this same group of 113 tibial hemimelia limbs was classified using the Paley classification, there were no ‘unclassifiable’ cases and no Paley types without cases. There were five Paley type 1, 11 Paley type 2A, eight Paley type 2B, four Paley type 2C, 12 Paley type 3A, six Paley type 3B, 16 Paley type 4A, four Paley type 4B, 19 Paley type 5A, five Paley type 5B, and 23 Paley type 5C cases. When the various classifications were compared, the Jones classification was by far the quickest and easiest to learn, use and memorize. In comparison, the Weber classification was very difficult to learn, use and memorize and was by far the most confusing and time consuming. The Paley classification, despite having more subtypes than the Jones classification, was still relatively easy to use, learn and memorize, as well as being relatively quick for classifying tibial hemimelia. Its + or − modifier was very helpful in conveying the picture of the associated deficiencies or duplications that were present. The ease of use of the Paley classification of tibial hemimelia, combined with its efficiency and comprehensiveness, suggest that it be proposed as the new standard. Brown published a surgical procedure for the treatment of Jones type I by fibular centralization in 1965 . This was usually combined with a Syme’s amputation. In his 15-year follow-up study , in which 40 of 56 patients were available for review , 18 required secondary surgery due to a knee flexion deformity, 21/22 were ambulatory, and all but two were wearing braces while ambulatory. Based on the results of the follow-up study, Brown recommended attachment of the patellar ligament to the fibula, pre-operative traction, as well as femoral shortening and soft tissue releases as needed to gain extension. He also recommended surgery before age 1 year for maximal ambulatory and fibular articulation potential. Inferior results were noted with an absent quadriceps muscle. Knee disarticulation has been described for treatment and also remains a salvage option for failed Brown procedures. Kalamachi treated three children with the Brown procedure, and all went on to subsequent knee disarticulations. The failure was attributed to knee flexion contractures and the absence of active quadriceps function, leading the authors to recommend early disarticulation of the knee without any attempt of reconstruction. Alternatively, if the femur was severely hypoplastic, a femoro-fibular arthrodesis was performed to effectively lengthen the femur, creating a longer lever arm for improved prosthetic fitting. Similar results and conclusions were drawn by Schoenecker et al. and Fernandez et al. . In the presence of a tibial anlage (Jones type Ib) or a proximal tibia (Jones type II), some authors report good results with tibio-fibular synostosis . The use of an external fixator prior to reconstruction was reported as helpful to overcome soft tissue contractures . Schoenecker recommended tibiofibular synostosis for Jones types Ib and II cases, combined with a Syme’s amputation. These patients were functional as below-knee amputees. Spiegel et al. described some potential complications of amputation in patients with Jones type II treated with distal amputation (Chopart or Syme) due to prosthetic irritation from the overgrowth and prominence of the fibular head. Since Brown introduced centralization of the fibula, many attempts to reconstruct the knee in the most severe types (Jones I) have met with poor results, as previously discussed. Similarly, poor results of reconstruction for Jones types I, II and IV have led most surgeons to conclude that through-knee amputation for Jones type I, through- or below-knee amputation for Jones type II and Syme’s amputation for Jones type IV are the best treatment for each type of tibial hemimelia. In light of the advances in modern prosthetics, the amputation option remains the gold standard and should be considered as the most tried and proven method of treatment. However, advances in the treatment of all types of tibial hemimelia offer new surgical options with excellent functional results as an alternative to amputation. Since the Paley classification was designed as a guide to treatment and prognosis, my discussion of surgical management is presented according to Paley type and subtype. These patients have intact stable knees and ankles. The proximal fibula is overgrown and may articulate with the side of the femur. The ankle joint is well formed and stable. There may be valgus malalignment in the tibia. If treated when the physes are open, the valgus can be corrected using hemi-epiphysiodesis. In adulthood, the valgus can only be treated by osteotomy. If bilateral, the biggest complaint of these patients is mesomelic disproportion and short stature. If unilateral, there is a leg length discrepancy. In both cases the treatment involves simultaneous deformity correction with lengthening, either uni- or bilateral. The overgrown proximal fibula can either be pulled down to station with differential lengthening of the tibia relative to the fibula or left in place while lengthening both the tibia and fibula together the same amount. Pulling down the fibula risks creating a knee flexion contracture through tightening of the biceps tendon. Fig. 4 a Antero-posterior (AP) and lateral radiographs of 20-year-old woman with bilateral Paley type 1 tibial hemimelia. The tibia is well formed at both the knee and ankle joints. The fibulas are relatively overgrown at their proximal ends and are articulating with the side of the femurs. The knees are both in valgus due to both tibial and femoral deformities. The tibias have mild procurvatum diaphyseal bowing. Since both tibias are relatively short compared to the femurs, the patient has a mesomelic disproportion and short stature. b AP and lateral radiographs after treatment. Both tibias were lengthened with external fixators. The tibial valgus-procurvatum was corrected. The fibulas were not pulled down. Bilateral femur varus osteotomies were performed after completion of the tibial correction. The lengthening restored the proportion of the tibias and femurs to normal If the foot equino-varus deformity exceeds the malorientation of the tibial plafond, which is due to bony deformity, the ankle should be distracted with an external fixator to correct the contracture followed by staged osteotomy to realign the tibia with the foot together. If the equino-varus does not exceed the tibial deformity, an osteotomy of the tibia for angular correction of the tibia with the foot, combined with lengthening, is carried out relative to the longer fibula. The circular external fixator extends from the femur to the tibia and foot. Fig. 5 a Radiographs of 2-year-old girl with Paley type 2A unilateral tibial hemimelia, with equino-varus deformity of foot and varus of tibial diaphysis. There is no diastasis of the distal tibio-fibular joint. The ankle joint is present. The ossification of the distal tibia shows a regular trumpet shaped metaphyseal line indicating that this is the region of the distal tibial physis. b Lateral radiograph of tibia. Taylor spatial frame (TSF) is in place with proximal tibial and foot rings programmed for gradual correction of foot deformity. There is also an independent mechanism (threaded rod with cube and two half pins connected to the proximal ring) to simultaneously lengthen the tibia through a proximal osteotomy. There is a distal fibular epiphysiodesis screw in place to slow the growth of the faster growing fibula. c Lateral ( left ) and AP ( right ) radiographs at the end of the foot correction and 8 cm of lengthening after a second stage surgery to openly reduce the talus to the tibia combined with axial pinning of the ankle joint. Syndesmotic washer-suture device (Ziptite™ Fixation System; Biomet Sports Medicine, LLC, Warsaw, IN) inserted to stabilize the lengthened tibia to the fibula at its new syndesmosis level. The tibial lengthening bone shows poor regenerate formation. d Plate fixation at time of removal of fixator to prevent fracture. The tibia is well aligned. The talus is under the distal tibia. The fibula is now at station at the ankle and the ankle is stable. The foot is plantigrade The bracket epiphysis can be oriented in any direction and does not always correspond to the deformity seen. The fibula is much longer than the tibia. The treatment in these cases is to consider the direction of the bracket in planning the surgery. To interrupt the bracket, the cartilage of the epiphysis and physis is cut, and an osteotomy is performed through the bone at the same level. To allow for acute correction of the deformity, part of the fibula must be resected. The acute correction is accomplished by an opening wedge osteotomy on the side of the bracket, with or without a partial closing wedge on the opposite side. The correction can be done with or without lengthening at the same time. With lengthening, it is done with the external fixator extending to the femur. Without lengthening, fixation is obtained with axial retrograde wires entering through the foot and if necessary also crossing the knee. Fig. 6 a Radiographs of a 3-year-old girl with unilateral tibial hemimelia, Paley type 2B tibial hemimelia + metatarsals/toes. The obvious delta tibia is seen with two secondary ossific nuclei. The foot has seven metatarsals and eight toes. The foot is in equino-varus. The ankle and knee joint are maloriented. The proximal fibula is relatively overgrown and sits proximal to the distal femoral physis. b Clinical photograph of same girl. c Arthrogram of knee and ankle showing joint malorientation and dysplasia. d AP ( left ) and lateral ( right ) radiographs with TSF in place and osteotomy lengthening and deformity correction of the tibia. The foot deformity correction is partially through the distal tibial reorientation. Note there is no osteotomy of the fibula and that it is only fixed to the distal tibial ring using one distal tibio–fibular wire and half pin. e AP ( left ) and lateral ( right ) radiographs following 8 cm of tibial lengthening and deformity correction with distal fibular transport. The frame was modified connecting the distal tibiofibular wire and fibular half pin to the proximal ring. This frees the ankle joint for distraction correction of the remaining foot deformity. Note that the proximal fibula has been pulled down almost to station. f Two years after removal of the external fixator the tibia is well consolidated. The fibula is already showing significant relative proximal and distal overgrowth. The distal fibular epiphysiodesis screw’s head is migrated into the epiphysis and screw shaft is broken rendering it mostly ineffective at this juncture. The foot varus deformity is slowly recurring. This will require another differential lengthening surgery in a year or two. g Clinical photos showing knee and ankle range of motion two years after lengthening. h This girl is very active despite recurrent leg length difference and mild foot deformity. Note how she plays with the other girls while she wears a shoe lift. She is the tall girl in the middle The salient feature in this type of tibial hemimelia is the delayed ossification of part, or all, of the tibia. When part of the tibia is affected, it is always the distal part. An MRI examination is useful to image the articulations between the tibia and the femur and those between the tibia and the talus. Based on these, a decision can be made as to whether the deformity of the tibia needs to be corrected in order to reorient the ankle to the knee. Since the fibula is longer than the tibia, two options can again be considered for managing the fibula: (1) resection to create a pseudoarthrosis of the fibula, or (2) lengthening of the tibia relative to the fibula. The ankle joint, while present in these cases, is not functional. The goal is to create a plantigrade foot with a stable ankle. This usually requires distraction of the foot through the ankle joint, followed by a secondary arthrotomy as described for type 2 deficiencies to best match the articulation between the talus and tibia. The syndesmosis may or may not need to be fixed with a syndesmotic suture washer device. Fig. 7 a Magnetic resonance imaging (MRI) scan ( left ), lateral radiograph ( middle ), and standing AP radiograph ( right ) showing Paley type 2C unilateral tibial hemimelia. The foot is in significant varus. The distal tibia has an unossified region contiguous with the ankle. There is no obvious distal tibial physis, but the plafond is present. Note that the ossification of the distal tibia is irregular and sloped, not like a normal metaphysis associated with a distal tibial physis . The proximal fibula is relatively overgrown and proximally migrated. b Arthrogram of ankle showing AP ( left ) and lateral ( right ) views. c Lateral ( left ) and AP ( right ) radiographs after arthrotomy of ankle, and open valgus-extension osteotomy and shortening of distal tibia to realign ankle joint by acute correction. Bone morphogenetic protein 2 (BMP2) was inserted in drill holes of the cartilage remnant of the distal tibia to get it to ossify. A second osteotomy was performed proximally for lengthening. The fibula is being pulled distally with an intramedullary wire hooked over the proximal epiphysis (see AP view). Because the tibial/ankle/foot deformities were corrected acutely, the external fixator is programmed for pure lengthening. The external fixator is extended to the femur with knee hinges to protect the cruciate deficient knee during lengthening while permitting knee flexion and extension motion. d Lateral ( left ) and AP ( right ) radiographs, after lengthening with excellent consolidation of the tibia, including ossification of the delayed distal tibia. The foot is plantigrade with forefoot supination deformity present. The proximal fibula is at station The foot is in equino-varus and internally rotated relative to the knee. The talus is proximally migrated relative to the distal tibia. The talus is at the correct level relative to the distal fibula. The foot is repositioned by gradual distraction of the foot from the tibia using a circular external fixator. To prevent physiolysis of the proximal and distal fibula, a 1.5-mm wire is drilled retrograde into the fibula and up the fibular diaphysis to exit through the proximal fibular epiphysis. The wire is brought through the skin proximally and then bent backwards on itself to form a hook. A small proximal incision is made, and the wire is pulled back into the fibular head to lock into the proximal epiphysis. Distally, the wire is also bent 180°, then shortened and buried under the skin. This creates a temporary epiphysiodesis of the proximal and distal fibula to prevent physiolysis during distraction . Fig. 8 a Standing ( left ), mortis view ( middle ) and lateral view ( right ) radiographs of a 2-year-old girl with Paley type 3A unilateral tibial hemimelia. The diastasis of the distal tibia and fibula with the talus in between is very evident. The talus always remains in line with the distal fibula and together they internally rotate around the distal tibia. The talus is shortened relative to the distal tibia but not relative to the distal fibula. There is relative overgrowth with proximal migration of the fibula. There is a mild distal tibial varus diaphyseal bowing. b AP ( left ) and lateral ( right ) radiographs showing TSF applied to the tibia and foot. There is no fixation in the fibula or talus. More current constructs would fix to these as described in the text. The foot is in internal rotation and equinus. c AP ( left ) and lateral ( right ) radiographs after gradual correction using TSF. The talus is under the distal tibial epiphysis and the foot and fibula have rotated externally relative to the tibia. There is no longer any tibio-fibular diastasis. The equinus deformity is also corrected. This gradual correction took 12 weeks. d AP ( left ) and lateral ( right ) radiographs after removal of the external fixator 3 months following open ankle reconstruction. The ankle reconstruction included a biologic arthroplasty to create a concave surface on the distal tibial epiphysis that is congruent to the talar dome convexity. The ankle joint was pinned with an axial wire and the diastasis of the tibia and fibula were fixed with a suture-washer syndesmotic repair (TightRope®, Arthrex, Naples, FL). The axial wire was left in place for another 3 months to prevent recurrent deformity at the ankle. Note the proximal fibula was brought down to station. e AP ( left ) and lateral ( right ) radiographs at age 14 years after she underwent two successful lengthenings; one external fixator lengthening at age 6, and one implantable nail lengthening at age 14 (Precice™; NuVasive Inc., San Diego, CA). She also had a supramalleolar and subtalar osteotomy. Note the ankle joint is stable and well preserved. The ankle has about 20° of motion. The proximal fibula is at station. Most of this hardware was removed at a later date. Due to the limited ankle motion, the leg lengths were intentionally corrected to leave a 1-cm difference In this type of tibial hemimelia there is a cleft between the tibia and fibula in addition to the diastasis. The first stage of treatment is the same as for type 3a tibial hemimelia. The talus is corrected out of equino-varus and brought down below the level of the distal tibial epiphysis. The second stage of surgery includes syndesmotic repair between the tibia and fibula, biologic arthroplasty of the tibio-talar joint and closure of the skin cleft. Fig. 9 a Preoperative photograph ( center ), and radiographs ( right on the left , left on the right ) of bilateral tibial hemimelia in a 3-year-old boy; Paley type 5A ( right ) and Paley type 3B tibial hemimelia ( left ). The patella on the right has not yet ossified. Other than the cleft on the left , this is very similar to type 3A. The cleft makes this a very rare type. It should be noted that the foot is found on the fibular side of the cleft on the left . Both feet are in severe equino-varus and even upside down. There is a greater than 90° flexion contracture and dislocation at the right knee. b Standing ( center ), right lateral ( left ) and left lateral ( right ) radiographs after the staged reconstruction method was completed, 2 years prior on the left and 3 months prior on the right . The Paley–Weber patellar arthroplasty was performed on the right , with insertion of BMP2 to ossify the patella and fuse it to the proximal fibular epiphysis. Note the preservation of the proximal fibular physis. On the left the talus was brought under the tibia, a biologic arthroplasty performed together with plastic closure of the cleft. The distal and proximal tibial and fibular physes are preserved on both sides. The fusion of the talus to the distal fibular epiphysis did not occur and may require revision in the future. Both feet are plantigrade. c Clinical photographs showing the patient standing with both feet plantigrade and both knees straight and well aligned Once the foot is plantigrade and the talus is under the fibula, a second surgery to fuse the ankle and transfer the fibula to the tibia is performed. A few days before this surgery, the only tibial wire is removed to allow its pin site to heal prior to surgery. The foot ring and wires are removed (similar to Fig. 12 d (i)). The pin sites are covered with an occlusive dressing (Tegaderm; 3M, Maplewood, MN) to minimize contamination during surgery. After the leg is prepped and draped free, a transverse lateral incision is made over the distal tip of the fibula (similar to Fig. 12 f (i)). The distal epiphysis of the fibula and the dome of the talus are exposed. The capsular connections between them are cut to mobilize both bones relative to each other. A small incision is made proximally over the fibular wire. The fibular epiphysiodesis wires are cut proximally and pulled out distally. Two new wires are immediately inserted in the same track to protect the fibula from fracture. The fibula is osteoporotic at this stage, and without an intramedullary wire it could easily fracture due to manipulation that can occur during surgery. These two wires are brought out proximally through the small incision made over the head of the fibula. The distal fibular epiphysis is cut across its ossific nucleus. The talar ossific nucleus is exposed by cutting across the dome of the talus parallel to the sole of the foot (similar to Fig. 12 f (i,ii)). The two ossific nuclei are then aligned, and the proximal wires are advanced through the talus and out the sole of the foot to hold the foot plantigrade to the fibula (similar to Fig. 12 f(iii,iv)). If a patella is present it can be moved to become a tibial plateau. This original concept was first published by Weber . The patella is moved on a vascular pedicle (called visor flaps ) from its normal position, anterior to the femur, to the distal end of the femur. The fibula is centralized to the patella and its epiphysis fused to the patella. This procedure is referred to as the Weber patellar arthroplasty or Weber procedure. Fig. 11 a Lateral ( left and center left ) and AP ( right and center right ) photographs and radiographs of the right leg of a 2-year-old boy with bilateral tibial hemimelia. Only the right side is shown. The right side has Paley type 5A tibial hemimelia and the left side Paley type 4A. Note the flexion contracture of the right knee and the equino-varus-adductus foot deformity. b Lateral ( left ) and AP ( right ) radiographs showing the TSF in place with femoral and foot rings. The fibula is secured to the foot ring with a transverse wire. Note the temporary epiphysiodesis wire in the fibula hooked at both ends. Also note the wire across the neck of the talus. c Lateral ( left ) and AP ( right ) radiographs at the end of gradual distraction with TSF. The fibular head is centered under the end of the femur. The foot position has not changed and the transverse fibular wires remains connected to the foot ring. d Lateral ( left ) and AP ( right ) radiographs showing that the transverse fibular wire was fixed to the proximal ring using a threaded rod and post. This wire was released from the distal ring to allow gradual correction of the equino-varus foot contracture and to bring the talus under the distal fibula. A second computer planning is carried out to generate a new adjustment schedule for the patient. Note that there is no ossification of the proximal fibular epiphysis. Also note the growth lines related to preoperative infusion of zolidronic acid to prevent disuse osteoporosis during distraction. e Intraoperative lateral ( left ) and AP ( right ) radiographs after the surgery to perform a patellar arthroplasty and fibula–talar fusion is completed. Note the hemovac drain can be seen at the knee. The Paley–Weber patellar arthroplasty was performed fixing the proximal fibular epiphysis to the patella with a hooked intramedullary wire secured to the bottom of the frame below the foot. The talus was fused to the distal tibial epiphysis. BMP2 was inserted into a drill hole in the patella and proximal fibula to lead to ossification and fusion of both the patella and fibular epiphysis. A transverse distal fibular wire is arced to the foot ring to apply compression across the fusion site. f Lateral ( left ) and AP ( right ) radiographs showing the patella and proximal fibular epiphysis are ossified and fused together with preservation of the proximal fibula physis. The patella now serves as a tibial plateau. The talus has also fused to the distal fibula but the distal fibular physis has closed. g Clinical photographs, frontal view ( bottom ) and medial view ( top ) showing that the right knee can bend to 90° ( top ). There is active motion present. The other leg was also successfully treated for type 4A tibial hemimelia Weber recommended performing the patellar arthroplasty as the index procedure combined with gradual correction of the remaining knee flexion contracture and foot equino-varus, using a circular external fixator (Ilizarov; Smith&Nephew, London, UK). Weber performed the patellar arthroplasty procedure through a longitudinal anterior incision. Fusion of the patella to the fibula was achieved using chondroplasty by suturing perichondral flaps of the patella and fibula together. A biologic arthroplasty of the ankle was carried out to stabilize the foot. If there is no patella, but the fibula is auto-centralized, then there is usually a quadriceps muscle in continuity to the fibula with a capsule present. The distal femur is usually less dysplastic in these cases. The knee still presents with a fixed flexion contracture and the foot presents as with Paley type 5A tibial hemimelia, i.e. dislocated and in extreme varus and equinus. The treatment is to distract the knee contracture until the fibula and femur are collinear with each other. The foot should also be distracted relative to the fibula to centralize it under the distal end of the fibula. This is again accomplished with a computer-dependent circular external fixator. Once the distraction correction at both the knee and ankle are completed, a second stage surgery is performed to reconstruct collateral ligaments at the knee and to advance the quadriceps muscles onto the fibula. Local tissue or allograft tendon may be used. An ankle fusion as described previously is performed. The after-treatment is with an HKAFO as described above. Fig. 13 a Antero-posterior ( left ) and lateral ( middle ) radiographs of a 12-month-old girl with Paley type 5B unilateral tibial hemimelia. The fibula is hypertrophied and centered on the femur. The foot is in equinovarus. A sagittal section of the magnetic resonance imaging scan ( right ) shows an absent patella, with a quadriceps muscle extending to the fibula. b Lateral radiograph showing a TSF device with six struts applied between the upper fibula and foot to correct the equino-varus foot deformity and to bring the talus under the end of the fibula. An Ilizarov apparatus on the femur connects to the TSF with hinges at the knee joint. A distraction mechanism is in place to correct the knee contracture while permitting removal of this mechanism to allow physical therapy to move and exercise the knee through the hinges. c Standing AP ( left ) and lateral ( right ) radiographs showing the fibula is centralized, hypertrophied and lengthened. A KAFO brace is used to protect the stability of the knee and promote hypertrophy. The talus is fused to the fibula with the foot in a plantigrade position. The distal and proximal fibular physes are both patent If there is no patella and the fibula is dislocated, the fibula can be centralized by distraction, as was done for Paley type 5A tibial hemimelia. An Achilles tendon tenotomy is carried out. Then, two temporary epiphysiodesis wires are inserted up the fibula and hooked over the proximal epiphysis. One wire is also hooked over the distal epiphysis, while the distal end of one of the two axial fibular wires is bent 90° and brought out laterally to be fixed to the foot ring initially and later to be connected to the femoral ring. This is to protect both proximal and distal fibular physes from physiolysis during distraction. Then, one proximal and one distal circular fixator ring is applied with two half pins in the proximal femur (one up the femoral neck and one transverse at the level of the lesser trochanter) and one wire on the proximal ring in the mid-femur. A distal ring on the foot is applied, with three anterior posterior wires in the foot (one from posterior midcalcaneus to the anterior mid-forefoot, one from posteromedial calcaneus to the anterolateral forefoot, and one from the posterolateral calcaneus to the anteromedial forefoot) and one transverse wire across the ossific nucleus of the talus. Six struts are connected between the femoral and the foot ring. The computer-dependent external fixator planning is done relative to the proximal ring for the knee joint contractures. Once the fibula is reduced at the knee and the knee flexion contracture eliminated, the fibular wire is connected to the proximal ring and the computer planning repeated for the distal ring and foot contractures. When both ends of the fibula are aligned to the femur and tibia, the second stage surgery can be performed. This is referred to as the Paley knee reconstruction . Fig. 14 a Preoperative AP ( left ) and lateral ( right ) radiographs of the right leg of a 15-month-old boy born with unilateral tibial hemimelia, Paley type 5C. There is no patella or quadriceps muscle. The knee and ankle have severe contractures. b Lateral ( left ) and AP ( right ) radiographs showing TSF in place with one ring on femur and one on the foot. There is a temporary epiphysiodesis wire in the fibula hooked at both ends. There is a transverse wire through the fibula to transport it distally. c Intraoperative (hemovac seen) lateral ( left ) and AP ( right ) radiographs after complete correction of the knee and ankle and after the second staged surgery to fuse the ankle and to temporarily arthrodese the knee using an axial wire. Tendon transfers were also done to replace the absent quadriceps muscle. d AP standing radiograph following removal of external fixator 3 months later. The axial wire was left in place to protect the knee for 6 more months. There is excellent alignment with significant leg length difference. e Standing lateral ( left ) and AP ( middle , right ) radiographs at age 5 yers, after lengthening of the femur and tibia and after a pelvic osteotomy was done to stabilize the hip. Separate intramedullary wires remain in place to protect the bones from fracture and to guide hypertrophy. A KAFO is used for several years—until the knee becomes stable—to allow knee flexion and extension while protecting varus and valgus bending on the hypertrophying knee joint for several years until the knee becomes stable
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Review
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biomedical
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en
| 0.999997
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28979645
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Between 2012 and 2014, 05 patients with unstable pelvic fractures; were treated by percutaneous sacroiliac fixation. This is 2 women and 3 men; the average age was 38 ± 10 years, all the patients were treated by percutaneous screwing. The initial radiological evaluation consisted of a radiograph of the pelvis and a CT of the pelvis; which allowed the classification of these fractures according to AO Tile modified classification; and all five patients had a fractured pelvis type C. The first patient had a fracture of the anterior column with a fracture of the obturator ring; and left sacroiliac disjunction . The second patient had a pubic disjunction associated with a fracture of the sacral aileron . The third case was suffering from pubic disjunction associated with sacroiliac disjunction . The last two cases had an obturator ring fracture associated with sacroiliac disjunction . In all patients there was a high-energy trauma, and all of these patients had multiple lesions associated; namely a head injury in two patients; an ankle fracture in two patients, a leg fracture in a patient. By cons they had no urological injury or a vascular - nervous. All patients have had surgery by the same surgeon under spinal anesthesia on a fracture table, the pool end of the table; with a pull of both lower limbs as well as calluses fessiers.il must absolutely ensure that nothing interferes with the image intensifier in the implications and Outlet Inlet. We started by reducing the anterior displacement in all patients. The operating time was about 48 hours in all patients except in one case with neglected fracture 10 months. So since the sacrum is oblique at 45°, it is seen from the front on the Outlet incidence; we will guide the drill to avoid the sacred holes; then, the sacrum is seen from above on the Inlet incidence there by guide the drill to the vertebral body and prevent the spinal canal. Two sacro iliac screws 7 mm in diameter in four patients were performed . All patients were put on anticoagulant to resume walking. The rehabilitation was started after surgery with isometric contractions; then passive and active gradually. Putting e Full support is done after the 12 th week. The average hospital stay depends on associated lesions; it averaged 15 days. Mean follow-up was 12 months (8 months -30 months), medium term full loading 9 ± 3 weeks. No secondarily revision surgery was necessary; an additional anterior stabilization was necessary in two patients. We have not encountered infection or nerve damage, or cases of nonunion of the posterior arch; not those of the pubic rami. Apart from the patient with a sacred nonunion; consolidation was not certain. According to the criteria of Matta to reduce pelvic fractures all patients had a satisfactory reduction. They were able to resume all their activities; except the patient with the neglected fracture of the sacrum. Unstable fractures of the pelvic ring injuries are serious, associated with a high rate of morbidity and mortality . Early surgical stabilization showed a reduction in pain, early mobilization of the patient, and in the end ensures good functional recovery in the long term . Conservative treatment does not offer precise reduction and confines the patient to bed with all possible complications . The purpose of this study was to describe the technique of percutaneous sacroiliac screw in unstable pelvic fractures; using conventional fluoroscopy and evaluate the perioperative complications and radiological results. Routt was the first to describe the technique of stabilizing the sacroiliac dislocation in the supine position under fluoroscopy. He demonstrated that it is a reliable and reproducible technique that can significantly reduce complications observed in the open techniques without sacrificing stability. Mears et al. have shown in vitro that mechanically a single screw offers the same biomechanical stability than an intact basin. Yinger K and Van Zwienen CM , in their two comparative studies indicate a high biomechanical stability with double sacroiliac screw in fractures with vertical instability. All patients were treated was using materials commonly available of osteosynthesis with a simple fluoroscopic guidance, probably the crucial element in the placement of screws and obtaining a good reduction of the fracture or joint sacroiliac and then confirming the ideal position of the sacroiliac screw by an X-ray profile intraoperative as she was described by Routt. The disadvantage of the percutaneous technique is that the Direct reduction is impossible. So an anatomic reduction is difficult. The functional outcome was always associated with poor reduction of the posterior arch of the pelvis ( Table 1 ). Postoperative reduction was good to excellent most cases (80%). Similar results were previously published [ 8 – 13 ]. Previous studies report a secondary displacement rate of 3% to 5% and nerve damage from 0 to 8% [ 5 , 8 , 14 – 17 ]. This is consistent with our data, even if the distribution of the severity of fractures identity could not be due to the use of different classification systems. The large share of complications related to the patient, not the technology itself ( Table 2 ). Although various techniques called scanno-guided or navigated insertion systems of computer screws have been described [ 18 – 21 ], the emergency use in the treatment of trauma patients is controversial. Especially with all their time to set up in the context of the emergency . In some studies, the operating time can be reduced by the use of computer-based systems [ 21 – 23 ], others are reporting an increase in time of the procedure . Indeed, the preparation of the configuration for navigation takes extra time. When navigation is based on preoperative CT, potential displacement fracture between scanner and surgery are rare. Clearly, inland systems have the advantage of a fluoroscopic time reduction and will improve the operating time in the future. Although greater accuracy of screw placement was described for the computer-assisted surgery others have found no difference between the system or sailed scanno-guided and conventional placement of screws; or on the occurrence of neurological injury .
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Study
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biomedical
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en
| 0.999997
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29019568
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A 60 years old man previously submitted to gastric sleeve bariatric surgery was admitted to the neurosurgery department of our institution after acute trauma that resulted in fracture of the 7 th cervical vertebra and spinal cord injury with tetraparesia. The patient was operated with fixation of bone lesions but was further admitted to intensive care unit for mechanical ventilatory support. Tracheostomy was performed and a nasogastric tube was passed in order to start enteral feeding. Due to persistent dysphagia he was referred to our artificial feeding team for percutaneous endoscopic gastrostomy. Upper GI endoscopy showed a small tubular stomach, difficult to distend and examine. Abdominal wall transillumitation (diaphanoscopy) was not obtained, preventing a safely percutaneous cannulation of the stomach. The patient underwent surgical laparoscopic gastrostomy a few days later without early complications. At the present, he maintains follow-up in our artificial feeding outpatient clinic with no long-term complications of gastrostomy feeding. Bariatric surgery is more and more used as a major tool on the treatment of severe obesity. Globally, surgical procedures may be classified in one of three groups: restrictive procedures (as the adjustable gastric band or the laparoscopic sleeve gastrectomy), malabsortive procedures (as gastric bypass) or procedures combining both gastric restriction and malabsorption (as the biliopancreatic diversion with duodenal switch) 2 . Although severely obese patients are not considered as a typical candidate to long-term tube feeding, they may develop any of the dysphagia causes that usually lead to gastrostomy. More, these patients frequently present severe vascular disease and are prone to develop stroke episodes, even after bariatric surgery. Growing need for gastrostomy after bariatric surgery is to be expected in the years to come.
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Review
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biomedical
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en
| 0.999996
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29082049
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An enterolith is a mass found in the small or large intestine. False enteroliths are formed from indigestible substances trapped in the intestinal tract such as bezoars, gallstones, or foreign objects, whereas true enteroliths are formed from the precipitation of enteric contents . Formation of true enteroliths is generally caused by bowel stasis due to strictures or diverticula, followed by precipitation of inorganic substances or bile acids. Such precipitation of materials contained in intestinal juice is thought to be facilitated by an acid-base imbalance and bacterial overgrowth [ 3 – 8 ]. Most cases with enteroliths were asymptomatic and did not require specific treatment. In symptomatic cases with impacted enteroliths causing ileus or inflammation, endoscopic treatment such as dilation for the stricture of the bowel and fragmentation will be attempted in some cases . If the enterolith is inaccessible via endoscopy devices or refractory for endoscopic treatment, surgical treatment is generally inevitable since enteroliths are unresponsive to medical treatment and successful chemical dissolution of enteroliths has never been reported. A 26-year-old Japanese woman presented with abdominal pain, fever, and watery diarrhea. The patient was diagnosed as having Turner syndrome at the age of six years and had been treated for Crohn's disease since the age of 18 years. She underwent left hemicolectomy at the age of 20 years due to complete obstruction of the descending colon. Adalimumab was administered previously, but it was discontinued due to hair loss as a side effect of the drug. The patient had been treated with 10 mg/day of prednisone on admission. A colonoscopy performed 15 months prior to her admission revealed ulceration and stenosis of the cecum ( Figure 1(a) ). A mass that appeared to be feces was observed in the semi-closed lumen in the cecum ( Figure 1(b) ). Ulceration was also observed in the anastomotic site ( Figure 1(c) ). She had a bowel movement once every day. On admission, computed tomography scanning demonstrated a calcified mass that was impacted in the cecum ( Figure 1(d) ) and fecalomas within the appendix ( Figure 1(e) ). Laboratory testing revealed slightly elevated levels of C-reactive protein (0.36 mg/dL), whereas the white blood cell count was within the normal ranges . An ileocecal resection was performed under the diagnosis of impacted cecal enterolith. Although appendiceal wall thickening was not noted, infiltration of neutrophils within the mucosa and lymphocytes and eosinophils within the subserosa and adipose tissue were confirmed microscopically. Thus, the final diagnosis of an enterolith impacted in the cecum and acute appendicitis was made. Her abdominal pain, fever, and diarrhea disappeared after the surgery. Since inflammation was pathologically noted in the appendix, we speculate that the impacted cecal enterolith induced appendicitis. Figure 2 shows the surgically removed enterolith of 3 × 2 cm in size ( Figure 2(a) ). Multiple-layered structures were seen in the cut surface, resembling annual rings of a tree ( Figure 2(b) ). The enterolith was cut into four pieces, and one piece was used in an infrared spectroscopy analysis. Infrared spectroscopy revealed that the enterolith was mainly composed of two components: fatty acid calcium and magnesium phosphate. Two enterolith pieces were placed in cell strainers with 40 μ m pores (Corning Inc., Corning, NY, USA). The cell strainers were set in 50 mL conical polystyrene tubes. A citric acid solution was prepared by dissolving citric acid powder for food additives (Kenei Pharmaceutical Co., Osaka, Japan) in double-distilled water. One piece ( Figure 3(a) ) was completely immersed in double-distilled water, and the other ( Figure 3(b) ) was immersed in a 2% citric acid solution. After 120 hours of immersion at room temperature (25°C) without stirring, the enterolith pieces were removed from the cell strainers and air dried for 30 minutes. The color of the enterolith piece immersed in citric acid solution turned black in color and appeared to have shrunken ( Figure 3(d) ), compared with the piece immersed in water ( Figure 3(c) ). The percentage of lysis was calculated by comparing the weight of preimmersion with that of postimmersion. The weight was 1.717 g at preimmersion and 0.842 g at postimmersion in double-distilled water, indicating a 51.0% decrease in weight. Meanwhile, the weight changed from 1.330 g to 0.440 g after immersing in 2% citric acid solution, indicating a 66.9% decrease in weight. Subsequently, we investigated the microstructure and elemental composition of the enterolith samples immersed in water and of those in the citric acid solution. We used S4800 scanning electron microscopy (Hitachi, Tokyo, Japan) and an EDAX Genesis APEX2 system (Ametek, Paoli, PA, USA). Elemental mapping of iron was also performed with S4800 scanning electron microscopy and EDAX Genesis APEX2 energy-dispersive X-ray spectroscopy. Scanning electron microscopy analysis of the enterolith piece immersed in water revealed a multilayered structure ( Figure 4(a) ), which was partly composed of crystalloid microparticles ( Figure 4(b) ). In the enterolith piece immersed in citric acid solution, crystalloid microparticles were absent (Figures 4(c) and 4(d) ). Elemental mapping revealed that the enterolith piece immersed in water contained calcium ( Figure 5(a) ), magnesium ( Figure 5(b) ), and phosphate ( Figure 5(c) ). It was noteworthy that the magnesium and phosphate were deposited in approximately the same areas, whereas the calcium was deposited in different areas from magnesium and phosphate. A photograph merged with scanning electron microscopy image ( Figure 5(d) ) and mapping images of calcium and magnesium clearly showed that the enterolith piece was composed of two kinds of layers ( Figure 5(e) ). Spectra obtained with energy-dispersive X-ray spectroscopy showed that calcium, magnesium, and phosphate existed in the enterolith piece immersed in water ( Figure 6(a) ), whereas the amount of these elements was decreased in the piece immersed in citric acid solution ( Figure 6(b) ). This report focused on the microstructure and dissolution of an enterolith removed from a patient with Crohn's disease. True enteroliths are mainly subdivided into two types: bile acid enteroliths and calcified enteroliths . Primary bile acids (i.e., cholic acid and chenodeoxycholic acid) are metabolized into secondary bile acids (i.e., deoxycholic acid and lithocholic acid) by anaerobic bacteria. These bile acids are relatively insoluble in the acidic milieu, leading to the formation of bile acid enteroliths in the proximal small bowel [ 7 , 11 – 13 ]. Meanwhile, calcified enteroliths are reportedly composed of calcium phosphate, calcium oxalate, and calcium carbonate. These salts are insoluble in alkaline environments and thus can precipitate and form calcified enteroliths most often in the terminal ileum . As described previously, precipitation of substances is generally induced by bowel stasis followed by acid-base imbalance and bacterial overgrowth. Diverticular disease of the bowel is the most common etiology to lead enterolith formation, followed by stricture and narrowing of the intestine because of tuberculosis or Crohn's disease and postsurgical alteration of the alimentary tract . The presented patient had a calcified enterolith in the cecum where stricture existed due to Crohn's disease. These features are in concordance with findings reported in earlier reports. In the present patient, the enterolith showed a multiple-layered structure, resembling annual rings of a tree . Infrared spectroscopy analysis showed that the enterolith was mainly composed of fatty acid calcium and magnesium phosphate. Moreover, scanning electron microscopy observation of the enterolith piece immersed in water revealed that calcium-containing layers and magnesium phosphate-containing layers constitute the multilayered structure of the enterolith . Consequently, we speculate that the enterolith gradually increased diameter because of deposition of fatty acid calcium and magnesium phosphate in an alternating manner. To our knowledge, this report is the first to investigate the in vitro dissolubility of calcified enteroliths induced by citric acid solution. The weight of the enterolith piece immersed in double-distilled water for 120 h showed a 51.0% decrease. We speculate that evaporation of water from the enterolith by air-drying is the main cause of the weight change, although some amount of substances might have been liquated from the cut surface into water. Meanwhile, the enterolith piece immersed in the 2% citric acid solution showed a 66.9% decrease in weight. Energy-dispersive X-ray spectroscopy revealed that the amount of calcium, magnesium, and phosphate was lower in the enterolith piece immersed in the citric acid solution, compared with that in water. These results suggest that calcium, magnesium, and phosphate were eluted by the citric acid solution. Moreover, based on the results obtained using energy-dispersive X-ray spectroscopy, we consider that crystalloid microparticles in the enterolith piece immersed in water ( Figure 4(b) ) were inorganic substances such as calcium, magnesium, and phosphate. As described above, calcified enteroliths are considered to be formed in alkaline environments. An in vivo equine study revealed that horses with enteroliths had higher calcium, magnesium, phosphorus, and sulfur concentrations and higher pH in colonic contents than control horses . Conversely, calcified enteroliths may partly dissolve in lower pH, as shown in the present study. We also speculate that the residue that remained after immersion in the citric acid solution ( Figure 3(d) ) was organic substances, since the enterolith piece contained fatty acid and a higher amount of carbon was detected ( Figure 6(b) ). This study has several limitations. First, because of the small size of the removed enterolith, only two pieces were used in the dissolution experiment. Therefore, statistical analysis was inapplicable to compare weight changes between the enterolith piece immersed in double-distilled water and that in citric acid solution. Second, the composition of calcified enteroliths is probably diverse in each patient , so an acidic aqueous solution may not be useful in dissolving all calcified enteroliths. Lastly, because we examined dissolubility of enteroliths in vitro, further study is required prior to the introduction of a citric acid solution into clinical practice. For example, although a citric acid solution can be ingested in patients without intestinal obstruction, the degree of acidity or alkalinity will be altered under the influence of digestive juices such as gastric acid, bile acid, and a mucus-rich, bicarbonate-containing, alkaline juice produced by Brunner's glands. A possible approach is infusing acidic solution into the diseased bowel via an ileus tube or endoscopy. Investigations with regard to the utility and safety of a citric acid solution for the treatment of enteroliths in clinical settings are required as well.
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Review
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biomedical
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en
| 0.999996
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29185625
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In November 2015, a 5kg female infant (36-week preterm) was admitted to the hospital due to status epilepticus and fever. Diazepam, phenytoin and ceftriaxone were prescribed. Cerebrospinal fluid contained 7 leukocytes, 150 mg/dL proteins, 1 mg/dL glucose, and gram positive cocci were observed. Cranial tomography suggested hypodense signs in the cerebellum, right temporal lobe and left basal nuclei, which was consistent with pneumococcal meningitis-induced infectious vasculitis. Other relevant medical history included HIV vertical exposure (4 sequential undetectable viral loads during follow-up). On December 15 th , warfarin 0.2 mg/kg/day was bridged with LMWH and adjusted according to INR . From Day 21-23, she received 0.3 mg/kg of warfarin, but INR remained unchanged. On day 24, she was allowed to eat (supplements, as per dietician’s prescriptions) and receive medications per oral route, when INR started to increase until therapeutic levels. From day 27-30 she received 0.7 mg/kg of warfarin and was discharged with INR=2.3, after clinical pharmacist’s education session. In summary, about 10 days were required to achieve therapeutic INR, and warfarin was adjusted five times, since initial dosing. In regards to drug-drug interaction, phenobarbital could have contributed with the highest warfarin dose ever reported, since it is known the drug interaction on CYP as enzyme inhibitor mechanisms. 3 Paradoxically, the use of corticosteroids could contribute to lower warfarin dose requirements to achieve therapeutic INR levels, as previously seen in patients with CYP2C9 polymorphisms. 7 However, in the present case, the use of prednisone and dose tapering strategy did not significantly affect INR and warfarin dose changes . Administering warfarin through enteral tubes has been associated with higher warfarin doses (0.28 mg/kg) in comparison 3 to children who are not on enteral feeding (0.16 mg/kg). In the present case, INR achieved therapeutic levels after removal of the enteral tube (day 24). It is noteworthy that, before day 23, a speech pathologist was consulted to verify the possibility to progress from enteral tube to oral diet, which consisted in supplement-based nutrition as per dietician’s prescription (breastfeeding was not allowed due to the HIV vertical transmission). In this case, the child received oral stimulation interventions and the risk of aspiration was excluded, before initiating oral nutrition. Notably, controls (thrombin time) were always the same during hospital stay (12.2s), and patient was not eligible for coagulopathy investigation, as infectious vasculitis was the primary cause of thrombosis. Additionally, this patient could be a candidate for VKORC1 and CYP2C9 polymorphisms assessments, as they are associated with different warfarin dosing requirements. 6 However, such exam is not routinely made in our institution and more studies are required in children. 6 , 8 It is worth noting that VKORC and CYP2C9 gene polymorphism screening have been issued as an essential laboratory test before initiating warfarin. 9 , 10 While the clinical value of such exam has been associated with improved safety, 9 , 10 the cost-effectiveness 11 of universal testing of patients initiating vitamin K antagonists still is to be determined, especially in public health systems. A randomized trial 11 of routine VKORC and CYP2C9 polymorphism testing will also analyze how cost-effective is such technology in Brazil, in order to assess the priority of such pharmacogenetics information.
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Other
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biomedical
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en
| 0.999998
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29225831
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Pacemaker lead perforation is a rare but serious and potentially life‐threatening complication of pacemaker implantation, ranging from 0.1% to 0.8% 1 . Lead perforations are recognized mostly during or shortly after implantation, subacute and late perforations are less frequent, and atrial lead is more concerned. We report here a case of delayed right ventricular perforation complicated by a tamponade in a patient with hypertrophic cardiomyopathy that we successfully managed by closed intervention without exposing the patient to surgery. Three days later, she presented with sudden onset of shortness of breath. Echocardiography showed massive pericardial effusion, with impending subsequent tamponade. An emergent bedside ultrasound‐guided pericardiocentesis was performed successfully using a subxiphoid approach. We decided to manage the patient conservatively. The ventricular lead was extracted and repositioned in the RV septum. Postprocedure echocardiogram confirmed no increase of the thin layer of pericardial effusion. No symptoms of tamponade were observed during or after the procedure in 6 months of follow‐up. Patients with late lead perforation might have a variety of presenting symptoms 2 , 3 . In our case, the initial presentation with chest pain and minimal pericardial effusion were disconcerting. Postimplantation pericardial effusion can be caused by a traumatic inflammation of the myocardium or irritation of the visceral pericardium via immune‐mediated mechanisms, but it can result from a lead perforation especially in the presence of risk factors such as age, female sex, and concomitant therapies such as anticoagulant or antiplatelet medication 4 . Patients developing postoperative pericarditis should be followed closely due to the risk of cardiac tamponade 5 . Late RV perforation is a rare but serious complication of PPM implantation. It may be completely asymptomatic or life‐threatening. Hypertrophic myocardium seems to be not absolutely protective. Postimplantation pericardial effusion should be followed closely due to the risk of cardiac tamponade. According to our case, this fatal complication can be successfully managed by closed pericardiocentesis and the RV lead repositioning, but careful hemodynamic and echocardiographic monitoring is necessary because of the risk of delayed retamponade as the site of perforation may not be fully closed.
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Clinical case
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clinical
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en
| 0.999996
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29409458
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Metastatic cancer in the thyroid is uncommon and accounts for about 1.4–3% of malignant solid tumours [ 1 – 6 ]. The most frequent primary cancers are renal cell (48.1%), colorectal (10.4%), lung (8.3%) and breast (7.8%) cancers, and soft tissue sarcoma (4.0%) . Large series reported also lymphoma as primary cancer or metastases from lung cancer other than usual epithelial thyroid cancers . Also parotid cancer and melanoma have been reported as primary cancers . Formerly, metastases to the thyroid were usually identified at autopsy . Thanks to the advent of more accurate diagnostic methods, it is now possible to clinically diagnose metastases to the thyroid, and initiate timely surgical and systemic treatment thereby improving outcome . We report the case of a 64-year-old woman who was diagnosed with left breast cancer in June 2011. The comorbidities were multinodular goitre of the thyroid gland, obstructive pulmonary disease (i.e. emphysema), left atrial enlargement with severe pulmonary hypertension, carotid stenosis (60–65%) and severe obesity. Clinical staging by chest X-ray, abdominal ultrasound and bone scan was negative, except for CEA = 10.7 (normal value < 5). The patient underwent wide excision of the breast lesion with axillary node dissection. Histology revealed a G2 invasive lobular carcinoma with lymph node metastasis, stage pT1cN3 (21/24 nodes), with positive staining for oestrogen receptor (ER 90%) and progesterone receptor (PgR 80%), a very low proliferation index (Ki67 < 10%), and without amplification of HER2-neu, suggesting a luminal A phenotype. Adjuvant chemotherapy with docetaxel and cyclofosfamide was administered, followed by endocrine therapy with aromatase inhibitor. At the first follow-up, clinical examination showed enlarged thyroid lobes with a multinodular structure; a thyroid function test was normal. Ultrasound revealed an enlarged thyroid with retrosternal development; the glandular structure was finely inhomogeneous in the right lobe, and the entire left lobe was occupied by a large nodule that had a mixed echo-pattern and areas of cystic and colloid degeneration and calcifications. Fine needle cytology was performed with a 23-G needle without suction. Smears taken from both lobes were Diff-Quik-stained and evaluated on-site. Cellularity was deemed to be satisfactory, and additional smears were taken and alcohol-fixed for Papanicolaou stain and for ancillary techniques. The right lobe smear was moderately cellular and showed only colloid and benign thyrocytes. Conversely, the left lobe smears revealed a second cellular population in a colloidal background mixed with small groups of benign thyrocytes . This second population was constituted by small cells, dispersed or aggregated into small, loosely formed groups; individual cells had a plasmacytoid-like aspect and occasionally a secretion vacuole. Given the patient’s history, we decided to use two smears fixed in alcohol to evaluate oestrogen receptor expression in the second cell population. Immunocytochemistry revealed positive oestrogen receptor staining , which suggested a diagnosis of metastases of the breast cancer to the thyroid. Positron emission tomography and total body tomography did not reveal other metastatic sites, and showed only enlargement of the left thyroid lobe and an inhomogeneous pattern of colloid and cystic degeneration and calcifications. Therefore, the patient underwent left hemithyroidectomy in February 2012. Histology revealed thyroid tissue with a colloid goitre containing dispersed neoplastic cells constituted by small atypical cells with eccentric nuclei . Immunohistochemistry revealed cytokeratin-19 and oestrogen receptor , but not tireoglobulin, e-cadherin or cytokeratin-7, thereby suggesting metastases from a lobular breast carcinoma. Thirty-two months after hemithyroidectomy, the patient is alive, although in May 2014, there was evidence of recurrence in bone. Hormonal treatment with fulvestrant is ongoing. She died in July 2015. Fig. 1 a Cytology of thyroid metastases and plasmacytoid-like aspect (inset). b Immunocytochemistry with positive estrogen receptor staining. c Histology of thyroid metastases Fig. 2 Immunohistochemistry showing cytokeratin 19 ( a ) and estrogen receptor ( b ) We searched PubMed to identify studies about metastases to thyroid from different primary tumours, including breast cancer. Searches were made using the terms ‘breast cancer’ and ‘metastases to thyroid’, with no limitation of language, publication date, or journal of publication. Eighteen articles were eligible according to our criteria; these were published between 1962 and 2012. Given the rarity of metastases to the thyroid and the limited number of reported cases, we performed only a descriptive analysis. Metastases to the thyroid gland are rare, but not as rare as previously thought. This is not surprising because the thyroid gland is the second most richly arterialized organ in the body. The probability of finding metastases in the thyroid gland depends on the method of investigation . Large autopsy studies found that the incidence of thyroid metastases in patients with a history of cancer ranges from 1.9% to 24% . Two of these studies suggested that thyroid metastases are more common than primary thyroid cancer . On the other hand, the incidence of thyroid metastases in clinical and surgical series was 3% . Reports of thyroid metastases have increased in recent years consequent to more sophisticated diagnostic methods, i.e. fine needle cytology and proton emission tomography with 18F–fluorodeoxyglucose . The characteristics of breast cancer patients with thyroid metastases are reported in Table 1 . We analyzed sex, age at diagnosis, histology, primary treatment, treatment failure, time between primary diagnosis and thyroid metastases and follow-up in 42 women with thyroid metastases from breast cancer reported between 1962 and 2012 [ 1 – 20 ]. The development of metastases of the thyroid gland does not appear to be age-dependent, and seems to be more frequent in women . The median age at diagnosis of metastases to the thyroid gland is 51 years (range: 22–83 years) . Time-to-detection and time from presentation to death differ among reports. The former ranges from 2 months to more than 15 years after the diagnosis of the primary cancer , and the latter from 1 to 34 months . In one case, thyroid metastases were synchronous to primary breast cancer . Table 1 Characteristics of breast cancer patients with metastases to thyroid in a clinical series Authors Study yrs No of pts Sex Age Histology Primary treatment Treatment failure Local Distant Time between BC diagnosis and thyroid metastasis Follow-up Shimaoka K et al. 1962 1955 1 F 44 carcinoma CT no LN, bone, liver, skin, CNS 5 yrs 4 months Wychulis AR et al., 1964 1907–1962 3 F 38 adenocarcinoma S no lung, bone 13 yrs 4 yrs. died of the disease F 51 adenocarcinoma S + RT Yes NR 3 yrs 5 months lost to FU F 51 adenocarcinoma S + RT NR NR Synchronous (0 months) 1 yr. lost to FU Harcourt-Webster JN, 1965 2 F 56 adenocarcinoma S no liver, bone F 50 adenocarcinoma S Pillay SP et al., 1977 1974–1976 2 F 58 adenocarcinoma no yes F 58 Nakhjavani MK et al. 1997 1985–1994 7 F 67 adenocarcinoma NR NR NR from 2 months to 22 yrs 3 patients < 3 months 4 pts. 3–23 months Chung SY et al., 2001 1995–2000 6 F 49 NR No lung, bone F 61 lung F 51 lung, bone, liver F 32 lung, liver F F 22 33 bone, peritoneum lung De Ridder M et al. 2003 1982–2002 1 NR HT No no 0 months Died after 2 years for disseminated disease Loo CK, Burchett IJ, 2003 1 F 52 neuroendocrine carcinoma HT No bone 8 yrs Wood K et al., 2004 1985–2002 1 F 72 adenocarcinoma No no 15 yrs 36 months alive Owens CL et al., 2005 2005 1 F 64 NR No shoulder subcutaneous nodule, liver 5 yrs Kim TY et al. 2005 1997–2003 5 F 36 ductal CT No Neck LN, lung 18 months 6 months alive F 34 ductal CT lung, ax LN, scal 25 months 17 months alive F 44 ductal CT Nil 37 months 4 months alive F 55 ductal CT lung, ax LN, neck 68 months 26 months alive F 45 ductal CT Neck LN, lung, bone 85 months 8 months alive Gerges AS et al. 2006 1989–2004 1 F 45 ductal S + CT + RT No bone 63 months 37 months alive post-thyroidectomy Cichon A et al., 2006 1984–2003 1 F 50 S No no 10 yrs 24 months alive Molina Garrido MJ et al., 2006 2005 1 F 43 NR mastectomy, lymphadenectomy CT + RT No lung, liver 30 months 1 month Papi G et al., 2007 1993–2003 5 F ductal No no 5 yrs. 1 alive F NR F NR F NR F NR Calzolari F et al., 2008 1995–2005 1 F NR No no 60 months died of the r disease Saber A et al. 2007 NR 1 F NR S + CT NR no 60 (range: 13–135 months) Egaña N et al., 2012 2007 1 F 83 NR mastectomy, lymphadenectomy HT No bone, liver and pelvic mass 3 yrs 1 month Current report 2011 1 F 64 ILC S + CT + RT No bone 6 months 18 months alive F female, CT chemotherapy, FU follow-up, LN nodes, yrs. years, HT hormonal treatment, S surgery, RT radiotherapy, NR not reported, ILC infiltrating lobular carcinoma, CNS Central Nervous System As shown in Table 1 , the clinical presentation of thyroid metastases is very heterogeneous. They are clinically evident only in a minority of patients and are frequently found incidentally during postoperative follow-up by ultrasonography. Thyroid metastases usually present in the context of widespread metastatic disease, and manifestations in the thyroid are not clinically significant. On the other hand, when thyroid metastases are the first presentation of recurrent disease, they usually appear as a palpable neck mass or, albeit less often, with dysphagia, massive tracheal involvement or dysphonia. Often, patient presented with painless neck mass . In the reports containing histological information, breast cancer is generically referred to as “adenocarcinoma” . Where indicated, the most prevalent breast cancer is ductal infiltrating carcinoma , reported in seven cases, while invasive lobular carcinoma was reported in only our case and in a case described by Egana et al. . Not all the studies reviewed reported the site of recurrence. In six cases. The thyroid was the first and only site of recurrence [ 2 – 4 , 6 , 13 ]. As shown in Table 1 , other sites of widespread disease were lung, liver and bone. In eleven cases, breast cancers recurred in different sites, but the metastatic site other than thyroid was not reported . When papillary and follicular carcinomas have a complex pathological pattern, cytology alone cannot reveal the origin of the metastatic tumour. The diagnosis is particularly difficult in case of less common primary thyroid cancers such as small cell, giant cell and spindle cell carcinomas, anaplastic cancer and the clear cell variant of follicular carcinoma. Therefore, biopsy is needed to reach a definitive diagnosis. In all the series reported so far, the diagnosis was confirmed cytologically and histologically . Regarding the cytological differential diagnosis, a non-cohesive cell population and a plasmacytoid-like aspect can mimic a medullary carcinoma of the thyroid. In medullary carcinoma, cytological smears are usually more cellular in a background without colloid, and frequently contain amorphous material consistent with amyloid. Tumour cells are predominantly isolated, but clusters and rosettes may also be seen. Cells have a plasmocytoid appearance and are uniform in size and shape with moderate or abundant, finely granular cytoplasm and eccentrically placed nuclei. Many smears show large cells with nuclear megaly, and bi-nucleated and multinucleated cells. These aspects were not observed in our patient. Indeed, in our case, the history of breast cancer, the absence of typical findings of papillary or follicular carcinoma, positive staining of oestrogen and progesterone receptors, negative staining of both thyroglobin and calcitonin, and the histological pattern of the primary and metastatic tumour enabled us to establish a diagnosis of metastases from thyroid. In particular, the following immunocytochemical markers were analyzed: cytokeratin 7, cytokeratin 19, E-cadherin, CD34, besides estrogen and progesterone receptors. The treatment of thyroid metastases depends on the site of the primary tumour, presence of other metastases and symptoms caused by the thyroid mass. Surgery is considered the gold standard treatment for thyroid metastases. Radical treatment of an isolated metastasis to the thyroid can be curative, and an aggressive surgical approach has been recommended especially in case of slow growing tumours such as breast or kidney carcinomas . The extension of surgical resection does not seem to significantly impact on survival. In fact, no significant differences in survival were found between total thyroidectomy and conservative surgery . Surgical treatment of isolated metastasis may prolong survival . However, more data are necessary regarding the best surgical approach in patients with a single thyroid metastasis . Reports of thyroid metastases span over more than four decades. It is not feasible to make a global evaluation of the outcome of patients because of the heterogeneity of treatments and some systemic therapies that have become obsolete. However, numerous case reports suggest that metastases to the thyroid gland are associated with a poor prognosis . Multifocal metastases seem to adversely affect prognosis. Indeed, a significantly worst survival has been reported in patients with multiple foci. Survival after surgical treatment is variable with some patients succumbing to metastatic disease within a few months, while others have a long-term survival. Data on prognosis cannot be extrapolated also in view of the many advances made in systemic treatment and in the identification of distinctive biological features of breast cancer from the first published case in 1962 until now. In particular, the introduction of taxanes as well as targeted therapies, such as trastuzumab and pertuzumab for HER2-positive tumours and bevacizumab for HER2-negative tumours, which have had an enormous positive effect on outcome. There are no case reports that describe the type of systemic treatment used, and patients were often treated with surgery, so that outcomes cannot be extrapolated to define the prognosis of breast cancer with metastases to the thyroid gland. In this review and case report we examine aspects of breast cancer metastases to the thyroid going from the diagnostic workup to the treatment. Metastases to the thyroid gland can present many years after treatment of a distant primary tumour; however, in a patient with a history of malignancy, a neoplastic thyroid nodule is more likely to be a metastasis than a new thyroid malignancy. Fine-needle aspiration biopsy of the thyroid gland should be performed in patients with breast cancer and a nodular goitre, even in the absence of clinical signs of metastatic disease. Biological features are important for treatment decision-making. Given the availability of targeted biological therapies, i.e. transtuzumab, pertuzumab and bevacizumab, that modify the natural history of metastatic breast cancer, it is no longer the time to disregard the thyroid metastases from breast cancer and other primary malignancies. The history of our patient suggested thyroid goitre and showed no clinical feature suggestive of metastasis. Our case report highlights that metastases, also such an unusual site as the thyroid, should be considered in patients diagnosed with breast cancer. Studies dealing with thyroid metastases are very heterogeneous in terms of the primary cancer, which makes it difficult to evaluate the impact of thyroid metastases on prognosis. Most patients with thyroid metastases have widespread metastatic disease but occasionally the thyroid may be the only site of disease. Although therapy of metastatic malignancies is often considered to be palliative, aggressive surgical treatment in isolated cases may be curative and may benefit survival. This highlights the importance of early recognition and management of thyroid metastases in prolonging survival in some patients and in preventing the onset of life-threatening complications.
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Review
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biomedical
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en
| 0.999997
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29416795
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A rare but well-recognized variant, gliosarcoma comprises approximately 2% of all cases of glioblastoma (GBM) and has a poorer prognosis . It is characterized by a biphasic appearance of mesenchymal or rhabdoid components on a background of the poorly differentiated astrocytic cells classically observed in GBM. Secondary gliosarcoma development is usually within the context of post-treatment GBM, although development from low grade glioma has been reported. Microdissection studies provide evidence that both the sarcomatous and classical components of gliosarcoma arise from a common cell of origin, which exhibits similar genetic alterations to GBM . However, gliosarcoma is less frequently associated with EGFR amplification and rarely exhibits IDH mutations. While TP53 mutations are more common [ 4 – 7 ], varying characterization methods and under-sampling make it difficult to compare reported mutation rates with larger cohorts such as TCGA, which contains few gliosarcoma samples. Given their usual occurrence outside the context of IDH1/2 mutations, the oncogenic role of TP53 mutations in gliosarcoma and primary GBM may be different than in IDH-mutant lower grade glioma and secondary glioblastoma. Examination of TCGA whole exome sequencing (WES) data collected on low grade glioma and primary GBM reveals that missense mutations at codon 273 were detected in 29% of samples, compared to only 6% of p53-mutant GBM samples. Moreover, the same missense mutations were completely absent in a recent series of 25 gliosarcomas profiled by WES . These differences may reflect the finding that missense mutations in various regions of the p53 DNA-binding domain (DBD) have different effects. For example, R248 and R273 make contact with DNA targets, while R175, G245, R249 and R282 control the conformation and therefore specificity of the DNA-binding surface . In epithelial cancers, TP53 mutations have been linked to the epithelial-to-mesenchymal transition (EMT), which is associated with acquisition of spindle cell morphology, vimentin expression, and nuclear expression of TWIST1 and SNAI2 . Many of these changes have been observed in the sarcomatous component of gliosarcomas, suggesting that EMT in carcinomas and sarcomatoid change in GBM may share common mechanisms. TP53 DBD mutations, in particular those affecting R175 and R248, have been implicated in EMT. These missense mutations appear not only to abrogate the tumor suppressor functions of wildtype p53, but also initiate aberrant binding with non-traditional transcription factors, oncoproteins, and gene regulatory regions important in EMT [ 10 – 12 ]. Here, in a detailed comparative analysis of bulk DNA and gliomaspheres isolated from an IDH-wildtype GBM and its post-treatment recurrence as a secondary gliosarcoma, we identify two p53 DBD missense mutations as drivers of sarcomatoid change in GBM. Leveraging matched pre- and post-treatment derived gliomasphere cultures, we also explored whether an analysis of temozomide-induced variants, ex vivo , would provide useful predictive information about the evolutionary in vivo trajectory exhibited by the tumor. A 57-year-old female patient was diagnosed with a 5 × 6 cm right temporal primary glioblastoma and underwent gross total resection . Histopathological analysis of the primary tumor (GBM1) demonstrated features of necrosis and microvascular proliferation consistent with glioblastoma. Staining for IDH1 R132H was negative and nuclear ATRX was intact. The Mib-1 proliferation index was 40%. p53 staining was positive in 5% of tumor cells. EGFR CISH staining revealed >20 copies of the gene per tumor cell . MGMT promoter methylation was negative by pyrosequencing, and 1p19q codeletion was not detected on FISH. Following a gross total resection of her primary tumor, the patient was treated with the Stupp regimen and remained clinically stable for 20 weeks. She completed cycle 1 of adjuvant TMZ on post-operative day (POD) 98 and cycle 2 on POD 130. At the 20-week follow-up MRI, mildly increased smooth enhancement of the periphery of the surgical cavity was noted, which was associated with slightly increased perfusion and permeability parameters, but no enhancing nodularity . Over the subsequent 6 weeks, the patient experienced a decline in her neurological condition. Repeat imaging demonstrated massive expansion of the thin rim of enhancement, filling in the surgical cavity. She underwent re-resection via right temporal craniotomy and recovered well. In contrast to the primary specimen, the recurrent tumor (SGS1) demonstrated a biphasic appearance of regions predominated by spindle cells with eosinophilic cytoplasm in a collagenous stroma, and other regions harboring the previously identified features of GBM . Tumor cells demonstrated patchy positivity for GFAP with strong reticulin staining in GFAP negative areas. The Mib-1 index was 40%. p53 staining was positive in 30% of tumor cells. EGFR CISH staining indicated the absence of amplification. MGMT promoter methylation was again negative by pyrosequencing. To elucidate the phylogenetic relationship between GBM1 and SGS1, we undertook Ion PGM targeted DNA sequencing of a panel of 150 genes (Oncomine Comprehensive Panel v2) known to contain mutational hotspots prevalent in the most common cancers. We analyzed the patient's germline DNA; bulk primary tumor in two sectors and corresponding derived gliomaspheres (sector A bulk tissue contained <10% tumor cells and did not produce gliomaspheres); and bulk recurrent tumor in three sectors and corresponding derived gliomaspheres and attached cultures grown in serum-containing medium (2D). By considering shared and private mutations, and changes in variant allele frequencies (VAFs) between samples, a phylogenetic tree was constructed . Alterations common to both tumors included CDKN2A loss, PTEN copy loss, EGFR G719D mutation, and a frameshift insertion in the remaining copy of PTEN at D153. Only the primary tumor and its derived gliomaspheres exhibited EGFR and MDM4 amplification. All bulk, gliomasphere, and 2D culture DNA from all three sectors of the recurrent tumor exhibited two TP53 missense mutations: TP53 R110C (c.328 C>T) and TP53 R175H (c.524 G>A). Whole transcriptome sequencing of all bulk and cultured specimens revealed additional variants in MOCOS , CCDC77 , ZBED6 , and MTFMT , and LAMA3 that were common to all the SGS1 samples, and which are predicted to be deleterious according to functional impact score . Few if any of these variants, however, have been reported in other cancers, making their possible role as drivers of SGS pathogenesis less likely than the two TP53 variants identified. Further analysis of the VAFs of the two TP53 missense in each of the three gliomasphere cultures derived from SGS1 revealed a reciprocal relationship with the VAFs always totaling 1.00, suggesting their presence in distinct clonal populations (Table 1 ). We plated SGS1 sector B gliomasphere cells as single cells and performed Sanger sequencing for both mutations on each of the resulting colonies after 6 weeks of growth. We were able to isolate 3 colonies out of a total of 30 sequenced that exhibited only the R175H mutation (the remaining 27 each exhibited both mutations), confirming the existence of these two TP53 missense mutations in distinct subclones . Taken together, our phylogenetic analysis suggests that GBM subclones with amplification of EGFR and MDM4 were eliminated by surgery and RT/TMZ treatment, while a population of tumor cells without the amplification remained viable. These surviving cells harboring TP53 missense mutations either were present in the primary tumor in rare numbers and survived treatment, or were an ancestral clone that acquired two distinct TP53 missense mutations as independent events in separate cells during treatment. By considering their proportions in each of the sectors of the bulk recurrent tumor and the early passage cultures (R175H:R110C ~2:1 in A and C, ~3:1 in B), we can infer that each subclone began expanding within a time interval of less than 2 cell doublings of each other, assuming constant doubling rates. We identified additional cases of both primary (PGS1 and PGS2) and secondary gliosarcoma (SGS2 and SGS3) with a matching primary GBM (GBM2 and GBM3, respectively) from the neuropathology archives. TP53 DBD missense mutations were identified in all specimens. Most were conformation mutations (G245S, G245V, R175H) but 1 contact mutation (R273H) and the unclassified mutations G244A, H233del, E286K, P75S and P72R were also identified. Interestingly, 3 of the 4 cases harbored two distinct TP53 mutations each, similar to our main subject. In the fourth case, PGS1, three mutations were all found at VAFs greater than 0.05 (Table 2 ). With robust gliomasphere cultures derived from both GBM1 and SGS1, we next quantified the population doubling rate of each culture over 70 days . The doubling time of GBM1 cells was 2.41 days (95% CI 2.34-2.49) compared to 2.24 days (95% CI 2.22-2.26) for SGS1. Volumetric analysis of the burden of contrast-enhancing disease on POD 188 after initial resection revealed a total tumor volume of 43 cm 3 . Assuming an estimated average cell size of 2000 μm 3 and tumor content of 50%, the numbers of R175H and R110C subclones at this time point were 6.7 × 10 9 and 3.3 × 10 9 , respectively. This placed the time point at which the subclones began doubling between POD 114 and 118, which was between the first and second adjuvant cycles of TMZ. These calculations are consistent with the finding of minimal smooth peripheral enhancement of the surgical cavity seen on the POD 141 MRI. Our targeted sequencing panel did not detect either the R175H or R110C mutations within the primary tumor at a sequencing depth of 2000X. To determine whether the sensitivity of GBM1 and SGS1 gliomaspheres to radiation and TMZ reflected the patient's actual clinical response to these treatments, we determined the IC 50 for TMZ for each culture . IC 50 values for SGS1 were more than an order of magnitude greater than GBM1 in each of three biological replicate experiments. We then treated each culture with five days of concurrent radiation and TMZ and found that, up to 3 months after treatment, GBM1 cells exhibited no evidence of repopulation in quadruplicate T10 flasks. In stark contrast, SGS1 cells showed little signs of cytotoxicity and continued to expand. Immunoblotting for γH2AX, a marker for DNA double-strand breaks, at 0 to 96 hours after exposure to a single 5 Gy fraction of radiation or 10 μg/ml TMZ for 24 hours demonstrated that peak expression of γH2AX in SGS1 spheres was significantly less than in GBM1 spheres after either treatment, indicating resistance to double-strand break formation due to chemoradiation . Although both tumors did not exhibit MGMT promoter methylation by pyrosequencing, we nevertheless found that GBM1 spheres had a far lower level of expression than SGS1 spheres . This may explain its significantly lower IC 50 for TMZ. To confirm that the observed mesenchymal phenotype of the recurrent tumor manifested at a transcriptomic level, we performed RNA sequencing of both bulk tumor tissue and gliomaspheres derived from GBM1 and SGS1. We used ssGSEA to classify each sample into one of three GBM molecular subtypes . Bulk tissue and gliomasphere RNA from GBM1 were enriched for the proneural and classical gene sets. The A and B sectors of SGS1 bulk tumor exhibited enrichment for the mesenchymal gene set, while the most medial C sector bulk expressed both proneural and classical genes and was transcriptionally more similar to GBM1 bulk tumor and gliomaspheres than SGS1 samples, possibly due to the presence of some residual GBM1 clones that did not go on to expand in culture. Gliomaspheres derived from the A and C sectors had highest enrichment scores for the proneural gene set, while B gliomaspheres were enriched for mesenchymal genes. This was associated with higher VAFs of R175H and PTPN11 G466V in the B compared to A and C cultures. Gene sets in MSigDB found to be most significantly enriched in SGS1 versus GBM1 samples included REACTOME_IMMUNE_SYSTEM, REACTOME_INTERFERON_SIGNALING, KEGG_LYSOSOME, and KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION (p<0.001, Fisher's exact test) (Table 3 ). As an orthogonal validation of these findings, we then used RT-qPCR arrays to compare the expression of core human transcription factors in SGS1 sector B gliomaspheres, GBM1 sector B gliomaspheres, and gliomaspheres derived from a secondary gliosarcoma resected from an unrelated individual (SGS2). This confirmed the presence of elevated STAT activity in SGS compared to primary GBM, as suggested by the RNAseq analysis . We further validated this finding with assays demonstrating a significantly lower IC 50 of the JAK2-inhibitor ruxolitinib compared to TMZ in both gliosarcoma cultures, while the IC 50 of ruxolitinib was modestly higher than TMZ in GBM1 . Significantly downregulated transcription factors common to both gliosarcomas were HOXA5, FOXO1, and CEBPA. We used oPOSSUM to identify transcription factor binding sites common to the promoter regions of genes in the secondary gliosarcoma that were significantly upregulated greater than 4-fold. We found that consensus binding sites for ELK1, an ETS family transcription factor, were present in all nine upregulated genes and overrepresented compared to a background set of 24752 genes . Another ETS transcription factor, SPIB, was also found to be enriched in the promoters of all nine genes, but at a lower significance threshold (Supplementary Materials). Our surprising finding of the nearly simultaneous expansion of distinct TP53 missense mutations in two separate GBM clones during treatment prompted us to ask whether this expansion could be replicated ex vivo . We split passage 10 gliomaspheres from GBM1 for irradiation, TMZ, or combined treatment. As a negative control, we also continued to passage untreated GBM1 gliomaspheres. Cells did not recover from combined treatment for further analysis; however, 12 weeks after treatment with TMZ alone, GBM1 cells had recovered sufficiently for NGS targeted sequencing. We detected p53 R175H and R110C at VAFs of 0.014 and 0.019 , respectively, at a coverage depth of 1999X (Table 5 ). No new variants were identified in the radiated and untreated cultures compared to the pre-treatment culture. TMZ was also administered to late passage (P24) untreated GBM1 cells. Sequencing of post-treatment recovered cells revealed multiple C:G>T:A transitions in an Np C pT or Np C pC context, although the same p53 mutations were not seen. We did, however, detect the expansion of a subclone harboring a deleterious CDH1 missense mutation , a gene that was also found to be mutated in sector A cells derived from SGS1, although at a different codon. Ex vivo treatment experiments carried out on two other MGMT promoter-methylated primary GBM cell cultures in our collection (GBM4 and GBM5) similarly detected expanded subclonal populations harboring deleterious C:G>T:A transitions in an Np C pT or Np C pC context in known cancer driver genes (Table 6 ). In two MGMT promoter-unmethylated primary GBM cultures (GBM6 and GBM7), no such populations were seen. These Signature 11 mutations were significantly more frequent in mutations detected only after TMZ exposure versus those present prior to TMZ exposure . In these four cases, matching recurrent GBM tissue was not available to evaluate the clinical significance of the mutations. Using detailed analyses of bulk tumor tissue and derived gliomaspheres from a case of secondary gliosarcoma, our results build a compelling case that TP53 DBD missense mutations can drive a sarcomatous phenotype transition in GBM. We observed the appearance of two subclonal TP53 missense mutations on a background of clonal EGFR missense and PTEN inactivating driver mutations that were shared with the matching primary GBM. Their appearance during TMZ adjuvant therapy coincided with an increase in gliomasphere proliferation rate, increased MGMT expression, a global transcriptional change towards a mesenchymal phenotype, and resistance to TMZ in vivo and ex vivo . Single-cell plating and VAF analysis of cultures derived from multiple tumor sectors demonstrated that the two mutations began to expand independently in separate GBM cells within a relatively short time interval, lending further support to the notion of their origin within a single 5-day TMZ cycle. TP53 R175H is a recognized gain-of-function mutation, while TP53 R110C has been observed in isolated cases of colorectal, squamous cell, prostate, and non-small cell lung cancer in the TCGA datasets but has not been specifically identified as a DBD conformational mutant. Our observation of the persistence of TP53 R110C in 2 of 3 bulk tumor sectors and all long-term serum-free culture suggests that it conferred a similar neoplastic fitness advantage to TP53 R175H. This study clarifies previous work identifying a high frequency of TP53 mutations in both primary and secondary gliosarcomas . Most recently, Cho et al. sequenced TP53 to a coverage depth of approximately 120x in 28 FFPE gliosarcoma specimens, including 6 with matched normal samples, and observed an overall mutation frequency of 71% . Synthesizing these studies with ours, we suggest that TP53 gain-of-function mutations are a key step in gliosarcoma pathogenesis. Although most molecular studies of gliosarcoma have reported specimens with wildtype TP53 , an increasing sensitivity of mutation detection methods appears associated with increasing frequencies of mutation observed. Furthermore, wildtype p53 glioasarcoma exhibits an improved clinical prognosis compared to mutant p53 gliosarcoma, and may be a distinct molecular subtype despite similar histopathology . Because TP53 gain-of-function mutations are also a hallmark of IDH-mutant astrocytomas and are frequently observed in IDH-wildtype GBM without any sarcomatoid features, they may not be sufficient for gliosarcoma pathogenesis. Other necessary factors may be stromal/microenvironmental or genetic. Possible stromal factors suggested by our RNAseq GSEA include infiltrating inflammatory cells contributing to cytokine signaling, which was also observed in the study by Cho et al . After TP53 SNVs, the most common genetic alterations we observed were copy number loss or inactivating SNVs of PTEN . Wildtype p53 is a recognized regulator of PTEN transcription, and PTEN acts to prevent degradation of p53 by MDM2 . Thus, mutations that reduce wildtype function of one gene may create a condition where acquisition of a deleterious mutation in the other is particularly advantageous. Our study sheds new light on which wildtype p53-regulated genes must be lost for gliosarcoma pathogenesis to occur, as well as the transcription factors with which mutant p53 may be aberrantly interacting. Compared to GBM1, SGS1 exhibited significantly downregulated expression of the transcription factors CEBPA, FOXO1 and HOXA5. Examination of another secondary gliosarcoma culture in our collection, SGS2, similarly showed significant downregulation of CEBPA and FOXO1. CEBPA is a tumor suppressor that has been shown in AML to be directly activated by p53 . FOXO1 and HOXA5 are not known to be directly regulated by p53, but studies in several cancer types suggest that these transcription factors may have p53-independent pro-differentiation and pro-apoptotic functions that potentiate the effects of wildtype p53 loss . Among the most upregulated transcription factors we identified in the secondary gliosarcoma, STAT4 is known to contain a p53 response element in its promoter , indicating that some wildtype binding specificities of p53 may be preserved despite the absence of the wildtype allele. Alternatively, STAT4 may be activated via other TFs such as NF-kB1 , which we found to be a key driver of sarcomatoid change in our causal network analysis. STAT4 is phosphorylated by JAK2, and we confirmed that the JAK2-inhibitor ruxolitinib was more cytotoxic at comparable micromolar concentrations than TMZ in two gliosarcoma cultures, meriting further exploration in preclinical models. We identified two ETS family transcription factors, ELK1 and SPIB, as possible mediators of gene upregulation in an analysis of DNA binding site motifs. Another ETS family transcription factor, ETS2, was recently found to mediate aberrant gene upregulation by mutant p53 through a direct protein-protein interaction, resulting in etoposide resistance in breast cancer cell lines . Our results are consistent with the postulate that other ETS family transcription factors may be similarly co-opted by p53 gain-of-function mutants. Binding partners of mutant p53 may have diverse effects that contribute to cancer progression, including cell cycle dysregulation , neoangiogenesis , and migration/metastasis . We speculate that R175H and/or R110C interacts with ELK1 to upregulate target genes that facilitate a switch to a sarcomatoid phenotype in GBM. The timing, relative to the patient's treatment course, of the expansion of the two TP53 mutant gliosarcoma clones suggests two possible scenarios. In the first, one or both mutations were present in a rare population of cells in the original tumor and, after treatment eliminated TMZ-sensitive p53 wildtype clones, these resistant subclones repopulated the tumor. Cho et al . have similarly reported the outgrowth of rare TP53-mutant subpopulations in recurrent gliosarcomas following treatment. Arguing against this in our case, however, is the fact that there was no evidence of recurrent tumor on the POD 82 MRI (approximately 36 doubling times or 6.7 × 10 10 cells expected), unless other factors prevented proliferation of the p53-mutant subclones during that time period. Alternatively, residual ancestral clones could have acquired the TP53 mutations at approximately the same time during the first adjuvant cycle of TMZ (POD 94-98) and immediately began to proliferate. In this scenario, the patient's radiographic findings are consistent with the in vivo growth rate predicted by the culture. The deleterious effects of TMZ mutagenesis in both low and high grade gliomas are well recognized . In SGS1, both TP53 mutations were C:G>T:A transitions that are consistent with the so-called Signature 11 mutations seen with alkylating chemotherapies. Although these transitions can also occur due to endogenous mutational processes such as spontaneous deamination of 5-methylcytosine (Signature 1), both were detected ex vivo , along with numerous other mutations bearing the TMZ mutagenesis signature, only after GBM1 cells were treated with TMZ. Although it seems unlikely that two distinct mutations in the same region of the same gene could be induced experimentally in this manner, we speculate that the location of the R110 and R175 codons at gene body CpG sites, which are highly methylated and thus less stable , increased their susceptibility to TMZ mutagenesis. Intratumoral heterogeneity and therapy-driven evolution are major barriers to the effective treatment of GBM and other solid cancers. Our finding that ex vivo treatment may generate an array of subclones that mirror the actual subclones that fuel tumor recurrence in vivo raises the possibility that evolutionary trajectories may be anticipated to a degree. Our work is limited by the number of GBM cultures analyzed, a paucity of post-treatment recurrent GBM tissue matched to newly diagnosed GBM gliomaspheres, and use of only a single culture microenvironment in which treatment was simulated. Further work will need to be done to determine what GBM molecular subtypes may be particularly amenable to, and what culture conditions or in vivo models might improve the yield of, this experimental method of ex vivo evolutionary modeling. Because robust GBM cultures can be derived in under 1 month, and their recovery from a cycle of TMZ can occur in less than 3 months, we foresee the possibility of obtaining predictive information well in advance of the 7-month median time interval at which clinical disease progression typically occurs. This may provide the opportunity for clinicians to rationally select targeted second-line therapies, even in the absence of a biopsy specimen of the recurrent tumor. In conclusion, this study of a striking case of secondary gliosarcoma provided a better understanding of the potential role TP53 DBD missense mutations have in activating EMT transcriptional programs and driving disease progression in GBM. Experimental treatment of cell cultures derived from the primary tumor revealed a method of modeling tumor evolution that merits further exploration. An improved ability to predict GBM evolutionary trajectories at the time of first diagnosis will facilitate the development of more rational, adaptive, and personalized therapeutic strategies. Genomic DNA extraction was conducted using Purelink Genomic DNA Min i kits (Thermo Fisher Scientific) to yield ample material for NGS. The Ion AmpliSeq Oncomine Comprehensive research panel version 2.0 was used to characterize relevant genes at high coverage for variant characterization purposes using a pool of multiplexed primers that amplify the targeted loci of frequent mutation in known oncogenes and tumor suppressor genes. After amplification, the libraries were prepared with the Ion AmpliSeq Library Kit 2.0 using Ion Xpress Barcode Adapters 1-96 Kit to barcode each single cell, group of pooled cells or bulk tumor, following standard manufacturer's instructions. Briefly, 30 ng of each sample were amplified using the Ion Torrent OCP v2.0 panel and specified Ampliseq cycling conditions for the pool. Following PCR amplification, the primers were partially digested with the proprietary FuPa enzyme and each sample was barcoded with a unique IonExpress barcode (1-96). Finally, a 1.5X bead purification was performed with Agencourt AMPure XP Reagent following the instructions in the Ion Ampliseq Library Prep protocol to clean up the sample and remove adapter dimers. All samples were quantified with the Ion Library TaqMan Quantitation Kit using a 1:100 dilution of each library in a 10 μL reaction volume, with 2 technical replicates per sample. Following quantification, all samples were individually normalized to 100 pMol and 2 μl of each normalized library were combined to form a pool of 96 uniquely barcoded samples at a final concentration of 100 pMol. 25 μl of this pool was used for priming the sequencing chip. Ion Torrent chip priming and sequencing were carried out using the Ion Torrent S5XL system and the Ion Chef instrument with reagents from the Ion 540 Kit-Chef . Briefly, the Chef was used to bind each library DNA fragment to Ion Sphere Particles (ISPs) and clonally amplify each fragment by emulsion PCR. Amplified DNA fragments were then bound to streptavidin-coated beads and template negative ISPs were washed away. Template-bound ISPs were then prepared for sequencing by loading onto one Ion Torrent S5 540 chip for sequencing on the Ion S5XL sequencing system. The primed 540 chip was sequenced on the Ion Torrent S5XL System with library read length set at 200 bp and 520 flows per chip, with all other instrument settings set to the manufacturer's default for the Ion 540 Kit. Analyses of sequencing raw data were performed with Ion Torrent Suite (version 5.0.2) using the “coverageanalysis” and “variantcaller” plugins (with somatic/low stringency settings for the “variantcaller”), with all other settings for the run report set to the manufacturer's default. The “variantcaller” output on each bulk and cultured sample was filtered to exclude variants occurring at a frequency of less than 0.05. These were further filtered to exclude identical variants occurring in the matched germline DNA sample, as well as non-coding or synonymous coding variants. The remaining variants were then sorted by number of samples affected in descending order. Variants that were detected in all samples were placed on the trunk and branching points were added to divide samples into progressively smaller groupings until each sample appeared on an individual branch. Reconfigurations of the tree, not affecting the underlying topology, were performed to group samples from the same bulk sectors together where possible. RNA-seq data were analyzed using the GATK best practices workflow to call SNVs. SNVs that differed between GBM1 and SGS1 samples at a significance threshold of p<0.02 (Fisher's exact test) were then used to cluster the samples hierarchically in an unsupervised fashion. Gliomaspheres were digested into single cells with Accutase and seeded in laminin-coated 96-well plates with serum-free medium. Plates were incubated at 37°C, 5% CO 2 , and 90% humidity until 50% confluence. The medium was then replaced with fresh medium containing temozolomide at various concentrations . Six technical replicates were performed for each concentration. After incubation for 66 hours, 20 ml of MTS reagent (Promega) was added and incubated for an additional 4 hours. Plates were read at absorbance 490 nm. Total RNA was isolated from cells and tumor tissue using RNeasy Mini kits (Qiagen) and provided to the Mount Sinai Genomics Core Facility for 100nt single-read sequencing on the Illumina HiSeq 2500 instrument to generate on ~42 million reads per sample. DEseq2 was used to identify differentially expressed genes between GBM1 and SGS1 samples at an adjusted p-value of 0.001 (Fisher's exact test). Identification of enriched pathways using Fisher's exact test was performed as previously described . Single sample GSEA was performed using the GSVA package in R with the options maseq=TRUE and mx.diff=FALSE . Gene set signatures were obtained from Wang et al . We de novo constructed a GBM regulatory network using a previously described procedure from 477 TCGA GBM tumor samples by integrating gene expression and DNA copy number variation data . We further incorporated the causal connectivity between miRNA targets and transcription factor (TF) targets into a network model as scale-free priors (see details in following section). Based on the causal network constructed, we performed a key driver analysis (KDA) to identify regulators for the gene sets. The KDA takes as input a set of genes and a gene causal (directed) network. The subnetwork of a set of genes was identified by searching their neighboring genes, and key drivers were identified by considering number of downstream nodes. To determine TF-target connectivity, we inferred sample-specific TF activity and miRNA activity based on gene expression profiles and miRNA expression profiles of 477 TCGA GBM tumor samples . We downloaded 205 position-specific weight matrices (PWMs) that represent individual transcription factors (TFs) from the JASPAR CORE database , and obtained the genome sequence for Homo sapiens from the R Bioconductor package BSgenome.Hsapiens.UCSC.hg19 . We further considered tissue-specific accessible DNA for TF binding. Specifically, we used DNase I hypersensitivity regions of two available glioblastoma cell lines A172 and H54 as the cis-regulatory sequence of each gene . The TF binding affinities were estimated based on the PWM of TFs and cis-regulatory sequences. For each sample, linear regression of the genome-wide mRNA expression on the total promoter affinity for each TF was performed. The regression coefficients of the total promoter affinity were interpreted as sample-specific TF activities. We performed this procedure with different sizes of cis-regulatory sequence, 1 kb through 10 kb of upstream and downstream sequences, then selected optimal sizes of cis-regulatory sequence by enrichment between genes with high total binding affinity and genes whose expression level are correlated with TF activities. The inferred TF activity with the selected optimal sizes of cis-regulatory sequence was used to determine its functional target genes that are defined as the genes with high total binding affinity by that TF and significant expression correlation with the inferred TF activity. To determine miRNA-target connectivity, we inferred miRNA activity based on expression levels of miRNAs and their predicted target genes in a previous study . We used a collection of predicted target genes for 1537 unique mature miRNAs from TARGETSCAN ( www.targetscan.org ) that considers all conserved miRNA binding sites inherited from 23-way alignments of UTR sequences . In order to obtain robust results, we filtered out miRNAs whose number of target genes are smaller than 100. Among these miRNAs, we further focused on miRNAs whose predicted target genes’ expression levels and their own expression levels are available, resulting in 149 miRNAs. The causal connectivity between miRNA and target was defined by the high correlation between miRNA activity and expression levels of predicted targets from TARGETSCAN.
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Study
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biomedical
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en
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29445561
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On physical exam, he was found to have bilateral parotid and submandibular gland enlargement and right eye proptosis. The patient disclosed that his brother has retroperitoneal fibrosis secondary to IgG4-RD. The initial abdominal computed tomography (CT) revealed a duodenal mass. Endoscopic retrograde cholangiopancreatography (ERCP) showed a mildly dilated common bile duct, not associated with mass or stricture. A biopsy of the intra- and infra-ampullary area demonstrated active chronic duodenitis without evidence of malignancy. Complete blood count and biochemical profile were remarkable for chronic anemia and hypoalbuminemia, with normal renal and hepatic function. Monoclonal protein evaluation showed elevated IgG level of 5410 mg/dL , and bone marrow biopsy demonstrated plasma cell dyscrasia (plasma cell count of 6%) with no evidence of lymphoproliferative disorder. Additional laboratory results revealed positive antinuclear antibody (ANA), low complement levels, elevated total IgG and IgG4 subclass, and elevated sedimentation rate ( Table 1 ). The QuantiFERON ® -TB Gold test was negative. Early recognition and treatment can prevent permanent organ damage since chronic inflammation leads to a tumefactive mass that can destroy the involved organ . There are no randomized controlled trials for IgG4-RD treatment. The International Consensus Guidance statement recommends initiation of treatment in all symptomatic patients, and glucocorticoids are the first-line agent for remission induction. However, patients can relapse after prednisone is tapered or discontinued. The use of steroid-sparing agents is controversial, and rituximab is an option for refractory cases . The study conducted by Carruthers et al. showed 97% complete remission after two doses of rituximab , using serum IgG4 level as an important tool to assess treatment response and to predict possible relapse .
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Other
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biomedical
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en
| 0.999998
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29480839
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It has been widely accepted that percutaneous catheter drainage (PCD), the first-line treatment modality of pyogenic liver abscess, is characterized by minimal invasiveness, high success rates, and well-established safety. Severe complications associated with PCD are uncommon. Furthermore, hepatic rupture is an uncommon but life-threatening liver injury with high mortality. Its management remains challenging because a delay in diagnosis may lead to fatal hemorrhagic shock. Liver rupture has not been described in association with PCD in the literature to date. Recently, we encountered an extremely rare case of liver rupture following PCD and managed it successfully. Herein, we present the clinical course of the case and our management approaches. The clinical significance, underlying causes, and current views on severe liver trauma management will also be discussed briefly. A 71-year-old man was admitted with a complaint of episodic fever for 1 week, accompanied by general malaise, nausea, and vomiting. His past medical history was negative, except for uncontrolled diabetes mellitus. On initial admission, his body temperature was 39.5 °C. Physical examination was unremarkable. Laboratory tests showed white blood cell counts 16 × 10 9 /L, neutrophil 91.6%, hemoglobin 116 g/L, C-reactive protein 134.4 mg/L, fasting blood glucose 17 mmol/L, and normal liver function tests (LFTs). Blood culture, tumor, and viral markers were all negative. Abdominal computed tomography (CT) scans revealed a 5 cm abscess located in liver segment IV . Insulin was administered subcutaneously to control his hyperglycemia. The initial broad-spectrum antibiotic therapy we had employed (cefoperazone sodium and ornidazole, intravenously) was ineffective; therefore, ultrasound guided PCD was attempted. After topical anesthesia with 2% solution of lidocaine hydrochloride, an 8-French pigtail catheter was introduced into the abscess cavity using the Seldinger technique, under ultrasound guidance. Pus was successfully drained; Burkholderia vietnamiensis was found in the pus culture. Within 24 hours following PCD, the patient complained of severe right upper quadrant pain. Three hundred milliliter hematic fluid was drained from the catheter. His hemoglobin and hematocrit levels continuously decreased (from 104 to 65 g/L and from 29.1% to 18.7%, respectively). LFTs revealed elevated liver enzymes: alanine aminotransferase 654U/L and aspartate aminotransferase 1210 U/L; while his hemodynamic status remained stable: blood pressure 112/83 mmHg, pulses 75 beats/min, Spo2 96% to 100% (room air). Creatinine, bilirubin, urinalysis, coagulation function tests, and plate counts were all within normal limits. Ultrasound indicated a 10 × 4 cm subcapsular hematoma in the right lobes. Abdominal enhanced CT further revealed intrahepatic and subcapsular hematoma extending from the right diaphragmatic face to the hilum, intra-abdominal fluid accumulation, and catheter shedding . Subsequently, emergent angiogram was performed, and revealed an absence of intrahepatic artery-venous fistula or active bleeding signs. According to these findings, a diagnosis of liver rupture without further progression was made. Under close monitoring, the patient accepted transfusions of 2 units of packed red blood cells, with hemostatic drug usage (aminomethylbenzoic acid and etamsylate, intravenously). The patient's antibiotic regimen was adjusted (imipenem and cilastatin, intravenously) according to pus culture sensitivity. After these conservative treatments continued for 5 days, the patient's fever subsided, and discomfort resolved gradually. Laboratory workup revealed that his hemoglobin had stabilized and LFTs normalized. The drainage fluid became yellow and clear. Thirty-four days after PCD, repeated abdominal enhanced CT disclosed that the previous hematoma had been absorbed significantly, with ascites resolution and abscess cavity closure . The local daily drainage showed a decreased volume, and the catheter was removed. The patient recovered uneventfully during following-ups. PCD is currently regarded as the first-line treatment modality for pyogenic liver abscess. In a recently published retrospective study, the success rate of PCD for pyogenic liver abscesses reached 95%. A meta-analysis, enrolling 5 randomized controlled trials, has demonstrated that PCD is more effective than percutaneous needle aspiration. Despite the established safety of this procedure, several cases involving serious PCD-related complications have been reported, including hepatocolic fistula and hemobilia. Hepatic rupture is frequently associated with blunt liver trauma. Other uncommon causes include obstetric diseases, coagulopathy and, rarely, peliosis hepatis. [ 6 – 8 ] To our knowledge, PCD-associated hepatic rupture has not been reported before. Severe liver trauma is a life-threatening situation with a high mortality rate of 4.0% to 11.7%, and its management is challenging due to emergency. Hepatic rupture, although uncommon, should be regarded as an even more urgent hepatic trauma because a delay in diagnosis may lead to fatal hemorrhagic shock. However, there are no established grading or classification systems currently available for hepatic rupture. Extrapolating from the American Association for the Surgery of Trauma (AAST) grading scale for liver trauma, our case would at least be classified as an AAST grade III liver injury. Recently, some authors have suggested that surgery is not necessary for liver trauma patients without hemodynamic instability. Even so, little is known about whether this treatment strategy is still applicable for iatrogenic liver rupture. Previously, there had been few reports of hepatic rupture managed by surgical and interventional approaches. In this case, the operation was not scheduled, mainly due to the low success rate of surgical repair for such extensive intrahepatic hemorrhage. Hepatic arterial embolization was also excluded because there was no contrast medium extravasation sign on angiography. Regarding both hemodynamic stability and serial examination findings, which indicated that the hematoma was not developing further, we initially managed our patient with medical treatments, which also turned out to be successful.
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Clinical case
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clinical
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29855598
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Elizabethkingia belonging to the family Flavobacteriaceae is a genus with 4 known species: E. meningoseptica, E. anophelis, E. miricola and E. endophytica . Since its discovery in 1959, E. meningoseptica 1 has been described to be involved in diverse human infections such as meningitis, keratitis and sepsis among immunocompromised individuals 2 , 3 . In 2003, E. miricola was reported for the first time from the condensed water samples of the Russian space station Mir 4 . E. miricola was later found to be associated with sepsis, bacteraemia and pneumonia 5 . E. endophytica isolated from corn has not yet been associated with any of the human infections 6 . In 2011, E. anophelis was discovered from the midgut of Anophelis gambiae mosquito 7 . It has been linked to neonatal meningitis 8 , nosocomial outbreaks 9 and catheter associated infections with high mortality rates 10 . Elizabethkingia strains have been found to encode metallo-betalactamases conferring carbapenem resistance 11 . Because of the bacterium’s innate resistance to several classes of antibiotics, treatment of Elizabethkingia infections is challenging 3 . Several studies have reported that patients with severe underlying diseases and a history of antibiotic exposure are more susceptible to Elizabethkingia related nosocomial infections 2 . Scant information is available on the potential modes of infection and their ability to adapt to diverse host environments. Hence, analysis of their genomes to study the potential for horizontal gene transfer leading to enhanced infection capabilities and survival abilities across various ecological niches assumes additional significance. Here, we have investigated a new E. anophelis endophthalmitis strain, a multidrug resistant pathogen isolated from a post-operative endophthalmitis patient 12 . After sequencing, CG analysis was performed with twenty-five other E. anophelis strains whose genomes were publicly available to get an insight into their phylogenetic position and also to understand the similarities and differences in their gene contents with the aim of determining the unique features of the organism isolated for the first time from an eye infection. Although the genome of the organism has overall similarities with the genomes of other E . anophelis strains, presence of several unique genes and the ability of horizontal gene transfer indicate its distinct origin. The isolate was initially identified as Elizabethkingia meningoseptica by Vitek-2. Subsequently, with the availability of additional Elizabethkingia genomes and 16 s rDNA sequence analysis, the genome of the study isolate was re-identified as Elizabethkingia anophelis . MIC analyses of 13 antibiotics revealed that the pathogen was resistant to penicillins, cephalosporins, monobactam, carbapenems, aminoglycosides and trimethoprim/sulfamethoxazole; and sensitive to levofloxacin and minocycline. The organism exhibited intermediate resistance to tigecycline and ciprofloxacin (Table 1 ). Table 1 Antibiotic susceptibility profile of E. anophelis endophthalmitis. S.no Antibiotic Class Antibiotic MIC (µg/ml) Resistance profile 1 Penicillins Piperacillin/tazobactam >=128 Resistant 2 Cephalosporins Ceftazidime >=64 Resistant 3 Cefepime >=64 Resistant 4 Monobactum Aztreonam >=64 Resistant 5 Carbapenems Imipenem >=16 Resistant 6 Meropenem >=16 Resistant 7 Aminoglycosides Amikacin >=64 Resistant 8 Gentamicin >=16 Resistant 9 Quinolones Ciprofloxacin 2 Intermediate Resistant 10 Levofloxacin 2 Sensitive 11 Tetracyclines Minocyclin <=1 Sensitive 12 Tigecycline 4 Intermediate Resistant 13 Trimethoprim Trimethoprim/Sulfamethoxazole 80 Resistant Antibiotic susceptibility test was performed using Vitek-2 as per clinical laboratory standards Institute (CLSI) guidelines. MIC – minimum inhibitory concentration of the antibiotic in µg/ml. 26 genomes of E. anophelis including the genome of the new E. anophelis endophthalmitis study strain were retrieved from NCBI database for CG analysis. The average size of the genomes is 4.03 Mb and average G + C% is 35.61%. The strain with the maximum size is NUHP1 (4.36 Mb) and the smallest genome is As1 (3.59 Mb) (Table 2 ). The predicted protein sequences of all the 26 E. anophelis genomes were used as input to conduct the core-pan genome analysis. CG analysis revealed that 1404 (40.79%) genes were shared between all the 26 strains, which may be considered to be “core genome”. The accessory genome varied from 656 to 2240 genes (avg. 59.2%) across the strains . Most notably, exclusion of the study isolate’s genome from the analysis led to an inclusion of an additional 844 genes in the core genome of the remaining 25 genomes. The study strain was found to have maximum number of exclusively absent (846) and unique (156) genes (Table 3 ), revealing that it has an open pan genome. Annotation of the pan-genome of all the 26 genomes to understand the enrichment of the COG and KEGG pathways has been mapped. Table 2 Comparison of genome characteristics of the 26 E. anophelis isolates used in analysis. Strain Name Year of Collection Accession id Genome size in Mb GC % No. of Contigs Genes Proteins 0422 1950 NZ_LNOG01000011 3.9599 35.6 26 3634 3548 502 2012 NZ_AVCQ01000001 3.96066 35.5 21 3617 3520 12012-2PRCM 2009 NZ_LPXG01000011 4.02331 35.6 83 3671 3554 Ag1 2010 NZ_AHHG01000001 4.04571 35.5 51 3723 3572 As1 2013 NZ_LFKT01000006 3.59087 35.5 12 3303 3229 B2D 2013 NZ_JNCG01000007 3.93625 35.5 50 3553 3473 CSID_3000521207 2016 NZ_CP015067 3.85345 35.7 1 3490 3390 CSID_3015183678 2016 NZ_CP014805 3.93122 35.8 1 3562 3461 CSID_3015183681 2016 NZ_CP015068 3.93122 35.8 1 3563 3461 CSID_3015183684 2016 NZ_CP015066 3.93122 35.8 4 3562 3458 EM361-97 2010 NZ_KV757122 4.08405 35.7 27 3729 3614 Endophthalmitis 2014 JSAA01000100 4.01982 35.5 167 3729 2302 FMS-007 Not available NZ_CP006576 3.93897 35.6 1 3578 3470 LDVH-AR107 2004 NZ_FTPG01000001 3.98893 35.7 108 3658 3538 NUH1 2012 NZ_ASYH01000001 4.33466 35.6 59 3993 3879 NUH11 2012 NZ_ASYK01000005 4.09148 35.6 59 3757 3642 NUH4 2012 NZ_ASYI01000001 4.23949 35.6 50 3912 3811 NUH6 2012 NZ_ASYJ01000011 4.1238 35.6 74 3812 3696 NUHP1 2012 NZ_CP007547 4.36983 35.6 1 4016 3898 NUHP2 2012 NZ_ASYF01000003 4.33465 35.5 59 3988 3882 NUHP3 2012 NZ_ASYG01000009 4.33411 35.5 71 3985 3871 Po0527107 2006 NZ_CCAC010000089 4.03206 35.5 89 3674 3573 PW2806 2012 NZ_CBYD010000038 3.91281 35.9 388 3612 3456 PW2809 2012 NZ_CBYE010000026 3.92215 35.8 278 3598 3452 R26 2006 NZ_ANIW01000066 4.03272 35.4 66 3726 3633 V0378064 2011 NZ_CCAB010000170 4.03675 35.7 214 3648 3556 Figure 1 The Core and pan genome of the compared 26 E. anophelis genomes. A total of 26 E. anophelis genomes have been analysed using the default parameters of the BPGA pipeline. The analysed E. anophelis genomes share 1404 core genes. Cyan colored boxplots indicates the change in number of pan-genome gene groups to the number of genomes added sequentially. Pink boxplots indicate the change in number of core-genome gene groups to the number of genomes added sequentially. A positive correlation is observed between the pan genome orthologous groups (POGs) and the genomes under analysis in the pan genome curve, while there is a negative correlation in the core-genome curve as the number of POGs were observed to decrease with the increase in the number of genomes. Table 3 Core, accessory, unique and exclusively absent genes in the 26 E. anophelis genomes after pan-core genome analysis using BPGA pipeline. Strain Name No. of core genes No. of accessory genes No. of unique genes No. of exclusively absent genes 0422 1404 1950 94 3 502 1404 1888 108 2 12012-2PRCM 1404 1930 131 10 Ag1 1404 2010 10 30 As1 1404 1693 3 149 B2D 1404 1868 101 5 CSID207 1404 1896 0 27 CSID678 1404 1958 0 0 CSID681 1404 1959 0 1 CSID684 1404 1956 0 0 EM361-97 1404 1964 113 3 Endophthalmitis 1404 656 156 846 FMS007 1404 1913 56 6 LDVH-AR107 1404 2006 21 16 NUH1 1404 2240 0 0 NUH4 1404 2185 22 0 NUH6 1404 2107 33 5 NUH11 1404 2097 12 1 NUHP1 1404 2236 0 0 NUHP2 1404 2236 0 0 NUHP3 1404 2238 2 0 Po0527107 1404 2032 45 0 PW2806 1404 1956 3 12 PW2809 1404 1948 5 13 R26 1404 2052 38 0 V0378064 1404 2035 20 0 Core genes – number (No.) of genes that are shared by all the study genomes, Accessory genes – Genes that are not shared by all the genomes, Unique genes – genes that are found exclusively in a particular genome, exclusively absent genes – genes that are exclusively absent in a particular genome but are otherwise found in the other genomes. Figure 2 Cluster of Orthologous Groups (COG) analysis of the 26 E. anophelis genomes. Comparison of the COG distribution between the core, accessory and unique genes of the 26 E. anophelis strains has been analysed using the default parameters of the BPGA pipeline. The COG categories are presented on the X-axis and the percentage of the genes enriched in each category of the COG classes are indicated on the Y-axis. Figure 3 KEGG analysis of the 26 E. anophelis genomes. Functional annotation of the core, accessory and unique genes of the 26 E. anophelis genomes has been performed using the default settings of the BPGA pipeline. The KEGG categories are mentioned on the X-axis and the percentage of the genes associated with each of the KEGG category are presented on the Y-axis. Phylogenetic tree was constructed to infer the relationship among these genomes using the concatenated sequences of 1,404 core proteins identified from the pan/core genome analysis. The tree separated the 26 E. anophelis genomes into two distinct branches. In the lower branch, genomes of 502, B2D, Endophthalmitis were found to be closely related. Genomes of E. anophelis from Singapore have clustered together (NUH6, NUH11, NUH1, NUHP1, NUHP2, NUHP3) excepting NUH4. Further, the genomes of the four wisconsin outbreak isolates CSID300521207, CSID3015183678, CSID3015183681 and CSID3015183684 have been found to cluster together 13 . The other branch was found to have two sub clusters. 12012-2PRCM, As1, Ag1, R26, 0422, PW2806 and PW2809 genomes grouped into one, while EM361-97, Po0527107, LDVH-AR107, V0378064, FMS007 and NUH4 genomes were part of the second sub cluster . The genome of the isolated strain included in the lower branch, is phylogenetically closer to the strains B2D and 502. However, unlike the test isolate being associated with endophthalmitis, the strains B2D and 502 were isolated from dental plaque and traumatic wound respectively. Figure 4 Core Phylogenetic tree: The core phylogenetic tree is based on the protein sequences of the concatenated core genes of the 26 E. anophelis genomes. The tree was generated by Neighbor Joining Method in MUSCLE using default parameters. The tree was plotted using the Perl package Bio::Phylo::Treedrawer available at http://search.cpan.org/~rvosa/Bio-Phylo-v2.0.1/lib/Bio/Phylo/Treedrawer.pm as implemented in BPGA pipeline. The scale bar presented at the foot of the tree indicates time period in millions of years (MYA). Screening of all the study genomes revealed the presence of bla GOB, blab and bla CME (excepting strain AS1) beta-lactamase genes in most of the strains. Further, vancomycin (VanW) resistance was predicted among all the 26 strains. A gene encoding bile salt hydrolase - Choloylglycine hydrolase (EC 3.5.1.24) was found in all the analysed genomes excepting As1. This enzyme has been previously reported to protect Brucella abortus in the host gut from the toxic and antimicrobial activity of the bile salts 14 . Genes associated with CzcCBA, a membrane bound protein complex aiding in heavy metal resistance 15 have been identified in all the 26 genomes. Genes coding for proteins conferring resistance to several heavy metals (copper, Zinc, cadmium, cobalt) have been discovered among all the study isolates. In addition, genes coding for the proteins leading to arsenic resistance have been predicted in all the genomes. Further, some of the strains (NUH1, NUH11, NUH4, NUH6, NUHP1, NUHP2 and NUHP3) were found to possess arsenic resistance operon repressor suggesting the inducibility of the system’s resistance. Several genes encoding for the multidrug efflux pumps including RND (CmeB – 26 strains, CmeC – 14 strains), multi antimicrobial extrusion protein (Na(+)/drug antiporter – 26 strains) belonging to the MATE family of MDR efflux pumps and acriflavine resistance protein (RND efflux pump transporter – 26 strains) 16 were found in the study genomes (Supplementary Table 2 ). Many genes that may be associated with invasion and intracellular resistance in humans have been identified. We have identified homologs of the gene encoding for an agmatine deiminase in all the 26 isolates. Agmatine deiminase has been reported to aid growth at low pH and biofilm formation, confer acid tolerance in addition to being a potential adherence factor in the colonization of vagina 17 . Putative hemolysin and a hemolysin secretion protein have been predicted among all the 26 genomes. Hemolysin has been implicated as a virulence factor among several gram-negative and gram-positive pathogens 18 . It has also been reported that hemolysin could be a potential ocular virulence factor in Bacillus cereus and Staphylococcus aureus leading to endophthalmitis 19 , 20 and keratitis 21 respectively. However, among the 26 genomes included in this study, arylsulfatase has been identified only in the current study isolate. Arylsulfatase has been implicated previously in E. coli infection of the brain microvascular endothelial cells (BMEC) of the host. Presence of arylsulfatase may contribute to the ability of the pathogen to cross the blood-brain barrier leading to meningitis 17 , 22 . An operon consisting of Quinolinate synthetase [EC 2.5.1.72], L-aspartate oxidase [EC 1.4.3.16], and quinolinate phosphoribosyl transferase [EC 2.3.2.19] involved in quinolinate biosynthesis has been identified in all the genomes being analysed (Supplementary Table 3 ). These genes are considered to have potential anti-virulence function as their activation was reported to inhibit invasion and intracellular spread among Shigella species 23 . MGEs are the major contributors for Horizontal Gene Transfer (HGT). A total of 59 prophage related regions have been identified across the study genomes. Of these, 56 of them appear to be incomplete prophage genomes in 23 study isolates. The other three strains were predicted to contain questionable prophage genomes. The size of the prophage genomes varied from 5.6 kb to 37.4 kb. Strains NUH1, NUH4, NUHP1, NUHP2 and NUHP3 were found to harbor maximum number of prophage regions (4 numbers) compared to the others. The average G + C% among these prophage genomes was 34.55% compared to the average G + C% of the study genomes (35.62%) (Supplementary Table 4 ). A total of 107 Genomic Islands (GIs) have been identified in 25 of the study genomes excepting B2D. The smallest of the predicted GI was 8.2 kb in the strain EM361-97 and the largest GI was 31.8 kb in NUH1 and NUHP3 strains. NUH1, NUH4 and NUHP2 were found to harbor 8 GIs. Maximum number of coding DNAs (66 numbers) were found in the GI (region III) of the strain 422. Several virulence factors, antibiotic resistance genes, pathogenicity islands, insertion sequences, prophage related genes and genes of the secretion systems have been identified in these GIs (Supplementary Table 5 ). Further, remnants of several Integrative and Conjugative Elements (ICEs) have been found in many of the study genomes. T6SS plays an important role in bacterial pathogenesis by allowing the transport of virulence factors, targeting the host cells as well as helping in competing with other bacteria in their niche 24 . They are widely distributed in the genomes of the phylum Bacterioidetes of which Flavobacteriaceae is a family. More specifically, T6SS iii has been reported to be prevalent among the members of the Flavobacteriaceae 25 . Consistent with earlier reports 25 , 26 , several of the study genomes were found to possess T6SS iii . Genes annotated to TssN, TssO and TssP proteins which are unique to only T6SS iii along with those coding for the other core components such as TssB, TssC and extracellular components VgrG and HcP have been identified in twenty-four genomes. Only strains NUH6 and As1 did not appear to harbor any genes coding for the T6SS components (Supplementary Table 6 ). Bacteria employ a host of mechanisms to protect themselves from the invading genetic elements. These include Restriction Modification systems (RMs) which are considered to be innate immune systems and Clustered Regularly Interspaced Short Palindromic repeat sequences (CRISPRs), considered to be adaptive immune systems 27 . Our analysis revealed the presence of Type I and Type II RM systems. Unlike all other genomes analyzed in the study, E. anophelis endophthalmitis was found to possess maximum number of RM system associated genes. The genome was found to possess 12 RM genes, while the strains 502 and B2D did not possess any genes coding for RM systems (Supplementary Table 8 ). Analysis for CRISPRs indicated that only four of the study genomes possess confirmed CRISPRs (Supplementary Table 9 ). Analysis for the presence of anti-restriction systems 28 led to the detection of an anti-restriction gene ArdA among 19 of the study genomes. ArdA protein was reported to support the MGEs in evading the Type I RM systems and augment the spread of resistance determinants 29 (Supplementary Table 10 ). CG analysis indicated that most of the DNA repair pathways are represented in all the study genomes. Most of the repair pathways appear to be intact. In the majority of the genomes excepting those of the wisconsin strains, there was no disruption in the mutY (Adenine DNA glycosylase) gene. In the genomes of the four Wisconsin strains, the 1,029 bp mutY gene was found to be disrupted by the insertion of a 62,212 bp ICE Ea1 13 . A total of 32 protein coding genes (excluding hypothetical genes) involved in transposition, excision of the conjugative transposon, heavy metal resistance and tetracycline resistance have been found inside the ICE. Natural transformation was observed after exposing plasmid DNA to exponentially growing cells. PCR analysis for the presence of BDNF gene in the plasmids isolated from the transformants confirmed that E. anophelis is naturally competent . However, natural competence was observed only when OD 600 reached 0.84. Genome analysis revealed three genes – (a) DNA internalization-related competence protein ComEC/Rec2, (b) Competence protein F homolog and (c) Competence/damage-inducible protein CinA involved in DNA internalization and transformation. These genes are present in majority of the analyzed genomes indicating that natural transformation may be occurring in other Elizabethkingia (Supplementary Table 11 ). Figure 5 PCR confirming the natural transformation in E. anophelis endophthalmitis. Lane 1: 1 kb DNA ladder. Lane 2: Positive control (pCMV-6 BDNF plasmid used as template). Expected band size of BDNF gene is 750 bp. Lane 3–5: PCR products from plasmid isolated from E. anophelis endophthalmitis after natural transformation. Lane 6–7: Negative controls. In this manuscript, we have described the uncommon features of a new strain of E. anopheles isolated from a post-operative endophthalmitis patient. This is the first ever isolate of the species from a patient suffering from this infection. Initial Vitek-2 analysis from the vitreous fluid of the patient led to the identification of the organism as Elizabethkingia meningoseptica 2 . Availability of several Elizabethkingia genomes due to the advent of whole genome sequencing and 16srDNA analysis lead to the unambiguous identification of the pathogen as Elizabethkingia anophelis , a closely related species to E. meningoseptica . Due to the unusual nature of the pathogen, an investigation of the patient’s eye drops, sinks and cubicle in the ward where the patient stayed was conducted for the presence of the pathogen. However, culture results did not indicate the presence of E. anophelis ruling out the possibility of nosocomial acquisition. This raised the possibility that alternate modes have been employed in the transmission of the bacterium leading to postoperative endophthalmitis. Our findings suggest that E. anophelis is a slow growing bacterium compared to E. coli and is capable of natural transformation during a narrow window of exponential phase of growth. CG analysis with 25 other sequenced strains of E. anophelis showed several differences. Pan and core genome analysis revealed that the strain E. anophelis endophthalmitis has undergone massive gene rearrangements indicated by the high number of unique and exclusively absent genes predicted in its genome. Exclusion of E. anophelis endophthalmitis genome from the pan-core genome analysis has led to an increase in the core genome size by 37% indicating the strain’s divergence. The presence of a large number of MGEs and the horizontally acquired genes would have contributed to the genome rearrangement in the organism, diverging it from other analyzed genomes. These data along with others described below suggest the possibility of the recent emergence of the strain. Survival in diverse environments such as mosquito mid gut and human tissues necessitates the bacterium to adapt to the respective niche environments. In such a scenario, possession of MGEs would help adjust and thrive. Analysis for MGEs revealed the presence of GIs, remnants of phage genomes and ICEs amongst several of the study genomes, indicating that the organisms with incomplete prophages and ICEs have further undergone gene gain/loss which may be of an evolutionary requirement for the pathogen to be successful in diverse ecological niches. Interplay between the bacterial defence systems (RMs, CRISPRs) and anti-RM proteins are known to decide the fate of the cell towards or against HGT 30 (Supplementary Table 12 ). Taken together, these observations highlight the potential of the organism to be involved in more robust HGT. The presence of T6SS iii and T4SS secretome further confirms that HGT is a norm and not an exception in E. anophelis . Given this scenario, it is not surprising to find several genes associated with antibiotic resistance, efflux pumps, virulence factors and competence. The finding of an exclusive virulence gene, arylsulfatase in the organism along with other genes with potential for pathogenesis and disease in humans, may provide further insights into the adaptation mechanisms of the pathogen to thrive under diverse ecological niches. From the features described, it is evident that E. anophelis endophthalmitis is a novel human pathogen with distinct characteristics. It is tempting to speculate how the organism could have been transmitted possibly by the mosquito vector to cause eye infection hitherto not associated with E. anophelis . Different mosquito species are highly prevalent in India, Africa and elsewhere. Thus, it is not unrealistic to suggest the transmission of the pathogen to human hosts by the mosquito vector in whose gut E. anophelis was first discovered. We speculate that the mosquito may have bitten near the eye after the patient has undergone surgery, thus transmitting the bacterium into the host’s ocular system. However, there could be alternate explanations which could account for the transmission. Also, further investigations are needed to confirm the transmission routes including zoonotic transmission of this enigmatic pathogen. A 67-year-old patient with complaints of redness, pain and loss of vision in the right eye after cataract surgery was admitted to the Department of Ophthalmology, Sri Sathya Sai Institute of Higher Medical Sciences, Prasanthigram, India. E. anophelis was isolated from the vitreous fluid of the infected eye 12 . Identification, antibiotic susceptibility testing (AST N281 card) and determination of Minimum Inhibitory Concentration (MIC’s) were performed using Vitek 2 (BioMérieux, France) as per CLSI (Clinical and Laboratory Standards Institute) guidelines. E. anophelis endophthalmitis cultures were harvested at an OD600 of 0.37, 0.54, 0.61, 0.75 and 0.84. A plasmid (pCMV6-BDNF) containing eukaryotic Brain Derived Neurotrophic Factor (BDNF) with an ampicillin selection marker was added at 0 ng/mL, 28.2 ng/mL, 56.4 ng/mL and 84.6 ng/mL concentrations and incubated for 90 minutes at 30 °C. Untransformed E. anophelis endophthalmitis was found to exhibit resistance to ampicillin (250 µg/mL). Hence, transformation mixtures were plated on LB-amp agar plates at a higher concentration (600 µg/mL) in three dilutions, i.e., 1:2, 1:20 and 1:100. PCR was performed for the presence of BDNF gene in the plasmids isolated from the transformaned colonies using specific primers (forward Primer: 5′-GGATCCATGACCATCCTTTTCCTTACTATGG-3′; reverse Primer: 5′-AAGCTTCTATCTTCCCCTTTTAATGGTCAGT-3′) in a final volume of 20 μl containing 10 μl of PCR Master Mix (Takara) which includes dNTPs, MgCl2, Taq DNA polymerase and PCR buffer), 0.5 μM of forward and reverse primers, template DNA (2 μl) and nuclease free Water (4 μl). The PCR conditions employed for the amplification of BDNF gene were 94 °C - 2 minutes followed by 30 cycles of 94 °C - 15 seconds, 55 °C - 30 seconds, 72 °C - 47 seconds and a final elongation at 72 °C - 7 minutes. PCR amplicons were analysed on 1.2% agarose gel. E.coli DH5α and untransformed E. anophelis endophthalmitis served as negative controls. Draft genome sequencing and assembly of E. anophelis endophthalmitis genome was recently reported 12 . The contigs from the draft assembly were subjected to gene prediction using PRODIGAL tool 31 with default parameters as recommended. Predicted protein sequences were annotated using BLASTp against UNIPROT bacterial proteins database with evalue < = 0.001, > = 70% as query coverage and %Identity > = 30. E. anophelis NUHP1 genome was used to construct the genome map of E. anophelis endophthalmitis . This led to successful organization of 111 contigs out of 167 contigs. A total of 3,729 ORFs encoding 2302 proteins were predicted from the assembled genome. All available (twenty-five other) E. anophelis genome sequences were obtained from NCBI Genomes database for CG analysis and RAST (version 2.0) annotation has been repeated to obtain unambiguous results (Supplementary Table 1 ). Bacterial Pan Genome Analysis (BPGA) 32 was used for comprehensive pan/core genome analysis, functional annotation of the core, accessory and unique genes to Cluster of Orthologous groups (COG) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using default parameters. Phage genomes were identified by PHASTER 33 . Antibiotic resistance genes were predicted by RAST (version 2.0) 34 , Resfinder (version 3.0) 35 and VRprofile (version 2.0) 36 . Virulence factors, genomic islands, Insertion sequences and T6SS Secretory systems were analyzed by VRprofile (version 2.0). T4SS genes were identified by SecReT4 (version 1.0) 37 . ICEberg (version 1.0) 38 was used to screen for ICEs. Restriction Modification (RM) and anti-restriction systems were identified by RAST (version 2.0). CRISPRfinder 39 was used to predict potential CRISPR gene clusters. Unless otherwise mentioned, all the above mentioned analyses were performed using default parameters. Supplementary information List of 26 E. anophelis genomes used for comparative genomic analysis after RAST annotation Genes associated with resistance to antibiotics and toxic compounds Genes associated with putative virulence factors and anti-virulence Putative prophage regions in the 26 E. anophelis genomes Genomic islands that have been predicted in the study genomes T6SS components that have been predicted in the study genomes T4SS components that have been predicted among the study genomes Predicted Restriction-Modification systems (RMs) in the 26 E. anophelis genomes. Putative CRISPRs found in the 26 E. anophelis genomes Predicted Anti-restriction proteins in the 26 E. anophelis genomes Putative competence related genes Overview of the Bacterial defence systems (Restriction-Modification systems, CRISPRs) and Anti-RM proteins in the study genomes
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Lacosamide (LCM) is a novel agent that has been approved by the US Food and Drug Administration for individuals aged 4 years and older for partial-onset seizures as monotherapy or adjunctive therapy. Intravenous (i.v.) LCM has safety and tolerability similar to that of oral LCM . Lacosamide has a novel dual mode of action. First, it has a functionalized amino acid that selectively enhances slow inactivation of voltage-gated sodium channels, increasing the proportion of sodium channels unavailable for depolarization. Such unavailability reduces pathological hyperexcitability without affecting normal physiological activity of neurons. Second, LCM binds to collapsin response mediator protein-2 (CRMP2), which enhances the drug's antiepileptic activity. However, this mechanism has recently been questioned . Many clinical studies had shown that LCM has a good response rate in adults with epilepsy and has a favorable side-effect profile . However, there is limited data on the efficacy of intravenous LCM in the pediatric population, especially in Asian children [ 9 – 12 ]. Therefore, a single center, prospective interventional study of the efficacy and tolerability of intravenous LCM as adjunctive treatment or monotherapy in Thai children aged less than 18 years with nonconvulsive status epilepticus or acute repetitive seizures was conducted. Patients were selected based on the following criteria: (i) patients with status epilepticus and/or acute repetitive seizures aged less than 18 years; (ii) patients who had uncontrollable seizures after first-line antiepileptic drug therapies; and (iii) patients with a contraindication to first-line antiepileptic drugs (allergy to drugs, comorbidity, drug interaction, and risk of side effects). The electrocardiogram and tests of kidney and liver function were done before the enrollment to rule out atrioventricular heart block and severe liver and renal diseases. Lacosamide therapy would be terminated if a patient experienced intolerable side effects or seizure aggravation. For the purposes of this study, acute repetitive seizures (ARS) were defined as two or more seizures in 24 hours, with self-limited seizures, and patients resuming their normal state after each seizure. Convulsive status epilepticus (CSE) was defined as continuous convulsive seizures lasting more than 5 min or two or more seizures during which the patient did not return to baseline consciousness. Nonconvulsive status epilepticus (NCSE) was defined as a change in mental status from baseline for more than 30 min with ictal discharge on the electroencephalogram (EEG) . Intravenous LCM was added to the medications administered as a part of a standard protocol, including a sequence of benzodiazepine, phenytoin, valproic acid, and/or phenobarbital. Thus the seizures in these patients were refractory to conventional treatments. The starting loading dose of LCM was 10 mg/kg/dose (maximal dose of 400 mg/dose) followed by the maintenance dose of 1-10 mg/kg/day which was administered twice per day for three days. LCM was given orally after the discontinuation of LCM i.v. Cessation of seizures was defined as the disappearance of EEG seizure activity (all patients with a diagnosis of nonconvulsive status epilepticus underwent continuous EEG monitoring) or the disappearance of previous ictal symptoms without any suspicion of ongoing subclinical seizure. The response to the treatment was defined by a comparison of baseline seizure frequency 1 month prior to the study to the frequency during i.v. LCM treatment at 24 hours and 1 week. It was classified as seizure-free, >75% reduction, >50% reduction in seizures, and ineffectiveness (all patients with less than 50% reduction). Children and adolescents with more than 50% reduction in seizure frequency during a minimum period of 1 week were considered responders. Wilcoxon rank test was used for statistical comparison between seizure frequency 1 month before the study and after using LCM i.v. for 24 hours and 1 week. Immediate side effects within 48 hours and short-term side effects (within 1 week) of i.v. LCM administration were also noted. Twelve patients met the inclusion criteria, but one was excluded from the study due to a noncompliance. Therefore, eleven patients were included in the study. Nine patients (81.8%) had acute repetitive seizures, and two (18.2%) had nonconvulsive status epilepticus. The demographic data are shown in the Table 1 . The patients were aged 7-16 years (median age 11 years) and were predominantly female (72.7%). Most patients (90.9%) had underlying preexisting epilepsy including focal epilepsy of unknown etiology (36.3%) and Lennox-Gastaut syndrome (27.2%) and had received a median of 3.5 AEDs (range 2-5) concomitantly. The mean age at seizure onset was 4.4 ± 4.3 years. Lacosamide was administered as the second-order and third-order antiseizure medication in 5 of 11 (45.4%) and 4 of 11 (36.4%) patients, respectively. A 9-year-old boy with a history of neuronal ceroid lipofuscinosis with acute repetitive seizures, in bedridden status, was admitted to the Phramongkutklao Hospital due to community-acquired pneumonia and had myoclonic seizures more than 100 times per day. Despite antiepileptic treatment which included topiramate 10 mg/kg/day, clonazepam 6 mg/kg/day, levetiracetam 40 mg/kg/day, valproic acid 60 mg/kg/day, and lamotrigine 6 mg/kg/day, the epilepsy was poorly controlled. At admission, intravenous benzodiazepine was started, followed by intravenous levetiracetam at 30 mg/kg/dose. Despite the treatment, the patient continued to have ARS, and therefore intravenous LCM was initiated (loading dose 8 mg/kg/dose followed by maintenance dose 5 mg/kg/dose twice per day). The patient experienced an 85% decrease in seizure frequency in 24 hours and a 70% decrease by the end of the study. Intravenous LCM is known to be an effective and well-tolerated treatment for SE and ARS in hospitalized adult patients . Currently, there are only limited data from retrospective trials in children. Arkilo et al. published a retrospective study of 47 pediatric patients who received intravenous LCM. The initial dose ranged from 2 to 10 mg/kg, with the effectiveness of 65%. Sedation was noted in 5 children without any other identified adverse events . Grosso et al. published a retrospective case study of 11 pediatric patients with status epilepticus who were administered intravenous LCM as third or higher line of antiseizure medications. Seizure cessation was observed in 45% of patients, with no identified serious adverse effects with high loading dose up to 14 mg/kg/day . Poddar et al. published a retrospective study of 9 pediatric patients receiving intravenous LCM for the treatment of status epilepticus. In this study, the success rate was 77.8%, and 44.4% of patients became seizure-free. Better outcomes were observed when LCM i.v. was given earlier with adequate dosing. The mean initial loading dose was 8.7 mg/kg. Bradycardia occurred in one patient within 24 hours after initiating LCM, but no other adverse effects were reported . Sample sizes in our study are similar to those in previously published studies, and our results support earlier findings regarding the efficacy and adverse effect profile of LCM. No significant adverse reactions or drug-drug interactions were observed. One patient from our cohort had transient bradycardia, which resolved without intervention, and the patient was hemodynamically stable. Extending previous reports, our study also demonstrated statistically significant reduction in seizure frequency at 24 hours and 1 week after initiation of i.v. treatment with LCM. There is a recent study on the possible association between LCM treatment and a change in CRMP2 function . The exact contribution of this reorganization to epileptogenesis is not yet fully understood. In a mouse model, CRMP2 has been associated with neurodegenerative diseases including NCLs . Due to this association, LCM may be a therapeutic option for NCLs or other neurodegenerative diseases, but available clinical data is limited. Interestingly, our study included one patient with the NCL who had favorable outcome in seizure frequency. We followed up with this patient every week for two months. His mother reported that the seizure frequency decreased more than 50% while the patient continued to take LCM orally. Therefore, our observation can provide a foundation for future use of LCM as an antiepileptic drug for the treatment of this particular disease.
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Other
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biomedical
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en
| 0.999998
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30050947
|
To overcome these disadvantages, a large number of biomaterials have been used alone or in combination with autografts in augmentation procedures [ 8 – 19 ]. Among the osteoconductive materials, allografts (fresh-frozen bone, freeze-dried bone, demineralized freeze-dried bone), xenografts (of bovine, equine, or porcine origin), and alloplastic materials (different combination of calcium-phosphate, bioactive glasses, polymers) were described in the dental literature as being able to enhance bone formation. Furthermore, several studies have shown that the biomaterials may not adversely influence clinical outcomes and implant survival when compared to autogenous bone . Six patients (3 males, 3 females, aged 50–72 years) who were healthy, nonsmokers, and with good oral hygiene were recruited in this study among those referred to Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, for implant-supported rehabilitation in the posterior atrophic maxilla ( Table 1 ). Inclusion criteria were maxillary partial edentulism in the premolar/molar areas, with a residual bone crest measuring ≤ 4 mm in vertical height and 3 to 5 mm in horizontal thickness as measured on computerized tomography (CT) scan. Exclusion criteria were being pregnant or lactating females, patients with impaired systemic conditions, smoking habit, and maxillary sinus pathology. After clinical and radiographic evaluation, the patients signed a written informed consent form to study participation. Surgery was performed under sterile conditions and local anesthesia (mepivacaine 2% with epinephrine 1:100.000, Carbocaine, AstraZeneca, Italy). A lateral window technique was used for sinus floor elevation. A slightly palatal crestal incision and two vertical releasing incisions were made mesial and distal on the buccal mucosa according to the sinus anatomy to elevate a mucoperiosteal flap ( Figure 1(a) ). On the lateral side of the sinus wall, the oval-shaped bony window was performed, with the inferior border about 5 mm from the alveolar crest and the superior portion left intact, to create a trapdoor effect ( Figure 1(b) ). The sinus membrane was carefully raised and, together with the bony window, was rotated inward and upward ( Figure 1(c) ). The subantral cavity was packed with the graft material ( Figure 1(d) ) and a resorbable membrane (Bio-Gide, Geistlich Biomaterials Italy S.r.l.) was placed over the lateral wall defect ( Figure 1(e) ). The mucoperiosteal flap was replaced and stabilized with resorbable interrupted sutures (5-0 Vicryl, Johnson & Johnson Medical, Norderstedt, Germany), which were removed after 2 weeks ( Figure 1(f) ). Postoperatively, the antibiotic therapy was prescribed for 1 week (Amoxicillin 875 mg + Clavulanic acid 125 mg twice a day) and, if necessary, the analgesic therapy was continued with Ketoprofene 200 mg. After 6 months clinical and radiographic examinations were performed and each patient was reappointed for biopsy and implant placement in the same location. Under local anesthesia, a full thickness flap was raised and a bone biopsy was performed using a 3.5 mm trephine bur under sterile saline solution irrigation, guided by the radiographic/surgical template in the selected implant site. A total of six bone samples were retrieved from the occlusal aspect of the alveolar crest, one from each augmented site and at least two implants (NobelParallel CC or NobelSpeedy, Nobel Biocare Italiana S.r.l., Italy), were placed according to the manufacturer's indications (Figures 1(g) , 1(h) , and 1(i) ). Under randomized conditions, each sinus augmentation procedure was carried out using one of the following six commercial bone substitute materials: mineralized solvent-dehydrated bone allograft (MCBA, Puros®; Zimmer Dental GmbH, Freiburg, Germany); freeze-dried mineralized bone allograft (FDBA, Organizzazione Toscana Trapianti, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy); anorganic bovine bone (ABB, Bio-Oss®, Geistlich Biomaterials Italia S.r.l.); equine-derived bone ( EB osteOXenon®- Bioteck S.p.A., Arcugnano (VI), Italy); synthetic micro-macroporous biphasic calcium-phosphate block consisting of 70% beta-tricalcium phosphate and 30% hydroxyapatite (HA- β -TCP 30/70, BioCer Entwicklungs GmbH, Bayreuth, Germany); and bioapatite-collagen ( BC, Biostite™, GABA Vebas San Giuliano Milanese, MI, Italy). The bone cores were retrieved and were immediately stored in 10% buffered formalin and processed to obtain thin ground sections. The specimens were processed using the Precise 1 Automated System (Assing, Rome, Italy) . The specimens were dehydrated in a graded series of ethanol rinses and embedded in a glycol methacrylate resin . After polymerization, the specimens were sectioned, along their longitudinal axis, with a high precision diamond disk at about 150 μ m, and ground down to about 30 μ m with a specially designed grinding machine Precise 1 Automated System (Assing, Rome, Italy). Three slides were obtained from each specimen. These slides were stained with acid fuchsin and toluidine blue and examined with transmitted light Leitz Laborlux microscope (Leitz, Wetzlar, Germany). Histomorphometry of the percentages of newly formed bone, residual grafted material, and marrow spaces was carried out using a light microscope (Laborlux S, Leitz, Wetzlar, Germany) connected to a high-resolution video camera (3CCD, JVCKY-F55B, JVC, Yokohama, Japan) and interfaced with a monitor and PC . This optical system was associated with a digitizing pad (Matrix Vision GmbH, Oppenweiler, Germany) and a histometry software package with image capturing capabilities (Image-Pro Plus 4.5, Media Cybernetics Inc., Immagini & Computer Snc, Milan, Italy). Mineralized solvent-dehydrated bone (MCBA). At low magnification, trabecular bone with large marrow spaces and biomaterial particles was observed ( Figure 3(a) ). The biomaterial particles showed different sizes and they were partially surrounded by newly formed bone. Newly formed bone was characterized by large osteocyte lacunae and bridged up greatest part of the biomaterial particles ( Figure 3(b) ). In some fields, osteoblasts were observed in the process of apposing bone directly on the particle surface. In the marrow spaces only few inflammatory cells were detected. Histomorphometry showed that newly formed bone represented 20.1%, marrow spaces 57.5% and the residual graft material 22.4%. Freeze-dried mineralized bone allograft (FDBA). At low power magnification, newly formed bone with marrow spaces and particles of residual biomaterial was present. In a marginal portion of the sample, preexisting bone with small remodeling areas could be observed ( Figure 4(a) ). At high power magnification, in some fields, the biomaterial particles were completely osseointegrated and areas of bone neoformation could be observed also inside the particles. Some of the biomaterial particles showed irregular margins, typical of a resorption process ( Figure 4(b) ). Bone neoformation areas could be seen both in contact with the biomaterial particles and in the marrow spaces, where few spindle cells could also be detected. Histomorphometry showed that newly formed bone represented 32.1%, marrow spaces 47.8%, and the residual graft material 20.1%. Anorganic bovine bone (ABB). At low power magnification, the specimen appeared to be formed by two separate fragments, each presenting several residual biomaterial particles ( Figure 5(a) ). At high power magnification, most of the biomaterial particles showed areas of bone neoformation in tight contact with the biomaterial surface ( Figure 5(b) ). The newly formed bone in contact with the biomaterial particles showed wide osteocyte lacunae, typical of a young bone. In some fields, new bone formation inside the biomaterial particles could be observed. Histomorphometry showed that newly formed bone represented 16.1%, marrow spaces 46.7% and the residual biomaterial 37.2%. Equine-derived bone (EB). At low magnification, trabecular bone with large marrow spaces and biomaterial particles was observed ( Figure 6(a) ). The particles were located in the apical portion of the biopsy and they were surrounded by new bone. In many fields the bone was in strict contact with the granules and in some areas osteoblasts were observed in the process of apposing bone directly on the particle surface ( Figure 6(b) ). Many large vessels could be detected. No inflammatory cells, or multinucleated giant cells, were present around the biomaterial or at the interface with bone. Histomorphometry showed that newly formed bone represented 22.8%, marrow spaces 47.1%, and the residual graft material 30.1%. Synthetic micro-macroporous biphasic calcium-phosphate (HA- β -TCP 30/70). In the examined sample, newly formed trabecular bone and preexisting bone with marrow spaces and residual biomaterial could be observed ( Figure 7(a) ). At low power magnification, the residual biomaterial was surrounded by newly formed bone and no gaps were present at the bone biomaterial interface. In some portions of the specimen the graft seemed to undergo resorption ( Figure 7(b) ). No inflammatory cells or multinucleated giant cells were present around the biomaterial or at the interface with bone. Many small and large sized vessels could be observed. Histomorphometry showed that newly formed bone represented 20.3%, marrow spaces 41.8%, and the residual graft material 37.9%. Bioapatite-collagen (BC). In the examined sample, trabecular bone with marrow spaces and residual biomaterial was observed ( Figure 8(a) ). Specifically, half of the sample was formed by residual biomaterial surrounded by newly formed bone, while in an apical portion of the sample many particles were partially covered by connective tissue. The new bone produced a network, ‘‘bridging” between the particles ( Figure 8(b) ). In a few fields, osteoblasts were observed in the process of apposing bone directly on the particle surface. Marrow spaces were colonized by small and large blood vessels in close proximity to the new bone and the biomaterial particles. Moderate inflammatory infiltrate and multinucleated giant cells, probably osteoclasts, were observed directly on the biomaterial particles surface ( Figure 8(c) ). Histomorphometry showed that newly formed bone represented 21.4 %, marrow spaces 53.3%, and the residual graft material 25.3%. Sinus augmentation is a well-documented technique for creating adequate bone volume to successfully place dental implants in resorbed maxillary posterior regions . However clinical and histological outcomes regarding bone substitute materials still remain open areas of investigation because an ideal grafting material should provide biologic stability, ensure volume maintenance, and induce a high rate of formation of vital bone and bone remodeling . Although numerous studies have compared grafting materials after sinus augmentation [ 7 , 9 , 16 , 19 , 27 , 37 – 39 ], no one has compared histological and histomorphometric results of MCBA, FDBA, ABB, EB, HA-TCP (30/70), BC, using a standardized two-stage sinus augmentation model. From the present histologic investigation, the MCBA sample showed the highest biocompatibility, because no signs of acute inflammation were present, which was furthermore affirmed by the ability to form and maintain new bone bridging the greatest part of the biomaterial particles, as reported by other previous studies . The use of MCBA tends to result in a slightly lower level of new bone formation compared to autologous bone, even if this tendency was not significant in a meta-analysis . At the histomorphometric examination the percentage of new bone (20.1%) was lower than the percentage found by Schmitt et al. (35.41%) , while the residual biomaterial (22.4%) was comparable to the value reported for other graft materials . Moreover, our results agreed with histologic examination of NOUMBISSI et al. , in which the graft turnover (resorption and replacement by new bone) occurred more rapidly in MCBA. Histomorphometry of FDBA sample showed that newly formed bone represented 32.1%, the highest value among the compared biomaterials. This data was similar to results of Kolerman et al. , who reported 27.5%, but lower than 41.1% described by Cammack et al. and confirmed the capability to form a larger volume of bone in shorter times during clinical trials, as reported by other investigations . Sbordone et al. found that FDBA had similar outcomes compared to autogenous bone in sinus grafting procedure even when the residual floor thickness was less than 3 mm . Furthermore, the evidence of resorption phenomena in our histology confirms that this material could influence long-term results in regenerated sites . ABB was used as grafting material in a great number of studies, taking advantage of its well- known osteoconductive properties . Some authors showed that microvascular density at 6 months in sinus augmented with ABB was not significantly different from microvascular density in sites augmented with autogenous bone . In the present investigation ABB sample showed areas of new bone formation in close contact with the biomaterial surface and no signs of inflammation, suggesting a neutral interaction of the grafted particles with the new bone tissue. Moreover, compared to the other biomaterials at the histomorphometric examination, ABB showed the lowest percentage of newly formed bone (16.1%) and a higher amount of remaining biomaterial (37.2%). This no homogenous bone structure could, avoiding bone resorption, guarantee long-term stability of the augmented maxillary sinus . Indeed, Mordenfeld et al. showed long-term maintenance of these results after 9 years and Traini et al. after 11 years. On 3D reconstruction and quantitative analysis, the HA/TCP scaffolds exhibited good performances in terms of both bone regeneration and vascularization, independently of the specific scaffold morphology (i.e., granules or blocks) . However, Giuliani et al. reported that the scaffold morphology could influence the long-term kinetics of bone regeneration by showing that block-based specimens presented better results than granule-based samples . The data of the present study is in agreement with other investigations concerning bone formation in maxillary sinus augmentation with HA-beta-TCP (30/70), after a healing period of 6 months . The histological and histomorphometric aspects of BC sample were similar to those of the other materials tested and confirm the osteoconductive property of this biomaterial as shown in previous studies . Moreover, the plastic and spongy consistency of this biomaterial renders it very easy to handle and to shape with scissors, allowing it to be used in sinus augmentation procedures without any membrane, in contrast to granular grafts, as suggested by some authors . Lastly the presence of collagen and glucosamine improves, respectively, fibrin formation and bone mineralization process as confirmed by Maiorana et al. .
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Other
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biomedical
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en
| 0.999996
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30241181
|
In March 2016, this patient presented with symptoms of cough, weight loss, hyporexia, and dyspnea. Initial work-up demonstrated a 3.1 × 2.3–cm posterior left upper lobe mass, multiple bilateral lung micronodules, as well as several enlarged lymph nodes (ipsilateral hilum, bilateral upper paratracheal, and para-aortic sites). Pulmonary transbronchial biopsy revealed an adenocarcinoma . 18 F-labeled fluorodeoxyglucose positron emission tomography showed increased uptake in primary mass, enlarged lymph nodes, and lymphangitic carcinomatosis (T2aN3M1a). This patient was administered erlotinib 150 mg/day concomitant with his immunosuppressant medications. The treatment was well tolerated, with only grade 1 skin toxicity after 3 weeks of erlotinib administration. After 5 weeks of treatment with erlotinib, the patient developed left pleural effusion, requiring thoracentesis and pleurodesis with immediate clinical improvement. After 7 weeks, a computed tomography scan showed progressive pleural, parenchymal, and mediastinal disease; chemotherapy with carboplatin and pemetrexed was started . No dose reduction or discontinuation was required. As of this writing, the patient presented with a partial response to chemotherapy and is receiving pemetrexed maintenance therapy. Lung cancer after solid organ transplantation seems to occur at a higher frequency than in the nontransplanted population, especially after heart transplantation. 3 Several studies have described potential risk factors (eg, age at transplantation, older age, male sex, smoking history, use and time of immunosuppression). 4 It is estimated that the mean interval between transplantation and diagnosis is approximately 35 months. One-year and 3-year survival after cancer diagnosis were estimated as 60% and 52%, respectively. 5 The management of advanced lung cancer in transplant recipients is complex as a result of many factors, such as the lack of cancer immunosurveillance, potential increased susceptibility to infections in patients receiving both chemotherapy and immunosuppressive treatments, unknown pharmacokinetic/pharmacodynamic interactions between oral tyrosine kinase inhibitors (TKIs) and immunosuppressive agents, and comorbidities. In addition, no large studies have established the safety and efficacy of epidermal growth factor receptor (EGFR)-TKIs in patients receiving immunosuppressive therapy, and those patients are usually excluded from clinical trials. The pharmacokinetic/pharmacodynamic effects of the combination of erlotinib (as well as other EGFR TKIs) and immunosuppressive agents are not well documented. However, it is recognized that CYP3A4 has an important role in the metabolism of erlotinib; likewise, CYP3A4-mediated metabolism occurs with tacrolimus, with potential increases or decreases in plasma levels of these drugs. As a consequence, clinically significant variations in plasma levels can occur, leading to unexpected adverse effects or lack of efficacy of these drugs. In this case, we did not check plasma concentrations of erlotinib as a possible explanation for disease progression after only 2 months in a patient with an EGFR deletion in exon 19.
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Clinical case
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clinical
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en
| 0.999996
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30363240
|
A 39-year-old machine operator presented with a 10-month history of pain, paresthesia and difficulty with dorsiflexion of the left foot. The pain initially commenced in his left hip, and then extended to the level of his left knee and calf after a further 2 and 5 months, respectively. Symptoms involved the plantar aspect of his left foot and hallux shortly thereafter. Cycling aggravated his symptoms. On examination, he was unable to flex his left hallux at the inter-phalangeal joint. He had reduced sensation on the plantar aspect of his first to fourth toes. Of note, he had no muscle wasting. MRI of the left knee demonstrated a multilobulated lesion with a vertical orientation in the vicinity of the proximal tibial nerve commencing at the popliteal fossa; this was 9.2 cm in length—as seen on the sagittal and coronal T 2 turbo spin echo fat-saturated images . Axial images display peripheral enhancement of the tubular cystic mass involving the tibial nerve within its sheath extending from the popliteal fossa to the gastrocnemius muscle bellies . The constellation of findings was believed to represent a multilobulated ganglion and was likely contiguous with the posterior joint capsule. Surgical exploration of the posterior leg revealed a firm multiloculated mass within the nerve sheath from the proximal end of the popliteal fossa deep to the lateral gastrocnemius muscle belly origin over a length of 22 cm. It was intimately related to the tibial nerve over this length making the dissection challenging. The nerve was preserved throughout. During dissection from the epineural sheath, a portion of the mass was entered and the typical gelatinous fluid of a ganglion cyst was encountered . There was no apparent communication with the knee joint, but the distal end passed deep to the origin of the lateral gastrocnemius muscle belly—heading in the direction of the proximal tibiofibular joint. Histology revealed a fibrous walled cyst measuring 15.5 cm in length. The apparent lining of the cyst was not true epithelial or endothelial lining, which was consistent with a pseudocyst or ganglion. The aetiology of these cystic structures is presumed to be secondary to trauma and synovial herniation, but remains unclear. Numerous hypotheses have been proposed for the pathogenesis of intraneural ganglia. Some of the earlier literature describe a degenerative process of connective and perineural tissue secondary to chronic mechanical “wear and tear.” Intraneural haemorrhage following trauma and the resultant formation of cysts after resorption of the bleed have also been proposed. However, this explanation is not convincing as the presence of haemosiderin deposits has been an infrequent finding. Trauma has also been implicated as a potential cause of this tumour formation, with several of the case reports indicating a history of trauma, albeit remote. Adn et al feel that trauma is more of a contributing factor rather than a causative factor. A new description based on analysis of clinical, operative and radiological findings has favoured a synovial origin of these intraneural ganglion cysts. This proposes that an articular nerve branch from a joint can act as the conduit for synovial fluid to leave the joint, which may be degenerative or traumatized. This was deemed the “unifying articular theory,” which was originally suggested for the intraneural ganglion cyst arising within the peroneal nerve. This was then later modified to include the tibial nerve as well. 5 Definitive treatment consists of surgical excision, with preoperative planning aided by MRI. The most recent treatment option entails decompressing the intraneural ganglion cyst, followed by disconnecting the articular branch and then resecting the synovium. Partial cyst persistence, or cyst recurrence is most often due to incompletely disconnecting the articular branch. Similarly, inadequate resection of the synovium can lead to extraneural occurrences. 5 New literature has described minimally invasive decompression techniques for the treatment of patients with intraneural ganglion cysts of the tibial nerve, the goal being to reduce nerve compression and secondary muscle denervation in patients wanting to avoid an open surgical approach. However, long-term follow-up studies are needed to determine cyst recurrence. 3
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Clinical case
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clinical
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en
| 0.999998
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30443451
|
A poorly feeding neonate presents the clinician with a diagnostic challenge. Frequently, feeding difficulties and irritability are attributed to sepsis, a common presentation in the immediate neonatal period that can present without other classic signs such as fever or temperature instability . However, the differential diagnosis of a poorly feeding and irritable neonate is broad and includes other conditions such as congenital heart disease, inborn errors of metabolism, non-accidental head trauma, neurological disease, as well as a vast variety of other pathologies . We present a case of a neonate with poor feeding secondary to a space occupying spinal cord tumor. A four-week-old female born at term via unremarkable spontaneous vaginal delivery presented with a one-week history of irritability, poor feeding, and progressive somnolence. Prior to the onset of symptoms, her newborn period was unremarkable with good appetite, growth, voiding, stooling, and weight gain. Per parental report, she had a normal neurological exam in the nursery and at her newborn and two-week well child evaluations. She then began to have progressive feeding difficulty, becoming very irritable with feeds. She also became irritable with any attempted movement of her upper extremities. There were no fevers or hypothermia noted at home. Family and social histories were noncontributory. On physical examination, she was afebrile with a heart rate of 130 beats/minute, respiratory rate of 40 breaths/minute, and irritable with any attempts at examination. Her head was normocephalic and her fontanel was soft and non-bulging. Her cardiac exam was without murmurs, her lungs were clear bilaterally, and her capillary refill was less than two seconds. Neurological examination was notable for absent bilateral Moro reflexes and decreased bilateral upper extremity grasp reflexes. Emergent computed tomography of her head was negative for an acute intracranial process. She was admitted to the inpatient ward where a lumbar puncture yielded slow-flowing, grossly xanthochromic fluid containing 132 nucleated cells with a normal differential. Ampicillin and cefotaxime were started. Blood, urine, and spinal fluid cultures were negative. She remained irritable and, over the next 12 hours, developed progressive hypotonia and areflexia of her bilateral lower extremities. Magnetic resonance imaging (MRI) of her brain was subsequently performed, which was also negative for acute intracranial pathology but demonstrated signal enhancement in the proximal cervical spinal cord . Due to this finding, further imaging with cervical, thoracic, and lumbar MRI was completed, revealing a near holocord hemorrhagic, intramedullary mass . Neurosurgery and oncology were urgently consulted and the patient was taken to the operating room for surgical resection on hospital day three. Pathology confirmed the diagnosis to be a congenital immature teratoma. Central nervous system (CNS) teratomas are exceedingly rare. Teratomas make up approximately 3% of all pediatric tumors and 0.1% of all CNS tumors . Of these CNS teratomas, roughly 0.2–0.5% occur in the spinal cord . Teratomas are cystic or solid tumors that often consist of elements from all three germ layers and are most commonly found in the ovary in adult females and in the sacrococcygeal region in children . Depending on the amount of tissue differentiation, they are classified as either immature, mature, or malignant . Mature teratomas contain tissues that are appropriately developed, including bone, hair, teeth, nerve, cartilage, and muscle while immature teratomas contain more primordial tissues such as neuroepithelial tissue . Malignant teratomas may consist of elements of both immature and mature subtypes, but also contain fragments of other germ cell tumors such as yolk sac tumors or choriocarcinoma . The diagnosis is made histologically either via biopsy or at the time of surgical resection. Operative tumor removal remains the primary therapy and gross total resection offers the possibility of cure . There are case reports of adding adjuvant chemotherapy and radiation in the case of subtotal resection, although no standard of care exists for these treatments . In relation to our present study, we employed both total surgical removal as well as adjuvant chemotherapy to rid the patient of any residual tumor that might be present to enable remission of her CNS teratoma. The relative paucity of literature renders the prognosis of these tumors difficult to estimate, thus many patients with immature intramedullary teratomas have died within one year following surgery .
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Clinical case
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clinical
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en
| 0.999996
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30584577
|
Between July 2011 and September 2013, out of 23 finger replantation procedures, 13 patients with Tamai Zone I and Zone II distal amputations were not suitable for systemic heparinization due to history haemorrhoids or gastric ulcer disease ( Table 1 ). Inclusion criteria were as follows: any patient who had distal digital replantation with venous congestion in the first 4 hours after the initial replantation and was not suitable for systemic heparin due to the associated comorbidity and tendency to bleed. Exclusion criteria were as follows: congestion more than 4 hours and patients suitable for systemic heparin solution administration. Initial replantation was done with standard arterial microvascular anastomosis followed by venous anastomosis. Dorsal veins were primarily used to establish the venous drainage. However, the volar veins were used to establish the venous drainage in Tamai Zone I due to the difficulty to find suitable dorsal veins. Postoperatively, the digits were monitored for any ischaemia or congestion. If any venous insufficiency was noticed, then revision surgery was performed within 4 hours. If this failed, then heparin infusion was subcutaneously injected into the replanted part through a small skin incision. Out of the 13 patients who received subcutaneous calcium heparin for postreplantation venous insufficiency, six patients have started to receive the heparin on the same revision surgery day, five on day 1 postoperatively, and two on the 2nd postoperative day. The patients have received 6-10 doses of heparin with the mean of 7.3. Bleeding continued for 3 to 6 hours, with a mean duration of 4.3 hours after the first dose of 1000 units. The bleeding continued for a shorter period after the 2nd dose ranging from 2.5 to 5 hours with the mean duration of 3.6. The third and all the subsequent doses have nearly the same effect with mean duration of 3.4 hours ( Table 2 ).
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Other
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biomedical
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en
| 0.999996
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30593191
|
Autoimmune pancreatitis (AIP) is part of a disease called IgG4-RD that often affects multiple organs including bile ducts, salivary glands, kidney and lymph nodes. IgG4-related sclerosing cholecystitis involves the gallbladder, and has been reported to present as either diffuse thickening of the gallbladder wall or a localized mass mimicking gallbladder cancer. The standard treatment of IgG4-RD is oral administration of corticosteroid (CS), but surgical resection is sometimes performed because of the difficulty in differentiating IgG4-RD from malignancy. About 20% to 30% of IgG4-RD present with a relapse during the reduction of CS, however, how and where disease relapse occurs has not yet been established. Abdominal ultrasonography showed symmetric wall thickening with echogenic foci . The inner layer of the gallbladder wall was enhanced by intravenous perflubutane (Sonazoid, a second generation ultrasonographic contrast agent) injection. The surface of inner layer was smooth and laminated . T2-weighted MR image showed gallbladder wall thickening and its inner signal was homogeneous, and high signal intensity spot indicating Rokitansky–Aschoff sinus was not detected . Inflammatory changes such as xanthogranulomatous cholecystitis were strongly suspected; however, the possibility of malignancy could not be excluded, and we therefore performed cholecystectomy. CS is effective for induction of remission, however, about 20% to 60% of cases relapse after reduction of CS dose. [ 5 – 7 ] Yamamoto et al reported that 50% of IgG4-RD patients presented with new organ involvements at relapse. However, the specific organ in which IgG4-RD tends to recur remains unclear. Generally, serum IgG4 concentration at the time of diagnosis was reported to correlate with the increase in number of organs affected by the disease, more extensive organ involvement and shorter time to disease relapse. [ 9 – 11 ] On the other hand, there have been several reports that IgG4 related lesions appeared in different sites from the primary site despite no elevation of serum IgG4 level, which is similar to our current case. Thus, we could not predict recurrence of IgG4-RD based on change in serum IgG4 level alone. For example, circulating plasmablasts and non-aspartic acid residue at position 57 of HLA-DQβ1 were reported as new biomarkers to predict disease relapse, however, the usefulness of these biomarkers has not been established yet. [ 12 – 15 ] IgG4-related sclerosing cholecystitis involves the gallbladder. A systemic literature search was conducted to identify cases regarding IgG4-related sclerosing cholecystitis through PubMed search , with following keywords: “IgG4” OR “Immunoglobulin G4” OR “autoimmune”, “cholecystitis” OR “gallbladder,” 197 articles were initially identified. After screening and reviews of the reference lists, 12 cases of IgG4-related sclerosing cholecystitis have been previously reported (Table 1 ). [ 16 – 25 ] Including our case, 5 of 13 cases showed diffuse wall thickening, while the remaining eight cases presented with focal mass formation mimicking gallbladder cancer. Previous reports have indicated the difficulty in diagnosing IgG4-related cholecystitis for 2 major reasons; only 6 of 13 cases showed serum IgG4 levels of ≧135 mg/dL at the point of diagnosis, for pathological diagnosis, the usefulness of endoscopic ultrasonography fine-needle biopsy (EUS-FNA) is limited to the mass formation type. From this perspective, a distinctive morphological finding of IgG4 related cholecystitis is needed.
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Study
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biomedical
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en
| 0.999994
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30671566
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Abdominal computed tomography (CT) demonstrated a heterogeneous right adnexal mass measuring 57 × 53 mm with fatty components and calcification , consistent with a mature cystic teratoma of the ovary. Rupture of the teratoma was suspected because of a bulging fatty nodule on the anterior side of the lesion and ascites underlining thickened and enhancing peritoneal layers . A similar 2 cm left adnexal mass was observed . These findings are suggestive of bilateral ovarian teratomas with right rupture and chemical peritonitis. Mature ovarian teratomas have a wide spectrum of radiological presentation. The typical radiologic finding is intratumoral fat (in more than 90% of the cases). The most common ultrasound finding is a cystic mass with a densely echogenic protuberance (known as Rokitansky nodule) projecting into the cystic lumen; this nodule often contains tooth, hair, bony structures or sebaceous components. Some sonographic signs, such as tip-of-the-iceberg sign (only a part of the lesion is visible due to posterior acoustic shadowing) and dot-dash sign (multiple thin echogenic bands due to hair), help for the diagnosis. Computed tomography (CT) and magnetic resonance imaging (MRI) have excellent sensitivity and specificity, and CT is particularly helpful in bringing out tiny calcifications.
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Clinical case
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clinical
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30941333
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Common variable immunodeficiency is a primary immunodeficiency disorder characterized by hypogammaglobulinemia as well as poor humoral response to antigens or vaccines ( 1 , 2 ). CVID is clinically and genetically heterogeneous, with onset of disease during childhood or adulthood. Patients typically present with a history of recurrent sinopulmonary infections, though some may have a predominance of autoimmune or immune dysregulatory features. Treatment universally includes gammaglobulin replacement. Less than 20% of CVID patients are identified to have familial cases or gene defects resulting in autosomal recessive or autosomal dominant forms of the disease ( 3 , 4 ). In these forms of CVID, the genetic etiology provides a window into disease pathogenesis and potential disease complications that can develop over time ( 5 ). We present a case of a teenage patient with childhood-onset, autosomal dominant CVID caused by a heterozygous loss-of-function mutation in the gene NFKB2 [NF-κB2; MIM 615577] who developed an unusually severe cutaneous herpes vegetans infection and herpes simplex virus (HSV) viremia requiring aggressive disease management. An 18-year-old female was diagnosed with CVID at age six. As previously described in Chen et al. she, her mother, and younger brother were found to have a heterozygous pathogenic variant in NFKB2 that results in an autosomal dominant form of CVID ( 6 ). She developed autoimmune manifestations, including acquired central adrenal insufficiency, alopecia universalis, vitiligo, and nail dystrophy. Her infectious history was significant for both bacterial and viral respiratory infections, recurrent herpes simplex of the lips and surrounding perioral skin, and chronic candidal onychomycosis. Adrenal insufficiency was treated with maintenance doses of hydrocortisone and stress dose adjustments during times of illness. Early-onset hypogammaglobulinemia required lifelong gammaglobulin replacement to prevent recurrent sinopulmonary infections. Recurrent herpes simplex infection was controlled with chronic suppressive oral valacyclovir therapy. A Luminex-based assay of the patient's plasma [1:100 dilution, as described by Ding et al. ( 7 )] identified the presence of autoantibodies against interferon-α (IFN-α) and interferon-ω (IFN-ω) . Next, patient plasma was incubated with control peripheral blood mononuclear cells and STAT1 phosphorylation was measured by flow cytometry after incubation in unstimulated or stimulated conditions as described by Burbelo et al. ( 8 ). The patient's plasma demonstrated neutralizing anti-IFN-α and IFN-ω antibodies which inhibited STAT1-phosphorylation in control cells, whereas control and parental plasma did not lead to inhibition . The affected sibling's plasma also demonstrated neutralizing anti-IFN-α antibodies, and partial blockade of IFN-ω signaling. At 16 years of age, the patient required intensive care hospitalization for decompensated septic shock of unknown etiology requiring vasopressor support. Prior to the hospitalization she had become non-compliant with medications, including gammaglobulin replacement. She developed acute renal injury, electrolyte disturbances, and adrenal crisis secondary to sepsis of unknown etiology which required stress dosing of steroids and electrolyte replacement. During this time, hypomagnesemia resulted in torsades de pointes and prolonged QT syndrome. Her persistent renal injury required chronic daily oral electrolyte replacement to prevent recurrence of arrhythmias. Two years later, the patient presented to the emergency department with a month-long history of progressive, painful, vegetative facial lesions. The lesions initially developed periorally, similar to prior herpes simplex outbreaks. Despite increasing valacyclovir to treatment dosing, the lesions became purulent and continued to spread, involving the nose and right cheek. She was treated for presumed bacterial cellulitis with oral cefdinir. When a bacterial culture reportedly grew group B streptococcus, cefdinir was transitioned to oral clindamycin. Valacyclovir was discontinued as the lesions did not improve while on the medication. She reported tactile fevers and chills with continued progression of the vegetative lesions despite antibiotic treatment. Upon hospitalization, laboratory evaluation identified leukocytosis (neutrophils 7,000 cells/μl; lymphocytes 7,900 cells/μl) and elevated C-reactive protein (11.6 mg/dL; normal range 0–1.5 mg/dL). Natural killer (NK) cell expression of CD107a was reduced, and NK cell functional assays demonstrated reduced cytotoxicity (Cincinnati Children's Diagnostic Immunology Laboratory). Her cutaneous exam revealed exophytic, thick, yellow-brown plaques involving the bilateral nares, right oral commissure, and adjacent medial cheek. The plaques were exudative and distorted the nasal architecture . A wound swab from the medial cheek was positive for HSV by polymerase chain reaction (PCR) assay. Other bacterial or viral infections often seen in immunodeficient patients, including varicella zoster and cytomegalovirus (CMV), were ruled out. The patient's systemic symptoms raised concern for HSV viremia, and a HSV peripheral blood PCR was positive. She did not have any neurological symptoms or meningeal signs; thus, HSV meningitis or encephalitis were not suspected. HSV type-1 was isolated from tissue culture of affected skin on the medial cheek; pathology demonstrated spongiosis and mixed granulomatous dermal infiltration with fat necrosis. Intravenous foscarnet therapy resulted in rapid improvement of her cutaneous eruption, including the associated pain, and systemic symptoms . Slower, continued resolution occurred over several weeks . The patient had recurrence of HSV vegetans and HSV viremia 3 months later. On this second occasion, early identification of HSV as the source of skin infection led to expedited hospitalization and early initiation of antiviral therapy. She had a significantly shorter hospital course with transition to oral valacyclovir at discharge when HSV culture demonstrated susceptibility to acyclovir. Herpes vegetans is a rare, atypical cutaneous herpes simplex infection most commonly described in patients with acquired immunodeficiency due to HIV infection ( 9 – 11 ). Herpes vegetans has also been identified in other immunodeficient states, including CVID, congenital T-cell immunodeficiency, Good syndrome, malignancy, and those receiving immunosuppressive medications ( 12 – 15 ). Peripheral blood plasmacytoid dendritic cells from a patient with HIV-HSV coinfection had reduced IFN-α production, likely contributing to his severe, chronic HSV skin disease ( 16 ). Herpes vegetans can include exophytic, ulcerative, exudative, or verrucous lesions, and plaques. Tissue biopsy, direct immunofluorescence, and culture help confirm the diagnosis, guide the choice of antiviral therapy, and rule out other infectious etiologies or co-infections within the lesions. While acyclovir or valacyclovir are first-line therapies, acyclovir-resistant strains are often cultured from the lesions ( 11 , 12 ) for which alternative antivirals including foscarnet, topical imiquimod, or intralesional cidofovir, should be considered ( 16 – 18 ). In our patient case, intravenous foscarnet treatment was initiated due to concerns for acyclovir resistance in the setting of apparent lack of response to oral valacyclovir, severity of infection, rapid progression of disease, and presence of HSV viremia. Foscarnet treatment should include careful monitoring for renal toxicity and electrolyte abnormalities including hypomagnesemia, hypocalcemia, and hypokalemia. Monitoring for foscarnet toxicity was particularly important in this case, given the patient's history of prior renal injury, long QT syndrome, and torsades des pointes. In the setting of a primary immunodeficiency such as CVID, skin infections that are non-responsive to standard antibacterial therapies should raise concern for an atypical or opportunistic infection. In this particular case, herpes vegetans skin infection, herpes simplex virus (HSV) infection with antiviral resistance, and/or a superimposed fungal, bacterial, or atypical mycobacterial infection were all considered in the differential diagnosis. In the patient's family, all three CVID-affected family members had a history of recurrent HSV skin lesions. Not surprisingly, loss-of-function NFKB2 mutations, leading to defective NF-κB2 protein function in the non-canonical NF-κB pathway, have been associated with susceptibility to viral infections, including HSV, varicella, herpes zoster, and molluscum contagiosum ( 6 , 19 – 21 ). A NFKB2 gain-of-function mutation resulting in a combined immunodeficiency phenotype has also been reported to have increased susceptibility to viral infections. One such patient developed CMV enteritis, severe Epstein-Barr virus (EBV) infection, warts, and herpes labialis ( 22 ). Thus, knowledge of the molecular or genetic pathogenesis of CVID or other PIDDs can be extremely important in specific disease screening and treatment decisions. In addition to infections typically seen in all patients with CVID, NF-κB2-deficient CVID patients are susceptible to viral infections and can develop adrenal insufficiency. The unique association of ACTH deficient-adrenal insufficiency in this genetic primary immunodeficiency disorder adds to the complexity of care in acute and chronic settings; stress dosing of steroids is critical in preventing life-threatening episodes of hypoglycemia and other complications associated with adrenal crisis ( 6 , 20 , 23 ). At least two mechanisms may contribute to the increased susceptibility to viral infections in patients with NFKB2 defects: (1) Defective NK cell cytotoxicity has been described in a patient with CVID-like disease due to NFKB2 mutation ( 24 ); NK cells are critical in the cytotoxicity of virus-infected cells including herpes viruses ( 25 ), and (2) neutralizing anticytokine autoantibodies to interleukins and interferons have also been reported in an unrelated case of a CVID patient with a loss-function mutation in NFKB2 who had severe recurrent bacterial and viral infections that improved after treatment with the anti-CD20 B-cell targeting monoclonal antibody, rituximab. Post-treatment, the patient had a significant reduction of autoantibody titers and no recurrence of invasive infections ( 21 ). In the current case report involving severe herpes vegetans and HSV viremia, abnormal NK cell function as well as neutralizing anti-IFN-ω and anti-IFN-α antibodies were identified, likely contributing to the recurrent and severe nature of the patient's HSV infection, and rituximab is being considered as a treatment option. CVID is one of the most commonly treated primary immunodeficiencies, with an incidence of ~1:10,000 to 1:50,000 individuals ( 26 – 28 ). Criteria for diagnosis of CVID includes: (1) Significantly reduced immunoglobulin G serum levels as well as low levels of immunoglobulin A and/or immunoglobulin M, (2) poor or absent responses to antigens including immunizations, and (3) absence of any other well-defined primary or secondary hypogammaglobulinemic state ( 2 ). IgG serum levels vary significantly with age, and thus, care should be taken to use age-adjusted normal ranges in the evaluation of CVID. As some children may have transient hypogammaglobulinemia of infancy, a diagnosis of CVID is often not made until the child is at least 2–4 years of age. Though CVID is more often diagnosed in adulthood, one European cohort of more than 2,000 CVID patients found that onset of disease prior to 10 years of age occurred in 34% of the individuals. Thus, a diagnosis of CVID should be considered in any individual with recurrent sinopulmonary infections, or a constellation of recurrent or unusual infections along with autoimmune or immune dysregulatory disease manifestations. NF-κB2, encoded by the gene NFKB2 , is the principal protein of the non-canonical NF-κB pathway which has key roles in B-cell maturation, thymic development, and peripheral lymphoid organ development ( 29 , 30 ). Loss-of-function mutations in NFKB2 result in a highly penetrant form of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and in many cases, endocrinopathy, or ectodermal features ( 31 ). The presence of autoimmunity and endocrinopathy in NF-κB2 deficiency could be explained by the importance of NF-κB2 in thymic expression of the AIRE gene, as demonstrated in murine models ( 32 , 33 ). AIRE (autoimmune regulator) protein is required for development of central tolerance and elimination of self-reactive thymocytes. Reduced AIRE expression leads to the presence of circulating autoreactive T-cells, increasing susceptibility to autoimmune disease, and particularly in the endocrine system ( 34 , 35 ). Endocrinopathies seen in NFKB2 defects include ACTH-deficient adrenal insufficiency, hypothyroidism, and growth hormone deficiency. Ectodermal defects and autoimmune conditions include alopecia areata, trachyonychia, and vitiligo. Sinopulmonary infections are predominant, mucocutaneous candidiasis can occur, and as highlighted in this case, NFKB2- deficient patients can have increased susceptibility to herpesvirus infections. Recognition of primary immunodeficiency diseases including CVID and NFKB2 defects allows for improved disease screening, targeted therapies, and the potential for research involving curative treatment.
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31019334
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Tuberculosis continues to be a major global health problem. According to the World Health Organization, it is the leading infectious cause of death worldwide ( 1 ) . It is also a significant cause of morbidity and mortality in children living in tuberculosis-endemic areas ( 2 , 3 ) . In 2016 alone, approximately 10.4 million new cases of tuberculosis were diagnosed worldwide, and there were approximately 1.7 million deaths from the disease. In that same year, there were 66,796 new cases in Brazil, which now ranks 18th on the list of the 20 countries with the highest tuberculosis burden. Brazil accounts for 0.9% of the estimated cases worldwide and 33% of those in the Americas. In comparison with other Brazilian states, Rio de Janeiro has the second highest rate of tuberculosis incidence-61.2/100,000 population-and the highest rate of tuberculosis-related mortality-5.0/100,000 population ( 4 ) . Tuberculosis is an infection of the airways. Most children acquire the infection at home after having been in contact with active tuberculosis cases (parents or caregivers). Adults with tuberculosis infect children in 30-40% of such cases, even when their infection is paucibacillary, with negative sputum culture results ( 3 ) . However, large pulmonary cavities are the most important factor determining how contagious the disease will be, because the high concentration of oxygen in such lesions favors an intense multiplication of bacilli, transforming tuberculosis patients into a significant source of environmental contamination ( 1 , 5 ) . The extent of lung involvement is another important factor for contagiousness, because the bacterial load, cough intensity/frequency, and the number of cavities can determine the propagation of the bacillus. In individuals with no prior contact with the bacillus, the primary infection can progress subclinically. When primary infection manifests as a disease, it is called primary tuberculosis ( 1 ) . Most cases of pulmonary tuberculosis in children are primary ( 6 - 14 ) . Given the difficulty in detecting bacilli in clinical specimens collected from children, the diagnosis of childhood tuberculosis is often based on the tuberculin skin test results, as well as on epidemiological, clinical, and radiological evidence ( 3 ) . Diagnosing tuberculosis in children poses a major challenge. Many pediatric patients (65-95%) present with nonspecific clinical findings or a nonproductive cough. Therefore, the diagnosis of tuberculosis in this age group depends on a thorough anamnesis, a complete screening of contacts, and radiological imaging ( 3 , 6 , 9 , 12 ) . The World Health Organization recommends that tuberculosis be diagnosed on the basis of contact tracing and chest X-rays, even in the absence of a positive tuberculin skin test. However, chest X-rays are not a good indicator of tuberculosis in children, because they have a sensitivity of only 40% ( 8 ) . That could have negative consequences for children with a history of contact with tuberculosis, in whom normal chest X-ray findings might lead to diagnosis of latent tuberculosis infection instead pulmonary tuberculosis, and hence undertreatment only with isoniazid instead a complete treatment with four drugs. Computed tomography (CT) is superior to conventional chest X-ray and can detect changes in children whose chest X-rays are normal or inconclusive ( 8 ) . In comparison with conventional chest X-rays, CT scans are much more sensitive in detecting the cavitations that can occur in children ( 5 , 6 ) . CT is also the method of choice to detect mediastinal and perihilar lymph nodes, which are very common in childhood tuberculosis, even if the lymph nodes are small ( 11 ) . CT shows lymph node enlargement in 60% of tuberculosis patients whose chest X-rays are normal ( 8 ) . In addition to mediastinal abnormalities, high-resolution CT scans can reveal findings in the lung parenchyma-such as miliary and centrilobular nodules-in patients with no evidence of such lesions on conventional chest X-rays. Studies on chest X-ray findings of tuberculosis in children under 36 months of age are relatively scarce in the literature, and such studies typically employ conventional chest X-rays ( 4 , 6 , 8 , 11 - 26 ) . We were motivated to conduct this study because we were made aware of CT findings of pulmonary cavitation in infants with tuberculosis in the radiology departments of two different hospitals in the state of Rio de Janeiro, Brazil. The main objective of the study was to describe the radiological findings of tuberculosis in children under 36 months of age. We present a detailed definition of the most common high-resolution CT findings in such patients, with the aim of helping reduce errors and delays in the diagnosis of tuberculosis among immunocompetent patients in this age group. This was a study of 20 consecutive cases of tuberculosis in immunocompetent children 1-36 months of age seen at two public hospitals in the state of Rio de Janeiro, Brazil between January 2004 and July 2013. The inclusion criteria were as follows: having undergone a chest X-ray and a CT scan at both hospitals; being ≤ 36 months of age; and having been diagnosed with pulmonary tuberculosis, as per the below-mentioned criteria. Children with any form of immunosuppression (HIV/AIDS, lymphoproliferative disease, or immunosuppressive drug therapy) were excluded from the study. The study was approved by the human research ethics committees of both institutions, in compliance with the ethical standards currently in force. A diagnosis of tuberculosis was established when two or more of the following criteria were met: positive bronchoalveolar or gastric lavage culture; previous contact with an adult with active tuberculosis; positive tuberculin skin test; and regression of radiological and clinical signs after the institution of specific treatment. We could not find any other possible causes for the clinical and radiological findings in any of the patients. All of the patients presented complete remission of symptoms and radiological improvement after the initiation of treatment for pulmonary tuberculosis. All patients underwent conventional posteroanterior chest X-rays as part of the initial assessment and were under radiographic follow-up for a mean period of two years. CT scans were performed 1-10 days after the chest X-ray (mean: 6 days). The indications for CT included the following: to investigate unusual findings on chest X-rays, such as mass-like pseudotumors and diffusely distributed nodules; to identify or confirm lymph node enlargement; to detect or evaluate complications, such as narrowing of the upper airways, atelectasis, emphysema, and pleural or pericardial tuberculosis; and to clarify diagnoses of cystic adenomatoid malformation, mediastinal tumor, or infectious neurological complications. All chest CT scans were obtained through volumetric acquisition with 5-mm collimation, after intravenous administration of iodinated contrast for the assessment of the mediastinum, with a slice thickness of 0.6-1 mm, an interslice gap of 8-12 mm, and a high-resolution technique to assess the lung parenchyma. Following the "as low as reasonably achievable" principle, which refers to the mandatory principle of keeping radiation doses applied to patients and technical staff as low as reasonably possible, the peak kilovoltage (kVp) and milliamperage (mAs) parameters were adjusted to 120-100 kVp and 30-100 mAs, respectively ( 27 ) . When necessary, sedation with a single dose of 80 mg/kg of 16% oral chloral hydrate was used, and there were no sedation-related complications. All chest X-rays and CT scans were reviewed. We then described the radiological findings, according to their type, number, location, and characteristics, using the terminology found in the radiology literature of Brazil ( 28 ) . The type and frequency of local and systemic complications were also registered. Two radiologists, working independently, analyzed all of the images, and any disagreements were resolved by consensus. The following data were evaluated: age and gender; multiple simultaneous radiological findings; consolidation/atelectasis; cavitation; nodules (size and type); ground-glass opacities; hilar or mediastinal lymph node enlargement, with or without calcifications; airspace disease; signs of upper airway obstruction; local complications; and systemic complications. Airspace consolidations, with or without atelectasis, were found in all 20 patients . A mass-like consolidation (pseudotumor) was found in one case only . Cavitations were seen in 10 (50%) of the patients , although they differed in some respects. A six-month-old infant presented cavitation and retractile opacities, accompanied by signs of chronic lung disease (honeycombing). All parenchymal cavitations were accompanied by radiological findings consistent with pulmonary consolidation and bronchial dissemination (airspace nodules, centrilobular nodules, and a tree-in-bud pattern), which most likely progressed from a primary focus, known as the Ghon complex. One patient had cavitations that evolved to extensive bullous lobar lesions and developed a systemic complication (meningoencephalitis). Nine patients (45%) had disseminated pulmonary nodules. In four of those patients (20%), the nodules were between 5 mm and 10 mm in diameter , whereas in the other five (25%), they were between 2 mm and 4 mm in diameter. Five of those nine patients also presented ground-glass attenuation. Only one patient presented miliary nodules , which were suggestive of direct hematogenous dissemination with concomitant involvement of the central nervous system. Children with tuberculosis present pathophysiological and immunological responses that differ from those seen in adults ( 8 ) . Most cases of childhood tuberculosis are primary, typically presenting enlarged lymph nodes and no cavitation. However, in some cases of primary tuberculosis in children, cavitations can develop, which might lead to confusion with post-primary, reactivation, or adult-type tuberculosis. Therefore, the only accurate predictor of this X-ray finding is the immune status of the patient, rather than the time since tuberculosis acquisition ( 9 ) . Knowledge about the pathophysiological progression of the disease is essential for understanding the pathogenesis of the chest X-ray findings ( 5 ) . Imaging tests have recently been the focus of studies in the radiology literature ( 29 - 35 ) . Although there have been several studies on the radiological imaging of childhood tuberculosis, our study is comparable only to those that have used CT and have involved patients in the same age group. Among such studies, those conducted by Delacourt et al. ( 15 ) , Kim et al. ( 6 , 14 ) , Pereira et al. ( 9 ) , and Peng et al. ( 7 ) are the most similar to ours. However, Pereira et al. ( 9 ) analyzed only four cases and Peng et al. ( 7 ) attempted to establish imaging differences between tuberculosis and community-acquired pneumonia. Our radiological findings were similar to the findings reported in those studies, except for the greater number of cases with cavitary lesions in our study. Lymph node enlargement is quite common in childhood tuberculosis and often manifests as extrinsic airway compression, which is a well-known complication of lymphadenopathy in primary tuberculosis. When the airway is partially obstructed, a ball-valve effect can occur, leading to distal hyperinflation; whereas when the obstruction is complete, the distal air is reabsorbed, leading to collapse of the lung parenchyma, with or without necrosis ( 5 ) . In tuberculosis, calcified lymph nodes and lymph nodes with central necrosis are common, although such lymph nodes are difficult to see on conventional chest X-rays ( 7 ) . In addition, conventional chest X-rays lack sensitivity to detect lymph node enlargement, which is the most important and common finding in childhood tuberculosis ( 10 ) . In the present study, lymph node enlargement was seen in 100% of the cases and calcified lymph nodes were observed in 35%. In 40% of the cases, lymphadenopathy caused bronchial compression. In 95%, the lymph nodes presented central necrosis. Obstruction of the upper airways by direct or indirect bronchial compression was another frequent finding (seen in 70% of the cases). The frequency of lymph node enlargement and its complications in the present study is in agreement with the findings of the aforementioned studies and underscores the importance of using CT in this clinical context ( 6 - 10 ) . Various studies have shown that consolidations are the most common imaging findings in childhood tuberculosis ( 3 , 5 , 6 , 8 , 9 , 11 ) . Airway involvement due to lymphadenopathy can lead to dissemination of the disease and the development of bronchopulmonary consolidations. The studies cited above have indicated the importance of persistent parenchymal opacities that do not improve after the use of antibiotics in this age group. Other studies ( 8 , 21 , 36 ) have reported mass-like pseudotumors-without satellite lymph node enlargement-in children under two years of age, although this is considered an uncommon finding. All of the patients in our sample presented consolidations. The radiological pattern of lobar consolidation was seen in 15 cases (75%). Consolidations with the appearance of a pseudotumor, resulting in a mass effect, were seen in one case. In the present study, parenchymal calcifications were seen in only two of the cases, both of them prior to the institution of specific treatment. Parenchymal calcifications were also seen in three of the four cases evaluated by Pereira et al. ( 9 ) , also before the specific treatment was initiated. In most studies ( 5 , 10 , 21 ) , calcifications were seen only after ≥ 10 months of follow-up. Marais et al. ( 2 ) stated that calcifications in preschool children are usually seen after a relatively short period of time. Those authors believe that their occurrence might be related to the immune response, disease progression, and initiation of specific treatment. They also believe that this finding could therefore be used as an additional diagnostic criterion for tuberculosis. In our sample, lymph node and parenchymal calcifications occurred in 40% of the patients and were probably related to an immune response evoked by long-standing disease, and calcification could therefore be considered another diagnostic criteria. When such calcifications are accompanied by lymphadenopathy, central necrosis, and signs of bronchogenic dissemination, a diagnosis of tuberculosis becomes more probable. It is common for cavitations to appear within consolidations. Chest CT usually shows areas of cavitation and parenchymal destruction that are not seen on conventional chest X-rays ( 4 ) . Kim et al. ( 6 ) , for instance, found cavitations within parenchymal lesions on the chest X-rays in two (8%) of 25 patients evaluated. However, 17 of those patients subsequently underwent CT, which revealed multifocal areas of low attenuation within consolidations in seven (41%) and well-defined cavitations in five (29%). The cavitation evolved to extensive bilateral bullous lesions in one patient, who subsequently died ( 6 ) . Cavitations are considered a classical manifestation of post-primary or adult-type tuberculosis. However, there are two other possible mechanisms involved in the formation of cavitations in children ( 4 ) : gradual dissemination from the Ghon complex; and bronchial obstruction by lymph nodes. Griffith-Richards et al. ( 5 ) evaluated children with pulmonary tuberculosis and identified cavitations in 63%. In the present study, we identified cavitations in ten (50%) of the 20 cases evaluated and cavitations within a consolidation in seven (35%). One 3-month-old infant presented extensive bullous lesions, initially diagnosed as a cystic adenomatoid malformation. Miliary tuberculosis, one of the most severe forms of tuberculosis, is secondary to the hematogenous dissemination of bacilli. Tuberculosis can progress to miliary tuberculosis at any point, such progression being due to the inability of the organism to control the infection. Miliary nodules can therefore coexist with elements of the primary complex, larger opacities, or cavitations ( 24 ) . Pulmonary tuberculosis can be fatal if it is not diagnosed and treated early. Diagnosing it can be difficult, given that the initial symptoms are nonspecific and the typical chest X-ray findings appear relatively late ( 37 ) . Miliary tuberculosis is an interstitial disease, presenting clinical, radiological, and physiological similarities with other diseases of its type, which makes early diagnosis even more problematic. That is of great importance because miliary tuberculosis is treatable, whereas many other interstitial lung diseases are either untreatable or are much more difficult to treat ( 38 ) . Local and systemic complications of pulmonary tuberculosis, observed in 40% and 25% of the patients in our sample, respectively, are indicators of the potential severity of the disease. In this context, CT is an invaluable method. Radiologists and pediatricians must be aware of the importance of these findings in an immunocompetent infant and must always correlate them with the family history. Early diagnosis and timely initiation of the appropriate treatment are crucial to halting tuberculosis progression and preventing its local and systemic complications, which might be irreversible.
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31032130
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Cryptococcus infection is an opportunistic infection that occurs primarily among people who are immunosuppressed. Cryptococcal meningitis is the most common presentation and causes significant morbidity and mortality , whereas infection of the lungs, skin, lymph nodes, and bones occur infrequently . There are two main Cryptococcus species currently described: Cryptococcus neoformans and Cryptococcus gattii . Over the years as molecular techniques evolved, it has been shown that Cryptococcus neoformans and Cryptococcus gattii have many features of highly evolved species and have strain-specific differences that correspond to their geographic locations, environmental niches, host predilections, and clinical manifestations. Further insight into the pathobiology of these encapsulated yeasts, including their capacity to adapt to environmental pressures, exploit new geographic environments, and cause disease, is needed . According to the U.S. Centers for Disease Control and Prevention, Cryptococcus neoformans is a major cause of illness in people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) with an estimated 220,000 cases of cryptococcal meningitis occurring worldwide each year with a case-fatality ratio of ∼12%. Cryptococcus gattii infections are rare, but the mortality rate ranges from 13 to 33% . Cryptococcal pneumonia has a variety of clinical manifestations and radiological appearances that are similar to other diseases. Although it is imperative to be aware of these presentations, diagnosis based purely on these features is difficult. A 25-year-old man from Ghana was admitted to our hospital for an altered mental state, weight loss, neck pain, cough, fever, nausea, vomiting, and photophobia for 7 days. He reported a cough with greenish phlegm and blood-tinged sputum and a weight loss of ∼20 lb in the last month. He reported that he could not eat because he was always nauseous and experienced nonbilious, nonprojectile vomiting. He denied chest pain, difficulty breathing and swallowing, diarrhea, dysuria, and skin rashes. His past medical history included intermittent asthma and migraines, but he was not on any medications. He did not have any significant family history or prior surgeries. He reported that he smoked 10 cigarettes a day for the past 5 years, drank alcohol occasionally, and denied illicit drug use except for marijuana. He reported that he last traveled to Ghana 6 months priorly, and he denied having contact with sick persons. He reported that he was sexually active with many partners but denied any prior sexually transmitted diseases. On admission, the patient tested positive for HIV with a CD4 count less than 20 and a high viral load. Pneumonia and meningitis resulting from opportunistic infections were considered, and he was treated for bacterial meningitis and tuberculosis (TB) even though the lumbar puncture was delayed because the patient was restless and uncooperative. The lumbar puncture results showed a pressure of 23 cm·H 2 O, a white blood cell count of 2, a red blood cell count of 57, a protein level of 102 mg/dl, and a glucose level of 25 mg/dl. The Gram stain and bacterial antigen tests were negative. On succeeding days, yeast was growing in the patient's blood cultures and a Gram stain of the patient's cerebrospinal fluid (CSF) showed presence of yeast cells. The titer of Cryptococcus in the CSF was greater than 1 : 1024 and was eventually identified as Cryptococcus neoformans . Thus, antibacterial meningitis treatment was discontinued, and the patient was started on amphotericin B and flucytosine. Anti-TB medications were continued. He underwent placement of a lumbar drain due to a persistent headache and photophobia. Antiretroviral treatment was not started, but the patient was treated with prophylaxis medications for opportunistic infections. At this time, the patient had four persistently negative acid-fast bacilli sputum smears and was negative for the sputum Mycobacterium tuberculosis PCR test. Cryptococcus infection remains the most significant and leading invasive fungal infection in the world today, and it accounts for an estimated 15% of all AIDS-related deaths globally. Humans likely become infected via inhalation. Although the factors that determine whether an exposed person develops symptomatic infection remain uncertain, one factor may include the size of the inoculum. The clinical manifestations of pulmonary cryptococcosis range from asymptomatic colonization of the airways to life-threatening pneumonia leading to acute respiratory distress syndrome . Common symptoms include cough, sputum production, hemoptysis, dyspnea, chest pain, fever, malaise, night sweats, and weight loss . The most common radiologic findings of pulmonary involvement include well-defined single or multiple noncalcified nodules, but pulmonary infiltrates, pleural effusions, hilar lymphadenopathy, and lung cavitation have also been observed . Radiographic features of pulmonary cryptococcosis are variable and have been described in many older case reports. In 1976, Hunt et al. published a case report which described cryptococcal pneumonia with multiple pulmonary nodules having central cavitation . In 1980, Zlupko et al. reported a case of Cryptococcus with solitary and a few well-defined, noncalcified, pleural-based nodules . In 1983, a case series of 23 patients by Feigin showed three different forms of radiopathologic findings including well-defined masses, segmental consolidation airway colonization with infiltrative masses, and colonization without parenchymal infiltrates . Later studies described cryptococcal pneumonia among immunocompetent and immunocompromised patients. A retrospective evaluation of 10 immunocompetent patients showed that the most common findings were multiple, small (<10 mm in diameter) pulmonary nodules in the middle and upper lobes . Pulmonary nodules were also observed in 12 patients with pulmonary cryptococcosis, the nodules were predominantly peripheral in distribution, and cavitation was observed in 40% of the cases . Another retrospective study done on 17 immunocompetent patients with pneumococcal pneumonia showed that airspace consolidation was common, but that small, single and multiple nodules were rare in this group . A study of 17 immunocompetent patients with pulmonary cryptococcosis by Shieh et al. in VGH-Taipei from 1967 to 1991 showed the following CXR findings: single nodule or mass (41.2%), multiple nodules (35.3%), and pneumonic patch or consolidation (23.5%). In addition, 29.4% had combined cavitary formation and 23.5% had pleural effusion . Clinical analysis of 76 patients who were pathologically diagnosed with pulmonary cryptococcosis showed 85.53% were predominantly peripheral findings on chest CT scan (nodular masses 55.26%, infiltrates 23.68%, and mixed type 21.05%) . In a normal host, pulmonary nodules are the most common presentation. The nodules are characteristically subpleural and may be solitary or multiple with varying size. In disseminated disease, pulmonary nodules are still the most common manifestation, but in these cases, both cavitation and mediastinal lymphadenopathy are frequent. Diffuse reticulonodular interstitial opacities or miliary pattern may be present as well. In an immunocompromised patient who is HIV seropositive, the radiologic presentation may vary from normal findings to asymmetric interstitial, nodular, alveolar infiltrate, or miliary nodules . Thambidurai et al. published a case series in 2017 which showed that cryptococcal pneumonia had varied radiologic presentations. In one case, there was a disseminated miliary/reticulonodular pattern which was diagnosed as cryptococcal pneumonia after axillary lymph node biopsy. It was concluded that in immunocompromised patients with multiple pulmonary nodules, cryptococcal pneumonia, Pneumocystis carinii pneumonia, and mycobacterial infections should be considered in the differential diagnosis of pulmonary infections .
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Probiotics, according to the revised definition of Food and Agriculture Organization (FAO)/World Health Organization (WHO, are considered as non-pathogenic live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Now probiotics are widely used in many countries in clinical practice and, frequently, are acquired by consumers with or without prescription . In most cases, probiotics, mainly strains of Bifidobacterium or Lactobacillus species, come from the gut microbiota of healthy humans or from dairy products . Probiotics also include species from the genera Streptococcus , Bacillus , and Enterococcus and the yeast Saccharomyces , which has been used as probiotics for many years . Among the main effects of probiotics at the intestinal level, the following are noteworthy: Balancing and restoration of the gut microbiota, protection against pathogens, immunomodulation, and maintenance of intestinal barrier integrity . Probiotics are widely used in dietary supplements, food, infant formula formulations, and medical devices . They have demonstrated significant potential as therapeutic options for a variety of diseases, mainly gastrointestinal diseases (including acute infectious diarrhea, antibiotic-associated diarrhea, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, or necrotizing enterocolitis), but also extra-intestinal disorders, such as hepatic encephalopathy . In a recent survey on probiotic-prescribing practices among health care providers and review of current guidelines and published large clinical trials, it was concluded that recommendations appear to be inconsistent, non-specific, and, frequently, upon patient request. In a significant proportion, the choice of probiotic was left to the patient or the pharmacist. The three most common clinical indications for probiotics were prevention and treatment of antibiotic-related side effects and irritable bowel syndrome . There is considerable published evidence that preparations containing dead cells and their metabolites can also exert relevant biological responses, restoring the normal intestinal homeostasis, in many cases similar to that seen with live cells, although with potential differences . After inactivation of bacteria, mainly by heat treatment, dead cells can release bacterial components with key immunomodulating effects and with antagonizing properties against pathogens. Different bacterial components, such as lipoteichoic acids, peptidoglycans, or exopolysaccharides (EPS), have been proposed to be mainly involved in these properties in preparations containing heat-killed bacteria . The most extensively-studied and widely-used probiotic bacteria are Lactobacillus and Bifidobacterium . Species of these two genera (including Bifidobacterium breve , Bifidobacterium longum , Lactobactillus fermentum , Lactobacillus plantarum , Lactobacillus casei or Lactobacillus rhamnosus ) naturally inhabit the human gastrointestinal tract, and are thought to play pivotal roles in maintaining human health . Therefore, the oral administration of probiotics is thought to reinforce the physiological functions of gut microbiota at the intestinal level. Probiotic bacteria confer anti-inflammatory responses by modulating different signaling pathways . Different anti-inflammatory effects at the intestinal level have been described with probiotics, for example, enhancement of the epithelial barrier function in the gut ; attenuation of barrier dysfunction due to pro-inflammatory cytokines ; or modulation of intestinal anti-inflammatory responses such as the expansion of the T-regulatory response, which may be relevant for its use in chronic inflammatory disease . Toll-like receptors (TLR) are a family of 11 transmembrane proteins (TLR-1-TLR11) expressed on various immune and non-immune cells that recognize specific patterns of microbial components and regulate the activation of both innate and adaptive immunity . The existence of several TLRs enables the innate immunity to recognize different groups of pathogens, while initiating appropriate and distinct immunological responses . In humans, TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 primarily respond to bacterial surface-associated pathogen-associated molecular patterns (PAMPs) . Multiple direct anti-pathogen effects have been described including inhibition of pathogens growth with the production of antimicrobial compounds, resource competition, counteracting of toxin effects, inhibition of virulence, anti-adhesive and anti-invasive effects, and competitive exclusion by competition for binding sites or stimulation of epithelial barrier function . Probiotic strains of Lactobacillus species have also been shown to reduce the biofilm formation in pathogenic bacteria, such as Listeria monocytogenes , through competition, exclusion, and displacement . Other concerns with the use of live probiotics are the possible acquisition/transmission of antibiotic resistance genes by the probiotic strains via horizontal gene transfer in the human digestive tract , the presence of deleterious metabolic activities, and the excessive immune stimulation in susceptible individuals . Strict assessment of the probiotic strains before marketing of the product should be performed, including genome strain characterization, to assure, among others, the absence of resistance determinants . A recent study has shown the ability of food-borne Lactobacillus in diffusing their antibiotic resistance traits to food pathogens under in vitro and in vivo conditions, thus raising concern of their use as probiotics or food supplements . In the case of neonates, there is also concern that live probiotic strains may form a persistent colony that could prevent normal colonization with other microbiota or with the normal core microbiome in the GI tract, with subsequent alteration of normal immune system development . In this regard, a combination of probiotic strains instead of a single strain has been proposed in neonates, taking into account the complexity of gut microbiome and the pathogenesis of certain diseases in preterm infants, such as necrotizing enterocolitis (NEC) . The use of heat-killed probiotics ( S. thermophilus ) in enteral formula in pre-term infants has also been proposed to avoid interference with gut colonization . This benefit–risk balance is particularly important in vulnerable patients, as concluded in a systematic review of randomized controlled trials in which probiotics were used for the prevention of Clostridium difficile -associated diarrhea (CDAD) in adults and children. The short-term administration of probiotics appeared to be safe and effective in combination with antibiotics in patients who were not immunocompromised or severely debilitated, thus concluding that vulnerable patients should be informed of the potential benefits and risks of probiotics . One important concern of safety of probiotic products is the risk of translocation and the subsequent bacteremia and sepsis. Some strains have good adherence properties on the intestinal mucosa, a mechanism associated with higher probability of bacterial translocation from gut to blood and other tissues, particularly in patients with epithelial barrier dysfunction . This risk is of particular concern in neonates, particularly in critically ill and/or extremely preterm neonates with potentially compromised gut integrity, as described in case reports , and animal models in which the presence of immune deficiency in neonates may put them at particularly high risk of probiotic sepsis . An eight-year-old patient in a pediatric surgical intensive care unit developed S. cerevisiae fungemia following treatment containing the yeast and a case of fungemia due to Saccharomyces cerevisiae var. boulardii has been reported in an immunocompromised 73-year-old patient on chemotherapy and on treatment with a probiotic product (Floratil ® , containing 0.5 × 10 9 cells of Saccharomyces cerevisiae var. boulardii /capsule) for the management of antibiotic-associated pseudomembranous colitis . Translocation of the yeast from the gastrointestinal tract to the blood was proposed as the most likely mechanism . A modified tyndallization process has been used to produce heat-treated industrially-grown bacteria for different uses . In most of cases, the tyndallized product contains cell fractions and supernatants , thus taking profit of both cell structures and excreted bacterial factors. Research studies are necessary to assess the influence of the tyndallization process on the bacterial cells, since the cell structure and cell components can be disrupted/graded to different extents. In L. rhamnosus strains, it has been reported that the tyndallization process altered the cell form, with the presence of shrunk and fragmented cells . Moreover, tyndallization and other heat-treatments can lead to rupture of cell walls, with the release of cytoplasmic contents (bacterial lysates), such as DNA; and cell wall components, such as peptidoglycans, lipoteichoic acids, or heat labile pili. The released bacterial components play key immunomodulating roles and can also have a role in the inhibition of pathogens . To date; however, the use of products containing heat-killed bacteria with health benefits is not completely widespread. Medical devices containing different tyndallized strains in combination with mucosal protectors, such as xyloglucan or gelatin tannate, are being recently marketed for the treatment of colic in children and adults (for example, xyloglucan plus tyndallized L. reuteri and B. breve strains) and for the treatment of diarrhea and for the prevention of gut dysbiosis associated to diarrhea (gelatin tannate plus tyndallized Lactobacillus acidophilus , Lactobacillus plantarum , Lactobacillus casei , Lactobacillus rhamnosus , Bifidobacterium bifidum and Streptococcus thermophilus ). In these products, synergism between mucosal protectors and probiotic strains are sought in terms of immunomodulation, cell barrier integrity, and competition against pathogens. Tyndallized Lactobacillus acidophilus HA122 (2 × 10 9 CFU/2 mL), in combination with extracts of Matricaria chamomilla and Melissa officinalis , is also marketed for the treatment of infantile colic. Contrary to what is commonly believed, bacterial viability or bacterial cell wall integrity is not an essential condition for the intestinal effects of probiotics, as reviewed in the next section of this manuscript. In fact, key molecules from gut bacteria, including LPS or peptidoglycan, interact with eukaryotic receptors when they are released into the environment from disrupted or completely-lysed cells or during the bacterial growth process . It has been recently shown that the degradation and lysis of bacteria by lysozyme enhance the release of bacterial products, including peptidoglycan, that activate pattern recognition receptors in host cells, this being the process important for the resolution of inflammation at mucosal sites . This is also supported by the localization of gut microbiota in the colon in the absence of mucosal damage, mainly present in the outer mucus layer, which offer nutrients, and distanced from enterocytes by a firmer inner structure, which is almost devoid of bacteria and confers protection to the host . Only certain types of bacteria, for example, Proteobacteria (including enterobacteria), are able to penetrate the mucus layers and reside in close proximity to the host cells . Therefore, in this scenario, one can speculate that the probiotic effects, exerted by both gut microbiota in normal conditions or by probiotics taken from supplements, are mainly derived from the release of bacterial products, which can pass through the mucus and stimulate the epithelial cells more directly than whole cells can . Therefore, in comparison with live bacteria, the use of heat-killed bacteria, providing disrupted cells and released bacterial components, could better reproduce in vivo the physiological conditions in the gut lumen and outer mucus layer, with key components reaching eukaryotic cells and enhancing the mucosal integrity. Additionally, taking into account the gut biogeography of gut microbiota, with three defined levels (lumen, outer mucus, and inner mucus) , the passage of active components from heat-killed probiotics to reach the epithelium seems to be a gradual process, where not all molecules would reach the eukaryotic receptors in vivo. Therefore, one can speculate that the benefits would concentrate in the apical side of the mucosa, maintaining its integrity. Moreover, the immunomodulatory properties of probiotics observed in in vitro models using different immune cells would probably be reduced in the human intestine in vivo, in which the mucus layers in the colon create a boundary between the gut lumen and the host tissue . Different strains, including lactic acid bacteria and bifidobacteria, are able to produce beneficial effects in their heat-inactivated form . There is also considerable data showing that not only dead cells, but also metabolites, cell fractions, and culture supernatants of probiotic bacteria can exert biological effects . The use of them is based on the evidence suggesting that individual effector molecules interacting with host cells may underlie probiotic effects . Although similar benefits can be obtained with the different strategies—live, heat-inactivated, or different fractions —relevant differences could exist among all of them . Various microbiological components, such as cell-free supernatants , exopolysaccharides (EPS) , teichoic and lipoteichoic acids , peptidoglycans, LPS , and metabolites have anti-inflammatory and immunomodulating activities, through stimulating the innate immune system , the adaptive responses and through their effect on the integrity of the intestinal mucous membrane . Heat-killed probiotics are also able to antagonize pathogens (with antimicrobial compounds and by competition with pathogens for adhesion and colonization) . Despite their biological importance, cell wall components of probiotics are poorly characterized . Peptidoglycan and lipoteichoic acids are the major cell wall components of Gram-positive bacteria and can be considered the pivotal components for the immunomodulating effects of most probiotics . While lipoteichoic acids and peptidoglycan from Lactobacillus species have been associated with immunomodulating effects in different models , in the case of bifidobacteria, the immunomodulating roles of these molecules have not yet been properly studied . The role of lipoteichoic acids as IL-12 inducers, thus activating the innate immune functions, have been demonstrated in L. plantarum in cultures of mouse spleen cells and splenic dendritic cells . Lipoteichoic acid from L. plantarum also confers anti-inflammatory responses, as observed in a study in porcine intestinal epithelial cell lines. Of note, lipoteichoic acids, suppressed poly I:C-induced IL-8 production, suggesting the capacity of these molecules to inhibit viral pathogen-induced inflammatory responses in intestinal epithelial models . A wide variety of EPS functions have been characterized in probiotic bacteria, including immunomodulating and pathogen protection properties . Due to their biological functions and physicochemical properties, bacterial EPS are being extensively studied due to their potential applications at the industrial, food, cosmetic, or medical levels . A growing number of studies are reporting in vivo and in vitro immunomodulating effects of EPS from strains of Bifidobacterium and Lactobacillus . EPS has been suggested to be involved in the cross-talk between probiotic bacteria and host immune system, potentially playing a role in intestinal homeostasis via interaction with intestinal epithelial cells . Cell-free supernatants contain batch culture medium, metabolites, and other secreted products that can cross the mucus layer and reach the intestinal monolayer of epithelial cells and interact with mucosal immune cells . Probiotic metabolites have anti-inflammatory and antioxidant activity, acting first on intestinal epithelial cells and then on immune cells, with differences depending on the probiotic strain . Reduction of the production of pro-inflammatory mediators have been demonstrated in in vitro models of immune cells upon exposure to secreted products from Lactobacillus and Bifidobacterium species . In a study with different probiotic strains (including L. delbrueckii , L. paracasei , L. salivarius , L. reuteri , L. rhamnosus , L. acidophilus , L. plantarum , L. lactis , L. casei , S. thermophilus , B. breve , and B. longum ) in peripheral blood mononuclear cells (PBMC), the anti-inflammatory immune responses observed were mediated by both metabolites and cell-surfaces of these bacteria . In models of colon epithelial cells, soluble purified peptides secreted by L. rhamnosus GG have prevented cytokine-induced cell apoptosis, thus promoting intestinal epithelial homeostasis , and cell-free supernatants of L. acidophilus , L. casei , and L. reuteri , containing metabolites, were able to downregulate the expression of PGE-2 and IL-8 . In a mice model of Salmonella infection, the combination of heat-killed multispecies of lactic acid bacteria (including L. acidophilus , L. plantarum , L. fermentum , and Enterococcus faecium ) was able to reduce Salmonella invasion and the induced inflammation , this being the effect attributed to lipoteichoic acids and EPS . Heat-killed L. plantarum also protected against Salmonella infection in mice and reduced translocation of this pathogen into different organs, such as spleen or liver, mainly by inhibiting pathogen adhesion and invasion . Protection against pathogens has been described in purified EPS from lactic acid bacteria and bifidobacteria , through their anti-adhesive properties against pathogens (mainly enterobacteria) and also through the stimulation of the immune response against pathogens. EPS has also been shown to decrease the cytotoxic effects of bacterial toxins in Caco-2 cells . In fact, some authors postulate that these protective actions of EPS-producing probiotics could be related to the formation of a protective film, preserving the host cells against injury, for example, by pathogens or their toxins . Moreover, EPS from bifidobacteria has been shown to facilitate the growth of lactobacilli along with other anaerobic bacteria . Bifidobacteria strains are popularly associated with EPS, with high structural diversity among strains. EPS form an interfacial layer separating the bacteria from its surrounding environment, considerably contributing to their anti-pathogenic activity . In animal studies, the administration of B. breve , producing EPS, reduced colonization of Citrobacter rodentium , in comparison with the mutant strain . EPS isolated from B. bifidum facilitated the growth of lactobacilli and other anaerobic bacteria and inhibited the growth of enterobacteria, enterococci, and Bacteroides fragilis . EPS from B. longum also inhibited pathogenic bacteria growth, including E. coli , Salmonella , S. aureus , B. subtilis , and B. cereus . In fact, EPS molecules from probiotics would have structural and biological similarities to other non-bacterial polymers, for example, xyloglucan, a vegetal polymer (from the seeds of Tamarindus indica ) contained in different medical devices and currently used in the management of different gastrointestinal diseases . Since xyloglucan also has protective film-forming properties against E. coli or Salmonella , synergism can exist with heat-killed probiotics, thus supporting their combined use in gastrointestinal diseases, as is the case of medical devices containing heat-killed probiotics and mucosal protectors (xyloglucan and also gelatin tannate). Bacteriocins are antibacterial small heat-stable peptides that are able to inhibit the growth of other bacteria, including enteric pathogens , (Bactibase Database http://bactibase.hammamilab.org/main.php ). Exceptionally, few bacteriocins, together with their native antibacterial property, also exhibit additional anti-viral and anti-fungal properties. Bacteriocins from Gram-positive bacteria, especially from lactic acid bacteria, have been thoroughly investigated considering their great biosafety and broad industrial applications . The same combination was also assessed in E. coli -infected CacoGoblet ® cells, with an increase in the transepithelial electrical resistance (TEER) and a reduction in the paracellular flux, being these effects more important than those observed with the heat-killed probiotic mixture alone, S. boulardii or the anti-diarrheal agent diosmectite. These results highlight the synergism between a mucosal protector and heat-killed probiotics to protect the intestinal barrier integrity and to prevent enteropathogens adhesion and invasion. Synergism has also been proposed in terms of onset of action, in which the presence of the mucosal protector would produce a faster onset of action of the probiotic mixture . The protective properties of tyndallized probiotics plus other mucosal protectors, such as xyloglucan, should deserve further research, in intestinal cells and also in other models, as nasal epithelial cells, based on the previous studies supporting the use of xyloglucan as protector of the nasal mucosal epithelial cells . In fact, xyloglucan in nasal formulations is an innovative strategy for the management of nasal disorders, as rhinitis and rhinosinusitis, based on their protective properties on the nasal epithelial cells, maintaining the barrier integrity and allowing the avoidance of allergens and triggering factors, as demonstrated in MucilAir™Nasal cells and in patients with rhinosinusitis . In this context, we can speculate that, while the effect of simethicone on SIBO is through its de-foaming properties, altering the elasticity of interfaces of mucus-embedded bubbles in the gastrointestinal tract , the effect of the medical device in reducing SIBO and the associated symptoms would be more associated with the protective effects against pathogens produced by the probiotic strains and the mucoadhesive properties of xyloglucan, with antiadhesive properties against enterobacteria, as already demonstrated in in vitro and in vivo studies . With the use of new sequencing techniques, gut microbiota and the characteristics of dysbiosis is currently being assessed in detail in pediatric populations, particularly in infants and preterm infants. Recent findings suggest that the immature intestinal mucosa and gut dysbiosis in infants precedes the development of relevant severe diseases, as late-onset sepsis or necrotizing enterocolitis (NEC) , and also as less severe, but particularly stressful for parents, infantile colic . It has been recently shown that at weaning the intestinal microbiota induces a vigorous immune response (the “weaning reaction”) that is programmed in time, and inhibition of this effect leads to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life . Infantile colic is a common condition (20% of infants) occurring during the first four months of life, defined as infant irritability, fussing, or crying that occur without obvious cause, without evidence of infant failure to thrive, fever, or ill health, presenting with recurrent prolonged periods . To date, infantile colic pathophysiology is poorly understood, with the presence of gut microbiota dysbiosis, barrier alterations, and mild chronic gastro-intestinal inflammation . Gut dysbiosis in colicky infants is characterized by decreased levels of bifidobacteria, lactobacilli, and butyrate-producing species and increased levels of Proteobacteria, leading to a more pro-inflammatory environment . Moreover, intestinal mucosal immaturity has also been reported, with the possible entry of toxic compounds from the gut lumen to the blood . A body of evidence indicates that the positive effects may be related to the type of probiotic strain, the method of administration, onset time, dose, and treatment duration . Several studies in mice have demonstrated that tyndallized L. rhamnosus and L. brevis strains can prevent the development of atopic dermatitis . Oral administration in mice of tyndallized L. rhamnosus at 10 8 , 10 9 , and 10 10 CFU/mL produced dose-dependent improvement in signs and symptoms of the disease, thus indicating their potential for the management of the disease . In a recent study in a murine model of atopic dermatitis, the oral administration of metabolites from lactic acid bacteria improved skin injury . Probiotics are the focus of interest at multiple levels, including consumers, patients, clinicians, scientific community, and pharmaceutical companies, and there is increasing interest to improve probiotic products, making them safer and more specific for each intended condition. In this context, new-generation probiotic products, including heat-killed strains, key components, or compounds with similar effects to living probiotic cells are being developed and already marketed, for certain indications, particularly for gastrointestinal disorders. To date; however, there is still a number of issues to be tackled for both live probiotics and for new-generation products containing inactivated cells, cell fractions, or purified components to develop rationally-designed beneficial therapies to provide enhanced protection against infections and other diseases . In general, a better understanding of the complex probiotic–pathogen interactions in the real human intestine will help to develop more specific products for each condition and to know the extent to which the bacterial-derived components are active in vivo , with a better defined benefit–risk ratio, particularly in vulnerable groups . Currently, the use of probiotics is framed within the strategies to avoid antimicrobial resistances and the need to avoid chronic pharmacological treatments and their adverse effects . In fact, in the current context of high levels of antibiotic resistances, acquisition and retransfer of resistance genes should be addressed in the safety evaluation of live probiotics , and should be considered in the development of future products . In this regard, the use of inactivated bacteria can provide important benefits, decreasing the risk of transmission of antibiotic-resistant genes. Based on the evidence from case reports, it is clear that standard safety evaluations have to be included in randomized clinical trials assessing probiotics , and safety issues also have to be transmitted to health care professionals, including pharmacists in the pharmaceutical offices, where recommendation of probiotics is widespread and often obtained without medical prescription. Comorbidities and vulnerable conditions can be frequent in patients taking probiotics and; therefore, information about the possible associated risks should be given. The risk of translocation with possible systemic infections should be taken into account in vulnerable patients, and also considering certain conditions that can favor translocation, such as the presence of dysbiosis and certain conditions altering gut microbiota (for example, immunosuppression) . In this regard, increasing interest is being focused on new-era products, with the use of heat-inactivated strains and purified key components responsible for the beneficial effects . Purified components, such as EPS, lipoteichoic acids, metabolites, and bacteriocins, might play an important role in replacing live probiotics. In this field, more research is needed in different aspects, for example, to identify specific strains for each condition; to assess the degree of bacterial cell disruption after heat treatments (and to identify the optimal conditions that can inactivated with maintenance of the cell structure); to identify the key components of the beneficial effect for a certain strain; and to test the synergism of different combinations, which could include different heat-inactivated strains and purified key components, as well as mucosal protectors, with protective barrier properties. Moreover, the in vitro results and animal models should be interpreted considering the particular conditions of the human intestine, particularly in the colon, with a stratified layer structure where gut microbiota is mainly present in the outer layer. The physiological effect that heat-killed strains and their release compounds can exert in vivo should be also taken into account, since a substantial presence of disrupted cells or released compounds in the outer mucus layers seems to be the most probable situation, rather than a predominant direct contact with the epithelial cells. As we have reviewed, the presence of key structures in the cell or supernatant fractions is able to confer probiotic properties, mainly through immune-modulation, protection against pathogens, and fortifying the mucosal barrier integrity. For the next generation products, the purification of these components and quantification of these effects would probably allow more standardization, leading to high specific and safe products intended for patient-tailored therapies. To compare and standardize these products, common activities among probiotic strains could be assessed, for example, their capacity to maintain mucosal integrity. Current existing evidence of heat-killed bacteria in relation to health benefits indicates that they can be safe alternatives to live probiotics in vulnerable populations, such as neonates , and also have a role in the management of gastrointestinal disorders in children and adults, including bloating and diarrhea . The synergism between tyndallized bacteria and mucosal protectors has been demonstrated in patients with bloating , while the role of this combination in other intestinal diseases and also in extra-intestinal diseases could also be explored.
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Coccidiomycosis is a fungal infectious disease caused by the Coccidioides species endemic to Southwestern United States. Also known as Valley fever, it is caused by Coccidioides immitis or Coccidioides posadasii . These organisms survive well in areas of low rainfall, few winter freezes, and alkaline soil in Arizona, New Mexico, West Texas, San Joaquin Valley of California, and parts of Mexico and South America. The primary method of infection is through inhalation of aerosolized arthrospores, although rarely, infection from a direct cutaneous inoculation is possible. The majority of infections are asymptomatic and self-resolving. Symptomatic patients typically present as community-acquired pneumonia with symptoms of fever, rash, and flu like symptoms. Uncommonly, in about 1% of infections, hematogenous extra pulmonary systemic dissemination involving skin, musculoskeletal system, and meninges occur. Involvement of the spine can range from discitis and paravertebral soft tissue infection to vertebral body erosion and neural compression . Extrapulmonary disseminated coccidioidomycosis with involvement of the spine, either localized or multiple segments is treated with antifungal drugs and/or surgical treatment. In this article, we present cases of spinal coccidioidomycosis treated at our institution and review the current literature. We conducted a retrospective review of medical records of all patients treated for spinal coccidioidomycosis at our institution. We queried the medical records of all in-patient admissions in our institution between January 2009 and December 2018 for the diagnosis of spinal coccidioidomycosis. We retrospectively reviewed patient demographics, clinical characteristics, presenting symptoms, radiological features, management, and outcomes of all patients treated for spinal coccidioidomycoses. Radiographic features of infection in the spine including the location of infection, characteristics of magnetic resonance imaging (MRI), number of vertebral segments involved, and involvement of neural elements and paraspinal structures were studied. An Institutional Review Board was done at our institution. A 28-year-old man presented with a one-month history of lower back pain, worsening shortness of breath, and intermittent fevers over a period of the month. He was initially treated with azithromycin at an outside facility, which failed to resolve his symptoms. The back pain was progressively severe and radiated to both lower extremities, limiting his ambulation. He had no history of sick contacts, travel, or history of exposure to tuberculosis patients. Initial treatment included empiric antibiotics and screening tests for HIV, tuberculosis with PCR, legionella, and a endemic mycosis serology panel that included histoplasmosis, blastomycosis, and coccidioidomycosis. A CT scan of the chest revealed lucencies throughout mid-thoracic spine with adjacent prominence of paraspinal soft tissues suggestive of osteomyelitis and discitis. MRI of the T spine revealed abnormal marrow enhancement seen with varying degrees of paraspinal soft tissue enhancement, the most significant being at T6 where diffuse marrow enhancement and vertebral height loss was seen . A biopsy of the lesion confirmed the coccidioidomycosis . He was initiated on antifungal therapy—voriconazole and amphotericin B—followed by surgical debridement and stabilization. He underwent bilateral T7–9 laminectomies and foraminotomies for decompression of the spinal cord. The abscess was identified and noted to be fibrous and adherent to the duramater. Caseating tissue was noted epidurally extending more in to the left lateral recess. Debridement and washout of all extraneous infected tissue was performed. Four days later, the patient underwent a transnasal approach for incision and drainage of pre-clival and retropharyngeal abscess. At 1-year follow-up, he continued to have moderate to severe axial sharp pain in the neck and lower back. An MRI demonstrated persistent marrow changes in lumbar spine and pelvis, as noted previously. A 62-year-old man with past medical history of pulmonary fungal infection presented with a seven-month history of back pain. He was initially diagnosed with coccidioides pneumonia seven years ago and was placed on a fluconazole long-term treatment, which was later discontinued by another physician due to renal adverse effects. He presented with symptoms of severe lower back pain, which exacerbated when sitting or lying down. The symptoms of pain were associated with weakness in the lower extremities and poor balance while walking. He had chronic non-radiating back pain. MRI of the lumbar spine revealed L1–2 discitis and osteomyelitis with a paraspinal abscess . Antibiotics therapy and fluconazole were started preliminarily. An image-guided interventional biopsy demonstrated coccidioidomycosis infection. Neurologically, having motor deficits and severe pain with imaging confirming compression of neural elements warranted surgical treatment. A lateral approach to the lumbar spine was undertaken to perform corpectomy of the L1 and L2 vertebral bodies along with discectomy and insertion of an expandable cage with a morselized bone graft. This construct was reinforced with a posterior instrumented fusion extending two segments superiorly and inferiorly . The intraoperative specimen showed coccidiodes spherules within the bone specimen, consistent with dissemination of the infection to the spine . A 54-year-old man with a past medical history of hypertension, C3–4 osteomyelitis, prevertebral/epidural abscess, and left septic knee who presented initially to his primary care physician with left upper extremity and lower extremity weakness, left knee pain, and lab results remarkable for elevated white blood cell count. Infectious disease workup and joint aspiration of the left sternoclavicular joint infection with coccidioidomycosis were confirmed. He was treated with intravenous fluconazole and vancomycin. The MRI and CT scan for evaluating the weakness revealed osteomyelitis/discitis of C3–4 and a focal epidural abscess . In addition, he was diagnosed with a left septic knee and underwent aspiration of joint effusion. A repeat MRI of the cervical spine later revealed improvement in the size and inflammation of the epidural abscess, and the patient was discharged on IV liposomal amphotericin B 50 mg per day. A few weeks later, the patient presented to the emergency room with fever, tachycardia, and tingling in the bilateral upper extremities. MRI of the cervical spine revealed retrolisthesis of C3 and C4, spinal canal stenosis, and cord compression due to extension of the epidural abscess into the level of the C5 vertebra. Furthermore, extensive discitis and osteomyelitis with collection in both the epidural and prevertebral regions were noted. The patient was clinically noted to have motor weakness in the left upper extremity and was transferred to our institution for a higher level of care and management. The abscess was surgically treated with incision and drainage of the prevertebral abscess, a C4 corpectomy, C3–5 fusion with placement of a cage, and an anterior plate from C3–5. Figure 3 a shows the Coccidiodes spherules in the ventral epidural abscess. During the hospitalization, he also underwent several debridement procedures and arthrocentesis of his infected left knee. Musculoskeletal involvement is a feature in about half of the disseminated forms with about 2–3% of this population being symptomatic. Vertebral and neurological involvement seems to be more common among Asian and African-American populations. Spinal coccidioidomycosis should be diagnosed early to prevent the local spread of infection and involvement of neural elements. Clinically, vertebral coccidioidomycosis commonly presents with symptoms of back pain or neck pain with associated radiculopathy, sensory disturbances, and motor weakness . Both symptomatic and asymptomatic pulmonary coccidioidomycosis infections can lead to spinal coccidioidomycosis, although it is more frequent in patients with symptomatic pulmonary infection . Therefore, patients with symptoms of back pain and associated neurological symptoms such as motor weakness or sensory symptoms, with travel or residence history in endemic areas should be evaluated for coccidioidomycosis . Coccidioides species titer serological tests must be obtained early and is helpful in establishing the diagnosis. IgM elevation is noted in 1–3 weeks of infection, and IgG elevation occurs in 2–28 weeks, with titers greater than 1 in 128 is suggestive of bone or joint involvement . Erythrocyte sedimentation rates and C-reactive protein, though not sensitive or specific to coccidioidomycosis, are frequently elevated. MRI, though not diagnostic, can demonstrate erosive defects in vertebrae and endplates and vertebral body collapse or paraspinal extension in more advanced cases. An MRI is more sensitive than a CT scan or plain radiographic films at detecting early changes due to infection. Typically, both active and necrotic lesions display T1 lengthening with contrast enhancement. Active lesions are hyper-intense in T2-weighted sequences. MRI cannot differentiate the findings in coccidioidomycosis, vertebral metastasis, tuberculosis, and other infectious diseases. Biopsy of vertebral lesions, generally CT-guided, to detect Coccidioides immitis / posadasii spherules is required for definitive diagnosis even with known involvement of other organ systems to rule out other alternative causes for spinal involvement. Several stains, including hematoxylin and eosin and periodic acid-Schiff stains (PAS), calcofluor white fluorescent, and Gomori methenamine silver, can identify the pathogen microscopically . Amphotericin has been used conventionally to treat coccidioidomycosis. Antimycotic treatment with azoles is more commonly being used as first line therapy to avoid the adverse effects of amphotericin, especially in cases with localized spinal infections. Fluconazole is most commonly used azole antifungal treatment for coccidioidomycosis. Other azole treatments include voriconazole and itraconazole. Voriconazole has shown to be effective in treating disseminated infection in contrast to fluconazole or itraconazole . More recently, posaconazole has demonstrated efficacy with superior osseous penetration . Immunocompromised patients and patients with meningitis are treated lifelong with azoles . Patients who respond poorly to azoles will them typically progress to polytherapy that includes amphotericin in addition to multiple azoles. Compliance with multiple medical therapy is a challenge in treating these patients, which is a major cause of relapse of infection, although progressive infection and decline are not uncommon while adhering to therapy . Surgical treatment is indicated in patients with severe disease or who are poor respondents to medical therapy or have intractable pain, the presence of neurological deficits, compression, or structural spinal instability . Surgical treatment with medical therapy is noted to be effective in alleviating pain and symptoms and limiting the disease compared to medical therapy alone . Titanium hardware has been safely used for spinal stabilization in coccidioidomycosis as with other spinal infections. These have been demonstrated to be resistant to biofilm formation and aid in eradication of infection by limiting spinal mobility in the involved segments . We have summarized the treatment details and relevant outcomes in some of the larger case series (with greater than 10 patients) reported in the literature ( Table 1 ).
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Clinical case
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biomedical
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en
| 0.999997
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31316953
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Chylothorax is a rare accumulation of chylous lymphatic fluid in the thoracic cavity, which arises from a wide spectrum of causes and can be encountered in diverse clinical contexts ( 1 ). With an estimated prevalence of 1:15,000 deliveries and a postoperative risk of 0.2–2% in pediatric surgery, chylothorax poses an omnipotent challenge, especially in the treatment of critically ill children worldwide ( 1 – 3 ). Chylothorax is an important cause of morbidity and prolonged hospitalization in pediatric patients. Despite the low prevalence of chylothorax there are several classification schemes for this disease that describes the etiologies ( 4 , 5 ). The anatomy and course of the thoracic lymphatic system can present with various differentiations. About 65% of the population has a “standard” anatomical route of the thoracic lymphatic system ( 4 , 6 ). It is clear that chylothorax can occur after any surgery performed in the vicinity of the thoracic duct or its lymphatic tributaries, which together transport about 4 Liters of chyle every day ( 7 ). Depending on the level of chylous effusion, fluid accumulations can occur at any place in the thoracic cavity. Accumulation in the pleural space is typical but also chylopericardium and chylous ascites may result after injuring the chyle-transporting thoracic duct ( 8 , 9 ). As effusions into the thoracic cavity lead to compression of the lungs and other intrathoracic structures, chylothorax can promote severe mechanical restrictions. Conservative as well as surgical therapeutic interventions are currently in use, but reports are scarce. Because of the rareness, the different etiology, and clinical presentation of chylothorax, single center studies may contribute to improve guidelines and facilitate treatment of these patients ( 10 , 11 ). The following data were extracted from patient files: age (days), gender, PICU stay (days), diagnosis at admission. Chylothorax etiology (congenital, postoperative, lymphangiomatosis, idiopathic, other). Chylothorax localization (right/left/bilateral), chest tube localization (right/left/bilateral). Type of thoracic surgery. Chest tube duration (days), drainage amount (ml/kgBW/day). Type of Nutrition: Milumil Basic-F (MBF) (Milupa GmbH; Puch bei Hallein, Austria), medium-chain triglicerides (MCT), duration of nutrition (days). Therapy with Somatostatin (Yes/No). Therapeutic Pleurodesis with beta-isadonna (BID)/Iodopovidone (Yes/No). Laboratory analysis (Triglycerides and Cholesterol in pleural fluid and blood). Surgical Interventions e.g., ligation, pleurectomy, percutaneous transluminal angioplasty (PTA), Thoracic Duct Embolization (TDE) (Yes/No). The objective of our study was to present a comprehensive and substantial evaluation of the various treatment strategies that have been practiced over the past years in children with chylothorax in our hospital. We therefore systematically reviewed the medical records of our patients with this rare disease and focused our investigations on underlying etiology, diagnostic pathway, and clinical survey of each individual case. Demographic data are listed in Table 1 . Distribution of gender (m/f) was almost equal (56%/44%) without any gender influence on the clinical course. This findings correspond with other reports ( 14 – 16 ). Chylothorax etiology is just as heterogenetic as described in the literature. Most patients in this study (28, or 82%) developed chylothorax after cardiothoracic surgery. Although we did not estimate the overall incidence of postoperative chylothorax in our hospital due to inaccessible or missing data, published literature estimated the incidence in children at 2–4.5% ( 17 ). The incidence of chylothorax in children is lower than in adults ( 4 ). In most cases traumatic chylothorax occurs 2–4 days after trauma or surgery. Those patients usually had already chest tubes, which suddenly start to present chylous fluid with oyster white color. Non-traumatic chylothorax and chylous-like disease are usually diagnosed by chest x-ray, CT-scan or sonography of the lungs because other diseases are concomitantly present ( 18 ). Bilateral effusions were most frequently observed and diagnosed. With regards to cardiac surgery, previous studies have shown that extrapericardial procedures, such as Blalock-Taussig shunt placement, aortic coarctation repair, patent ductus arteriosus ligations, and Glenn procedures, are mostly responsible for the formation of chylothoraxes ( 17 , 19 – 21 ). Among all study patients, 32 children had biventricular and only two children univentricular physiology. None of the patients had hetorotaxie. Description of the diagnostic pathway has been an important part of our study. In six children the peak values for triglycerides in the pleural fluid were below 110 mg/dl, indicating the diagnosis chylous-like disease (pseudo-chylothorax) for those children. This group of patients were treated similarly to the patients with chylothorax. Another crucial point in our study was to present a therapeutic overview about all the different management strategies that have been performed. In 14 patients a combination of different therapies was necessary to decrease the amount of effusion above 60%. Figure 2 provides an overview about the frequency of therapeutic interventions practiced in this study. We hereby differentiated between conservative, surgical, and other-therapies. All study patients received chest tubes to drain the pleural fluid to relieve respiratory symptoms. It is well known that feeding restricted to medium- or short-chained triglycerides results in reduced lymph flow in the TD and may enhance spontaneous healing ( 21 ). While this conservative approach alone could not resolve the chylothorax in all cases, we were quite successful in the treatment of 14 children who received only this therapy. Median chest tube output before starting MBF/MCT therapy was 24.5 (17.7–45) ml/kgBW/day and dropped to 1.1(0–2.8) ml/kgBW/day, just before or on the day chest tubes were removed. This equates to a drop from 100 to 4.7% (0–22.3). Previous studies have shown that any type of enteral feeding, even with clear fluids, can cause an increase in the TD-flow ( 22 ). Therefore, some authors recommend chest tube drainage, withholding of oral feeds, and providing total parenteral nutrition for the optimum management of chyle leaks ( 21 ). The use of iodopovidone (BID) for pleurodesis is also considered as a well-established therapy, which was shown to be effective in several studies ( 23 – 25 ). In our study, this technique was performed on seven children , with two children receiving BID as the only therapeutic option beside the nutritional therapy and five children receiving BID in combination to other therapies. Cessation of chylous flow occurred in most patients between 3 and 15 days after the installation of BID. Chemical pleurodesis with “Arista glue” was performed in one patient, with a modest outcome. We did not use other agents for chemical pleurodesis, such as talc, although these have been widely used and well-established ( 26 – 28 ). Furthermore, high rates of efficacy were reported for the use of somatostatin in few reports, with the therapeutic effect usually occurring within the first 6 days of treatment ( 29 – 32 ). In our patients, somatostatin was applied in 11 children, with four children receiving somatostatin as the only therapeutic add-on to nutritional therapy. Three children received somatostatin in combination to BID and four children either had to undergo surgery or be treated with somatostatin combined with other management strategies. In general, surgical interventions are required for intractable cases when chylothorax remains resistant despite prolonged drainage and conservative management ( 17 , 21 ). Because of the small number of patients (six children) with partially incomplete documentation, it is difficult to determine the therapeutic role of surgical management in our unit. Due to the retrospective character of our study, there are few limitations which is important to mention: first, a complete documentation of parameters is necessary for a coherent and sound interpretation. Relevant data, such as the daily chest tube flow, was unfortunately only partially/poorly documented. Second, one has to consider that the clinical survey of chest tube flow is also influenced by several factors that have not been considered in our methods. Increased systemic or venous pressure, as well as other co-morbities such as pre-existing heart insufficiency or vascular disease, might have affected the course of chest tube flow and contributed to prolonged hospitalization in some cases. We noted that a combination of different conservative therapies such as nutritional modification (MBF) and somatostatin was successful in most of our patients. Therefore, conservative therapy is recommended as the preferred therapy in the presence of chylothorax and chylus-like diseases [see Figure 3 ; Clinical Algorithm modified; ( 13 )]. Surgical therapy may be an alternative approach that can be used when conservative therapy has failed. Early diagnosis and treatment of potential complications (high central venous pressure > 15 mmHg, heart failure) may further improve the success rate of conservative therapy especially in patients with postoperative chylothorax. In summary, appropriate therapy of this condition may be lengthy but can prevent significant morbidity and mortality. Therefore, a suitable protocol is needed to define uniform diagnosis criteria and treatment modalities for this special medical condition.
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Review
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31341687
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Paraneoplastic syndromes are often a diagnostic challenge to doctors and may present as any of a wide variety of clinical syndromes resulting from the release of self-peptides or self-like peptides to the production of autoimmune antibodies. Humoral hypercalcemia of malignancy (HHM), hypercalcemia caused by systemic secretion of parathyroid hormone-related protein (PTH-rP) by malignant cells, is considered a paraneoplastic syndrome, and it is most commonly caused by squamous cell cancer (e.g., of the head and neck, esophagus, cervix, and lung) and renal, ovarian, endometrial, and breast cancer . Paraneoplastic neurological syndromes (PNS) may have a heterogeneous presentation, including polyneuropathies, and can occur with any type of cancer, especially small cell lung cancer, ovarian and breast cancer, neuroendocrine tumors, thymoma, and lymphoma. Interestingly, PNS more commonly develop prior to the cancer diagnosis and are frequently associated with antineuronal antibodies that can be measured in serum and cerebrospinal fluid . Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune peripheral neuropathy frequently described in association with several types of cancer, especially hematologic malignancies. We present the first case of combined hepatocholangiocarcinoma (CHCC) presenting with HHM in a patient with a CIDP. A 56-year-old man was referred to our internal medicine unit with abdominal pain, fatigue, and persistently elevated aminotransferases for 18 months. Three months earlier, he had been evaluated for numbness and weakness starting over the distal aspects of his four limbs and slowly progressing proximally over the last three years. Neurological examination performed at that time revealed walking difficulties and moderate muscle weakness in both lower and upper limbs ( F = 3.5-4), generalized tendon areflexia, and mild sensory loss with stock and glove distribution. Electromyography/electroneurography (EMG/ENG) showed diffusely reduced motor and sensory nerve conduction velocity (mean motor nerve conduction velocity 22 m/s), with a dishomogeneous pattern, and absent F waves. Isolated hyperproteinorrachia (1.15 g/L) was found on cerebrospinal fluid (CSF) examination. The clinical, EMG/ENG, and CSF results were consistent with a diagnosis of CIDP, which was subsequently successfully treated with IV immunoglobulins. On admission, the patient's temperature was 36°C, heart rate 125 beats per minute, blood pressure 110/80 mmHg, and oxygen saturation 94% while he was breathing ambient air. On physical examination, peripheral edema, bibasal pulmonary rales, hepatomegaly, and severe sensory and motor deficits located to the upper and lower limbs were noted. Laboratory data on admission showed the following values: aspartate aminotransferase (AST) 166 IU/L (normal range 17-59 IU/L), alanine aminotransferase (ALT) 64 IU/L (normal range 21-72 IU/L), gamma glutamyl-transferase 358 IU/L (normal range 15-73 IU/L), alkaline phosphatase 173 IU/L (normal range 38-126 IU/L), total bilirubin 1.28 mg/dL (normal range 0.20-1.30 mg/dL), albumin 2.8 g/dL (normal range 3.6-5.5 g/dL), lactate dehydrogenase 993 IU/L (normal range 313-618 IU/L), total serum calcium level 14.1 mg/dL (normal range 8.8-10.2 mg/dL), phosphorous 2.8 mg/dL (normal range 2.9-4.8 mg/dL), C-reactive protein 14.6 mg/dL (normal range < 1.0 mg/dL), and ferritin 1669 ng/mL (normal range 20-325 ng/mL). Viral markers for hepatitis B and C were negative. Serum intact PTH was low (4 pg/mL) (normal range 20-104 pg/mL). Moreover, anti-ganglioside antibodies (GD1bIgG and GM1IgG) were found in serum. Given the predominantly infiltrative pattern of altered liver function tests and the severe hypercalcemia with low serum intact PTH, imaging studies and further blood tests were performed to rule out cancer or metastases. Whole body multidetector computed tomography (MDCT) scan showed a large hypoattenuating hepatic mass in the right lobe (maximum axial dimension 13 cm) characterized by heterogeneous peripheral enhancement, associated with secondary lesions located in the spleen and lung (more than 30 nodules); no evidence of bone metastasis was found . The following magnetic resonance imaging, performed to confirm the diagnostic hypothesis from the previous CT study, showed typical findings of peripheral CHCC . Alpha-phetoprotein was 247.8 ng/mL (normal value < 9 ng/mL), gastrointestinal cancer antigen (GICA) was 132 U/mL (normal value < 37 U/mL), and carcinoembryonic antigen (CEA) was 9.14 ng/mL (normal range 0-5 ng/mL). PTH-rP was markedly high (147 ng/mL; normal range 8.5-20.0 ng/mL). Percutaneous ultrasound-guided biopsy of the hepatic tumor showed a mixed epithelial neoplasia comprising: (1) trabeculae and solid nests composed of large cells with pleomorphic nuclei and granular cytoplasm intermingled with (2) branching pseudoglandular structures composed of cuboidal/columnar cells with atypical nuclei. Nests and trabeculae showed strong immunohistochemical staining for cytokeratin 8/18 and HepPar1 while pseudoglandular structures stained selectively for cytokeratin 7 and cytokeratin 19 . A diagnosis of “Stage IV CHCC associated to HHM and CIDP” was made. Hypercalcemia of malignancy is typically found in patients with advanced stage cancers and is one of the most life-threatening metabolic disorders. It may result from a marked increase in osteoclastic bone resorption or release of PTH, PTH-rP, or 1,25-dihydroxyvitamin D by the tumor. Acting through a common PTH/PTH-rP receptor, PTH-rP inhibits calcium excretion from the kidney and promotes bone resorption leading to hypercalcemia . As shown in studies investigating the prevalence and prognosis of different paraneoplastic syndromes in HCC, HHM can be found in 4-8% of HCC . HHM has rarely been reported in patients with cholangiocarcinoma (CC) and represents a marker of poor prognosis of the disease [ 5 – 9 ]. CHCC is a rare tumor with poor prognosis, with incidence ranging from 1.0% to 4.7% of all primary hepatic tumors . To the best of our knowledge, this is the third case of CHCC associated with HHM and the first one in a patient with recent diagnosis of CIDP. Involvement of the peripheral nervous system is common in patients with cancer, and any part can be affected . The most frequently reported malignancies associated with CIDP are hematologic (Hodgkin's and non-Hodgkin's lymphomas, Waldenström's macroglobulinemia, chronic myelomonocytic leukemia, hairy cell leukemia, and multiple myeloma). However, CIDP has been described in patients affected by gastrointestinal malignancies (pancreatic, rectosigmoidal, esophageal, and gastric), renal cell carcinoma, lung cancer, seminoma, Kaposi's sarcoma, orbital neurogenic tumor, breast carcinoma, and melanomas, and a possible paraneoplastic pathogenesis of this neurological disease has been suggested [ 14 – 33 ]. It is challenging to determine whether the association of cancer and CIDP is a coincidence or could be explained by a paraneoplastic process. In our patient, CHCC diagnosis was made 3 years after the onset of neurological symptoms and 3 months after the CIDP diagnosis. Since many reported cases identified CIDP prior to the diagnosis of cancer, we supposed that CIDP could represent a paraneoplastic manifestation of CHCC. Although no association between CIDP and CHCC has been previously described, few cases of CIDP associated with HCC [ 34 – 36 ] have been described. Interestingly, one case of CIDP associated with CC has been reported , and in that case, cancer was diagnosed about 8 months after the onset of neurological symptoms and 5 months after the CIDP diagnosis. In conclusion, we report the first case of CHCC associated with HHM and CIDP. Given our case and the other ones reported in the literature, primary hepatic tumors such as HCC, CC, and CHCC should always be included in the differential diagnosis of hypercalcemia of malignancy. Furthermore, in patients with CIDP and elevated aminotransferases, we suggest ordering a full panel of liver function tests, including ALP, yGT, and total bilirubin, looking for a primary hepatic tumor and considering that CIDP associated with primary biliary cirrhosis has been described as well . On the other hand, we suggest that CIDP should be ruled out in patients known to have a primary hepatic tumor presenting with a compatible clinical picture suggesting a demyelinating polyneuropathy.
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Clinical case
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biomedical
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31477144
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Currently, the bone graft materials commonly used in the surgical treatment of thoracic tuberculosis include autologous iliac crest, particulate bone graft, allogeneic bone graft, adjacent rib graft, and titanium mesh with bone powders, while transverse process bone grafts have rarely been reported. Traditional grafting with an iliac bone block, adjacent rib graft, and titanium mesh with bone powders is associated with a long operative time, massive intraoperative blood loss, and a slow postoperative recovery. A particulate bone graft has a loose structure that cannot provide sufficient mechanical strength . To address this issue, we sought a new bone grafting method to minimize donor site complications, ensure sufficient support strength and a satisfactory fusion rate, and help patients achieve a quick recovery after surgery. We conducted a retrospective analysis of 94 patients with single-segment thoracic tuberculosis who met the inclusion criteria for spinal surgery from January 2013 to September 2017 in our hospital. The selected patients were divided into three groups according to the type of bone graft: group A, transverse process bone graft fusion and internal fixation (30 patients); group B, autologous iliac bone graft and internal fixation (28 patients); and group C, titanium mesh fusion and internal fixation (36 patients). No significant differences in age, gender, body mass index, or disease duration were found between the four groups ( P > 0.05, Tables 1 , 2 , and 3 ). Table 1 Comparison of preoperative clinical features between the three groups Group Case Age (year) Gender BMI Course of illness (month) Male Female Transverse bone (A) 30 44.33 ± 14.16 20 10 21.22 ± 2.91 18.03 Iliac bone graft (B) 28 46.32 ± 14.07 12 16 22.09 ± 3.74 24.50 Titanium mesh (C) 36 49.97 ± 16.36 21 15 20.97 ± 3.08 26.00 P value >0.05 > 0.05 >0.05 > 0.05 Table 2 Comparison of clinical features between the three groups ( x ± s ) Group A Group B Group C P AB P AC P BC Fusion time (m) 7.3 ± 2.1 8.4 ± 3.1 7.5 ± 3.4 0.642 0.101 0.616 Hospital stay (days) 18.8 ± 5.1 24.0 ± 12.7 26.1 ± 9.5 0.022 0.031 0.424 Operation time (min) 205.5 ± 38.1 240.7 ± 68.4 238.4 ± 45.4 0.036 0.005 0.901 Operation blood loss (ml) 372.8 ± 151.1 480.9 ± 241.8 603.1 ± 443.2 0.045 0.004 0.586 Postoperative drainage (ml) 292.1 ± 126.0 381.0 ± 212.2 377.6 ± 139.0 0.715 0.672 0.998 Preoperation CRP (mg/l) 39.0 ± 32.2 31.7 ± 21.3 29.5 ± 27.83 0.459 0.661 0.111 Postoperation CRP (mg/l) 53.7 ± 31.8 52.1 ± 31.7 51.0 ± 30.1 0.667 0.456 0.382 Preoperation ESR (mm/h) 22.1 ± 17.9 14.4 ± 10.8 18.2 ± 16.2 0.247 0.375 0.460 Postoperation ESR (mm/h) 31.2 ± 24.7 31.7 ± 27.9 33.2 ± 19.1 0.701 0.503 0.196 Preoperation VAS score 6.1 ± 1.9 5.9 ± 1.7 5.9 ± 1.5 0.002 0.447 0.813 Follow-up end VAS score 1.4 ± 1.4 1.3 ± 0.9 1.3 ± 1.1 0.780 0.472 0.695 Preoperation ODI 55.0 ± 9.9 54.3 ± 15.2 57.9 ± 12.3 0.912 0.545 0.655 Follow-up end ODI 14.2 ± 6.5 15.7 ± 6.3 16.9 ± 8.2 0.682 0.125 0.265 ESR erythrocyte sedimentation rate, CRP C-reactive protein, P < 0.05 compared with preoperation Table 3 Comparison of the imaging features between the three groups ( x ± s ) Group A Group B Group C P AB P AC P BC Preoperation Cobb angle (°) 25.3 ± 7.1 26.7 ± 5.6 29.1 ± 4.8 0.247 0.287 0.391 Postoperation Cobb angle (°) 15.5 ± 4.1 15.1 ± 2.4 14.5 ± 2.9 0.133 0.732 0.386 Follow-up end Cobb angle (°) 16.9 ± 4.4 15.5 ± 2.9 16.2 ± 4.0 0.248 0.725 0.486 Preoperative height (cm) 10.6 ± 1.8 11.1 ± 1.5 11.2 ± 1.6 0.972 0.799 0.879 Postoperative height (cm) 14.1 ± 1.3 13.9 ± 1.4 13.9 ± 1.5 0.195 0.985 0.907 Correction height (cm) 3.3 ± 0.8 2.9 ± 1.1 3.3 ± 1.8 0.467 0.413 0.585 Follow-up end height (cm) 12.6 ± 1.5 12.0 ± 1.5 11.9 ± 1.5 0.939 0.528 0.796 Loss height (cm) 1.5 ± 0.5 1.9 ± 1.1 1.9 ± 0.7 0.953 0.066 0.323 P < 0.05 compared with preoperation Cobb angle; P < 0.05 compared with postoperation Cobb angle The inclusion criteria for the patients in the three groups include the following: (1) patients with single-segment thoracic spinal tuberculosis (involvement of a single segment and a lesion requiring removal), varying degrees of vertebral destruction or collapse, and narrowing or disappearance of the intervertebral space as confirmed by preoperative X-ray, computed tomography (CT), and magnetic resonance imaging (MRI) examinations; (2) patients in good condition who can tolerate surgery; (3) patients with surgical indications who underwent posterior-approach bone graft fusion surgery alone and a diagnosis of tuberculosis confirmed by postoperative pathological examination; and (4) patients with complete follow-up data. The exclusion criteria for the three groups of patients include the following: (1) patients complicated with severe heart and lung dysfunction or other chronic diseases who cannot tolerate surgery; (2) patients with incomplete clinical data; (3) patients with a history of thoracic spine fractures within 6 months and a previous history of thoracic spinal surgery; (4) patients with severe local kyphosis requiring osteotomy and orthosis; (5) patients with active tuberculosis and intestinal tuberculosis; and (6) patients with malignant tumors, mental illness, or hyperthyroidism. The patient was placed in the prone position after induction of general anesthesia with tracheal intubation. C-arm fluoroscopy was performed to identify the diseased vertebra. A posterior median incision was used to expose the spinous process, lamina, facet joint, and transverse process of the normal vertebral body above and below the diseased vertebra via subperiosteal dissection. A needle was inserted for localization of the diseased vertebra. C-arm fluoroscopy was used to confirm the diseased segments. Pedicle screws were placed in the one or two normal vertebrae above or below the diseased vertebra and in the diseased vertebrae if possible. The bilateral laminas of the diseased segment were removed to expose the dural sac and the nerve root. Spinal decompression was performed under direct vision. A connecting titanium rod with a suitable length and curve was installed. The lesion tissue (inflammatory granulation tissue, necrotic intervertebral disc, and lesioned bone) was completely scraped out until fresh oozing on the vertebrae was observed, and the lesion site and wounds were repeatedly washed with a large amount of normal saline. The intervertebral space was properly expanded to form a bed for the bone graft, and the different types of bone grafting were then performed for the designated groups . Fig. 1 Transversus bone graft group: a - c A transverse process was harvested from a normal adjacent vertebra. Both ends of the transverse process were trimmed and ground to create a columnar cage with annular cortical bone on the sides and cancellous bone at both ends. d According to the size of the intervertebral space defect, one to two cages created from transverse processes were implanted. A pedicle screw system was used to immobilize bone grafts and vertebral segments Fig. 2 a - h A 40 years old male with T6-7 tuberculosis. a - c Preoperation X-ray, CT and MRI images showed irregular destruction of the edge of T6-7 vertebral body and intervertebral space stenosis; ( d - e ) Six months postoperation X-ray and CT showed good internal fixation position. f - h Thirty months postoperation X-ray, CT and MRI showed good internal fixation position. i - l Iliac bone graft group: a 41 years old male with T10-T11 tuberculosis ( i - j ). Preoperation X-ray and MRI images showed that T10-T11 vertebrae presented osteolytic bone destruction and intervertebral space stenosis; ( k - l ) twelve months postoperation X-ray and CT showed T10-T11 bone fusion. m - p Titanium cage graft group: a 69 years old male with T11-12 tuberculosis. m - n Preoperation CT and MRI images showed that T11-12 vertebrae presented osteolytic bone destruction and intervertebral space stenosis; ( o - p ) eighteen months postoperation X-ray and CT showed T11-T12 bone fusion The imaging parameters include the improvement and loss of the Cobb angle and intervertebral height before surgery, after surgery, and at the final follow-up. The Cobb angle is defined as the intersecting angle between lines vertical to the endplates of the adjacent upper and lower normal vertebrae on the lateral view of a radiograph. Intervertebral height is defined as the vertical height between the upper and lower vertebral bodies of the fused segment on the lateral view of a radiograph. Evidences for bony fusion were defined as the presence of trabecular bone bridging between the bone grafts and the vertebrae on CT sagittal planes. Bone graft fusion was evaluated using the Bridwell criteria . The operative time for bone grafting was 206.1 ± 38.6 min in group A, 240.8 ± 68.4 min in group B, and 238.4 ± 45.0 min in group C. The operative times for bone grafting in group A was significantly shorter than those in groups B and C ( P < 0.05). No significant differences were found between groups B and C ( P > 0.05). The length of hospital stay was 18.8 ± 5.1 days in group A, 24.0 ± 12.7 days in group B, and 26.1 ± 9.5 days in group C. The lengths of hospital stay in group A were significantly shorter than those in groups B and C ( P < 0.05). No significant differences were found between groups B and C ( P > 0.05). The postoperative neurological function of the patients was improved compared with that before surgery. In the transverse process graft group, neurological function was improved from grade C to grade D in two patients and from grade D to grade E in 14 patients. In the iliac bone graft group, neurological function was improved from grade C to grade D in one patient and from grade D to grade E in seven patients. In the titanium mesh group, neurological function was improved from grade B to grade C in one patient, from grade C to grade D in three patients, and from grade D to grade E in five patients. No significant differences in ASIA classification grades before and after surgery were found between the three groups ( P > 0.05), but the ASIA grades after surgery were significantly improved compared with those before surgery in the three groups ( P < 0.05). The principles of spinal tuberculosis surgical treatment include thorough lesion removal, relief of spinal cord compression, correction of local segmental angular deformities, and restoration of spinal stability . The stability of the spine is conducive to the relatively stable and static state of local tuberculosis lesions as well as tissue repair and prevention of tuberculosis recurrence . Therefore, bone grafting plays important roles in bone defect repair after the removal of a tuberculosis lesion, correction of kyphosis, and reconstruction of spinal stability. In recent years, posterior approach debridement combined with bone graft and pedicle screw fixation has been used to treat spinal TB. The main advantage of the single posterior approach was that the same incision was used to complete lesion debridement, orthopedic bone grafting, and internal fixation, So we all use this surgical approach [ 11 – 14 ]. As the most widely used bone block graft material, the iliac bone block is the gold standard for bone grafting compared with other graft materials . This graft type has a three-sided cortical bone structure with high mechanical strength and good osteoconductivity and osteoinductivity and is also rich in cancellous bone, which can significantly improve the bone graft fusion rate. From the perspective of biomechanics, Jutte suggested that the bone graft, as a three-sided cortical bone graft, provides good support and is conducive to bone fusion. However, in a study on structural autogenous bone grafting, Tuli suggested that bone fusion occurs only within a depth of a few millimeters of the surface and in the region in close contact with the blood supply in the receiving site, whereas osteonecrosis occurs in the bone graft center. Moreover, the shortcomings of iliac bone grafts include the limited source of the iliac bone, pain in the donor site (more than 6 months of pain and sensory disturbance), and infection. The transverse processes of the thoracic spine protrude to the left and right sides from the junction of the pedicle and the lamina. The transverse process is located between the superior and inferior articular processes and belongs to the posterior column structure. The mature thoracic transverse process is cylindrical and extends to the posterolateral side. It also has a three-sided cortical bone structure, similar to that of the ilium bone and ribs. The harvested transverse process is a ring-shaped cortical bone block that can be trimmed to a suitable size according to the specific shape and length of anterior column bone defects caused by lesion removal. The study by Thanapipatsiri et al. showed that harvesting a transverse process is a safe and feasible procedure without damage to important blood vessels, nerves, muscles, or tendons as long as careful subperiosteal detachment and gentle operative techniques are strictly followed. According to the anatomy of the transverse process of the thoracic spine, we summarized the requirements for transverse process bone grafting. The study by Panjabi et al. revealed the heights of the vertebral bodies and the lengths of the transverse processes from the three-dimensional quantitative anatomy of the human thoracic vertebrae (T1–T12). In humans, the average length of the transverse process of the thoracic spine is 17.4 mm, the average height of the vertebral body is 14.1–22.7 mm, and the average height of the intervertebral disc is 2–6 mm . These data indicate that in the treatment of single-segment thoracic tuberculosis, the “thick and strong” thoracic transverse process can meet the needs of bone grafting when upper or lower affected vertebral bone destruction does not exceed 1/2 of the height of the vertebral body, or the total height of the damaged upper and lower vertebral bone does not exceed 1/2 of the height of the vertebral body. Our studies have shown that the transverse process grafting in the thoracic spine is superior to traditional iliac bone grafting and titanium mesh implantation in terms of operative time, intraoperative blood loss, and length of hospital stay. No differences in VAS and ODI scores, ESRs, CRP levels, the Cobb angle of local segmental kyphosis, or intervertebral height of the surgical site were found between the three groups. Compared with traditional iliac bone grafting and titanium mesh implantation, transverse process grafting can reduce intraoperative trauma and postoperative complications and accelerate postoperative recovery. This new type of bone grafting is associated with minimal surgical trauma and can achieve satisfactory bone fusion, provide good biomechanical strength, and maintain spinal stability.
|
Other
|
biomedical
|
en
| 0.999998
|
31565452
|
Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm (MPN) that results in an increased number of platelets in circulation. The current 2016 WHO classification for diagnosis of ET requires major criteria of a platelet count equal to or over 450 × 10 3 /L, demonstration of JAK2 , MPL , or CALR mutation, bone marrow biopsy with mature megakaryocyte proliferation but without significant production of neutrophils, erythrocytes, or reticulin fibers, and lack of meeting criteria for other myeloproliferative diseases. ET can alternatively be diagnosed by meeting three of the major criteria in addition to lone minor criteria of a clonal marker or absence of evidence for reactive thrombocytosis . The presence of distinct genotypes is central to both the diagnosis and, at times, treatment of MPNs. Where some MPNs are the result of an individually distinct mutation, others may stem from various genetic aberrations. For instance, polycythemia vera (PV), a form of MPN that leads to an increased concentration of hemoglobin and hematocrit, is associated with a JAK2V615F mutation that has been seen in approximately 95% of cases. In contrast, JAK2 mutations are typically seen in 50-60% of ET cases . In ET cases that lack JAK2 mutation, CALR and MPL genes have been shown to possess mutation. Past cohorts studying ET patients found that these mutations ( JAK2 , CALR , and MPL ) are seen in 62-64%, 22-24%, and 4%, respectively . While patients with ET are at a known increased risk for thrombotic conditions such as cerebral vascular accidents, myocardial infarction, pulmonary embolism, and pregnancy complications, there is a lesser known association between ET and glomerulonephropathy. Various forms of glomerulonephropathy have been reported in patients with ET including IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), diffuse mesangial sclerosis, and fibrillary glomerulonephritis [ 6 – 8 ]. Described here is a case of a 57-year-old man diagnosed with ET that was subsequently diagnosed with IgAN. A 57-year-old Caucasian man with a history of chronic kidney disease (CKD), essential hypertension, migraines, and obstructive sleep apnea presented to the clinic for establishment as a new patient. Besides occasional migraines, he did not have any other immediate complaints. His blood pressure was mildly elevated at 148/92 mmHg while on lisinopril 10 mg and propranolol 160 mg daily, and physical examination was benign, including lack of lymphadenopathy, rashes, or edema. Review of his laboratory results was notable for worsened renal function in the past year from a serum creatinine (SCr) of 1.10 mg/dL and globular filtration rate (GFR) of 69.25 mL/min to a SCr of 1.66 mg/dL and GFR of 42.91 mL/min. Initially, this was attributed to his angiotensin-converting enzyme inhibitor (ACE-I); however, its discontinuation did not result in recovery of renal function. Additional review of records dating 6 years ago revealed thrombocytosis of around 600 × 10 3 / μ L which was more recently in the 418‐440 × 10 3 / μ L range. The patient had never experienced arterial or venous thrombotic events, and etiology of his thrombocytosis had not been investigated in the past. Several laboratory studies were ordered with focus on his CKD and thrombocytosis. Two months later, investigation of his progressive chronic kidney disease had revealed proteinuria with 560 mg/24 hours urine protein content, and he was seen by a nephrologist. The electrolytes, uric acid, glucose, serum lipid profile, hepatitis panel, liver function tests, prostate serum antigen, and serum complement levels of C3 and C4 were normal. Serum and urine protein electrophoresis did not identify significant paraproteins. Further testing for autoimmune and systemic disease was negative, which included sedimentation rate, C-reactive protein, antinuclear antibody, and antiproteinase 3. Ultrasonography revealed normal renal parenchymal echogenicity of both kidneys, which measured 10.9 cm in length on the right and 9.9 cm on the left. There was minimal postvoid bladder residual volume of 21 mL, and no hydronephrosis or solid renal mass was seen. In the following months, the patient was monitored routinely for findings such as hematuria, increased proteinuria, and swelling. He was continued on lisinopril for mild proteinuria. Repeat testing 3 months after his prior results found an elevated SCr of 1.91 mg/dL and GFR of 36.50 mL/min. Urine testing at that time however found improved proteinuria with 23 mg/24 urine. On subsequent follow-up visits, the patient's blood pressure remained in the range of 118-140/82-92 mmHg. His platelet count in the 6 months after his renal biopsy remained consistently between 797 and 876 × 10 3 / μ L without cytoreductive therapy. Subsequently, given that his SCr remained 1.6-1.7 mg/dL with proteinuria less than 300 mg per day, it was decided to continue the ACE-I without immunosuppressive therapy unless further progression became evident. The development of glomerulonephropathy in patients with MPNs is not well understood and is infrequently encountered. While cases have been described within many of the myeloproliferative neoplasm subtypes, this association seems to be more commonly documented within PV and primary myelofibrosis (PMF). Cases of PV describing the development of nephrotic range proteinuria often report FSGS following renal biopsy [ 7 – 9 ]. While FSGS is described in most PV cases, some cases of PV-related nephropathies have also described IgA nephropathy . Furthermore, there is a reported case for which Said et al. proposed the term “MPN-related glomerulonephropathy” to distinguish MPN-related glomerular disease from other common glomerular diseases based on histopathologic findings. MPN-related glomerulonephropathy was characterized by (1) mesangial sclerosis and more pronounced mesangial proliferation, (2) a lack of nodular mesangial sclerosis, (3) absence of immune deposits, (4) presence of intracapillary hematopoietic cell(s), and (5) segmental duplication of the glomerular basement membrane with findings that mimic chronic thrombotic microangiopathy (TMA) but without intracapillary fibrin thrombi, arteriolar thrombotic lesions, or features of microangiopathic hemolytic anemia . On comparison of the ET and glomerulonephropathy previously described cases with ours, only the ET case in Said et al. had the histological appearance of the proposed MPN-related glomerulonephropathy. Four of the ten were consistent with FSGS, two were not given an official diagnosis, two IgAN (including our case), one fibrillary glomerulonephritis, and one MPN-related glomerulonephropathy. Mesangial proliferation was a common finding as it is stated in 9 out of 10 of the cases. Another is immune complex deposition, being stated in 6 out of the 10. Our case shared the mesangial proliferation and deposition of immune complexes, which may be an affected process with the shared pathophysiology of ET. A possible pathogenic correlation between ET and glomerular disease could be with platelet-derived growth factor (PDGF) and its role in fibrotic processes such as glomerulosclerosis and myelofibrosis. In a study of fibrogenic growth factors in IgAN and FSGS, Stein-Oakley et al. concluded that these glomeruli express higher levels of PDGF receptors which were strongly associated with disease severity, particularly with FSGS. Likewise, the amount of mesangial proliferation was associated with the higher expression of PDGF in glomeruli of patients with IgAN and FSGS . In studies comparing ET and PDGF levels, mutations of JAK2 , CALR , and MPL have been linked to increased concentrations of PDGF, with CALR mutations leading to three times higher levels than with the other mutations. This has been used to offer an explanation as to the significantly higher incidence of primary myelofibrosis in patients of ET and CALR mutation . Similarly, PV-associated nephropathies have been thought to involve fibrogenic cytokines such as PDGF. Additionally, it has been proposed that with the resultant hyperviscosity of PV, chronic increases in blood volume and viscosity can lead to vascular damage to the intima of vessels, with subsequent microthrombi causing renal capillary occlusion that ultimately decrease glomerular filtration. This is supported with findings of pronounced hypertension and hyperuricemia in patients with PV-related glomerulonephropathy (8 of 23 described cases being IgA nephropathy) . In the present case, cytoreductive therapy was not found to be necessary given the lower risk and stable levels of thrombocytosis. Interestingly, the use of anagrelide in ET has been found to decrease the levels of PDGF which may carry an important implication in the treatment of glomerulonephropathies in patients with ET . In consideration of the importance of PDGF in the shared pathogenesis of these conditions, other cytoreductive therapies such as interferon and hydroxyurea would benefit from a study of their effects on plasma PDGF levels. Even so, potential renal impairment directly from these agents should be considered if treatment is initiated. MPN patients who are on cytoreductive therapies with profound renal impairment, which does not recover with dosage decrease, may benefit from renal biopsies to identify a concurrent glomerulonephropathy.
|
Review
|
biomedical
|
en
| 0.999996
|
31616610
|
Whole pancreas transplantation has become an accepted form of treatment for type I diabetes mellitus. Based on Organ Procurement and Transplantation Network (OPTN) data as of May 22, 2019, 8,789 pancreas and 23,959 simultaneous kidney-pancreas transplants have been performed since January 1988. In 2018, there have been 192 pancreas and 836 kidney-pancreas transplants reported. Early graft loss is rare but is generally related to technical complications. Such complications are most commonly related to vascular thrombosis and intestinal anastomotic leaks. Traditionally, these complications are grave and graft salvage is not attempted. Retransplantation is also seldom attempted given the morbidity of the first operation. The patient is a middle-aged female with type I diabetes mellitus. She suffered from difficulties with glucose control and hypoglycemic unawareness. She also developed the sequelae of diabetes, including retinopathy and peripheral neuropathy. As a result, the patient received a pancreas transplant. The patient had preserved kidney function with a glomerular filtration rate (GFR) of 107 ml/min and a protein to creatinine ratio of 138 mg/g. Vascular reconstruction was performed using a standard donor iliac Y-graft to the superior mesenteric and splenic arteries on the graft end. The common iliac artery of the donor was reconstructed to that of the recipient. The donor portal vein was anastomosed into the inferior vena cava. The duodenum of the donor was then drained using a standard two-layer, hand-sewn anastomosis to the recipient ileum. Initially, the patient had an uneventful postoperative course. About a month later, she presented with increasing pain and diarrhea. Cross-sectional imaging revealed an abscess . Upon drainage, the abscess was found to communicate with the intestinal tract, and a leak was diagnosed . An exploratory laparotomy was performed to assess the findings. She was found to have a large abscess cavity, and after adequate drainage, we did not find a leak at the duodenal anastomosis. The staple line at the proximal duodenum, however, had a 1-cm gap in it. The graft was initially thought to be unsalvageable. The edges of the leak were inflamed and devitalized. With intestinal contents passing by, any primary repair was guaranteed to fail. There was also not a precedent for a diversion this early after transplantation. We eventually decided to repair the defect with running non-absorbable monofilament stitches and performed a diverting loop ileostomy . The patient healed well, and the drains were removed. The pancreas continued to function well with excellent glucose control. Eight months later, we performed a planned revision of the ileostomy. We feared a simple closure of the ileostomy would reproduce the leak, so we decided to exclude the pancreas by taking down the ileostomy and performing an ileoileal anastomosis distal to the donor duodenum . This essentially produced a defunctionalized Roux limb to drain the pancreas. The patient healed well and was discharged a few days later on a regular diet. Several months later, she is reported to have an Hgb A1C of 5.3 % and a fasting C-peptide of 1.4 ng/ml. The patient continues to enjoy excellent glucose control from the pancreas and normal gastrointestinal function. Pancreas transplantation has long been the most effective therapy for type I diabetes mellitus . This is especially true for patients who develop hypoglycemic unawareness and other complications associated with end-organ damage . In fact, some end-organ damage has been shown to reverse after successful pancreas transplantation, including nephropathy , retinopathy , and neuropathy . Kidney function seems to be preserved for longer after simultaneous pancreas-kidney transplantation than pancreas transplantation alone . Solitary pancreas transplantation in well-selected patients reverses diabetic complications, including proteinuria . Our patient had a preserved GFR of 74 ml/min at a year post-transplant, with no change in proteinuria at 182 mg/g. She continues to maintain such function at the time of this publication close to two years out. The surgical complications of pancreas transplantation have been well-described . The most concerning complications are vascular thrombosis and duodenal leaks, historically leading to unsalvageable grafts in general . Duodenal stump leaks have been reported to occur in 5% to 20% of all pancreas transplant recipients, including pancreas alone transplant, pancreas after kidney transplant, and simultaneous kidney-pancreas transplant . Mauricio and Cesar described a case where a leak occurred after enteric conversion . In this particular scenario, a well-healed pancreas was converted from bladder drainage to enteric drainage, and then an anastomotic leak occurred. The technique used was relatively similar to ours; however, the reported leak was minor and occurred neither immediately after transplantation nor after the induction of immunosuppression. Also, the graft had been well-incorporated. Duodenal leaks are devastating complications after pancreas transplantation. Drainage, repair, and diversion can be utilized to salvage the transplant. These principles are applicable to other types of intestinal leaks, such as perforated acute diverticulitis, as well. This case report illustrates that two-staged diversion followed by revision can be safely and effectively used in salvaging leaks early after pancreas transplantation. Early recognition of the complication and swift salvage are paramount to success. Further case reports and series will be helpful in establishing the reliability and reproducibility of this technique.
|
Review
|
biomedical
|
en
| 0.999995
|
31637745
|
Chimeric antigen receptor transduced T cell (CART) therapy has demonstrated clinical activity in multiple malignant tumors. 1 In 2017, the United States Food and Drug Administration approved CD19‐targeted CART cells (CARTs) as a salvage treatment for recurrent and/or refractory patients with B cell malignancies. 2 , 3 In recent years, several CART clinical trials for multiple myeloma (MM) conducted worldwide have shown good clinical response, with target antigens including BCMA, CD19, and others. 4 , 5 , 6 , 7 , 8 , 9 In addition to the clinical efficacy of CART therapy, it is important to pay attention to the possible adverse reactions, to reduce the severe, irreversible treatment‐related mortality and to ensure that toxicity is managed well. Prolonged pancytopenia should also be a focus beyond unique acute cytokine release syndrome (CRS). 1 Such complications may bring the risk of fatal infection and bleeding, and could increase the hospital stay and economic burden of patients. Here, we report one patient with relapsed and refractory MM who developed bone marrow failure and severely prolonged pancytopenia after receiving sequential CD19‐ and BCMA‐specific CARTs. His hematopoiesis was successfully restored by the infusion of cryopreserved autologous stem cells. Case presentation: A 41‐year‐old male was diagnosed multiple myeloma with IgG lambda in March 2018 after presenting with anemia, mildly elevated creatinine and multiple bone lesions. He received induction therapy with four cycles of bortezomib, thalidomide and dexamethasone (BTD), which resulted in maximum efficacy of partial remission according to the International Myeloma Working Group (IMWG) response criteria. 10 At this time, the patient was determined to have developed the complication of grade 2 peripheral neuropathy with pain. Autologous stem cells were collected after the administration of high‐dose cyclophosphamide (3 g/m 2 of body surface area). The harvest in June 2018 contained 7.1 × 10 8 /kg of mononuclear cells and 7.1 × 10 6 /kg of CD34‐positive cells. Unfortunately, the disease progressed during the wait for autologous stem cell transplantation (ASCT). Subsequent second‐line treatment included lenalidomide and dexamethasone (Rd) beginning in July 2018. However, the response was poor, and the disease continued to progress. In September 2018, high‐dose conditional chemotherapy (busulfan 9.6 mg/m 2 and cyclophosphamide 3.6 g/m 2 ) was followed by salvage ASCT. The graft for ASCT was half the amount of the collection. The ASCT resulted in stable disease for 2 months. Considering this poor prognostic finding, the patient was later enrolled in the reported CART trial in our center in December 2017. 11 A bone marrow aspirate showed weak CD19 expression (0.08%) and strong positive BCMA expression (94.5%) on the clonal plasma cells by flow cytometry. The patient's treatment and administration schedule is shown in Figure 1 A. The patient presented a fever of 38.8°C ten hours after infusion of the first dose of CARTs‐CD19, and the peak of temperature was 39.8°C on day two, and lasted for a total of 9 days. The peak serum ferritin level was also nearly four times higher compared to the baseline . Peak serum interleukin (IL)‐6, IL‐10 and interferon‐γ levels were detected on day two postinfusion . According to the guidelines of the CARTOX Working Group, 12 the patient had developed grade 3 CRS at this time. We treated the patient with a single 6 mg/kg dose of the IL‐6R inhibitor tocilizumab. However, he continued to clinically deteriorate and experienced hypoxemia grade 1, elevated creatinine grade 2, elevated bilirubin grade 2, 13 and hypotension requiring support with a 0.40‐0.45 μg/kg/min drop rate of norepinephrine. This toxicity culminated on day three post CART therapy. Methylprednisolone 2 mg/kg was administered to minimize the toxicity and to improve the patient's clinical symptoms. There was no neurologic toxicity. After IL‐6R antibody and steroid administration, his cytokine levels, organ functions and clinical manifestations were dramatically ameliorated. On day eight postinfusion, we were able to discontinue the norepinephrine infusion . However, the patient exhibited long‐term grade 4 hematological toxicity after CART treatment. The onset of pancytopenia occured after fludarabine and cyclophosphamide regimen for lymphocyte depletion. The patient presented only with severe pancytopenia without any other manifestations, such as fever or organ damage. Granulocyte colony‐stimulating factor and thrombopoietin support did not work after the CRS reaction was completely subsided. The patient was platelet‐ and red blood cell transfusion‐dependent from day two until more than 30 days after CARTs infusion. The gene mutations related to hemophagocytic lymphohistiocytosis testing, such as LYST, PRF1, CD27, RAB27A, BLOC1S6, UNC13D, STXBP2, TCN2, AP3B1, ITK, STX11, SH2D1A, XIAP and MAGT1, were normal. Parvovirus B19 and cytomegalovirus were negative. Bone marrow aspirate and biopsy specimens demonstrated extreme aplastic bone marrow (<5% cellularity) with no megakaryocytes and reticulin fibrosis at 1 month postinfusion. On the 35th day post‐CARTs, autologous cryopreserved stem cells, containing 3.05*10 6 /kg CD34‐positive cells, were infused considering the limited value of tandem ASCT. As expected, the patient's hematopoietic function was gradually reconstructed on the 11th day after infusion of autologous stem cells . The trends of the patient's serum IgG concentration and the serum monoclonal protein concentration (M spike) throughout the treatment are shown in Figure 1 E. The serum monoclonal protein became undetectable 4 months postinfusion and remained undetectable until July 2019. After CART therapy, bone marrow aspirate and biopsy also confirmed that the patient achieved stringent complete remission , including minimal residual disease negative by flow cytometry. The laboratory characteristics of the patient's bone marrow before and after CART treatment are shown in Table 1 . The CARTs maximum amplified 16.34‐fold on day eight postinfusion, and sustained for 29 days by quantitative PCR using a transgene‐specific primer/probe pair. Multiple hematologic toxicities may occur following CARTs infusion, including the development of anemia, thrombocytopenia and neutropenia. Prolonged cytopenias have been previously reported in limited clinical trials. 2 , 7 However, the extent of suppression and effective management measures have not been described in detail. Conditioning chemotherapy may contribute to the development of pancytopenia. However, this effect can generally be restored within 1 to 2 weeks. In this trial, the CARTs targeting CD19 may have resulted in CAR‐mediated damage to normal B lymphocytes, but this effect did not explain the suppression of multiple hematopoietic series in the patient. Cell‐stimulating factor support did not improve the blood test results. The biochemical parameters and elevated ferritin profile did not fulfill the hemophagocytic lymphohistiocytosis diagnostic criteria. 12 Therefore, the adverse event probably had other causes. We determined that the patient's bone marrow hematopoiesis was in a state of exhaustion and failure. His serum IL‐6 level increased more than 3000‐fold, and his IFNγ level also increased dozen‐fold compared to the patient's baseline levels. This study demonstrated that CART treatment may have caused some damage to early hematopoietic cells, including hematopoietic stem/progenitor cells. Considering that CARTs targeting CD19 and BCMA probably have no direct damage to normal early hematopoietic cells, we speculate that this result is most likely due to a large amount of inflammatory cytokine release. In summary, our work demonstrated that autologous stem cell infusion may be considered in cases of life‐threatening pancytopenia post‐CART. Seriously prolonged pancytopenia may also emerge in more CART therapy clinical practices. Research priorities include achieving a better mechanistic understanding the reasons for the cytopenia observed after CART therapy. This patient's inflammatory factors had returned to the baseline level and had no significant expansion of CARTs in vivo when receiving stem cell infusion. Improved animal models and CART clinical trial data will likely provide more evidence for addressing this question, and further determining the time of intervention for stem cell infusion.
|
Clinical case
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biomedical
|
en
| 0.999998
|
31752236
|
Laparoscopic approaches in pediatric surgery have increased significantly , but some studies indicate that laparoscopic hernia repair is not superior to open surgery in terms of the severity of post-operative pain . As an example, if an adequate analgesic protocol was not applied, then the median face, legs, activity, crying and consolability (FLACC) score was still five (95% confidence interval (CI) 3.97 to 6.03) two hours after laparoscopic inguinal hernia repair in toddlers . Pain from laparoscopic surgery is caused by both somatic- and pneumoperitoneum-induced visceral pain . Therefore, although regional analgesia affects somatic pain, it is unlikely to fully alleviate the response from visceral stimulation . Accordingly, convincing systemic analgesic methods need to be further studied. We hypothesized that systemic lidocaine would provide reliable analgesia in children undergoing laparoscopic hernia repair surgery. We focused on how many children would need rescue opioid analgesia after surgery and whether systemic lidocaine could reduce this number. Accordingly, we assessed post-operative pain in children using the FLACC scale at the post-anesthesia recovery care unit (PACU), and rescue opioid was administered if the FLACC score was four or greater . The primary outcome was the number of patients who received rescue analgesia in PACU. The analgesic effect of lidocaine was evaluated using the FLACC score and the parents’ postoperative pain measure (PPPM) score 48 h after surgery. Children aged 6 months to <6 years, who had an ASA (American Society of Anesthesiologists) physical status of 1 or 2 and were scheduled for elective laparoscopic inguinal hernia repair surgery between December 2013 and June 2015, were enrolled in this study. Patients were excluded if they had clinical evidence of cardiopulmonary, renal, or hepatic disease; cerebral dysfunction; or neurological disease. In addition, children who had been taking analgesia within 2 weeks of the date of surgery, with a history of respiratory infection during the preceding 2 weeks, or those with a known allergy to lidocaine, were excluded. General anesthesia followed the conventional pediatric anesthesia protocol of Severance Hospital (Seoul, Republic of Korea). According to the hospital’s policy, patients were admitted early on the morning of the day of surgery, and intravenous catheterization with a 24 gauge angiocatheter was performed in the ward. When the patient arrived at the pre-operative treatment room, the attending anesthesiologist checked their medical history and undertook a physical examination to check for exclusion criteria. Because only the patient is allowed to enter the operating room in our institution, the patient was sedated in the pre-treatment room before being separated from their caregiver. Intravenous atropine (0.01 mg kg −1 ), lidocaine (1 mg kg −1 ), and Propofol (2–3 mg kg −1 ) were administered in the pre-treatment room. As soon as the child was sedated, they were transferred to the operating room quickly, and the attending anesthesiologist started assisted mask ventilation with 100% oxygen and 3%–4% sevoflurane; routine monitoring, including pulse oximetry, capnography, electrocardiography, and non-invasive blood pressure measurements, was conducted simultaneously. After confirming that there was no eyelash reflex or other signs of consciousness, rocuronium (0.4–0.6 mg kg −1 ) and fentanyl (1 µg kg −1 ) were administered. Then, after 2–3 min, endotracheal intubation was performed. Anesthesia was maintained with 0.8–1.2 MAC (minimal alveolar concentration) of sevoflurane in a mixture of 40% oxygen. Ventilation targeted an end-tidal carbon dioxide concentration of 4.7–5.3 kPa, with a delivered tidal volume of 6–8 mL kg −1 . The surgical procedures were performed with three trocars. After the trocar had been introduced, a pneumoperitoneum was created with 10 mmHg intraabdominal pressure. The surgeon approached the internal ring level and ligated it with a non-absorbable purse string suture. When the trocars were removed, fentanyl (0.5 µg kg −1 ) was administered for post-operative analgesia. At the end of surgery, sevoflurane was discontinued, atropine (0.01 mg kg −1 ) and neostigmine (0.02 mg kg −1 ) were administered for the reversal of residual muscle relaxation, and the child was ventilated with 100% oxygen at 6 L min −1 . Extubation was performed when the patient presented all the following signs: grimace, eye opening, crying face, spontaneous turning of the head, and purposeful movement of limbs. Our sample size was calculated from data obtained in a previous study, which demonstrated that the incidence of moderate to severe pain in children undergoing laparoscopic appendectomy was 80% . We assumed that the incidence of patients presenting with a FLACC score of 4 or more after surgery would be reduced from 80% to 50% by administering lidocaine. Fisher’s exact test showed that the required sample size would be 30 patients in each group, with a significance level of 5% and a power of 90%. A final sample size of 33 children per group was selected, to allow for a dropout rate of 10%. The statistical analysis was performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). Univariate statistical analyses were conducted to analyze the baseline characteristics. Under the assumption of normal distribution, we used Shapiro–Wilk tests. According to the normality of the data, continuous variables (age, height, weight, duration of operation, duration of anesthesia, and the highest FLACC score) were analyzed using Student’s t -test or the Mann–Whitney U test, and are reported as the mean ± standard deviation or median (interquartile range, IQR). All categorical and ranking variables (sex and ASA physical status) were analyzed using the χ 2 test or Fisher’s exact test, and are expressed as n (%). For primary outcome analysis, categorical variables are expressed as n (%) and analyzed by an χ 2 test. p <0.05 was considered statistically significant. For the secondary outcome analysis of the highest FLACC scores in PACU, we analyzed the FLACC scores using Student’s t-test, and expressed the results as the mean ± SD. Because the FLACC scores in the ward were measured at four different times for the same patient, a Bonferroni correction for four comparisons was used, and p <0.012 was considered to be statistically significant. Serial data were analyzed using a linear mixed model with unstructured covariance, with fixed effects including time, group, and interactions, as well as with a random effect on the response variable. The PPPM score was analyzed using a Mann–Whitney U test, and adverse events were analyzed using the χ 2 test. A p -value <0.05 was considered statistically significant. Unlike in adults, lidocaine intravenous infusion in children has not been extensively studied. So far, only two randomized controlled studies have been published. In one study, a lidocaine bolus dose of 1.5 mg kg −1 , followed by a continuous infusion at a rate of 1.5 mg kg −1 h −1 for six hours, was administered to children undergoing major abdominal surgery. This treatment attenuated the increase in serum cortisol levels, reduced daily fentanyl requirements, hastened the return of bowel functions, and reduced the length of the hospital stay for the children . The other published study indicated that lidocaine (1.5 mg kg −1 over five minutes followed by 2 mg kg −1 h −1 ) decreased postoperative vomiting in children undergoing an elective tonsillectomy . The serum’s lidocaine concentration was measured in both studies, and in no cases were toxic plasma concentration, neurological disturbances (seizures, numbness, tingling, or paresthesia), or cardiovascular collapses detected in any of the participants . University Children’s Hospital Zurich, Switzerland implemented the protocol of intravenous lidocaine infusion for children undergoing laparoscopic surgery, and adverse effects were not reported . According to the Cochrane analysis, in adults undergoing open or laparoscopic abdominal surgery, a continuous lidocaine infusion rate of 1.5 mg kg −1 h −1 reduced pain immediately after, and until 24 h, with no increased risk of adverse effects such as death, arrhythmias or signs of lidocaine toxicity . Considering both the effectiveness and safety of these previous trials, we used a bolus injection of 1 mg kg −1 , followed by a continuous infusion of 1.5 mg kg −1 h −1 . According to our results, the administration of lidocaine for about 60 min statistically lowered the pain score (mean FLACC 3.8 in Group L vs. 5.3 in Group C) immediately after surgery and for up to two days after surgery. However, since rescue analgesia was to be administered if the FLACC score was four or greater , the number of patients who needed rescue analgesia in the PACU was not significantly reduced by lidocaine administration. One possible reason for this is lidocaine’s mechanism of action. Through various mechanisms, systemic lidocaine is thought to prevent central sensitization, as well as spinal or peripheral hypersensitivity in response to nociceptive surgical stimuli, along with wound healing, and anti-thrombotic and anti-inflammatory effects . In other words, the effects of lidocaine on post-operative pain reduction are assumed to result from indirect mechanisms. Therefore, lidocaine itself may not be sufficient as a sole analgesic immediately after operation. When systemic lidocaine is incorporated into one element of multimodal analgesia, its role in reducing the severity of pain, and its prolonged analgesic effects, will be augmented if combined with any modalities or drugs for acute postoperative pain control. In this study, we focused on how many children would need rescue opioid analgesia after surgery, as well as whether systemic lidocaine could reduce the number of patients who received a rescue opioid. In children, pain control is required if the FLACC score is four or greater after surgery. Contrary to the VAS (visual analogue scale) for pain, no guideline exists for the minimal differences in FLACC scores that signify clinical importance. Therefore, it was difficult to define how much of a reduction in the FLACC score would be statistically and clinically significant. This is why our primary outcome was defined as the number of patients with FLACC scores of four or more points. Some adult studies have demonstrated that systemic lidocaine can enhance the quality of recovery . Since no verified scoring system for this exists for children, such as the quality of recovery-40 (QoR-40) for adults, we used a PPPM scale to assess pain as well as quality of recovery in children . PPPM applies a pain threshold scale that uses a yes (score of 1) and no (score of 0) system to assess daily routines or children’s behavior, and the questions ask whether a child’s behavior has changed compared with before surgery. According to our results, the mean PPPM score was 1.3 in the lidocaine group, which was significantly different from the 3.2 in the control group. It is debatable if this statistical difference correlates to clinical significance in terms of pain, since a PPPM score of six or higher is considered to be significant pain. However, from the parent’s perspective, 48 h after surgery, only 5 out of 30 children in the lidocaine group, compared to 19 out of 30 children in the control group, showed behavioral changes in three or more questions. Therefore, as it does for adult patients, systemic lidocaine is likely to help children return to their daily activities and improve their quality of life after procedures that require anesthesia and surgery. Apart from the doses used, the limitations of this study include safety issues and the pain scale used. First, we only included children aged six months to less than six years, due to the concerns of possible systemic toxicity for patients younger than six months of age. We could not include children aged six years or older because the FLACC scale is a tool for assessing pain in children under seven years of age. Second, the analgesic protocol in the ward and at home was not standardized. However, almost all children presented pain lower than the threshold that required treatment (FLACC ≥4 and PPPM ≥6) in the ward or after discharge. Third, since laparoscopic hernia surgery is a minor surgical procedure, the PPPM score for evaluating long-term post-discharge recovery was quite low in both groups, and the clinical implications are questionable. Therefore, we recommend studying the recovery effect of lidocaine on major operations with moderate to severe pain after surgery.
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Other
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biomedical
|
en
| 0.999999
|
31772799
|
A spinal extradural arachnoid cyst (SEAC) is a relatively rare disease in which the arachnoid membrane prolapses through a dural defect and expands to form an extradural cyst that induces spinal cord symptoms . In the Nabors classification , spinal arachnoid cysts are classified into three types based on the location and presence or absence of nerve tissue in the cyst. A SEAC has an extradural location and contains no nerve tissue, which makes it a type 1 cyst. Here, we report a case of a patient with a SEAC that manifested with severe low back pain. Physical findings on admission showed percussion tenderness in the thoracolumbar junction. There is no obvious range of motion restriction in the hip joint, and the Patrick test was negative. The score on a manual muscle test of the bilateral lower limbs was 5/5, and there was no sensory disturbance or bladder and rectal disturbance. The femoral nerve stretching test (FNST) and straight leg raising (SLR) test were both negative. The patellar tendon reflex (PTR) was normal on the bilateral sides, but the Achilles tendon reflex (ATR) was enhanced on the bilateral sides. Surgery was performed to ligate the communication pathway and excise the cyst. The anesthesia was total intravenous anesthesia (TIVA) and the body position was prone. And we use a nerve stimulator. In laminectomy for T11 and T12, the bone cortex of the T12 vertebral arch was excluded by the cyst and thinned and a bulging cyst was present just below the resected arches. When the cyst was dissected from the dura under a microscope, a communication pathway for cerebrospinal fluid was present in the axillary region of the left T12 nerve root. Thus, this region was ligated and the cyst was excised. The cyst did not adhere to the dural canal . Histological findings showed a cystic lesion comprised of fibrous connective tissue. Psammoma body formation in the wall and aggregation of some meningothelial cells were also observed. Low back pain rapidly resolved immediately after surgery, and there has been no recurrence of pain or of the cystic lesion on imaging for 10 months after surgery. SEAC accounts for 1% of spinal tumors , with its development in the thoracic vertebra, thoracolumbar vertebra, lumbosacral vertebra, and other sites accounting for 65%, 12%, 13%, and 10% of cases, respectively, and the cyst extending over 5 vertebrae on average . In our patient, the cyst arose in the thoracolumbar vertebra and expanded over 3 vertebrae. SEAC causes neurological disorders by excluding the spinal cord and nerve root with the expansion of the cyst, but the cause of expansion is unclear; however, the check valve mechanism and secretion system have been suggested as a cause . In our patient, contrast medium flowed into the cyst and no secretory cells were observed histologically, suggesting that the cause was cyst formation through the check valve mechanism. Cho et al. showed that visualization of the communication pathway to the cyst using myelography was important for preoperative planning . Similarly, in our patient, the communication pathway for inflow of contrast medium into the cyst was confirmed on myelography. This helped in making a definite diagnosis and in preoperative planning with regard to ligation of the pathway. Lee et al. reported that the recurrence rate after ligation of the communication pathway was 2%, whereas that without ligation was 66.7%, showing the importance of ligation of the pathway . In our patient, total excision of the cyst and repair of the dural defect were performed, and the course has been favorable, with no recurrence of pain or the cystic lesion in 10 months postoperatively. Excision of the cyst with obliteration of the communicating dural defect is the mainstay of treatment in symptomatic patients . Concomitant fixation with excision has not previously been described, but Takagaki et al. reported that kyphosis developed in 67% of patients treated with laminectomy of multiple vertebrae and recommended the application of laminectomy to as few vertebrae as possible . In our patient, we did not perform fixation, because of no facet joint damage and only two-level vertebral arch resection. But no progression of kyphosis was noted at the final follow-up.
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Clinical case
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biomedical
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en
| 0.999997
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31804364
|
Synovial osteochondromatosis (SOC) is a monoarticular, synovial, proliferative disorder. It is a rare entity which presents with multiple cartilaginous nodules in synovial joints, bursae or tendon sheaths. [ 1 – 3 ] SOC most commonly involves knee joint with a frequency of 50% to 65%. Other places that are involved frequently include hip, elbow, shoulder, and ankle joint. [ 1 – 3 ] Observed clinical symptoms were pain, swelling, numbness and limitation of joint movements at the involved area. Secondary osteoarthritis findings such as generalized joint effusions, locking, tenderness, and snapping may also occur. [ 1 – 3 ] Therefore, early diagnosis and proper treatment of this unique disease is of great significance. Although rare, SOC should be considered in differential diagnosis of cases presenting with similar symptoms. To the best of our knowledge, this is a less-documented case of giant synovial osteochondromatosis of the thigh in a man presenting with continuous progressive hip pain, local numbness and swelling, who underwent total resection of the space-occupying lesions. In the follow-up visit, the patient's conditions improved significantly postoperatively. After reviewing pertinent literatures, we discussed common clinical considerations in patients with giant synovial osteochondromatosis of the thigh and management considerations for these patients. A 63-year-old previously healthy man presented to our institution with a 4-year history of continuous progressive hip pain and local numbness of right thigh in January 2018. Upon examining and questioning, the patient stated he has been experiencing a gradual increase in his hip pain, as well as worsening numbness and swelling of the right thigh. In the medical journal of his current illness, the pain in his right hip can reach 4–5 points using the visual analogue scale and cannot be alleviated with rest and hot compresses. One month ago, the patient felt that the above symptoms were aggravated, especially during sleeping and sitting. He denied history of injury and any other underlying diseases. No pertinent family history was identified, including hypertension and cancer. Physical examination showed a mass sized 12 × 24 cm in the proximal thigh, which was hard in texture, unclear in boundary, adherence to surrounding tissues, poor mobility, and no tenderness. However, low skin temperature and varicose vein were not found on the surface of the mass. Routine laboratory studies were almost within normal range, except that the tissue polypeptide specific antigen was significantly elevated to 101.55 U/L (normal: <80 U/L). Plain radiographs showed irregular shadow of a soft tissue mass in his right thigh . Computed tomography (CT) showed multilocular cystic-solid mass in the right thigh root, with high suspicion of malignancy . Magnetic resonance imaging (MRI) of the hip revealed the irregular mass in his right thigh mimicking a parosteal sarcoma . Considering the large volume of the mass and possibility of malignancy, surgical exploration and complete tumor resection were performed according to the designed surgical procedure. After successful anesthesia, the patient was placed in a supine position, with the right buttock being cushioned high. During the operation, multiple cystic masses in the deep muscles were seen, with a size of about 24 × 15 × 10 cm extending from the upper middle of the thigh to the right hip . Each capsule contains clear yellowish and reddish liquids, which are filled with a large number of round, tough, oval-shaped, white translucent, cartilage-like granules with a diameter of about 0.5 to 2.0 cm. The chondroid granules in the capsule were cleaned completely, the wall of the capsule was separated from the surrounding tissues, and the capsule was excised completely and sent for pathological examination. The incision was closed. Intraoperative blood loss was approximately 900 mL, thus we used erythrocyte 2U. The postoperative pathology confirmed the diagnosis of synovial osteochondromatosis of the thigh . Pathological result was positive for Vimentin and S-100. Biopsy samples were negative for AE1/AE3 and EMA, with 5% Ki-67 positive nuclei. Synovial osteochondromatosis (SOC) is a benign disorder of nodular cartilaginous neoplastic development of the synovium that can lead to multiple loose bodies within the articular space. [ 1 – 3 ] SOC can be originated from any joint, tendon sheath, or bursae that has synovial tissue, which is characterized by cartilaginous nodule formation secondary to synovial metaplasia. [ 1 – 4 ] Although it is generally progressive in nature, it can limit itself and regress. This condition is usually a monoarthritic disease and affects the knee joint in more than 50% of all cases suffering from SOC. [ 1 – 3 , 7 ] To date, few reports of SOC of the thigh causing clinical symptoms have been documented so far. Therefore, the management of our reported case has certain educational significance in clinical practice. Delay in diagnosis of synovial chondromatosis may occur due to slow progression of disease course and calcification of free cartilage fragments at later stages. Clinical manifestations of the patients with SOCs are usually due to mechanical and oppressive effects of the mass. Milgram defined 3 stages of SOC: Stage 1 (early stage) is the active intrasynovial stage during which there is no free articular body. Stage II (mid-term stage) is the transition stage from intrasynovial lesions to free bodies. In this stage, there are both active intrasynovial lesions and free articular bodies. In stage III (late stage), there are multiple free articular bodies in the absence of intrasynovial involvement. [ 1 – 3 , 10 , 11 ] The most common radiologic findings, free bodies with varying sizes, can be seen at any place in the tumor cavity. Calcification occurs at the last stage and may not be observed in some patients at earlier stage. Intraarticular liquid-like masses, non-calcified masses or swellings which can be differentiated with MRI or CT scan. [ 12 – 15 ] However, difficulties of diagnosis despite CT and MRI should also be considered. In neglected cases or in cases with a long-term disease course, changes in bone or joint cartilage induced by multiple intraarticular lesions, bony erosion, or presence of local osteoporosis make accurate preoperative diagnosis much more difficult. Imaging studies including CT, MRI, bone scan and PET/CT are non-specific, making it difficult to differentiate SOC from other common occupying lesions. [ 15 – 17 ] However, imaging studies may play a crucial role in the decision making of surgical intervention. In our case, the entire size of SOCs was 24 × 20 × 12 cm, and our case had been one of the biggest SOCs ever reported in literature. Differential diagnosis of synovial osteochondromatosis includes many other occupying diseases. SOC should be differentiated from multiple benign or malignant lesions such as synovial hemangioma, pigmented villonodular synovitis, synovial cyst, osteosarcoma and synovial sarcoma. [ 18 – 21 ] Malignant transformation was reported in few cases at long-term follow-up visit. While the literature describes the knee as the most common location of the usual form of SOC, the location in the thigh is extremely a rarity. The “gold-standard” diagnosis of SOC relies on pathological findings. The main pathological characteristic is chondroid metaplasia of the subintimal tissue of synovial joints. [ 1 – 3 , 23 , 24 ] Further reports and analyses of the giant form of SOC are necessary to improve our understanding of this pathological entity and its differences from the usual form to optimize proper clinical management. In our reported case, pathology results showed significant chondroid metaplasia without cellular atypia, which was consistent with synovial osteochondromatosis. The treatment of first choice for SOC is surgical excision with an open or arthroscopical approach. [ 1 – 3 , 25 – 27 ] In the literature, early arthroscopical or open debridement, synoviectomy, and removal of free cartilage masses at an early stage before cartilage damage occurs have shown to be efficient treatments. [ 25 – 27 ] Severity of disease course and affected location should also be considered when surgeons decide whether surgery should be performed. Additionally, in some cases that had osteochondroplasty after debridement osteoarthritis did not relapse in 2-years follow up and successful results were achieved. [ 25 – 28 ] Under this circumstance, surgical extent, surgical procedures, and postoperative complications are critical factors that need further investigation. According to our single-center experience, we prefer and recommend open surgery for patients with giant SOCs due to the size of the mass. In conclusion, this is the first report of giant synovial osteochondromatosis of the thigh in a patient. Although uncommon, synovial osteochondromatosis of the thigh should be part of the differential when the patient presents with atypical symptoms. Surgical treatment is a definite therapy of first choice. Our case highlights the significance of accurate diagnosis and proper treatment for synovial osteochondromatosis. With an accurate diagnosis, proper planning, and accurate surgical manipulation, synovial osteochondromatosis can be diagnosed and managed much more effectively.
|
Review
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biomedical
|
en
| 0.999996
|
32059817
|
The initial diagnostic hypothesis was subcutaneous mycosis and the patient was referred for complete lesion excision. The material was sent for histopathological analysis and granulomatous inflammatory process was observed with suppuration and sporangia grouped within the cytoplasm of the macrophages . The sporangia were stained by Period Acid-Schiff (PAS) and Grocott, and presented a morula appearance . Part of the skin fragment was sent for mycological examination and fungal culture, with no growth of agents. Figure 2 Presence of a granulomatous inflammatory process with suppuration. In the middle, the sporangia (Hematoxylin & eosin, x40). Figure 3 Presence of sporangia grouped within the cytoplasm of macrophages (Hematoxylin & eosin, x400). Figure 4 The sporangia appear stained by PAS (x400). Figure 5 The sporangia appear stained in black by Grocott (x400). Human protothecosis is rare, but the incidence is higher in immunocompromised patients (local or systemic corticosteroids, immunobiologicals, 7 hematologic malignancies or cancer, diabetes mellitus, AIDS, solid organ and bone marrow transplant recipients, alcoholism or autoimmune disease). In the literature, only 219 cases of human protothecosis have been described worldwide, of which 11 were reported in Brazil, 1 , 4 including this one. Among the cases of human protothecosis, there are only 15 reports of cases in solid organ receptors, 4 , 7 , 8 9 in renal transplant recipients and 1 in liver/kidney transplantation. In Brazil, it is the first case described in a renal transplant recipient. In man, protothecosis is caused mainly by P. wickerhamii and manifests itself in three forms: cutaneous, articular and systemic, with an acute or chronic course. The cutaneous form is the most observed. Lesions have a slow evolution and variable appearance: plaques, papules, nodules, ulcerations and eczematous eruptions. The most common presentations are vesiculobullous lesion and ulceration. 9 In the present case, the patient presented a nodular lesion, reminiscent of the phaeohyphomycosis, a mycosis by dematiaceous fungi described in the recipients of solid organ transplantation. In histopathological examination, there is a granulomatous inflammatory infiltrate, consisting of lymphocytes, macrophages, giant cells and neutrophils. In staining with PAS or Grocott, we can observe sporangia internally containing sporangiospores, which may be inside macrophages or free in the exudate. Sporangia are surrounded by a capsule that can vary from 7 to 30 μm; P. zopfii tends to be larger (7–30 μm) than P. wickerhamii (3–15 μm). 6 A feature of P. wickerhamii is to exhibit sporangiospores with a rounded central endospore, and this characteristic has been described as morula-like, daisy-like or raspberry-like. 6 In the histopathological examination of the our patient, sporangiospores were better evidenced with PAS and Grocott staining, so routine screening with special staining for nodular or nodule-cystic lesions in transplant recipients should be included.
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Other
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biomedical
|
en
| 0.999996
|
32154259
|
There is an increasing trend for primary and revision arthroplasties in the United States (US) ( 1 ) and in Europe ( 2 , 3 ). The incidence of periprosthetic joint infections (PJI) ranges from 0.5 to 2.0% ( 4 ). Twenty-five to thirty-eight percent of knee replacements are due to infections and have been associated with a significant morbidity and a 5-fold increase in mortality at 1 year ( 4 , 5 ). The management of peri-prosthetic joint infections is challenging and therefore requires a multidisciplinary approach, typically including infectious diseases specialists, microbiologists, and orthopedic surgeons to decide which of the following options may be the best in each case: 1 or 2-stage exchange, DAIR (Debridement, Antibiotic, and Implant Retention), ablation of the prosthesis (Girdlestone procedure for example), arthrodesis or amputation. He consulted at a private clinic where a blood test showed a C-reactive protein (CRP) at 50.9 mg/L [0–10 mg/L]. An arthrocentesis was performed which revealed 156,660 leucocytes/μL (36% neutrophils), 70,000 erythrocytes/μL, and direct examination showed the presence of gram-positive cocci. A treatment with cefuroxime administered intravenously (IV) was initiated. The next day, the patient's condition deteriorated with hypotension not responding to IV fluid administration. Antibiotic treatment was changed to amoxicillin-clavulanate 2.2 g IV and the patient was transferred to our hospital. On arrival, the patient was in septic shock and blood tests revealed a CRP at 426.5 mg/L [0–10 mg/L], and an acute kidney failure with creatinine at 355 μmol/L [62–106 μmol/L] (eGFR 15 mL/min/1.73 m 2 ). He was promptly taken to the operating room (OR) where a large amount of pus was collected around the prosthesis and a DAIR procedure with exchange of moving parts was performed considering an acute PJI. Cultures of the purulent material obtained in the OR became positive for S. dysgalactiae subsp. equisimilis and antibiotic therapy was initially changed to ceftriaxone 2 g/day IV and subsequently to penicillin G 4 MioU six times daily, after excluding an infective endocarditis. A second and third look were performed, because of steady increase in CRP on post-operative day (POD) 4: the prosthesis was ablated with the placement of a spacer with decision of a 2-stage exchange. However, abscesses of the right foot were formed requiring a new surgical intervention on POD14 and the treatment was empirically changed to amoxicillin-clavulanate 1,000/200 mg four times daily. Operative samples showed S. epidermidis and vancomycin 1 g IV twice daily (bid) was introduced. Clinical response was documented, and antibiotic treatment was subsequently narrowed down to fusidic acid 500 mg orally (PO) three times daily with rifampicin 600 mg PO once daily. He received a total of 6 weeks of antibiotics after the prosthesis was removed, and eventual reimplantation on POD90. Cultures obtained during this surgery were all negative. Six months after reimplantation, the patient presented with fever, shivering and right knee pain. Upon presentation, he was again in septic shock and on clinical examination he had a warm, red, and swollen right knee with a clear cellulitis extending to the leg. Blood tests showed a leukocyte count of 16,400 cells/μL [4,000–11,000 cells/μL], CRP 310 mg/L [0–10 mg/L]. Arthrocentesis revealed opaque fluid, with 120,338 leukocytes/μL (98% neutrophils), 193,306 erythrocytes/μL, and direct examination showed gram-positive cocci. The patient was quickly taken to the OR where a DAIR was performed and treatment with cefazoline 2 g three times daily IV and vancomycin 1 g twice daily IV was initiated post-operatively. Blood cultures obtained on admission and perioperative cultures became positive for S. dysgalactiae subsp. equisimilis . Although a chronic, insufficiently treated infection was suspected, in view of the cellulitis with lymphedema and chronic vein insufficiency, the origin of this second episode was considered to be the cellulitis with S. dysgalactiae bacteremia and secondary seeding. A DAIR was therefore a valid option, particularly after considering the recent implantation of a revision implant. In order to confirm the source of this infection (relapse or new infection), we performed a genomic analysis of the strains GE-044 and GE-045 ( Table 1 ) recovered from the periprosthetic purulent aspirate of the first and second episode, respectively. Genomic sequences were generated in the same sequencing run on an Illumina iSeq 100 benchtop system with 2 × 151 cycles. Comparison of sequence contigs revealed that the two strains had an average sequence identity (ANI) ( 7 ) of only 98.81%, while each strain showed higher, >99% ANI to several S . dysgalactiae subsp. equisimilis isolates available in the NCBI database ( https://www.ncbi.nlm.nih.gov/assembly ). The seven MLST alleles of strains GE-44 ( gki _3, gtr _3, murI _2, mutS _8, recP _9, xpt _6, atoB _6) and GE-45 ( gki _3, gtr _2, murI _4, mutS _2, recP _20, xpt _1, atoB _3) perfectly matched (100% alignment and 100% identity) those of sequence types ST-20 and ST-55, as revealed using the BIGSdb software at the S . dysgalactiae MLST website ( https://pubmlst.org/sdysgalctiae/ ) ( 8 ). gki _3 was the only allele common to both isolates. A single ST-55 strain previously reported in the PubMLST database was collected in Europe (Portugal). Eleven ST-20 type strains already present in the PubMLST database originated from four continents (Asia, Australia, Europe, North America). The results of our genomic analysis suggest a new infection rather than relapse. Antibiotic treatment was transitioned to penicillin G 4 MioU every 4 h IV on day 1 after surgery for 2 weeks with good response and hospital discharge by day 15 on clindamycin 900 mg three times daily PO for 4 additional weeks, for a total of 6 weeks of antibiotic treatment post-surgical intervention. Subsequently, the patient was put under suppressive antibiotic therapy with penicillin V 0.5 MioU twice daily considering the high risk of recurrence and a second severe streptococcal infection within 6 months. At 1 year post-surgical procedure, the patient had no further relapse. The time between arthroplasty and infection should also be considered, historically divided into early (within the first 3 months), delayed (between 3 and 12 months) and late (>12 months) post-operative infections. For instance, early post-operative infections are usually due to more virulent bacteria, such as Staphylococcus aureus and gram-negative bacilli. During the delayed post-operative period, infections are mainly due to less virulent bacterial pathogens, including Cutibacterium acnes and Staphylococcus epidermidis , among others. Finally, during the late post-operative period infections may be due to low virulent pathogens, but also due to direct inoculation and/or hematogenous seeding in the setting of a concomitant transient or sustained bacteremia ( 12 ). In this case report, despite the isolation of the same type of organism in two episodes of PJI within a period of 9 months, the second episode represented a new infection, as suggested by: (i) the clinical presentation compatible with cellulitis of the leg, favored by chronic lymphedema and venous insufficiency which are known risk factors ( 13 ), with bacteremia and consequently a hematogenous PJI and (ii) a genomic analysis, which revealed that the two isolates collected at a 9 month interval were genetically distant. Notably, streptococci are the second most frequent cause of PJI of hematogenous origin after S. aureus ( 14 ). Therefore, because of the hematogenous origin, a management by DAIR with exchange of moving parts instead of complete exchange of prosthesis was considered, thus a new surgery could be avoided. Next-generation sequencing (NGS) provides better resolution for strain differentiation than other molecular methods. Starting from a cultured isolate, or directly from a clinical specimen, genomic sequence of a pathogen may be obtained and analyzed in <30 h ( 15 ) when NGS is implemented as a routine procedure. While direct NGS of a clinical specimen greatly reduces the overall turnaround time (by bypassing the need to culture bacteria), the completeness of the genomic sequence obtained for a given pathogen depends not only on the sequencing depth but also on the efficacy of human DNA removal, bacterial load and the nature of infection (monomicrobial vs. polymicrobial or monoclonal vs. polyclonal). In the present research study, the reagent cost of NGS for genomic testing of two samples was ~700 CHF. This figure does not take into account labor costs and infrastructure (NGS and computational) investment. Implementing of NGS in routine diagnostics may substantially reduce the cost per sample by multiplexing more samples in the same sequencing run; labor costs for data analysis and interpretation will depend on the computational resources, the level of automation of bioinformatics processes, the availability of curated databases and the nature of each individual clinical case. Suppressive antibiotic therapy was administered in this patient presenting with a second S. dysgalactiae infection with the necessity of hospitalization in the intensive care unit. According to Thomas et al., penicillin as a suppressive treatment is effective in preventing recurrent cellulitis, although the protective effect gradually decreases once treatment is stopped ( 16 ). Furthermore, streptococcal PJIs treated with DAIR have a high recurrence rate, with 42.1% treatment failure ( 17 ). This high rate of failure has led some experts to suggest suppressive treatment for at least 1 year for streptococcal infections. Additional data suggest that suppressive antibiotic therapy may be associated with better outcomes in streptococcal PJI (93 vs. 57%, p = 0.002, median follow up of 13 months, range 0.5–111 months) ( 18 ). Although long-term follow-up data are not available for this patient, he remained without recurrent episodes for at least 1 year on low-dose penicillin secondary suppressive prophylaxis treatment. Identification of the same organism in recurrent PJIs, found in 31% of cases ( 19 ) is commonly considered as indicative of either chronic or relapsed infections. Our case report, based on NGS data analysis, illustrates the fact that recurrent infections due to same bacterial pathogens could represent a new infection, which could have significant implications in the management of those patients. A multidisciplinary approach, including infectious disease, microbiology, and orthopedic surgery specialists, to take into account the case as a whole and determine the best management strategy is required. Genomic sequencing, by the virtue of precisely determining genetic relatedness of sequentially collected clinical isolates from the same patient, can occasionally be the determinant factor for choosing the best approach. In fact, this case report is the first to demonstrate a clear contribution that genomic sequencing can make to the strategy of peri-prosthetic joint infections management.
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Review
|
biomedical
|
en
| 0.999998
|
32181085
|
Cervical spine injuries in the paediatric age group are exceedingly rare. The reported incidence of 1.0-1.3% is far less than half of that of the adult population . However, the sequelae in children are more disastrous with reported mortality to be around 40-50% and 60% of those suffering from permanent neurological deficits . Hence, the presence of cervical spine injuries in children may raise alarm and place the treating team in duress, more so if it involves the complex and challenging craniovertebral junction which has an even higher morbidity and mortality rate. We report a unique case where the anterior arch of atlas failed to fuse due to the failure of formation of the anterior midline synchondrosis, and this mimicked a Jefferson fracture. To the best of our knowledge, it is the first such case to be reported in scientific literature. The initial impression was a rare sub type of Jefferson Type 1 fracture, whereby only the anterior arch of atlas is fractured . However, upon reviewing the CT scan findings, the fracture line was noted to be smooth with presence of sclerosis, as opposed to a fracture line which would be slightly jagged with sclerosis, only a late feature which is associated with the healing process. Furthermore, the patient subsequently was pain free and had full range of motion of his neck without any pain or neurological symptoms. The patient’s diagnosis was then revised as non-fusion of anterior arch of atlas with failure of anterior midline synchondrosis formation. Following clinical confirmation of spinal stability, the cervical collar was removed and the patient was discharged home well after being observed for possible signs and symptoms of neurological deterioration. In a retrospective study of a large number of patients who underwent CT scan of the cervical spine for various reasons, approximately 1.5 to 5% of the patients had posterior arch of atlas defects, whereas approximately 0.46% had a combination of both anterior and posterior defects and the prevalence of an isolated anterior arch of atlas defect was 0.03% . We extrapolate the true incidence of isolated anterior arch of atlas defects in the population to be rarer than this. The sample population was of those who underwent cervical CT following clinical suspicion of pathologies and not a population-wide prevalence study.
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Clinical case
|
clinical
|
en
| 0.999998
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32383177
|
Identification of clinical predictors of outcome in these patients likely involves analysis of many potential interacting factors including psychological and cognitive‐behavioural factors such as fear avoidance behaviour, negative outcome expectancy , pain catastrophizing , depression, anxiety and physical factors . While such multidimensional predictors of outcome to inform surgical patient selection are valuable and may guide alternative clinical pathways of care, the predictive value of sensory nerve fibre function has yet to be systematically investigated in people with painful lumbar radiculopathy. In patients with lumbar radiculopathy, QST has been used to assess the function of sensory nerve fibres in the affected dermatome pre‐ and post‐lumbar decompression surgery . Interpretation of findings is limited, however, as only one study assessed all QST parameters mediated by large and small sensory fibres , and for this study, healthy control data were missing. Furthermore, no study to date has established the QST sensory profile of this patient cohort in relation to their main pain area (MPA), as typically performed in the classification of neuropathic pain . Sensory profiles in the MPA may differ to profiles in the distal dermatome, as observed in patients with cervical radiculopathy . Nerve root compression may affect large and/or small sensory fibres , and the extent of sensory fibre damage may account for heterogeneity of symptoms . Whether these differences are important as predictors of surgical outcome in radiculopathy has yet to be established. The aims of this study were as follows: To establish the QST somatosensory profile of patients with lumbar radiculopathy/radicular pain pre‐ and post‐microdiscectomy in their MPA and affected dermatome. To investigate if there is an association between pre‐surgical QST parameters and clinical outcome (functional status) post‐surgery. The Oswestry Disability Index (ODI) was used as primary outcome measure to quantify functional status (disability). The scoring of the ODI is between 0–100 (where ‘100’ is considered the maximum disability). Ten points, or a 30% change, is defined as the cut‐off point for qualification of a minimal clinically important change . Assuming a 10% rate of persistent pain, a sample size of 40 patients was required to detect 10 units of change from pre‐ to post‐surgery, with a power of 80% and level of significance at 0.05. Patients diagnosed with unilateral L5 or S1 radiculopathy due to posterolateral disc prolapse at L4/5 or L5/S1, respectively, were recruited from the elective neurosurgery waitlist (for lumbar microdiscectomy) between October 2014 and April 2016. Seventy‐eight patients gave verbal consent to participate, and of those ultimately 53 patients gave written consent and participated (mean age 38 ± 11 years, 26 females). In order to minimize the variability in outcomes attributed to differences in surgical protocols, patients were selected from one neurosurgeon's waitlist only (CL). The inclusion criteria for the patients were: Age 18–65 years; Symptom duration of >3 months; Clinical diagnosis of lumbar radiculopathy [defined as a conduction block along a spinal nerve or nerve root, manifesting clinically with dermatomal sensory loss or myotomal weakness or reflex changes ]; Leg pain in L5 or S1 dermatomal distribution; Demonstrable clinically relevant abnormality on imaging studies indicating nerve root compression at L4/5 for L5 radiculopathy and L5/S1 for S1 radiculopathy; Listed on the elective neurosurgery surgery waitlist for the procedure of unilateral L4/5 or L5/S1 microdiscectomy. Multidimensional aspects of pain were included as clinical measures, consistent with the IMMPACT guidelines . Functional status was assessed using the ODI . Based on the ODI score, patients can be classified into five groups: minimal disability (0%–20%), moderate disability (21%–40%), severe disability (41%–60%), crippled (61%–80%), patient is bed‐bound or exaggerates symptoms (81%–100%). The Short Form‐36 health questionnaire (SF‐36v2®) was used to assess health‐related quality of life. The questionnaire contains 36 items measuring health on eight dimensions: physical functioning, role physical, bodily pain, role emotion and mental health plus one time that measures health transition. A physical and a mental composite summary score can be calculated. A higher score indicates better health status. The painDETECT questionnaire was used to screen for neuropathic pain and to quantify descriptors of neuropathic pain . Each descriptor is weighted from 0 to 5, with ‘0’ indicating the person ‘never feels the sensation’, 1 = ‘the sensation is hardly noticed’, 2 = ‘slightly noticed’, 3 = ‘moderately noticed’, 4 = ‘strongly noticed’ and 5 = ‘very strongly noticed’. A painDETECT score of ≤12 indicates that a neuropathic pain component is ‘unlikely’, a score of ≥19 indicates a likely presence of a neuropathic pain component. Scores between 13 and 18 reflect an ambiguous result. Standardized QST was performed according to the QST protocol of the German Research Network on Neuropathic Pain . This protocol comprises all of the somatosensory sub‐modalities that are mediated by primary afferents (C‐, Aδ‐, Aβ‐). The protocol included the following assessments: cold and warm detection thresholds (CDT, WDT), the number of paradoxical heat sensations during the procedure of alternating warm and cold stimuli; cold and heat pain thresholds (CPT, HPT); mechanical detection threshold (MDT); mechanical pain threshold (MPT); stimulus‐response functions: mechanical pain sensitivity (MPS) and dynamic mechanical allodynia (DMA); wind‐up ratio (WUR) ; vibration detection threshold (VDT) and pressure pain threshold (PPT). A detailed description of the methodology can be found in Rolke et al . All participants undergoing unilateral L4/5 or L5/S1 microdiscectomy were operated on by a single surgeon (CL). After induction of general anaesthesia and endotracheal intubation, patients were positioned prone on a Wilson frame with upper and lower limb joints flexed and with pressure points well padded. Skin on the dorsal aspect of the lumbar region was prepared with alcohol swabs and paramedian placement of a spinal needle performed to plan the midline incision in line with the L4/5 or L5/S1 disc to be operated. Alcoholic chlorhexidine preparation (2%) was applied, followed by iodine‐impregnated incise disposable drapes. With sterile technique, the skin and unilateral thoracolumbar fascia was incised and monopolar diathermy was used to separate unilateral paraspinal muscles from the side of the spinous processes and hemi‐laminae. A dissector was placed in the interlaminar space with lateral x‐ray repeated for confirmation of the level. An operating microscope was brought into the field. A small amount of bone was drilled from the L4 or L5 hemi‐lamina and ligamentum flavum removed to expose the dorsal aspect of the L5 or S1 nerve root in the lateral recess. The nerve root was gently retracted and the sequestered disc prolapse (with or without adjacent loose disc material from the adjacent part of the involved disc space), was removed. Polyglyconate (1 and 2‐0) interrupted sutures were used to close the fascial layers and 3‐0 monofilament absorbable running subcuticular stitch, used to close the skin. Adhesive tapes were placed laterally across the wound and a waterproof dressing applied. The patient was returned to the supine position on the bed then de‐sedated, extubated and recovered before returning to the ward. Most patients were discharged home on postoperative Day one, and all within 3 days of surgery. At 3‐month follow‐up, QST was performed in the patient's previously tested MPA and affected dermatome. Repeat testing of the contralateral side was not performed. QST was not repeated at 12‐month follow‐up for reasons of practicality. Patients had to attend the hospital at 3‐month post‐surgery to be reviewed by the surgeon and QST was performed at the same time. We anticipated that patients would likely not attend the 12‐month appointment, just for QST, as some patients lived quite a distance away from the hospital. The following clinical measures were obtained at 3‐ and 12‐month post‐surgery: Functional status (ODI) Pain intensity (NRS) Bothersomeness of back and leg pain, pain descriptors Change in symptoms (Patient Global Impression of Change Scale) Health‐related quality of life Return to work (yes/no) Medication intake All data were analysed using the IBM SPSS statistics 24. Age, sleep quality, anxiety and depression scores and the physical and mental component summary scores of the SF‐36 were compared between patients and HCs using parametric (independent T ‐test) or non‐parametric tests (Mann–Whitney U ‐Test), as appropriate based on the data distribution. Pre‐ and post‐surgical comparisons for clinical variables for patients with lumbar radiculopathy were assessed using parametric (paired T ‐test) or non‐parametric tests (Wilcoxon Signed Rank Test), according to the data distribution. Prior to statistical analysis, QST data were log‐transformed except where raw data were normally distributed and z ‐transformed for each single parameter using the following expression: Z ‐score = (Mean single proband − Mean healthy controls )/ SD healthy controls . This method allows site‐specific normalization of QST data, where each individual parameter is related to its region and age/gender‐specific reference range, and is displayed as the number of standard deviations above or below the HC mean. Z ‐values above ‘0’ indicate a gain in function, that is the patient is more sensitive to the tested stimulus compared with healthy controls (hyperalgesia, allodynia), whereas z ‐scores below ‘0’ indicate a loss of function, referring to a lower sensitivity (hypoalgesia, hypoaesthesia). Z ‐transformation of QST data allowed the documentation of the number of individual participants within the patient group who demonstrated altered QST values (outside 95% confidence interval of reference data), reported as either a loss or gain of function. In contrast to a group comparison, this analysis allows the identification of individual patient differences and the potential identification of subgroups within a specific diagnostic patient group. Frequencies of sensory abnormalities lying outside of the 95% confidence interval (i.e. z ‐score < −1.96 or >1.96 standard deviation) of our HCs were calculated for each test site on the symptomatic body side. Additionally, z ‐transformation of QST data allowed the comparison of sensory profiles between patients who improved at follow‐up post‐surgery (defined as a ≥30% change based on ODI) and those who did not demonstrate clinically important improvement at follow‐up post‐surgery (defined as <30% change on the ODI). Independent T ‐tests were performed for the comparison of pre‐surgical z ‐score QST data between these two groups (< or ≥30% change) at 3‐ and 12‐month post‐surgery. In order to assess associations between QST measures and clinical outcome (< or ≥30% change), logistic regression analysis (adjusting for gender, anxiety, depression and pain catastrophizing) was performed for QST parameters that were significantly different between groups. The patient characteristics are outlined in Table 1 . Symptom duration ranged from four to 50 months, with a mean of 12 months. Twelve patients were diagnosed with L5 radiculopathy and 41 patients with S1 radiculopathy. Twenty‐five patients had the clinical diagnosis of sensory radiculopathy (i.e. only sensory dermatomal deficits, no motor deficits) and the remaining 28 patients had a diagnosis of motor and sensory radiculopathy (sensory and motor deficits). Based on the classification by Pfirrmann et al and as determined by the surgeon (CL), lumbar imaging (MRI, n = 40; CT, n = 13) demonstrated nerve root compression in 38 patients (72%), nerve root deviation in 13 patients (24%) and for the remaining two patients (4%), the affected nerve root was just in contact with disc material. The radiculopathy group differed from HC with significantly poorer sleep quality, lower physical and mental component summary scores of the SF‐36 and higher anxiety and depression scores ( p = <.001 for all comparisons), however 68% of anxiety and 89% of depression scores fell within the normal range (Table 1 ). The Tampa Scale of Kinesiophobia mean score of 44 (±7) indicated clinically significant fear avoidance levels in the patient cohort. Pain catastrophizing scores for the patient group lay within the normal range (Table 1 ). For the MPA, the z ‐score QST sensory profiles of the symptomatic and asymptomatic side are illustrated in Figure 2 . Mean values of all QST parameters for both the symptomatic and asymptomatic side fell within the 95% confidence interval of the reference group. For the dermatome, the mean value for VDT in the symptomatic leg fell outside the 95% confidence interval of the reference group, indicating a significantly different value from HCs . The z ‐score QST sensory profiles of the dermatome of the symptomatic and asymptomatic side are indicated in Figure 3 . Compared to HCs, patients with lumbar radiculopathy were characterized by a significant loss of function in all sensory fibre populations in the symptomatic leg in both the MPA (thermal, mechanical, vibration detection, mechanical pain threshold, mechanical pain sensitivity p < .041) and affected dermatome (thermal, mechanical, vibration detection p < .002) . There was also a significant loss of function in all sensory fibre populations in the symptomatic leg compared to the asymptomatic leg in both the MPA (thermal, mechanical, vibration detection, mechanical pain threshold, mechanical pain sensitivity p < .024) and dermatome (thermal, mechanical, vibration detection p < .030) (Table S2 ). Tables S1 and S2 demonstrate raw QST rather than z ‐score QST data for easier visual comparison. The frequencies of patients presenting with z ‐scores indicating a loss of function (< −1.96) were as follows, and shown consecutively for MPA and dermatome: CDT ( n = 5, 9%; n = 6, 12%), WDT ( n = 4, 8%; n = 8, 16%) TSL ( n = 9, 18%) MDT ( n = 29, 55%, n = 27, 53%) MPT ( n = 14, 26%), VDT ( n = 7, 13%; n = 15, 29%) and PPT ( n = 10, 19%). In comparison with HC data, a gain of function was evident for one nociceptive parameter only, with increased cold pain sensitivity evident in the MPA ( p = .001) . The cold sensitivity in the MPA was, however, not significantly different compared to the patients’ asymptomatic side (Table S2 ). WUR was present in the MPA in 47 patients. DMA was demonstrated by two patients in the MPA. One patient reported paradoxical heat sensation once in the MPA, two patients reported it twice and one patient reported it three times. One paradoxical heat sensation in response to three cold stimuli is not pathological . The frequencies of patients presenting with z ‐scores indicating a gain of function (>1.96) in the MPA were as follows: CPT ( n = 2, 4%), HPT ( n = 7, 13%), MPS ( n = 1, 2%), MPT (0%), WUR ( n = 7, 15%), PPT ( n = 6, 12%). Three‐month outcome measures were obtained from all 53 patients (100%) (Table 2 ). Twenty‐three patients (43%) reported that their leg pain had disappeared the day after surgery. One patient developed a spinal abscess at 2‐week post‐surgery, which necessitated multiple hospital visits and >15 days of hospitalization. At a group level, patients had significantly improved at 3 months’ post‐surgery in all clinical outcome measures ( p < .001) (Table 2 ). Compared to baseline measures, the frequency of the most commonly reported pain descriptors felt by patients at a moderate to very strong level, was significantly reduced ( p < .001). Based on the PGIC, 30 patients (57%) reported that they had improved ‘very much’ since surgery, 16 patients (30%) had improved ‘much’ and five persons (9%) had improved ‘minimally’. One person felt ‘minimally worse’ and one person felt ‘much worse’. The latter was not the patient who had developed the spinal abscess. The patient with the abscess reported he had improved minimally at 3‐month post‐surgery. The percentage of patients taking pain medication at 3 months (28%) was reduced compared to pre‐surgery (Table 2 ). At three months post‐surgery, there was a significant improvement in pre‐surgical altered QST measures (mechanical and vibration detection, mechanical pain threshold) in the MPA ( p < .010), with the exception of thermal thresholds and mechanical and cold pain sensitivity . The patient group were more sensitive to pressure pain in their MPA at post‐surgery ( p = .045). In the dermatome, all pre‐surgical altered QST measurements improved significantly post‐surgery ( p < .018) . One patient demonstrated DMA in the MPA, also evident at baseline. Two patients reported paradoxical heat sensation three times in the MPA. One of these patients had also demonstrated the same response at baseline. Based on the ODI score, nine patients (17%) documented <30% change on the ODI between baseline and 3‐month post‐surgery. There were no significant differences in baseline clinical measures between patients with <30% change compared to patients with ≥30% change except for leg pain intensity over the last 24 hr ( p = .046) and bothersomeness of leg pain over the last 2 weeks ( p < .001) (Table S3 ). Patients with <30% change had less leg pain [NRS 4.7 (1.9)] pre‐surgery compared to the patients with ≥30% on the ODI [NRS 6.1(1.9)] and the leg pain bothered them less compared to the group with ≥30% change on the ODI (Table S3 ). Prior to surgery, eight of the nine patients with <30% recovery on the ODI had been identified as having nerve root compression and in one patient the nerve root had been displaced by disc material. Of the patients with <30% change on the ODI, seven did have a great deal of confidence that they would recover after surgery and two had been moderate confident. There was no significant difference in any baseline QST measures in the MPA or dermatome between patients with <30% and with ≥30% change on the ODI. There was a statistically significant association between ODI and PGIC improvement indicators at 3 months (χ 2 (1) = 39.43, p < .001), with strength of association measure Phi (φ) = −0.863, p < .001) also indicating a strong association between the improvement indicators. Outcome data on the PGIC were obtained from 47 patients. Based on the PGIC, 30 patients (64%) had improved ‘very much’ since surgery, eight patients (17%) had improved ‘much’ and four persons (8%) had improved ‘minimally’. One person indicated ‘no change’, one person felt ‘minimally worse’ and two persons felt ‘much worse’. In comparison with outcome data at 3 months, the percentage of ‘very much’ improvement had increased by 7%, but the percentage of ‘much’ improvement fell by 13%, one patient had ‘no change’ at all and two patients felt much worse, compared to only one patient at 3 months. Seven patients (15%) documented <30% change on the ODI between baseline and 12‐month post‐surgery. Of these seven patients, four also reported <30% change at 3‐month post‐surgery, that is at no follow‐up time point did they show a clinically significant improvement. Out of these four patients, three patients obtained a repeat lumbar MRI post‐surgery which demonstrated granulation tissue around the pre‐surgery affected nerve root and in two cases, swelling of the nerve root. The fourth patient did not undergo any repeat imaging. For the remaining three patients, post‐surgery imaging was obtained for one patient which did not demonstrate any nerve root compromise. Prior to surgery, six of the seven patients had been identified as having nerve root compression and in one patient the nerve root had only contact with disc material. Five patients did have a great deal of confidence that they would recover after surgery and two had been moderately confident. ODI improvement indicators at 12 months were significantly associated with PGIC improvement indicators (χ 2 (1) = 48.00, p < .001), with strength of association measure Phi (φ) = −1.000, p < .001 also indicating a strong association between the improvement indicators. The baseline z ‐score QST profile in the MPA of patients with <30% change on the ODI showed a significantly smaller loss of function in mechanical detection compared to the z ‐score QST profile of patients with ≥30% change on the ODI ( p = .008) . MDT was significantly associated with group outcome (OR 2.63, 95%CI 1.09–6.37, p = .032). The odds of patients with more profound loss of function pre‐surgery improving by at least 30% on the ODI at 12 months were over 2.6 times higher than for patients with less profound loss of function pre‐surgery. The Fisher's exact test indicated no significant difference in the proportion of patients with z ‐scores < −1.96 SD between groups ( p = .416).Two patients (20%) in the patient group with <30% change on the ODI demonstrated MDT z ‐scores < −1.96 SD compared to 23 patients (56%) in the group with ≥30% change on the ODI. There were no significant differences in baseline z ‐score QST profile of the dermatome between patients with <30% and patients with ≥30% change on the ODI at 12 months . Patients with <30% change on the ODI demonstrated a trend towards a larger loss of function in WDT and VDT compared to patients with ≥30% change . The baseline loss of function measured in both groups in all parameters (CDT, WDT, MDT, VDT) did not improve significantly for patients with <30% change . There was a trend to improved function in cold and mechanical detection, but warm and vibration detection remained unchanged . For patients with ≥30% change in ODI scores baseline loss of function improved post‐surgery for all measurements ( p < .031) . This is the first study to document QST somatosensory profiles in patients with lumbar radiculopathy in their affected MPA and dermatome prior to and post‐microdiscectomy and to explore associations between tested QST parameters and clinical outcome at 3 and 12 months after surgery. The strength of our study lies in the robust methodologies, using clearly defined inclusion criteria for radiculopathy, adhering to best practice recommendations for clinical pain studies , use of laboratory QST , including small and large fibre function assessment and comparison to matched HC data for each body region assessed. These QST data are also linked with clinical outcomes at 3‐ and 12‐month post‐surgery. Collectively, our findings indicate in this group of patients with lumbar radiculopathy, a significant loss of function in the symptomatic leg in the MPA (thermal, mechanical, vibration detection, mechanical pain threshold, mechanical pain sensitivity) and affected dermatome (thermal, mechanical, vibration detection) and a gain of function (cold sensitivity) in the MPA at baseline. At 3‐month post‐surgery, this loss of function had improved significantly for measurements of mechanical and vibration detection and mechanical pain threshold in the MPA and for all pre‐surgical altered QST measurements in the affected dermatome. The patient group also became more sensitive to pressure pain in their MPA at 3‐month‐post‐surgery. Baseline loss of function in mechanical detection in the MPA was associated with poorer functional outcome (<30% change on the ODI) at 12 months post‐surgery. In our patient cohort, a loss of function was the predominant sensory phenotype, and this was evident in the distal dermatome (foot), as well as in the more proximal related dermatomal pain area. These negative sensory signs are indicative of nerve root compromise. Pre‐surgical loss of function occurred for all primary sensory afferents (C‐, Aδ‐, Aβ‐fibres), consistent with findings in some studies on lumbar radicular pain . Other studies documented selective loss of function in Aδ‐and Aβ‐fibres , or dysfunction in only Aδ‐fibres . However, in these studies not all patients had clinical signs of a radiculopathy. Nerve fibre damage depends on the compression force and duration , as well as the degree and speed of compression . While some animal studies showed large myelinated fibres seem more susceptible to nerve compression compared to small fibres , slow compressive nerve compression over 3 months caused preferential degeneration of small fibres . Furthermore, abnormal intra‐epidermal nerve fibre density, a measure of small fibre impairment, has been demonstrated in the affected dermatome in 30% of 23 patients with lumbar radiculopathy . While speculative, the mean symptom duration in our cohort was beyond 3 months (11.7 months), raising the possibility that sub‐clinical small fibre damage may have been present, although parameters still fell within the 1.96 SD QST cut‐offs. Our patient cohort demonstrated only one significant gain of function parameter, namely cold hypersensitivity in their MPA. This finding is consistent with our data from patients with cervical radiculopathy , but contrasts to findings in other lumbar radicular pain cohorts, using the same DFNS QST protocol . In fact, in two of these previous studies, no gain of function was detected at all , possibly due to QST being performed in the foot dermatome, rather than in the MPA. The underlying mechanisms for cold‐evoked pain likely include peripheral , as well as central nervous system mechanisms . While cold hypersensitivity can be a sequel of peripheral nerve injury , it has also been evident in patients with no nerve injury and in patients with no pain . Based on our previous data , we anticipated an association between cold hypersensitivity and pain persistency in our cohort, however, cold sensitivity was not associated with poorer clinical outcomes at 3 or 12 months. While heightened pressure sensitivity has previously been reported in patients with lumbar radiculopathy , in our cohort, no significant difference compared to HC data was demonstrated at baseline. However, as both mixed loss and gain profiles are shown in our pressure pain sensitivity data, both lowered and elevated PPTs may have cancelled each other out in the group analysis. Our cohort showed significantly increased pressure sensitivity at 3‐month post‐surgery, whereas reduced pressure sensitivity at 1 week, with further reduction at 12 months, has been demonstrated by others post‐decompression surgery . The different temporal points in these studies may influence these differing pressure pain sensitivity profiles. In our cohort, loss of function showed recovery in the dermatome and MPA, except for thermal detection thresholds (small fibres) in the MPA. From the literature, reports on improvement of sensory nerve fibre function post‐surgery in lumbar radiculopathy are conflicting , and not readily comparable to our study, due to differing QST methodologies. However, one comparable study reported differential recovery rates: large fibre function recovery in the dermatome as early as 1 week after surgery ; small myelinated fibre function improved after 6 months , whereas C‐fibre function had not improved at 12 months . In comparison, our patient subgroup with <30% change on the ODI at 12 months, demonstrated no significant improvement of C‐fibre and large fibre (vibration detection) function in the dermatome at 3‐month post‐surgery, and a further loss of large fibre function (mechanical detection) in the MPA. It remains unknown if these sensory alterations persisted at 12‐month post‐surgery, as we did not repeat QST testing. Reasons for these divergent outcomes remain speculative. Pre‐surgical loss of function may have been caused by ischaemic conduction block due to the nerve root compression, which improved with normalization of blood flow to the nerve root post‐surgery . This may explain patients reporting immediate post‐surgery pain relief , as also observed in 43% of our patients. Regeneration of demyelinated fibres with preserved axons and associated functional recovery would likely occur faster than regeneration of more specific axonal damage. In fact, it is not known if in the above studies, including ours, nerve root compression caused any structural changes of the tested sensory fibres. Whereas QST provides information about the function of somatosensory afferents, it does not provide information about structural nerve fibre integrity. Interestingly, sensory profiles differed between the dermatome and MPA, that is thermal thresholds improved in the dermatome, but not significantly in the MPA. Furthermore, loss of mechanical detection in the MPA was associated with clinical outcome at 12 months, but not for MDT in the dermatome. These observations may point to differing underlying pathophysiological mechanisms in radiculopathy. While loss of function in a pain‐free dermatome may reflect structural nerve fibre damage, loss of function in a painful area may reflect secondary hypoesthesia mediated at the spinal cord level or possibly cortical changes associated with central plasticity . Our findings suggest that the assessment of sensory profiles in the MPA is important in the search for associations with pain persistency post‐microdiscetomy. Surprisingly, for the majority of our patients, the baseline anxiety, depression and pain catastrophizing scores were within normal range. However, this is not necessarily unheard‐of. In a large cohort of patients with painful radiculopathy , only 4.6% of patients had severe anxiety, 4.8% had severe depression and 37% had moderate depression . It is possible that our patients might have developed better coping strategies for their pain conditions compared to other cohorts. One reason may be that our patient group had a specific reason for their pain with a clear condition‐specific diagnosis provided and they were given the prospective of improvement with surgery. In contrast, patients with, for example, chronic low back pain often do not know the cause of their pain, as documented by Daniel et al. comparing psychological and physical function in patients with post‐herpetic neuralgia and patients with nociceptive low back pain. Factors are likely complex and may represent a case mix too. We chose the conservative cut‐off of <30% change on the ODI (i.e. 10 points) as a clinically meaningful difference, others suggest a cut‐off of 20 points to ensure meaningful change after surgery . This suggested cut‐off was not feasible as 36 (68%) of our patients scored <20 points at baseline (i.e. creating a potential floor effect). However, further analysis revealed that our results were comparable using the PGIC, which as an outcome measure, is independent of baseline values. Our subgroups of patients with <30% change on the ODI at 3 and 12 months were small and the risk of a type II error cannot be excluded. The intake of pain medication may have influenced QST and clinical outcomes. Surgery was performed by the same surgeon which limits generalizability of our results.
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Other
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biomedical
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en
| 0.999998
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32775093
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A 63-year-old gentleman with a past medical history of HIV, diabetes mellitus, and intravenous drug use presented to the hospital for epigastric abdominal pain and unintentional weight loss of roughly six kilograms over the previous six months. He also reported a loss of appetite, generalized weakness, and fatigue. On examination, he was in mild distress and cachectic looking. He had a temperature of 36.6°C, a heart rate of 82 beats per minute, a blood pressure of 126/70 mmHg, and an oxygen saturation of 97% on room air. He had diffuse abdominal tenderness, marked distention with shifting dullness, and decreased bowel sounds, but no hepatosplenomegaly was appreciated. The examination of his lungs, heart, and extremities was unremarkable. Extensive infectious workup was done looking for an infectious etiology behind the leukocytosis, including chest X-ray, which did not reveal infiltrates. A urinalysis was clean. Multiple blood cultures were negative. Even the ascites seen on abdominal ultrasound was tapped and cultured; however, there was no growth. The patient was also tested for novel coronavirus twice and both times was negative. Despite being on empiric broad-spectrum antibiotics, whilst being worked up, his white blood cells failed to come down. Rather it was up trending to 64.5 cells/µL. The infectious disease team recommended discontinuing antibiotic therapy given negative infectious workup and no response to five days of broad-spectrum antibiotics. His leukocytosis was attributed to the advanced malignancy. Hyperleukocytosis in cancer is considered a poor prognostic marker and suggests an aggressive course of the disease with a large proportion of these patients dying soon after diagnosis, like our patient above . It has been observed in in vivo studies that the colony-stimulating factors also enhance the growth of the malignant cells, thereby imparting a worse outcome . Some have even postulated that colony-stimulating factors act as autocrine growth factors, resulting in malignancy proliferation and metastasis . Treatment of the underlying malignancy can lessen the leukocytosis and progression of the malignancy can worsen it; hence, it can also be used as a marker for disease progression in such patients .
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Other
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biomedical
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en
| 0.999996
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32872674
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Congenital defects are structural or functional abnormalities that result from errors arising during embryonic development and are present at birth . While reliable data on the incidence of congenital anomalies in domestic animals are not available, a frequency of about 3–4% is estimated in cattle . Such anomalies can range from purely biochemical abnormalities to gross anatomical defects and can include disorders of function, metabolism, and behavior . Congenital malformations of the central nervous system (CNS) can affect the CNS alone or the CNS, the craniofacial structures, and the vertebral column; they are attributable to genetic or environmental causes or to environmental–genetic interactions . This case report describes an unusual, complex congenital cephalic malformation observed in a male crossbreed calf. A 3-day-old male crossbreed calf was referred to the Mobile Clinic Service, Veterinary Teaching Hospital (VTH), Department of Veterinary Science of Turin (Italy) because of an abnormal facial conformation and inability to stand on forelimbs and hindlimbs since birth. No complications were reported during gestation or birth, and the dam had given birth to other normal calves previously. Clinical examination disclosed a dome-shaped cranial vault. The face was flat, with a short snout, a median cleft lip, and an increased intraorbital distance clearly suggesting hypertelorism. The frontal region of the head was remarkable for a fluctuant, sac-like protrusion (5 × 7 cm) covered with haired skin . The rim of the underlying cranial bone defect could be felt around the base of the sac-like protrusion on palpation. Neurologic examination performed by a board-certified neurologist (ADA) revealed a mildly obtunded mental status. The calf demonstrated intermittent left head tilt, inability to stand unassisted, and non-ambulatory tetraparesis, when supported, with only minimal voluntary movements. Proprioception and postural reactions were absent on all four limbs. Cranial nerve examination revealed a bilaterally absent menace reaction. Nostril sensation was diminished on stimulation of the right nostril. Physiological nystagmus was absent/severely reduced bilaterally, whereas abnormal positional jerk nystagmus changing in the direction was present bilaterally. Positional ventro-lateral strabismus of the left eye was noted. Spinal reflexes were normal on all four limbs, and palpation of the vertebral column elicited no pain. Based on the findings of the neurologic examination, a multifocal intracranial lesion affecting the prosencephalon and the central vestibular system was suspected. The severity of the gait deficits could be related to a brainstem localization without involvement of the ascending reticular activating system or to an additional cervical spinal cord localization. A congenital malformation was suspected based on the animal’s age, history, and clinical presentation. At necropsy, the calf showed a dome-shaped cranial vault with a 4-cm long cranioschisis along the midline at the level of the frontal bones. Upon dissection, the frontal sac-like protrusion was filled with CSF and internally lined with meningeal tissue, indicating a diagnosis of meningocele. The intraorbital distance was increased (hypertelorism), although both eyes were normally developed. Moreover, the rostral maxilla was shorter than the mandibula (prognathism); a complete median cleft lip and maxilla without cleft palate was present. The nose appeared abnormal, with a broad base and a bifid nasal tip. The single, rudimental nasal cavity identified after head sectioning opened rostrally into the oral cavity through the upper jaw defect. The abdominal and thoracic organs were macroscopically normal. The vertebral column was normal. On gross examination of the CNS, both fresh and after formalin fixation, the cerebral hemispheres, actually consisting in a single cerebral sphere, appeared as a thin, irregular layer of nervous tissue adherent to the skull bones. The convolutional pattern of the gyri was abnormal and slightly smooth. There was massive bilateral symmetrical loss of brain parenchyma; the frontal and parietal cortex and the olfactory bulbs and tracts were absent (olfactory aplasia). The cribriform plate of the ethmoid bone was also absent with a direct communication between the calvaria and the single nasal cavity. A single, dilated ventricle, presumably derived from the confluence of the two lateral ventricles, occupied nearly the entire intracranial space and was filled with abundant CSF. A rudimental dural septum (falx cerebri) was attached to the ridges of the occipital bone caudally. The corpus callosum, fornix, rostral commissure, and septum pellucidum were absent. Multifocal vestiges of nervous tissue were irregularly distributed, particularly on the floor of the cerebral hemispheres on both sides of the diencephalon. The rostral diencephalon was undersized and incompletely organized, whereas the organization of the caudal fossa was preserved: no gross abnormalities were observed in the pons, cerebellum, and cervical spinal cord. Brain and cervical spinal cord were routinely processed for histology. The tissues were fixed in 10% formalin phosphate-buffered solution and stained with hematoxylin and eosin (H&E). Selected sections of telencephalic and diencephalic parenchyma were also immunohistochemically stained with antibodies against glial fibrillary acidic protein , neuron-specific enolase (NSE; Mab antihuman; 1: 200 dilution; clone BBS/NC/VI-H14; Dako, Agilent Technologies Italia S.p.A. Bioscienze ed Analisi Chimica, Cernusco sul Naviglio, Milano, Italy), and vimentin (Mab antihuman; 1:50 dilution; clone V9; code number MO725; Dako, Agilent Technologies Italia S.p.A. Bioscienze ed Analisi Chimica, Cernusco sul Naviglio, Milano, Italy) followed by the Vectastain ABC-AP Kit Universal (Vector Laboratories, Burlingame, CA, USA). After heating sections at 98 °C for 25 min in citrate buffer for antigen retrieval, 3% v/v H 2 O 2 was added for 5 min to quench endogenous peroxidase activity. Primary antibody was added for 2 h in a humidified chamber at 4 °C, and biotinylated link antibody and peroxidase-labeled streptavidin were added for 10 min followed by 3,3′-diaminobenzidine tetrahydrochloride (DAB). Nuclei were counterstained with hematoxylin. Positive controls were represented by bovine brain sections, and negative controls were carried out by omitting the primary antibodies. Microscopically, the cerebral parenchyma was reduced to a thin layer of white and gray matter covered by the meninges. The histological organization of the cortex was generally maintained , but newly formed hyperemic blood vessels were disseminated throughout. Multifocal hemorrhages, particularly in the periventricular area, and small multifocal clusters of stem cells in the subventricular zone and in the cerebral gray matter were present. Scattered phenomena of white blood cells vessels margination in the gray matter and multifocal slight mononuclear cells infiltrates in the overlying meninges were also detected. Histological sections of the diencephalon revealed poor differentiation between the gray and the white matter, which was sometimes mixed with small, rudimental multifocal neuronal nuclei of different size, consistent with the absence of thalamic cleavage. Small rudimental ventricles covered by ependyma and disseminated small blood vessels were also observed at this level. The neuroanatomic findings and distribution of lesions attributable to malformations of both the face and the CNS in this calf are not easy to classify and trace to a specific condition. Computed tomography/magnetic resonance, which would have helped in defining the morphology of these malformations that notoriously change post-mortem , were not performed for financial reasons. The craniofacial abnormalities identified at clinical evaluation and necropsy can suggest a median cleft face syndrome. This syndrome describes a congenital failure of fusion of the facial process during fetal development; it may involve both soft and hard tissue of the face and can have diverse phenotypic manifestations . In human medicine, median cleft face syndrome was first described by DeMyer and colleagues in 1967. They identified as phenotypic features the presence of ocular hypertelorism associated with six other median facial defects: a low V-shaped frontal hairline, cranium bifidum occultum, median cleft nose, median cleft upper lip and premaxilla, median cleft palate, and primary telecanthus. Moreover, four facial types are distinguished according to the defects and their degree of severity . The syndrome has also been reported in calves. Moritomo et al. morphologically described a series of 13 calves with cleft face. According to the cleft type and site, four groups of malformation were distinguished: median cleft lip and jaw (CLJ); median cleft lip, jaw, and palate (CLJP); lateral CLJ; and cleft palate (CP), including unilateral and bilateral type. Median CLJ was characterized by clefts extending to the dorsal portion of the nose until the subcutaneous tissues or to the labial portion. When the cleft was longer and extended also vertically (creating a bifid nose), as well as to the median lip and the rostral part of the palate, a condition of CLJP was defined. Lateral CLJ referred to the presence of bilaterally symmetrical lip clefts between the nostrils and the mouth. Finally, CP included clefts of the hard and soft palate, which were either unilateral or bilateral. A number of systemic malformations and clinical signs were reported to be associated with these syndromes . While the necropsy findings of this calf fit within the cleft lip, jaw, and palate (CLJP) group, the meningocele and the severe brain malformations detected in this calf were neither reported nor described in Moritomo’s paper . A more recent classification for median cleft face syndrome in veterinary medicine was devised by Reinartz and colleagues in 2015. According to this system, defects can involve the upper lip, jaw, palate, and nose alone or combined and can be classified as unilateral on the right or left side, median, or bilateral, based on the morphology and location in the rostral face. In addition, midline facial malformations are further subdivided in syndromic or non-syndromic depending on the presence or not of abnormalities in other organs . Congenital facial malformations are often associated with brain malformations, which is probably due to the close correlation between the embryological development of brain, epidermis, and skull . In 1975, DeMyer and colleagues investigated whether the observation of the craniofacial syndrome could predict the underlying brain anomalies . Their study was focused primarily on the eye position within the face; they found that ocular hypotelorism combined with other median plane facial anomalies due to defects in the intermaxillary segment is usually correlated with very severe brain malformations, such as holoprosencephaly . Differently, ocular hypertelorism associated with median cleft due to failure in the apposition of the frontonasal prominence along the median facial plane is typical of so-called median cleft face syndrome or frontonasal dysplasia (FND), and it is usually associated with normal or mild brain malformations . In human medicine, some syndromic forms of FND are associated with brain malformations (e.g., corpus callosum agenesis, periventricular nodular heterotopia, interhemispheric lipoma, hydrocephalus) that usually cause mild or no intellectual disability . In veterinary medicine, some mild brain malformations associated with median cleft face syndrome have been reported in calves, including cerebellar hypoplasia, hypoplasia of corpus callosum, and an unequal development of cerebral hemispheres . Frontal meningoencephalocele has rarely been reported in human patients with median cleft face syndrome because the fusion defect of the two halves of the frontal bone is not sufficient to cause the protrusion of normal meninges and brain. Active pressure needs to be present to cause these organs to bulge out . In human medicine, one characteristic associated with meningoencephalocele is agenesis of the third ventricle resulting from absence of thalamic cleavage, which blocks CSF flow and increases pressure within the abnormal brain . However, the pathological findings of the brain in this calf are not completely consistent with the above definition of FDN. Histopathology disclosed a severe brain malformation characterized by thinning of the cerebral cortex, absence of several lobes of the cerebral hemispheres (i.e., frontal, parietal, and olfactory lobes), absence of the corpus callosum, and confluence of the two lateral ventricles, with a huge compensatory hydrocephalus. The presence/absence of CSF flow obstruction was impossible to confirm. These findings suggest hydranencephaly, a cerebral abnormality in which the cerebral cortex is reduced to a thin, neuroparenchymal, and meningeal membrane, usually resulting from the viral destruction of germinal layer cells and differentiated neopallial neurons. These two processes produce aplasia and atrophy of the cerebral hemispheres, respectively, especially in their dorsal, medial, and caudal aspects, resulting in their replacement by two fluid-filled sacs containing the two dilatated lateral ventricles with compensatory hydrocephalus and absent ependymal layer . However, by definition, hydranencephaly involves only the neopallial structures of the cerebral cortex, while paleopallium, archipallium, diencephalon, mesencephalon, pons, and cerebellum are typically spared . Only cerebellar lesions, such as cerebellar hypoplasia and atrophy, are present in some cases . Moreover, the cranial cavity is usually normal in size and shape . In cattle, hydranencephaly is often caused by intrauterine viral infection (e.g., Bluetongue virus, BVDV, Shmallenberg virus, Akabane virus, Aino virus), and the degree of lesion severity depends on the viral agent and the point during gestation when the infection occurred . Sometimes, evidence for an inflammatory and/or ischemic peripheral process with lymphocytic perivascular cuffs, gliosis, and the mineralization of necrotic tissues is observed histologically in the surviving brain parenchyma . In this calf, signs of inflammation of the cerebral parenchyma were identified together with disseminated newly formed small blood vessels in the cerebral cortex. More severe abnormalities of the paleopallial structures (e.g., absence of olfactory bulbs, peduncles, and piriform lobe cortex) and of the diencephalon (e.g., incomplete thalamic cleavage) are typical of holoprosencephaly (HPE) . HPE is a sporadic malformation encountered in domestic animals; it has been described in calves only twice to date , while it is more common in lambs , especially in Border Leicester lambs in which an autosomal recessive transmission has been identified as cause . HPE is characterized by an incomplete midline division of the prosencephalon during embryological development, which results in a single telencephalic vesicle accompanied by absence of the rostral commissure and corpus callosum, septum pellucidum, septal nuclei, and olfactory system . Different types of HPE have been classified based on the degree of severity that includes lobar, semilobar, and alobar forms: in lobar HPE, the interhemispheric fissure is present along nearly the entire midline, but the most inferior portions of the frontal lobes are fused; in semilobar HPE, there is only a partial separation between the two cerebral hemispheres, with interhemispheric fissure and falx cerebri that may be present posteriorly; finally, the most severe form is alobar HPE, in which there is a single midline forebrain with a primitive monoventricle often associated with a large dorsal cist . There are various analogies between the features of alobar holoprosencephaly and the findings from this calf in which the facial abnormalities seem more consistent with those typical of holoprosencephaly, except for the hypertelorism. Furthermore, the absence of the longitudinal cerebral fissure that separates the two cerebral hemispheres, a hallmark feature of holoprosencephaly, is missing in the present case. There was a poor distinction between the white and the gray matter of the cervical spinal cord. These spinal cord abnormalities have never been reported before in calves based on Cho and Kisipan papers . Indeed, spinal cord abnormalities reported in cattle with intrauterine viral infection (BVDV, Shmallenberg virus, Akabane virus, Aino virus) are different. They are bilateral symmetrical spinal lesions characterized by hypomyelination, axonal dysplasia, Wallerian-type degeneration, and neuron loss in the spinal cord ventral white matter and the ventral horns of the gray matter . Moreover, the calf of the present study tested negative for BVDV, Blue tongue virus, and Shmallenberg virus at rtPCR. Akabane virus and Aino virus were not investigated because they are not currently reported in Italy . The neuroanatomic findings and distribution of lesions in this calf may be attributable to an inherited disorder, manifesting in malformation of the face and the CNS. Although an infectious agent or an environmental factor cannot be definitively ruled out in the present case, the features are not consistent with those correlated with these agents and previously described in calves . Most of the environmental agents that are reported to be teratogenic for cattle, such as mechanical (e.g., intrauterine pressure) or chemical (e.g., poisonous plants, therapeutic drugs) determine mostly skeletal malformations but not neural defects . Hydranencephaly, porencephaly, hydrocephalus, and cerebellar hypoplasia are the main malformations of the central nervous system due to bovine viral diarrhea virus (BVDV), Schmallenberg virus (SBV), blue tongue virus (BTV), Akabane virus (AKAV), or Aino virus (AV) . Intrauterine infection of the fetus during the susceptible periods of development may cause these brain disorders, which in the case of SBV, AKAV and AV infections may be associated with deformity of the axial and appendicular skeleton (e.g., arthrogryposis multiplex congenita ) . Intrauterine Zika virus (ZIKV) infection in pregnant women is a cause of microcephaly and other serious brain anomalies that can be accompanied by findings consistent with craniofacial disproportion . However, no natural transmission of ZIKV in non-human vertebrate populations has been demonstrated to date . To our best knowledge, a similar association between such severe congenital abnormalities of the CNS and the craniofacial structures has never been reported in calves before and warrants further investigation. In conclusion, this case report describes a particular complex of congenital abnormalities affecting both the central nervous system and the craniofacial structures in a calf, not easily to classify and trace to a single specific condition. The craniofacial abnormalities identified suggested a median cleft face syndrome, while the central nervous system changes had features consistent with both alobar holoprosencephaly and hydranencephaly. To the authors knowledge, a similar association between such congenital abnormalities has never been reported in calves.
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32973665
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Neurological manifestations have been described in one third of patients with COVID-19. Some of these neurological symptoms have proved to be quite specific, e.g., loss of smell or taste, but other ones are non-specific, e.g., headache, dizziness, or reduced level of consciousness ( 1 ). However, whether the neurological symptoms associated with SARS-CoV-2 are attributable to secondary mechanisms (i.e., multiorgan dysfunction or systemic inflammation), an abnormal immune response or the direct injury of the virus is still unknown. Conversely, a recent pathological study on postmortem human brain tissues found that anosmia and dysgeusia, described in up to 20% of patients, are more likely due to the direct viral invasion of the olfactory nerve and bulb ( 2 ). In addition and in line with this observation, a COVID-19 patient with anosmia showed magnetic resonance imaging (MRI) abnormalities in the olfactory bulb and in the inferior frontal lobe, as a conceivable result of the direct invasion of SARS-CoV-2 through the olfactory pathway via trans-synaptic retrograde spreading ( 3 ). A 57-year-old man developed dysgeusia, cough, and fever of up to 39°C lasting for 5 days. At 12 days after the resolution of the symptoms, he complained of numbness and tingling in the feet and, a few days later, also in the hands. Over 10 days, the patient developed distal limb weakness and severe gait impairment, so he was referred to the emergency department. A neurological examination showed weakness in the dorsiflexion of the foot and the extension of the toes [Medical Research Council (MRC) score: 3/5 on the right side and 4/5 on the left side], weakness in the extension of hand and fingers (MRC score: 4/5 bilaterally), gait ataxia, loss of touch and vibration sensation in the feet and ankles, weak tendon reflexes in the upper and the lower limbs, but absent ankle jerk reflex. The cranial nerves were spared. The chest radiography was negative for pneumonia, and a nasopharyngeal swab testing for SARS-CoV-2 with real-time polymerase chain reaction assay (RT-PCR) was negative, too. At this stage, the patient was admitted to our unit for further diagnostic workup. The nerve conduction studies, performed 4 weeks after the neurologic onset, showed reduced or absent compound muscle action potentials and sensory nerve action potentials in the lower limbs, absent F wave response in the lower limbs, and prolonged F wave response in the upper limbs. The electromyography showed very rich spontaneous activity (fibrillation potentials and positive sharp waves) in the lower limb muscles ( Table 1 ). The cerebrospinal fluid (CSF) examination disclosed normal cell count and normal proteins, normal CSF/serum albumin ratio, and absence of oligoclonal banding. Serum SARS-CoV-2 IgG was detected (Maglumi, Snibe). Anti-GM1, anti-GD1b, and anti-GQ1b IgG and IgM were negative (ELISA, Bühlmann). The laboratory investigations demonstrated high C-reactive protein (18.9 mg/dl). The serological tests for HIV, syphilis, cytomegalovirus (CMV), Epstein–Barr virus (EBV), and Mycoplasma pneumoniae (MP) were negative, except for anti-EBV, anti-CMV, and anti-MP IgG. An intravenous immunoglobulin (IVIG) cycle at 0.4 g/kg/day over 5 days was started, leading to a significant improvement of the weakness in the upper limbs and the left foot but a poor benefit on the right foot and gait ataxic. The patient was then transferred to the rehabilitation unit. He slowly improved through physiotherapy and, after 1 month, he was able to walk without aid and was discharged. Figure 1 shows a timeline of the clinical milestones of the patient. We reported a patient showing a stepwise progression of numbness, tingling, and weakness 12 days after the resolution of fever, cough, and dysgeusia. The clinical features and the electrophysiological findings along with the epidemiological context and the presence of IgG to SARS-CoV-2 supported the diagnosis of post-COVID-19 GBS. In particular, the neurophysiological examination was consistent with an acute motor-sensory axonal GBS (AMSAN) variant, with level 2 diagnostic certainty for GBS according to the Brighton Criteria (consistent clinical features and supporting nerve conduction study, but not CSF) ( 4 , 5 ). Active SARS-CoV-2 infection was excluded by a complete recovery of the typical antecedent symptoms, absence of the viral genome in the nasopharyngeal swab, and negative chest radiography. The detection of serum IgG to SARS-CoV-2 is in line with the chronological profile of the antibody appearance. Indeed IgG seroconversion in COVID-19 patients is reached within a median of 13 days from the clinical onset ( 6 ). More than half of GBS cases appear 1 to 2 weeks after an underlying infection. Campylobacter jejuni is the most frequent precipitant of GBS, but viral infections, including EBV,CMV, and Zika virus, are also frequently reported ( 7 ). The association of GBS with other coronaviruses was described only in two cases ( 8 , 9 ). Recently, SARS-CoV-2 has also been related to GBS and Miller Fisher syndrome (MFS), wherein an autoimmune post-infectious mechanism, such as molecular mimicry or bystander activation, targeting self-ganglioside epitopes in spinal roots and peripheral nerves, might be involved, in analogy with all the other post-infectious cases. The age of the patients ranged between 23 and 77 years (mean ± standard deviation: 59 ± 12), with a male prevalence (63.2%). The severity of COVID-19 manifestations, defined as mild, severe, and critical, according to a previously described classification ( 39 ) was as follows: mild in 30/38 (78.9%), severe in 5/38 (13.2%), and critical in 3/38 (7.9%). The time elapsed from onset of the COVID-19 symptoms to the clinical GBS manifestations ranged between 3 and 28 days (mean 12 ± 6). Notably, the timing of the majority of cases was consistent with the parainfectious profile rather than a post-infectious paradigm. In two patients, the onset of GBS actually preceded by a few days the first manifestations of COVID-19, but an earlier presentation of COVID-19 characterized by very mild or even absent symptoms could be taken into account in both cases. Almost all patients were treated with IVIG and/or plasma exchange, whereas one mild case received only symptomatic treatment. The recovery timing and the outcomes varied widely, but in 14/38 cases, a rapid improvement was reported. In 12/38 cases, the improvement was instead slower and required admission to rehabilitation facilities, whereas 6/38 patients had a poor outcome (prolonged stay in the intensive care unit and long-lasting severe disabilities). Two cases were fatal, and in 4/38 cases, the outcome was not available. Of relevance is the fact that it does not seem that COVID-19 severity at onset is correlated with GBS outcomes. Moreover, the clinical features of post-COVID-19 GBS did not differ from those of cases related to other viruses, with the notable exception of a remarkable respiratory involvement ( Table 3 ). It is indeed crucial to highlight that respiratory failure was present in 15 /38 cases (39.5%) of GBS related to SARS-CoV-2, a percentage higher than that observed in previous GBS cohorts (ranging from 20 to 30%) ( 5 ). This suggests that COVID-19 pneumonia may overlap with GBS-associated respiratory muscle weakness and increase the number of cases needing a respiratory support. The reported observations indicate that physicians should always consider GBS in the differential diagnosis of a respiratory insufficiency in COVID-19 patients, especially in cases of normocapnic or hypercapnic respiratory failure (pointing to a restrictive respiratory pattern in contrast with the interstitial pattern of COVID-19 pneumonia) or when a discrepancy between chest imaging and respiratory parameters occurs. An additional explanation for this latter scenario is that the respiratory failure in GBS associated with COVID-19 may also be driven by a dysfunction of the cardiorespiratory centers in medulla oblongata directly induced by the virus ( 40 ) since the SARS-CoV-2 genome has also been detected in the human brainstem ( 2 ).
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Alström syndrome is a rare autosomal recessive multi-organ disorder caused by homozygous or compound heterozygous predominantly truncating variations in the ALMS1 gene, with a prevalence of <1 case per 1,000,000 individuals . The clinical presentation, largely overlapping with ciliopathies, is associated with retinal dystrophy, hearing loss, obesity, insulin resistance, type 2 diabetes, dilated cardiomyopathy, and progressive hepatic and renal dysfunction . Retinal dystrophy of the cone-rod type is one of the earliest manifestations and presents with photophobia and nystagmus in early infancy . It is characteristically rapidly progressive, with blindness by the teenage years. ALMS should be suspected in children with obesity, retinal dystrophy, and dilated cardiomyopathy. ALMS1 is composed of 23 exons and encodes a large protein of 4,169 amino acids, initially shown to localize to the centrosome and basal body and also perturb actin filament organization , suggesting a role in primary cilia function. Although mechanistic details are still lacking, ALMS1 is thought to be implicated in endosomal trafficking, actin organization, maintenance of centrosome cohesion, and transcription . Clinical diagnosis of ALMS is often challenging in view of the heterogeneity of the clinical phenotype and overlapping features with other syndromes, in particular the Bardet-Biedl syndrome with which it is often misdiagnosed . The retina often manifests disease first, misleading to a diagnosis of congenital achromatopsia, Leber Congenital Amaurosis, or isolated cone-rod dystrophy . More than 230 pathogenic variations have been reported so far of which all are truncating variations . We report here the case of a 14-year-old female who presented with a very mild and unusual retinal phenotype displaying exclusive cone dystrophy with complete preservation of rod function on serial electroretinograms (ERGs), a cardiomyopathy, and a slight, bilateral, and symmetric hearing loss. Two novel class 4 variations (likely, pathogenic) according to the American College of Medical Genetics and Genomics were identified within ALMS1 . However, in view of the mild phenotype, the diagnosis was initially questioned. We, therefore, demonstrated that both ALMS1 variations were in trans confirming the biallelic status of the variations. Interestingly, one of the variations occurred de novo . The diagnosis of ALMS with the following ALMS1 genotype was confirmed: c.[286C > T];[1211C > G], p.[(Gln96 * )];[(Ser404 * )]. A 14-year-old girl born to non-consanguineous healthy French parents presented with central vision loss and photophobia at the age of 6. There were no symptoms of night blindness. Mild high frequency hearing loss was present, associated initially with recurrent otitis media. Past medical history revealed an episode of acute illness aged 1 month caused by hypokinetic cardiomyopathy. Her cardiac disease was stable aged 14 with residual left ventricular dilatation of a non-progressive nature and managed with 5 mg/day of enalapril. Body mass index was normal with no endocrine abnormalities and a normal intellect ( Supplementary Table 1 ). Aged 14, visual acuity was limited to logMAR 0.60 in both eyes with no nystagmus. Low hyperopia associated with myopic astigmatism was present. Color vision was absent. Fundus examination revealed irregularity of the retinal pigment in the foveal region but normal peripheral retinal appearance, optic discs, and blood vessel caliber . Ocular coherence tomography (OCT) scanning of the macula demonstrated irregularity of the ellipsoid zone, including the photoreceptors bilaterally . Peripheral visual fields demonstrated mild loss of peripheral vision and loss of sensitivity in the central retina . ERG was first performed aged 7 and demonstrated cone dysfunction, with complete preservation of rod function. Repeated ERGs aged 9 and 13 confirmed absence of cone responses, with undetectable photopic ERG white flash responses and undetectable 30 Hz flicker responses. However, full dark-adapted rod responses were present, in keeping with an isolated cone dystrophy . Although, the retinal phenotype was very unusual for ALMS, the diagnosis was considered because of the association of a retinal dystrophy with cardiomyopathy in infancy. Genetic analysis with family segregation was carried out to confirm the diagnosis. The patient was referred for clinical investigations to the Alström National PHRC (“Programme Hospitalier pour la Recherche Clinique”) program held at the reference center for rare genetic eye disorders in the University Hospital of Strasbourg (CARGO, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique). The study protocol had been approved by our Institutional Review Board “Comité Protection des Personnes” , and written informed consent was obtained. Our research complied with the Declaration of Helsinki. Best corrected visual acuity (BCVA) was assessed with a retroilluminated decimal Parinaud scale on a Luneau Charts Display L40. Semi-automated kinetic visual fields were performed with the Octopus 900 perimeter (Haag-Streit International, Wedel, Germany). Color vision was assessed with the Farnsworth Panel D-15 color vision cups and Ishihara plates. Slit lamp and dilated fundus examination were performed after pupillary dilatation with tropicamide 1%. Full-field ERG testing was performed with a modified version of the International Society for Clinical Electrophysiology of Vision (ISCEV) protocol under scotopic and photopic lighting conditions using Diagnosys LLC (Lowell, MA, US) device. Both spectral domain OCT and fundus autofluorescence images were acquired using the Spectralis HRA + OCT unit (Heidelberg Engineering, Heidelberg, Germany). High throughput sequencing of the patient’s sample was performed on the Ion Torrent PGM (Thermofisher) according to the manufacturer’s protocols. DNA libraries were constructed using the HaloPlex Target Enrichment system (Agilent Technologies, version D.5). The libraries were barcoded using HaloPlex ION Barcodes (Agilent Technologies) and then pooled by eight samples. Emulsion PCR was performed on the Ion One Touch 2 system (Life Technologies) and the emulsion PCR products enriched on the One Touch 2 Enrichment System using the Ion PGM Template OT2-200 kit (Life Technologies). Ion sphere particles (ISP) were enriched using the E/S module, charged on one Ion PGM 316 v2 chips and sequenced with an Ion Torrent PGM in a 200-bp configuration run. With an ISP loading of 55%, 149 Mb were produced in total out of 1,264,061 reads, with a median length of 116 bp, of which 12.3 Mb could be used for our patient. Sequencing data were analyzed by the Torrent Suite Software v4.2.1 with alignment to the reference human genome (GRCh37/hg19) and base calling. Variant annotation and ranking were performed by VaRank configured with the Alamut batch software (Interactive Biosoftware, Rouen, France). Filtering criteria were applied to identify the disease causing variations, including: (1) removing variants with an allele frequency >1% in public variation databases, such as the 1000 Genomes and the ExAC/gnomAD databases or our internal patient database (350 samples); (2) removing variants in 5' and 3' UTR downstream and upstream locations, respectively and synonymous variations without pathogenic prediction of local splicing effect. The analysis was focused on compound heterozygous and homozygous variants consistent with a recessive mode of transmission. Each candidate variations were also checked using the Integrative Genomics Viewer (IGV) software . The ALMS1 nomenclature is based on the RefSeq accession number NM_015120.4 and the identified variation. The qPCR reactions were prepared using the iQ SYBR Green Supermix according to the manufacturer’s instructions using 2 μl of cDNA. Reactions were set up in triplicate (three seperate controls and three separate DNA extractions for the patient). The cycling parameters were as follows: 95°C for 5 min, 45 cycles of 95°C for 15 s, and 60°C for 35 s, followed by the generation of melt curves by heating in 0.5°C increments (5 s/step) for the temperature range 65–95°C. Gene expression levels were quantified relative to the reference genes GAPDH and HPRT using the efficiency-corrected comparative cycle threshold (C T ) method using the CFX Manager Software V.1.5 (BioRad). Primers are available in Supplementary Table 2 . Three sets of primers (1F-6R for amplicon 1, Allele1F-6R for amplicon 2, and 1F-Allele5R for amplicon 3) were designed from a cDNA sequence according to the RefSeq identifier NM_015120.4 using the Primer3 software 1 . PCR reactions were carried out using 50 ng of cDNA, the Taq DNA polymerase , a PCR mix 5X containing a PCR Buffer 10× (100 mM tris-HCl, pH 8.3, 500 mM KCl), a solution of MgCl₂ (25 mM), and the four dNTP (200 μM). PCR conditions were as follow: denaturation at 95°C for 3 min followed by 35 cycles at 94°C for 30 s, 72°C for 30 s, and a final extension of 10 min at 72°C. High throughout sequencing of a panel of 31 ciliopathy genes including ALMS1 revealed compound heterozygosity with the identification of two novel rare nonsense variations in the ALMS1 gene . The two pathogenic variations include a C > T substitution at nucleotide 286 in exon 1, and a C > G substitution at nucleotide 1,211 in exon 5, resulting, respectively in the replacement of glutamine at position 96 and serine at position 404 by premature stop codons (c.[286C > T(;)1211C > G]; p.[(Gln96 * )(;)(Ser404 * )]). Family co-segregation studies confirmed the paternal heritance of the c.286C > T (p.(Gln96 * )) but no variation could be observed in the mother’s DNA, suggesting that the c.1211C > G (p.(Ser404 * )) was a de novo variation . However, one cannot exclude a possible de novo occurrence on the paternal allele, especially in the context of an unusually mild phenotype. Thus, to confirm the potential consequences of the nonsense variants to the patient’s disease, we showed a highly reduced level of ALMS1 RNA level and demonstrated the biallelic status of the variations using two allele-specific PCR reactions on the patient’s cDNA , confirming that both ALMS1 pathogenic variants were indeed in trans . Both variations have never been reported in previous studies , however the c.286C > T is listed in ClinVar under the following identifier RCV000672767.1 . ALMS is a multisystemic autosomal recessive disorder associated with retinal dystrophy of the cone-rod type and severe early onset visual impairment . Visual symptoms are often the first manifestation of the disease with nystagmus and photophobia in infancy or rarely in the pre-school years . Our proband presented with early-onset cardiomyopathy, associated with ALMS in 62% of cases, but normally accompanied or closely followed by the development of visual impairment and a cone-rod dystrophy, pointing toward the diagnosis . In this case, the late onset of visual symptoms, aged 6, was unusual as early-onset visual difficulties have been reported as universal in ALMS . In the largest reported series of ALMS-related phenotypes , 98% of patients developed nystagmus and photophobia during the first year of life, with all patients in the series legally blind by the age of 15 . However, variability in the severity of the ocular manifestations of ALMS has previously been described . Malm and collaborators reported a patient with a mild ophthalmic phenotype who, aged 10, still had near-normal looking vessels and optic discs, diminished pigmentation of the fundus and visual fields with normal peripheral limits . However, in this mild case, both cone and rod function was mildly reduced upon ERG testing. A milder ophthalmic phenotype was also reported in a 26-year old female diagnosed with achromatopsia in infancy due to the presence of nystagmus and photophobia at birth, who demonstrated residual vision (20/640 and 20/800, right and left eyes, respectively) in her mid-20s with visual field constriction in the left eye to 20–45 degrees and a remaining crescent of paracentral visual field in the right eye . Weiss et al. also reported a late presentation in a child presenting age 6 with nystagmus and impaired vision diagnosed with Leber Congenital Amaurosis. The child developed systemic features of ALMS (obesity, hypothyroidism, elevated transaminase levels, fatty liver, and acanthosis nigricans) in adolescence, confirming the importance of large-scale genotyping screening . The classical association of ALMS with hypokinetic cardiomyopathy was present, occurring aged 1 month and resulting in stable left ventricular hypertrophy as a consequence. Fortunately, the episode proved non-progressive and without functional consequences, however, she remained on 5 mg of enalapril. Hypokinetic cardiomyopathy is a well know feature of ALMS, with highly variable long-term clinical consequences . In a case series, dilated cardiomyopathy was reported in 62% of patients, with 43% of cases occurring in infancy . In some patients, the infantile cardiomyopathy may be reversible with treatment, but a risk of recurrence remains . Our patient also had mild bilateral sensorineural, predominantly high-frequency, hearing impairment evolving throughout childhood. Hearing loss is reported in 89% of patients with a mean age of onset of 5 years . Other atypical presentations of ALMS have been reported and include a case of putative isolated cardiomyopathy in a 2-month old child followed up until the age of 4.5 months . The infant did, however, develop significant weight gain (>95th centile; +3 SD) in the short follow up period (up to 4.5 months) and no formal visual assessments were conducted . In this case, molecular analysis confirmed two novel compound heterozygous truncating variations in ALMS1 . Compound heterozygosity and truncating variations are well described in ALMS, with many affected individuals displaying variations through exons 8 (25%), 10 (27%), and 16 . The majority (96%) of the variations are nonsense or frameshift variations (insertions or deletions) leading to premature stop codons producing a truncated protein, or no protein at all . We highlight that nonsense-mediated decay (NMD) is likely to occur for our variants as both nonsense variants fall into the NMD-competent regions (NMD+) according to NMDEscPredictor , a finding corroborated by the very low amount of RNA identified in the patient’s cells. Given the mild phenotype, one could question whether, although unlikely, the second variation that appeared de novo could have arisen on the same allele as the first variation. We thus worked on the patient’s fibroblasts and demonstrated the biallelic status of the two variations using allele-specific amplifications. To our knowledge, this is the first description of a de novo pathogenic variation in ALMS1 . De novo variants contributing to autosomal recessive diseases are rare, as highlighted by large scale studies of whole exomes on more than 5,000 cases with developmental diseases. These studies did not report a single de novo variation contributing to a recessive condition, despite reporting more than 400 autosomal recessive molecular diagnoses . Black et al. recommended the reporting of de novo variations in autosomal recessive disease, as he uncovered two unrelated cases of an autosomal recessive disorder caused by the combination of one de novo and one inherited variant in a small series of nine families with severe fetal malformation . According to the literature, the human de novo mutation rate ranges from 1.0 to 1.8 × 10 −8 per nucleotide per generation, leading to <90 de novo variants per genome among the 4–5 million variants identified by WGS . The rate increases with paternal age, and 80% of de novo variants are of paternal origin. In our case however, the de novo nonsense variant occurred on the maternal allele and the mother’s age at conception was 32. The finding of a de novo variant contributing to ALMS in our proband has important implication for genetic counseling, since a clinical diagnosis of ALMS carries a reported recurrence risk of 25%. However, in this case because one of the causative variants arose de novo , the recurrence risk is markedly reduced, with significant implications for future reproductive decisions. A small finite risk remains, however, owing to the possibility of germ-line mosaicism in the father/mother. Recurrence risks given by clinical geneticists in such cases are generally stated around 1%. However, one must remain cautious as depending on the gene or disease, parental germline mosaicism levels may be much higher ranging from 5% to as high as 15% . Our analyses confirmed the biallelic status of the variations in the context of a mild phenotype. To date, contributing factors to phenotypic variability in ALMS remain largely unexplored and may include the presence of modifier alleles and the influence of epigenetic and/or environmental factors. The lifespan of patients with ALMS may not exceed 40 years , however early diagnosis and intervention can moderate the progression of some of the disease phenotypes and improve longevity and quality of life for patients.
|
Review
|
biomedical
|
en
| 0.999996
|
33005545
|
Roux-en-Y gastric bypass (RYGB) is effective in the treatment of morbid obesity and its associated metabolic derangements . However, complications such as small bowel obstruction can rarely occur and may be observed in approximately 5% of cases . Obstruction via hiatal herniation of the gastric pouch and alimentary limb occurs even less frequently, with only four cases reported in the literature . We present a case of acute small bowel obstruction 12 years after RYGB caused by herniation of the gastric pouch and proximal Roux limb into a hiatal hernia as well as our management of this condition. A 68-year-old female presented with a one-year history of progressive nausea, emesis, and sharp epigastric abdominal pain leading to eventual acute intolerance of oral intake for four days. She previously underwent a retro-colic Roux-en-Y gastric bypass (RYGB) surgery 12 years prior for treatment of her morbid obesity. Eight weeks prior to presentation, she underwent magnetic resonance cholangiopancreatography for evaluation of her chronic symptoms. Imaging revealed a large hiatal hernia containing the gastric fundus and the absence of any additional acute processes . On presentation to the emergency department, a computed tomography (CT) scan of abdomen without contrast was obtained due to her worsening epigastric abdominal pain and intolerance to liquids and solids, which showed the gastric pouch and Roux limb herniated into the thorax with obstruction of Roux limb and a clear transition point at the esophageal hiatus . Given these concerning findings, the patient was taken to the operating room for emergent laparoscopic hiatal hernia repair. An optical trocar was utilized to gain entry into the abdominal cavity. Exploration of the esophageal hiatus was performed. A type IV hiatal hernia involving the entire gastric pouch and proximal Roux limb was identified. The bowel was distended and edematous but viable. The pars flaccida was opened with a laparoscopic bipolar vessel sealer, which demonstrated the left crus being densely adherent to the Roux limb. After careful dissection, the hernia sac and contents including gastric pouch and proximal Roux limb were reduced out of the hiatus. The gastric pouch and Roux limb were closely inspected, both of which appeared viable. The anterior and posterior hernia sacs were separated from the bilateral crus and mediastinal structures until the contents were reduced and adequate esophageal length was obtained. A posterior cruroplasty was performed with 2-0 Ethibond suture. Intraoperative upper endoscopy confirmed smooth passage along the length of the esophagus, a normal appearing gastric pouch, patent gastrojejunostomy free from stricture and ulceration with a dilated yet viable Roux limb. Upper gastrointestinal study on post-operative day one demonstrated no leak or obstruction of contrast passage. She was discharged on post-operative day three with resolution of her symptoms except mild nausea. According to the American Society for Metabolic and Bariatric Surgery, 252,000 metabolic operations were performed in 2018 for obesity and its associated metabolic derangement, with RYGB accounting for 17% of the total operations . Hiatal hernias are common in patients undergoing weight loss surgery, occurring in up to 40% of patients. Often times, morbidly obese patients have hiatal hernias identified when undergoing weight loss surgery . Utilizing the Metabolic and Bariatric Surgery Association Quality Improvement Project patient use files, paraesophageal hernia repairs have been reported in 16% of patients undergoing weight loss surgery . This represents a significant percentage of weight loss surgery patients who have paraesophageal hernias repaired at the time of their operation, but based on reported rates of hiatal hernias in patients having weight loss surgery this indicates that a significant number of patients do not have their hiatal hernia repaired during their index weight loss surgery. Particularly, small hiatal hernias may not be repaired during the index operation, especially in patients having a gastric bypass compared to sleeve gastrectomy and, thus, may set the patient up for subsequent complications at a remote point from their operation . Hiatal hernia occurrence after RYGB can occur quite frequently after gastric bypass . The relatively small size of the gastric pouch, dissection injury to sling fibers, and tissue strength changes related to rapid weight loss may all predispose patients to post-operative hiatal hernia occurrence after gastric bypass. Several small case series have been published describing the repair of hiatal hernias after gastric bypass with the largest series reporting seven patients with hiatal hernia repair after gastric bypass . In the event of acutely worsening abdominal pain, nausea, and vomiting, clinicians should have a high suspicion for acute small bowel obstruction in RYGB patients and be quick to proceed with evaluation and surgical intervention. Patients with hiatal hernia after gastric bypass may present similar to this patient with chronic symptoms and may include dysphagia, post-prandial epigastric pain, or nausea and/or vomiting . Diagnostic imaging and upper endoscopy may reveal the diagnosis of gastric bypass pouch herniation into the esophageal hiatus, but rarely patients may present acutely with a bowel obstruction from Roux limb herniation. A review of the literature identified four reported cases making our patient only the fifth reported case of bowel obstruction from a hiatal hernia after gastric bypass (Table 1 ) . Of the four previous cases, all presented with abdominal pain, nausea, and emesis. Additional reported symptoms included shortness of breath and constipation. Time to presentation ranged from four to 48 months (mean 16.75 months) after the index RYGB. Only one case included herniation of the omentum and transverse colon in addition to the gastric pouch and Roux limb. Two of four cases (50%) had a history of hiatal hernia repair at the time of RYGB, thus representing a recurrent hiatal hernia. All cases were successfully managed with anterior (1/4 cases) or posterior (3/4 cases) cruroplasty with or without mesh and did not require bowel resection. Follow-up ranged from four weeks to 12 months with no reported recurrence of symptoms. Due to the limited number of cases, it was not possible to evaluate any effect of hiatal hernia repair at the time of RYGB, gastric pouch size, amount of weight loss, or retro-colic versus ante-colic Roux limb position. In the presented case, a diagnosis of obstruction was suspected based on the patient’s history of protracted, intermittent abdominal pain, nausea, vomiting, and constipation. Although a large hiatal hernia containing gastric pouch was identified on MRI, the Roux limb was not within the hernia, suggesting spontaneous herniation of the alimentary limb leading to the patient’s acute-on-chronic symptoms. This would explain the patient’s prior intermittent symptoms, which worsened upon Roux limb incarceration a few days prior to presentation. This phenomenon of acute-on-chronic symptoms has also been observed with internal hernias leading to acute presentation requiring operative intervention . A laparoscopic approach to this patient was undertaken for the demonstrated benefits of laparoscopic versus open paraesophageal hernia repair in the non-bariatric surgery patient . Key tenets of the repair of hiatal hernias after gastric bypass include those pertinent to non-gastric bypass patients with what we feel are some additional components when repairing hiatal hernias after gastric bypass . First, it is important to carefully dissect the gastric pouch along its lateral margin where it is often densely adherent to the remnant stomach due to the adjacent staple lines. At this point, separation of the gastric pouch and remnant stomach should be undertaken if any cephalad retraction of the pouch is present once the rest of the hernia reduced, if adequate intra-abdominal esophageal length cannot be obtained, or to aid in adequate exposure of the left diaphragmatic crus. Next, care should be undertaken along the left crura and left side of mediastinum as the gastric pouch staple line can be densely adherent to adjacent structures. Bioabsorbable mesh can be considered depending on the status of the cruroplasty. Lastly, internal hernias should be inspected for during the operation as well as anytime a patient with a gastric bypass is returned to the operating room for an intra-abdominal procedure.
|
Clinical case
|
clinical
|
en
| 0.999997
|
33047078
|
This retrospective analysis was an institutional based, observational study at MD Anderson Cancer Center (MDACC) in Houston, Texas. Cases from January 2000 to April 2018 were retrieved from in the pathology database at MDACC; the diagnosis of DFSP from any site of the body was searched. A total of 458 patient medical record numbers were obtained. Patient charts were analyzed for the following: date of birth, race, gender, confirmation of DFSP diagnosis, body location of DFSP, and date of DFSP diagnosis. In addition, the patient’s notes were reviewed to determine if the individual had a history of surgery in the same site as the DFSP. If the information was available, the type and date of original surgery was obtained. The diagnosis date was defined as the date when the DFSP biopsy was performed. Ninety-four patients with a DFSP diagnosis in our database had records and pathology specimens sent to MDACC but were not seen as patients by a MDACC physician; therefore, these individuals were not included in our analysis.
|
Other
|
biomedical
|
en
| 0.999996
|
33133827
|
As of July 23, 2020, the novel causative virus - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - has affected 14,971,036 people and caused 618,017 deaths, with a case fatality rate (CFR) of 4.12 globally . Recent studies have shown that mortality in the Takotsubo syndrome (TTS) variant of myocardial involvement in coronavirus disease 2019 (COVID-19) has been higher than mortality in TTS without COVID-19 and it affects both genders almost equally . In this report, we present a case of acute hemolytic anemia with acute myocarditis and cardiogenic shock in a male patient with COVID-19 infection. A 20-year-old male presented to the emergency department with a one-day history of low-grade fever that had peaked to 101 °F just the night prior to the hospitalization with minimal flu-like symptoms. Physical examination on presentation showed blood pressure of 90/60 mmHg, heart rate of 120/minute, respiratory rate of 30 breaths/minute, and 92% oxygen saturation on room air. The patient had no significant past or family medical history. Laboratory tests on day one showed an elevated C-reactive protein (CRP) of 26 mg/L, erythrocyte sedimentation rate (ESR) of 75 mm for one hour, and elevated serum glutamic-pyruvic transaminase (SGPT) of 213 IU. On day two of admission in the COVID-19 intensive care unit (ICU), laboratory findings returned with a hemoglobin of 1.9 gm%, total white cell count of 22,000/cmm with a reduced platelet count of 44,000/cu mm. Peripheral smear showed normocytic hypochromic anemia with few fragmented RBCs and schistocytes with reticulocytosis with the possibility of hemolytic anemia due to smear features of fragmented RBCs. Lactate dehydrogenase (LDH), which is often a surrogate marker of both hemolytic anemia and inflammation, was elevated at 960 mg%. Elevated cardiac biomarkers, viz. troponin I of 9,565.2 ng/L and brain natriuretic peptide of 8,000 pg/ml, were also recorded. Lactate was 7.15 mmol/L and serum creatinine was 0.89 mg/dl. Electrocardiogram was mimicking of acute coronary syndrome, showing mild ST depression and T wave inversion . Echocardiography revealed global hypokinesia, with a preserved wall thickness , and left ventricular ejection fraction (LVEF) of 30%. High-resolution CT thorax (Video 1 ) and CT of abdomen-pelvis were unremarkable. The patient was managed in the ICU on inotropes. COVID-19 was strongly suspected despite normal high-resolution CT. Differential diagnoses included acute coronary syndrome, sepsis, acute fulminant myocarditis, and vasospasm in the setting of COVID-19 infection. A nasopharyngeal swab was positive for high viral load (by cycle time) for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR). Given his positive COVID-19 test and hemoglobin of a mere 1.9 gm%, the decision was made to defer coronary angiography. The patient was transfused pack cell volume to correct anemia along with IV noradrenaline infusion, low molecular weight heparin, IV vitamin K, and a low dose of diuretics and steroids in the form of injection methylprednisolone pulse therapy. Clinically, the patient developed cardiogenic shock during the course of hospitalization and required up-titration of norepinephrine. He stabilized over the next two to three days and was finally discharged on day 10 with a hemoglobin level of 8.5 gm%. COVID-19 has been primarily a respiratory disease, but many studies have reported that it affects multiple systems. Cardiogenic shock due to myocarditis has been extensively reported as among the most common cardiovascular complications of COVID-19 . Previous studies have reported that angiotensin-converting enzyme 2 (ACE2) receptors mediated effects on lungs, kidneys, heart, vascular endothelium by downregulating their expression and enhanced vasoconstriction with deleterious effects of the unopposed reticuloendothelial system . It is also likely that virus-mediated immune response can cause consumption coagulopathies, acute hemolytic anemias, and other blood cell dyscrasias . Cardiac findings of previously published autopsy series of patients with COVID-19 have reported cell necrosis without lymphocytic-myocarditis with no evidence of direct viral cytotoxicity . Both acute myocarditis and acute hemolytic anemias and consequent severe anemia can together or alone produce acute heart failure and dilated LV/poor LV function. In this report, we presented a case of a COVID-19 patient who developed acute myocarditis and severe acute hemolytic anemia, as evident from peripheral blood smear showing schistocytes (fragmented RBCs) in peripheral smear with acute severe anemia along with elevated LDH, which is also a surrogate marker for hemolysis. Acute heart failure with cardiogenic shock with possible stress cardiomyopathy is often characterized by transient severe global LV dysfunction in the absence of significant coronary artery disease. The cardiogenic shock was diagnosed based on the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) definition: systolic blood pressure of 90 mmHg that requires more than 30 minutes of inotropic support. Exclusion of sepsis was supported by the normal value of serum procalcitonin apart from the corroborative echo finding of severe LV dysfunction . In this patient, despite low oxygen saturation, the CT scan was clear, and the low saturation could be explained by central oxygenation impairment apart from peripheral vasoconstriction due to low cardiac output and inotropes that were being administered to the patient. PaO 2 and SaO 2 correlation varies more widely below 95% saturation and hence may be misleading. Severe acute myocarditis may sometimes manifest with low forward output and minimal pulmonary congestive manifestations . It is hypothesized that high catecholamines, exaggerated inflammatory/immune-mediated response, and direct viral cytotoxicity and consequent effects of acute anemia (high CO state) may be the mechanism behind the development of such reversible transient stress cardiomyopathy secondary to acute heart failure due to acute myocardial damage and/or rapid RBC breakdown .
|
Clinical case
|
biomedical
|
en
| 0.999998
|
33264305
|
To date, data on killer whale health and disease are from captive animals [ 5 – 7 ] or case reports from free-ranging individuals or mass-stranded animals . An overview identified 15 infectious agents in killer whales and an additional 28 pathogens from sympatric cetacean species with a potential to affect killer whales . Non-infectious health concerns include impacts from accumulated persistent organic pollutants (POPs) [ 11 – 13 ], human interactions including vessel collisions , interaction with fishing gear [ 15 – 17 ], the effects of noise [ 18 – 22 ], and consequences of reduced prey availability [ 22 – 24 ]. Killer whale stranding response was permitted through multiple letters of authorization from NOAA to stranding networks in CA, OR, WA, AK, and HI. Records from killer whales that stranded in the North Pacific Ocean and Hawaii from January 2004 through December 2013 were reviewed. For each case, data included the stranding location and date, sex, ecotype or population, individual animal identity, age class, event history, post mortem images, nutritional condition, gross findings, morphologic diagnoses, and incidental findings. Ancillary diagnostic studies existed for some cases and included computed tomography (CT) scans, magnetic resonance imaging (MRI), viral, bacterial and fungal cultures, serologic assays and molecular screening for specific pathogens. Heavy metals and POPs were measured in some cases and when present, parasites were collected at necropsy and submitted for speciation. Pathology reports from all necropsied killer whales were examined by four board-certified veterinary pathologists with extensive marine mammal experience and data were aggregated to identify significant findings by mutual consent ( Table 1 ). Using this approach they identified proximate cause of death (COD) (the disease, injury, or process that initiated a sequence of events, which led to death) and ultimate COD (the final process that killed the animal), which were classified as congenital, environmental incident, euthanasia, infectious, inflammatory, metabolic, nutritional, traumatic (either resulting from a human interaction (HI) or non-HI), or unknown. Environmental incidents reflect mortalities where whales were out of habitat (freshwater rivers) or mechanically stranded due to beach conformation and abrupt ebb tides. Metabolic cases represented instances where a catabolic derangement, such as hypoglycemia or electrolyte imbalance, did not appear to be associated with long-term nutritional limitation and was deemed the primary mortality factor. Nutritional cases included neonates with failure to thrive and older emaciated animals that did not exhibit evidence of underlying chronic disease. In some cases, a definitive diagnosis could be made (e.g. vessel strike for a traumatic COD). Occasionally important secondary pathologic findings were identified, but a proximate or ultimate COD could not be determined. Photo-identification and morphometric data were used to classify animals as calves (includes fetus, neonate, and young calves), sub-adult, or adult. Fetuses included pre-term or aborted animals measuring less than 200 cm (straight length; measured from the tip of the rostrum to the deepest part of the fluke notch). Neonates were calves exhibiting structures such as fetal folds, vibrissae, colonic meconium or a patent umbilicus. Calves, including one fetus and three neonates, ranged from 201 to 360 cm long. Sub-adults were 361 to 500 cm, likely representing animals between 2 and 12 years of age and adults measured greater than 501 cm representing animals older than 12 years of age. Photo-identification, stomach content, or genetic sequencing of the mitochondrial control region (d-loop) were used to identify the ecotype, population, and individual, when possible. Killer whales are long-lived mammals with an extended growth period; thus, it is likely that blubber thickness and the BCI both change with age. In the absence of data on age for many of the stranded killer whales, body length was used as a proxy. Generalized linear models (GLM) were used to evaluate relationships between body length and blubber thickness measurements across the entire data set and by age class [fetus/neonates/calves (152.4 to 357.5 cm body length) and sub-adult/adult killer whales (375 to 792.5 cm body length)]. Based on the outcome of the GLM, ANCOVA or ANOVA was used, as appropriate, to determine differences in blubber thickness measurements across the three sites for the two age classes separately. Prior to performing these analyses, normality was confirmed by Shapiro-Wilk tests and equal variance was confirmed by Levene (for ANCOVA) or Brown-Forsythe (for ANOVA) tests. Because the relationship between body length and BCI is nonlinear, Spearman Rank Order Correlation was used to test for correlation between these two variables. Association between COD (e.g. trauma, infectious, or nutritional) and body condition (blubber thickness and BCI) was evaluated. Due to a small sample size, killer whales with infectious COD or nutritional COD were combined; both chronic infectious mortality and malnutrition were anticipated to be associated with poor body condition . T-tests (normality confirmed by a Shapiro-Wilk test and equal variance confirmed by a Brown-Forsythe test) or Mann-Whitney Rank Sum Tests (when the normality test failed) were used to evaluate differences in body length, blubber thickness measurements, and BCI between killer whales that died from trauma and killer whales that died from infectious or nutritional CODs (combined). Because we had an a priori assumption that killer whales that died from trauma would have thicker blubber and higher BCI values than killer whales that died from infectious or nutritional causes , one-tailed hypothesis testing with T-tests were used for these comparisons when tests for normality and equal variance passed . Otherwise, Mann-Whitney Rank Sum Tests were used,. A P -value of 0.05 was the critical statistical level of significance for all statistical tests. The generalized linear model analysis was conducted using ‘stat’ package in R Version 3.6.0. All other statistical and graphical analyses were conducted using SigmaPlot 14 Software (Systat Software, Inc., San Jose, CA, USA). Over the 10-year period, 53 stranded killer whales were examined ( Table 1 ). Of these, 22 (42%) had sufficient information to determine a cause of death. Significant ancillary diagnostic findings that were not considered to be associated with COD were identified in an additional seven animals. Likely due to some combination of length of the coast line , killer whale density, and detectability, 29 (55%) animals were from Alaska, nine (17%) from British Columbia (Canada), six (11%) from Washington, five (9%) from California, two (4%) in Oregon (USA) and two (4%) from Hawaii. Collectively, 62 significant pathologic findings were documented from combined proximate COD, ultimate COD, and important secondary pathologic findings ( Table 3 ). In 23 cases, the carcasses presented with either advanced autolysis or were poorly inaccessible and as a result limited data were collected providing insufficient opportunity to identify significant pathologic findings ( Table 3 ). A 245 kg neonate measuring 250cm and a 203 cm long calf were thin. Neonate 20130904 had serous atrophy of epicardial and mesenteric fat and no gastric contents. A third neonate, a 238 cm male transient , appeared to have been born alive, breathed, consumed a small quantity of colostrum and then died. Histopathology of multiple levels of the lung of this calf disclosed partially inflated alveolar spaces with a small number of widely scattered squames and a sparse meconium. In all three cases, the proximate COD was determined to be nutritional with an ultimate cause of death likely metabolic from hypoglycemia. None of these cases had associated data reflecting maternal condition. One calf died of sepsis, secondary to ingestion and impalement by a fishhook. This Alaskan resident had a large halibut hook perforating the oropharynx . Additional findings included bronchopneumonia and necrotizing hepatitis. The traumatic perforation of the oropharynx was the proximate COD and emaciation in this case was considered secondary to the chronic inflammation, possibly compounded by difficulty swallowing. On gross examination, numerous superficial erosions, ulcerations and lacerations were also noted within the lingual, oropharyngeal and cranial esophageal mucosa, which were most likely related to the embedded fish hook, heavy gauge line and snap trailing from the lateral commissures of the mouth. The mixed bacterial population identified in the cellulitis were likely secondary opportunists, environmental contaminants or oral commensals; Edwardsiella tarda was isolated from a lymph node and likely accounted for the septicemia. Of the six sub-adult animals for which a COD was determined, three animals died with gross findings consistent with trauma. Two traumas were vessel strikes (northern resident ID# C021 and southern resident ID# L098) and one was blunt force trauma of unknown origin (southern resident ID# L112). Northern resident C021 was a thin, 470 cm sub-adult female with extensive cervical skeletal muscle hemorrhage, hemothorax, hemoabdomen and a subpleural hematoma of the left lung. Southern resident L098 was a 7-year-old socially isolated male that had no apparent interaction with other killer whales for 5 years. Witnesses reported that this habituated animal approached a vessel and was inadvertently drawn into the propeller. Despite intensive efforts, only a 31 kg portion of blubber, skin and pannicular skeletal muscle from the eye patch was recovered and the other remains of the carcass were never found. Southern resident L112 had extensive subcutaneous bruising on the caudal head and neck, which extended deep into the adjoining epaxial musculature and tracked dependently along the hypodermis to the throat. On the right side of the carcass, the bruising extended to the anterior insertion of the pectoral fin. For two sub-adult animals, the proximate COD was nutritional. The first, an emaciated female that stranded alive in Hawaii, was subsequently euthanized. The nutritional condition was difficult to determine at the time of examination, but the pathologist’s review of gross photos and collective necropsy findings concluded that emaciation/inanition was the most likely cause of stranding. Photographs revealed a significant depression behind the head at the location of the nuchal fat pad, prominent rib profiles in the thorax, and a “thin” tail stock . Blubber depth measured at the time of necropsy was 2.9–3.9cm. In addition to the poor nutritional condition, histopathology revealed moderate lymphoplasmacytic cholangiohepatitis with occasional bridging fibrosis, hemosiderosis and biliary ductular hyperplasia. As with the other animal that stranded in Hawaii , there was nonsuppurative adrenal adenitis and numerous irregular 3-5cm diameter cutaneous erosions and ulcerations, often infested with cyamid crustaceans . The thin Alaskan transient was a case of inanition subsequent to a period of six weeks or more up the Nushagak River. The specifics of this case are presented in the adult mortality section because that animal was one of three in a mass stranding event. In 2007, a female transient (ID# T086) succumbed to catastrophic propeller strike. The carcass was not recovered but the intact dorsal fin, and a portion of the saddle patch were recovered on the beach . The deep parallel serrated incisions, abrupt, stepwise or repeating angulated margins and shearing of the blubber from the hypodermis characteristic of propeller strike formed the margins of the retrieved tissue . The second adult that died from trauma, an offshore male (ID# O319), had moderate hemorrhage within the musculature of the left thoracic wall and an acute transverse closed simple fracture of the left rib with associated hemothorax. There was also a pre-existing healed fracture of the same rib located approximately 12cm ventral to the fatal fracture. A transient female (ID# N018) necropsied in California had an extensive intramuscular bacterial abscess that included the vertebral bodies of the caudal peduncle. The infection was associated with a prior traumatic wound and secondary microbial contamination. Environmental incidents were attributed as a proximate COD in 4 adult orcas. Two transient killer whales that stranded near Cordova, Alaska were likely feeding in shallow water when the ebb tide abruptly receded. A necropsy exam was complete in one animal and due to human safety concerns, was cursory in the second whale. In both cases, the animals were in good nutritional condition with no lesions suggesting co-morbidity or mortality beyond the environmental incident. The second environmental event occurred in 2011 when two transient adults and a sub-adult swam up the Nushagak River from Bristol Bay near the town of Dillingham, Alaska. The animals were monitored in the freshwater river for six weeks before there was an abrupt drop in water level at which time the whales apparently live stranded on a sand bar and subsequently died. One near term pregnant female and a sub-adult whale were examined, and both were severely emaciated. Based on dehydration and starvation associated with the lack of available prey during this extended extralimital period, nutritional stress was the proximate cause of death. Incomplete fusion of the dorsal process of C6 (spina bifida occulta) was identified postmortem in a sub-adult female southern resident (ID# L112) but did not appear to contribute to antemortem morbidity or stranding. The defect was approximately 1cm and the paravertebral soft tissue was unremarkable. Similarly, an adult female transient (ID# T171) presented with severe irregular bone remodeling of the vertebral periosteum involving vertebrae caudal to T6, with no apparent bridging spondylosis. While this change was extensive, it was not believed to have contributed to impaired mobility or the foraging ability of this animal. An adult transient female that live stranded and died of an undetermined cause had multiple firm, white, well-defined masses associated with the fallopian tube, uterus and mesovarium . The masses varied in size from 2-8cm in diameter and histologically, were identified as leiomyomas. Immunohistochemistry was positive for vimentin with variable expression of both desmin and smooth muscle actin and staining for CD10 and calmodulin were negative. The contribution of this tumor to impaired fecundity and clinical disease could not be determined. Moderate cholangiohepatitis was also diagnosed in this case. Gastric helminths were observed in five animals. Parasites from three cases were not speciated, however verminous gastritis was noted in ID# 20070520. Numerous Anasakis simplex were observed in the stomach, proximal duodenum and in the lumen of the gall bladder of a nursing 358cm long female Alaskan resident calf . The trematode Odhneriella subtila was identified in the small intestine of this animal; however, stomach, small intestine and gall bladder were not examined microscopically. A 3-year-old female southern resident (ID# L112) had approximately 30 Anisakis simplex aggregated in the nonglandular fore-stomach mucosa. Histopathology of the junction of the glandular and nonglandular compartments revealed hyperplasia of squamous epithelium with ortho- and parakeratotic hyperkeratosis, transverse mucosal clefts and a few superficial, luminal nematode parasites. Crassicauda sp. were also detected in the peribullar sinuses and fibrovenous plexus. Sinusitis was observed at necropsy and histopathology showed luminal adult parasites and necrotic exudate contained within edematous mucosa with dilated vascular/sinusoidal spaces demonstrating collapsed profiles of nematodes and very large numbers of thick-shelled nematode eggs containing partially developed larvae. Sloughed sinus epithelium contained moderate numbers of round cell "ghosts" interpreted as infiltrating leukocytes. In one animal , a presumptive calcified renal parasitic granuloma was diagnosed microscopically, though nematodes were not identified in the lesion. Blubber thickness ranged from 1.1 to 3.4 cm in the near-term fetus/neonates/calves (152.4 to 357.5 cm body length) and from 2.1 to 9.2 cm in sub-adult/adult killer whales (375 to 792.5 cm body length). The generalized linear model found a significant association between body length and blubber depth at all three sites for all animals combined as well as for the sub-adult/adult killer whales (p<0.05, all sites). However, there is no association between body length and blubber depth at any of three sites (dorsal: p = 0.4, lateral: p = 0.06, ventral: p = 0.09) for the fetus/neonates/calves. Based on the results of the GLM, an ANCOVA and an ANOVA were used to assess variability in blubber thickness across the three sites for the sub-adults/adults and fetus/neonates/calves, respectively. For the older animals, blubber thickness increases with body length (p < 0.001), there is no interaction between blubber sample site and body length, and blubber thickness differs significantly across measurement sites (P = 0.01). Pairwise comparisons show that dorsal blubber thickness is greater than lateral blubber thickness (p = 0.008). In contrast, for the fetus/neonates/calves, blubber thickness does not differ across the three blubber measurement sites (P = 0.2). In contrast to blubber thickness, there is no relationship between body length and the body condition index (BCI; Spearman Rank Order Correlation, p = 0.3). BCI ranged from 0.54 to 0.73 for the near-term fetus and calves and 0.56 to 0.77 for older animals . Instead, BCI values appear to be related to cause of death . BCIs for individuals that died from trauma (range = 0.61–0.77, mean = 0.67 ± 0.05 SD) are significantly greater (Mann-Whitney Rank Sum test, p = 0.04) than BCIs for individuals that died from infectious and nutritional causes (range = 0.54–0.70, mean = 0.59 ± 0.06 SD). Four out of seven (57%) animals that died from nutritional causes had BCI values that were ≤ 0.60 and three out of four (75%) animals that died from systemic infections had BCI values that were ≤ 0.56. All six killer whales that died from trauma and the one killer whale that died from entanglement had robust BCI values (> 0.60), which would be expected for healthy animals that died peracutely from a catastrophic event. BCI values ≥ 0.70 may be artifactually inflated due to carcass bloat or pregnancy . Determination of the nutritional condition of stranded animals in the context of pathologic findings in this study was a challenge. Cetaceans have minimal visceral adipose stores. The greatest reserves accumulate in the subcutaneous adipose (blubber) layer and vary with food availability, elements of seasonality including hormones cycles, reproductive status, water temperatures, migration and prey availability [ 36 – 38 ]. Blubber loss also varies by site in emaciated cetaceans. For example, blubber thickness in the thorax of starved porpoises (9-11mm) was reduced to 50–60% of that of normal animals (18-20mm); however, very little tailstock blubber was lost . Although blubber thickness measurements can inform nutritional condition assessments, the interpretation of these measurements can be complicated. There are many potential underlying causes of malnutrition and poor body condition. These include reduced prey availability; impaired ability to successfully forage, apprehend, or consume prey (such as with a broken or deformed jaw); inappetence due to an underlying condition; reduced intestinal absorption of nutrients (malabsorption); increased protein loss such as with protein-losing nephropathy or enteropathy; or increased metabolic demands such as is seen in pregnancy, lactation, increased energy expenditure to meet physiologic needs, or with cachexia of chronic inflammation. Because the necropsy examination is a “health snapshot” at the time of death, the role of weight loss as a precursor versus the product of general poor health can be difficult to determine. Typically, a pathogenesis of cause may be inferred based on staging significant necropsy findings and review of environmental information. Observer variation in determination of the nutritional status of animals at the time of death further complicated this assessment. Based on review of field observations and necropsy reports, relatively few animals were identified as thin or emaciated. However, in several cases, field observations indicating that animals were in good condition were uncorroborated by blubber thickness (relative to body length) and/or BCI values. While blubber depth was the prime nutritional condition objective measure for this determination in dead animals, site- and body length- specific ranges had not yet been produced to make these measurements more than a crude evaluation. In terrestrial animals and humans, serous atrophy of fat and bone marrow are key indicators of emaciation. Due to the limited distribution and absolute amount of bone marrow in cetaceans, this method has not been routinely employed to assess nutritional status in stranded killer whales. Conventional indicators of reduced or poor body condition in cetaceans include a loss of fat in the nuchal crest resulting in formation of a cervical indentation, a condition known as “peanut head.” Additional subjective determinations include reduction in blubber identified by concavity along the epaxials, a visible rib pattern in the skin over the thorax, loss of pericardial and epicardial fat, and generalized muscle loss. These can be difficult to detect in free-swimming animals and are likely late-term indicators of poor body condition. In fact, 11 of 13 southern resident killer whales noted with these signs between 1994 and 2008 subsequently died . One clear conclusion from this review is that a defined body condition score with objective measures is needed to better assess killer whale nutritional status. In this case series, blubber thickness increased with body length and as few animals of similar body length strand, it is difficult to rely on blubber thickness alone as an indicator of nutritional condition. Furthermore, in terrestrial mammals, emaciation is characterized by a loss of subcutaneous, epicardial, and mesenteric adipose as well as an associated prominence of the ribs, vertebrae and pelvic bones. Additional changes can include muscle, liver and fat atrophy. The body condition index, which accounts for changes in total body girth relative to body length, correlated with COD in most of the stranded killer whales. As subtle changes in blubber thickness can occur, BCI provides a more sensitive assessment of body condition. For example, a lactating southern resident female that stranded in 2002 (ID# L060) and an entangled male transient killer whale that stranded in 2015 had the lowest BCIs of the more robust animals. Lactation is a metabolically expensive process that can deplete energy stores , and the entangled killer whale died with fishing gear still attached, suggesting the animal was trailing gear for some time prior to death. Decreased body condition is often noted in entangled baleen whales and is related to increased drag caused by entangling gear and subsequent increased energy expenditure required for swimming . Because blubber reduction may not be as significant as changes in epaxial and hypaxial musculature beneath the blubber layer, BCI values are likely better indicators of body condition than blubber thickness measurements alone. For example, a recently stranded 300 cm long killer whale calf that died of malnutrition had blubber thickness measurements not consistent with emaciation; however, its BCI was 0.57, placing it within the range of a malnourished animal . In this case, blubber measurements alone would not have properly assessed the body condition in this animal. In other odontocetes, the limitations of interpreting blubber measurements to overall nutritional status of individuals have been attributed to a lack of relationship between blubber thickness and blubber lipid content and variability of blubber depth across the body. However, the post mortem state of a carcass should be considered when assessing BCI. Two killer whales, one that died from malnutrition and one that died from a systemic infection (ID# L095) had relatively high BCIs but presented with advanced autolysis, which contributed to bloat that was not noted on necropsy. Based on morphometric data for the three killer whales with body condition indices of > 0.70 , bloat, poor post-mortem condition with fat lysis, and pregnancy can artifactually inflate the body condition index. This suggests that using BCI as an indicator of health status of stranded killer whales is best limited to carcasses in moderate to good post-mortem condition. Other criteria, such as blubber lipid content, gross appearance of the blubber (oily vs. dry), and muscle condition may be used for killer whales found in advanced autolysis. Differentiating causes of poor body condition (e.g. infection versus nutritional) in killer whales solely using BCI values for stranded individuals or aerial photogrammetric images for free-swimming whales, is impossible, given analytical limitations, including sample size. Despite some mischaracterizations of observed body condition, there was still a preponderance of more robust animals in the stranding dataset. For example, approximately two thirds of the stranded killer whales for which valid BCIs were determined were in good condition. This suggests that animals in moderate to good body condition are positively buoyant and are more likely to be recovered than animals in poor condition with less blubber. However, since one third of these killer whales had poor BCI values, it is evident that other factors (e.g. carcass bloat, geographic location) beyond body condition contribute to the likelihood of carcass recovery, as has been described . Furthermore, as mentioned above, biological samples are necessary to tease apart mechanisms leading to poor body condition. Traumatic injuries distinct to vessel strike were identified in six strandings. In three cases (ID#s O319, N018, and L112) the origin of trauma could not be determined. Conspecific aggression was a prime consideration for offshore O319. This animal presented with a simple complete transverse closed rib fracture not commonly associated with catastrophic blunt force injury, but rather with a focused traumatic event, such as intraspecies aggression associated with a forceful bite or head strike. The transient N018 also had a focal septic comminuted closed vertebral fracture, which may also represent intraspecific aggression. In contrast, the sub-adult southern resident L112 exhibited massive blunt force trauma and lesions consistent with a glancing blow. While the origin of the trauma could not be determined, a vessel strike could not be ruled out. Based on field observations or necropsy findings, vessel strike was confirmed in two animals (ID#s L098 and T086) and suspect for one additional whale (ID# C021) (9.3% of trauma cases were related to vessel strike). Moreover, an 18-year old male southern resident (ID# J034) was found dead near Sechelt, B.C. with extensive subcutaneous and epaxial hematoma in the left dorsolateral thorax. The hemorrhage indicated that J034 was alive at the time of impact and based on the extent and severity of the lesion, was likely struck by a vessel. In a separate case series, Williams and O’Hara identified ten killer whales that were struck by vessels in British Columbia waters between 1995 and 2005. Five were non-fatal strikes, two were fatal (one being L098), two were classified as serious injury and one animal died a year after being injured. Prior to that, Ford et al. identified two northern residents that were struck by propellers and survived and described a killer whale calf (suspected to be A021) that was struck by a ferry in 1973 and likely later died. Visser identified propeller scars on two of 117 photo-identified killer whales in New Zealand and reported an additional fatal vessel strike in a third animal. Historically, vessel strike has not been considered an important anthropogenic cause of morbidity or mortality in killer whales; however, based on findings from this pathology review and other observations of vessel strike , this risk factor may be an underappreciated but important threat to the population status of endangered killer whales in the eastern Pacific. Although fatal fishing interactions are infrequent in stranded animals, ingestion of fish hooks may pose a health concern, particularly in younger, less experienced animals. Fishing hooks have been documented in stranded resident killer whales as early as 1973. Ford et al. reported that of 8 examined resident killer whales, two contained hooks or lures designed for salmon fishing and two other animals had ingested hooks used for Pacific halibut fishing. In Alaska, killer whales are known to depredate sablefish ( Anoplopoma fimbria ), Pacific halibut and Greenland turbot ( Reinhardtius hippoglossoides ) longlines . Depredation by killer whales has also been documented in other regions of the world. Off the coast of the Crozet Islands, reproductive success of killer whales has been associated with consumption of Patagonian toothfish ( Dissotichus elegenoides ) off longlines in contrast to conspecifics that do not rely on hooked bait fish . Although no southern resident killer whales have been reported to have died from fishery interactions to date, based on prior field observations and case findings in other regions in the eastern Pacific, southern residents do interact with fisheries, but incidents may not be well documented. On August 1, 2015 a 12-year-old male southern resident killer whale (ID# J039) was photographed with a salmon flasher hanging from its mouth. The rigging was consistent with a squid lure 3/4” barbless hook (point to shank) on 30lb test line and if ingested, the hook would have extended up to 24" to 44” into his esophagus. This whale was monitored and the flasher was present 5 days later, then lost the following day. Currently J039 is alive with no apparent adverse effects from this incident. Evidence of fishing interaction appears more frequently with younger animals and suggests that depredating fish from longlines without ingesting the hook could be a learned behavior that improves with experience. The calf that died of septicemia, secondary to hook ingestion, may have been in the process of learning this behavior. Of course, it is possible for whales to capture and consume fish that have broken away from fishing gear and taken some or all of the gear with them. Alternately, an older animal that depredated the fish and hook could have shared the depredated fish with this younger animal . Due to the small sample size, the potential impact of depredation on resident whale populations could not be determined. The incidence of depredation may vary by fishing intensity in the region, cultural learning in the pod, hook type and possibly age structure of the whale population. Based on these findings, fisheries interactions should be further evaluated as a potential health hazard to killer whales and appropriate practices considered to limit these events if they are found to jeopardize population viability. Infectious disease was identified as a proximate cause of death in two whales and an ultimate cause of death secondary to trauma in two additional animals . Bacterial infections also were associated with ingestion of foreign bodies and were likely involved with the fibrinous peritonitis diagnosed in an emaciated female adult killer whale . The mixed bacterial flora recovered from sampled tissues in both cases suggest disruption of the gastrointestinal mucosa as the source of bacterial invasion and infection. Only one case of bacterial septicemia from a single agent ( Salmonella Newport) was recovered. In this case, the origin of the infection was likely maternal bacteremia with localization to the placenta and introduction to the fetus via the umbilicus . The proliferative costochondritis (ribs) and age of this animal indicated fetal sepsis with possible growth plate involvement. Salmonella sp. was also isolated from an adult female killer whale ; however, in this case, the lack of associated gross and histopathologic lesions suggest that this animal was an asymptomatic carrier, rather than actively infected. In examining future cases where Salmonella spp. may be recovered, it is imperative that the isolate is placed in appropriate clinical context with regards to associated nutritional status and pathologic findings of the animal. Serotyping or genotyping should be pursued to determine if the bacteria may have been terrestrially sourced or may cycle exclusively in the marine environment. Fecal hormone analysis of southern resident killer whales documented early embryonic loss and fetal resorption or abortions in 69% of detectable pregnancies with approximately 20% late term pregnancy losses. These findings coupled with up to 50% of neonate and yearling calf mortalities (in animals sampled) substantiate the importance of reproductive disease in southern resident killer whales. Prey availability and contaminant loads were prime considerations in reproductive failure in this study and in our case series only a single abortion was documented . However, reproductive failure was also confirmed in a 19-year-old full term pregnant female southern resident killer whale (ID# J032) that stranded outside of our time series in 2014, due to fetal loss and septicemia. Although the cause of abortion and in utero mortality are not readily apparent, the scat analysis field study and cases in this post mortem cohort highlight that reproductive disease does occur in this species and contributing factors such as nutritional status, pathogen exposure and anthropogenic activities should be investigated. Myocardial fibrosis was diagnosed in two adult killer whales . This lesion is commonly identified in older odontocetes and seems to correlate with increasing age. The pathogenesis of this lesion is likely complex and potential causes include toxin exposure, such as domoic acid or mercury, resolving and possibly progressive fibrosis, inflammation, pathogens, nutritional (vitamin E or selenium deficiency), stress reactions, gas bubble disease, and serotonin excess . At present, the etiology of this condition is unknown. The lack of associated cardiomyopathy and pulmonary and hepatic congestion discounts impaired cardiovascular function as the COD; however, the lack of these lesions does not preclude the possibility of an arrythmia or other non-congestive cardiac abnormalities. Congenital disorders were identified as the proximate cause of death in a neonate and calf. These conditions were incompatible with neonatal development beyond a few weeks or months post-partum. In contrast, a variety of skeletal malformations have been reported in other killer whale populations and have been identified in all age classes. Both thoracic kyphosis and scoliosis have been documented in Norwegian killer whales , and one case involved a calf with no evidence of trauma. In a second calf (neonate) with scoliosis caudal to the dorsal fin, there was observed trauma to the dorsal fin suggesting that this spinal pathology may have been acquired. Lordosis and kyphosis were described in two live New Zealand killer whales as well . Hiatal hernia has not been previously been recognized in cetaceans. Familial inheritance of hiatal hernia occurs in humans with evidence of direct male-to-male transmission and suggests an autosomal dominant mode of inheritance . Because of inbreeding concerns with certain males being over-represented as sires in the southern resident killer whale population, heritable conditions like this could represent population threats . In this case, increased intra-abdominal pressure associated with dystocia and protrusion of the stomach through the hiatus may also be a consideration. Complete necropsies provide an opportunity to address knowledge gaps about the composition and pathology associated with metazoan and protozoal parasites in killer whales. Metazoan parasites previously reported in killer whales include: the Acanthocephalans Bolbosoma nipponicum and B . physeteris , the cestodes Diphyllobothrium physeteris and D . polyrugosum , the nematodes Anisakis pacificus , A . simplex [ 62 – 66 ], and Halocercus sp. , and the trematodes Campula sp., Fasciola skrjabini , Hadwenius subtilla , Oschmarinella albamarina , Phyllobothrium sp., and Trigonocotyle spasskyi [ 62 – 64 , 68 ]. Although Anasakis sp. have been reported in killer whales, ID# 20070520 may be the first case with associated gastritis. The trematode Odhneriella subtila identified in the small intestine of ID# 20050826 was not unusual and may be the same species previously reported in a killer whale described as Hadwenius subtila by Adams and Rausch . The identification of Crassicauda sp. in the peribullar space of L112 likely represents a novel nematode reported in killer whales. Interestingly, Crassicauda sp. were also found in the peri-bullar region of an 18-year-old female southern resident (ID# J032; Table 2 ). Sinusitis was grossly (for L112) as well as microscopically (for J032) associated with the presence of these nematodes. Toxoplasma gondii antibodies have been detected in a killer whale from Japan , and we detected dual infection with T . gondii and Sarcocystis neurona in an adult female (ID# N018) . The clinical and pathologic consequences of protozoal parasites on free-ranging killer whales is not known. However, these parasites are terrestrially sourced and efforts to mitigate discharge of infectious pathogens by appropriate control measures is critical, particularly as the largest water borne infection of T . gondii in humans worldwide was reported in municipal drinking water in Victoria, British Columbia . We did not detect the ciliate, Kyaroikeus cetarius , which has been identified in 5 of 6 captive killer whales , in any stranded animals. This case series sets the foundation for understanding killer whale mortality and health concerns and provides a basis for enhanced monitoring and improved management of killer whales, especially for endangered populations. Consistency in sampling and morphometric measurement protocols is critical for continuity of health monitoring in killer whales. Because blubber thickness varies by body length, BCI may be a more suitable tool for assessing body condition in deceased killer whales. However, the finding that neither blubber thickness nor BCI measurements are adequate for differentiating proximate mechanisms for poor body condition has implications for monitoring health in free-ranging killer whales. Without additional biological samples, it is impossible to differentiate animals in poor body condition due to metabolic imbalance, such as during periods of reduced prey availability, from those that are diseased. The results of this case series also suggest that human interaction cases may be more prevalent than previously understood for killer whales in the northeastern Pacific. Continued analysis of necropsy cases will be important for adaptive management efforts.
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Bonnevialle conducted a prospective cohort study, 126 cases of patients with distal tibia and fibula fractures were treated by fixing tibia with external fixator, intramedullary nail or plates, while fibula is not fixed, or fixed with intramedullary nail or plates. The results showed that fibula fixation was helpful to restore tibial length, reduce lateral movement of fracture and maintain the stability of the tibia in shaft direction. However, some other studies found that standard open reduction and internal fixation of tibia with intramedullary nail or minimally invasive percutaneous plate osteosynthesis (MIPPO), without the fibula being fixed, had good reduction stability of tibial fracture, reduced the risk of soft tissue injury and infection, and had a good prognosis of function [ 7 – 9 ]. Javdan reported that dynamic compression bone plate (DCP) or tubular plate fixation of fibula had no significant difference in influence on tibial fracture healing, reduction of postoperative complications and recovery of affected limb function. In addition, a few studies have shown that fibular plate internal fixation can increase the rate of delayed healing and non-healing of tibial fractures . In summary, in previous studies on the fixation of fibula fractures was with plate-screw internal fixation, elastic intramedullary nail or non-fixation, no attempt has been made to fix the fibula with Kirschner wires (K-wires). External Fixators always is indicated in open fractures, they are advised in periarticular unstable fractures, floating knee injuries or most commonly in compound fractures in diaphyseal area [ 11 – 13 ]. Besides they are also commonly used always in limited economic reality . The purpose of this study was to compare the efficacy of simple external fixation, external fixation combined with plate-screw osteosynthesis, external fixation combined with K-wire internal fixation for the treatment of extra-articular open fractures of distal tibia and fibula. The operation time, intraoperative blood loss, surgical and implants costs, fracture healing time, postoperative complications, and American Orthopaedic Foot and Ankle Surgery (AOFAS) scores were compared among the groups . Fig. 1 Graphic abstract (AOFAS: American Orthopaedic Foot and Ankle Surgery) The inclusion criteria for this study is as follow: (1) open fracture of distal tibia and fibula, fracture type: AO-42; (2) surgical methods: simple external fixation, external fixation combined with plate-screw osteosynthesis, external fixation combined with K-wire intramedullary fixation; (3) regular follow-up. Exclusion criteria: (1) ankle joint surface damaged severely, normal correspondence congruence and joint space can’t be restored through fixation; (2) associated with serious hypertension, heart disease and other serious diseases, reduced operative-tolerance; (3) associated with brain and spinal nerve functional impairment, severely affected the function of the lower limbs; (4) previous history of severe degenerative arthritis, rheumatoid arthritis, cerebral infarction, and dyskinesia in the lower extremities. From January 2017 to July 2019, 91 cases of open fractures of distal tibia and fibula were enrolled into this study, among which 35 patients were treated by simple external fixation (group A, n = 35), 30 patients were treated by external fixation combined with plate-screw osteosynthesis (group B, n = 30), and 26 patients were treated by external fixation combined with K-wire (2.0–3.0 mm) intramedullary fixation (group C, n = 26). There was no significant difference in gender, age, cause of injury, Gustilo classification and AO classification among the three groups ( P > 0.05) (Table 1 ). Table 1 General information Group Patients (n) Gender Age (years, x ± s) Mechanism of injury Gustilo classification AO classification Male Female Traffic injuries Others I II III 42-A 42-B 42-C A 35 27 8 46.83 ± 15.83 25 10 4 12 19 13 16 6 B 30 25 5 44.27 ± 12.37 21 9 7 11 12 11 14 5 C 26 22 4 44.96 ± 14.48 19 7 3 7 16 11 11 4 P – >0.05 >0.05 >0.05 >0.05 >0.05 Group A: simple external fixator fixation Group B: external fixator combined with plate-screw osteosynthesis Group C: external fixator combined with k-wire intramedullary fixation In group A, closed reduction was performed first, fracture ends were antagonized traction and restored with the help of C-arm. If the reduction is not ideal, cut a 3–4 cm incision for exposing fracture ends of tibia and cleaning soft tissue and blood clots embedded in the fracture site. Then the fracture end could be reduced by traction and temporary fixation assisted with bone-holder or K-wire. After the initial reduction of the fracture, inserted screws into the proximal and distal segments of tibia fracture end, the calcaneus or the first metatarsal bone depending on the location of the fracture, installed the fixation clips for each screw and connected them with a biplanar external fixators. The C-arm fluoroscopy was used to examine and adjust the reduction to be in good alignment, then the screw of the fixator was fastened completely. Fracture ends of fibula were not fixed . Fig. 2 A1-A2 Anteroposterior and lateral radiograph of distal tibiofibular fractures before operation. B1-B2 Bedside X-ray examination 2 days after operation (anteroposterior and lateral views). C1-C2 The fracture showed radiological signs of healing 7 months after operation (anteroposterior and lateral views). D1-D2 The external fixator was removed completely 10 months after operation (anteroposterior and lateral views) External fixation combined with K-wire intramedullary fixation was conducted in group C. Firstly, fracture ends of fibula were fixed intramedullary with a K-wire. A 0.5 cm incision was made 2.0 cm above the tip of fibula, and a K-wire of 2.0–3.0 mm diameter was inserted retrograde into the fibular marrow cavity from the bottom to the top. If necessary, a hammer could be used to tap the tail of the Kirschner needle to help insert the needle. During the process of inserting the needle, the K-wire should be parallel to the long axis of the tibia, the multi-segment fractures of fibula were restored in turn with the help of assistant. Adjust the K-wire under the C-arm examination until the fracture of the fibula was in good alignment. The tip of the K-wire should be 10.0 cm more passed through the proximal end of the fibula fracture so as to achieve an effective fixation. The tail of the needle is reflexed outside the skin for easy daily disinfection and care. After fibula fracture was fixed, external fixator was used to fix tibia fracture in the same way with group A . Fig. 4 A1-A2 Bedside X-ray radiograph 2 days after operation (anteroposterior and lateral views). B1-B2. The K-wire was removed 8 weeks after operation (anteroposterior and lateral radiograph). C1-C2 The fracture showed radiological signs of healing 5 months after operation (anteroposterior and lateral views). D1-D2 The external fixator was removed completely 8 months after operation (anteroposterior and lateral views) All the patients were given routine antibiotics in the perioperative period to prevent infection, and postoperative analgesia, improving circulation, bone strengthening, prevention of thrombosis and other symptomatic supportive treatment. The wound was treated by dressing change or replacement of VSD regularly and the tail of the K-wire was disinfected with iodophor every day to prevent the infection of wound and pin tract. The patient’s contact information was registered at the time of discharge, and the patient was reviewed periodically. Fracture healing of the tibial and fibula has been observed with X-ray diagnostic techniques. After 8 ~ 12 weeks of follow-up, the K-wire was removed according to the status of external fixation and fracture healing. Later, the patients were followed-up every 3 months and the external fixator was removed when the clinical healing of the fracture was confirmed. During the subsequent visit, professional rehabilitation training guidance should be given according to the different stages of the patients’ recovery. The patient’s limb function was evaluated at the last follow-up. The operation time, intraoperative blood loss, surgical and implants costs, fracture healing time, postoperative complications and AOFAS scores at the last follow-up were recorded in the three groups. Fracture healing was assessed by X-ray examination and union was defined as dense callus bridging at least three of four cortices on positive and lateral X-ray examination. Delayed union was defined as radiographic union after > 8 months. Nonunion was defined as lack of any healing within 12 months . Data analysis was performed by SPSS software, version 25.0 (SPSS, Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± SD and differences in continuous variables among groups were examined using analysis of variance (ANOVA) and repeated measure of ANOVA. Pearson’s chi-squared analysis (χ 2 test) and Fisher’s exact test were used for categorical variables. The level of significance was set at P < 0.05. In this study, 87 cases were followed up regularly and 4 cases were lost. The follow-up period ranged from 5 to 35 months, with an average of 14.2 months. Four patients who were lost to follow up because they all came from other places. After the operation, the patients returned to the local hospital for further treatment. The results are presented in Table 2 . Table 2 Comparison of statistic data for major results after operation among the three groups Group Patients (n) Operation Time(min) Blood Loss (ml) Costs* Imageological healing time of fracture(months) Complications Ankle function excellent and good rates(%) Fracture union, n Infection, n Delayed union Non-union Total Wound infection Pin tract infection Total A 33 142.27 ± 47.05 177.27 ± 134.68 6.48 ± 1.11 6.90 ± 1.33 6 7 13 2 2 4 69.70%(23/33) B 29 184.00 ± 48.56 a 206.21 ± 112.48 9.37 ± 2.16 a 6.70 ± 1.12 7 4 11 4 3 7 72.41%(21/29) C 25 114.92 ± 36.09 ab 157.60 ± 72.98 5.24 ± 1.21 ab 5.67 ± 1.42 ab 1 1 2 ab 1 2 3 84.00%(21/25) P – <0.05 >0.05 <0.05 <0.05 – – <0.05 >0.05 >0.05 >0.05 >0.05 Group A: simple external fixator fixation Group B: external fixator combined with plate-screw osteosynthesis Group C: external fixator combined with k-wire intramedullary fixation Costs*: include surgical costs and implants costs such as external fixator, steel plate, screws and kirschner wire a P <0.05 compared with Group A b P <0.05 compared with Group B Open double fractures of the distal tibia and fibula are complex injuries, if not treated properly, they may cause delayed union or nonunion of fractures, severe cases may lead to traumatic arthritis, which seriously affects the function of ankle joint. In 2015, Professor Raman Mundi et al. published an update of the treatment guidelines for open tibial fractures in JBJS REV magazine. At present, intramedullary nail is recommended for open tibial shaft fractures, but the incidence of ankle stiffness, residual ankle pain and traumatic arthritis after intramedullary nail fixation is high. In addition, intramedullary nail has poor fixation effect on distal tibial comminuted fractures. Compared with the intramedullary nail, composite external fixator is flexible in assembly, simple in operation, short in operation time, and less in intraoperative blood loss. The external fixator can perform compression fixation, stretch fixation and neutral fixation according to different types of tibial-fibular fractures. It is a limited elastic fixation, which reduces the stress shielding of static locking fixation, and is beneficial for the fretting of the longitudinal axis of the shaft at the same time. As a result, it can promote the healing of the fracture by making the fracture end get physiological stress. However, pin tract infections are the big problem which is commonly occur in children with additional trauma and the people lack of selfcare . So, external fixator is traditionally used as temporary fixator for open tibia and fibula fracture, which requires second-stage operation to be converted to internal fixation . In recent years, many studies have shown that external fixator can also be used for definitive fixation of open tibia and fibula fractures [ 19 – 22 ]. Some research reported that external fixation showed similar results to intramedullary nailing for treatment of open fractures of open tibia and fibula in terms of infection rate, malalignment, bone healing and quality of life [ 23 – 25 ]. The other researchers found that compared with simple external fixation, external fixation combined with limited internal fixation is an effective and safe alternative for management of open tibial diaphyseal fractures. It provides superior initial reduction, better stability and decreases the risk of inferior alignment and delayed union without increasing the risk of infection [ 26 – 28 ]. Through the comparative study of three different fixation methods of fibula combined with tibia external fixation, it was found that external fixator combined with plate-screw osteosynthesis in the treatment of open fracture of distal tibia and fibula prolonged the operation time, but had no obvious advantages in promoting fracture healing, reducing postoperative complications and functional recovery of affected limbs. The good news is that the K-wire group shortened the operation time and fracture healing time, reduced the costs and complications of fracture healing when compared with the other two groups. However, there was no significant difference among the three groups in terms of intraoperative blood loss, postoperative infection complications and the score of ankle function. The main reason led to this situation may be that the open fractures of distal tibia and fibula was often caused by high-energy trauma, which usually accompanied with other partial fractures and severe soft tissue contusions. K-wire was first introduced as an internal fixation implant in 1909 by Martin Kirschner and it had been used for more than 110 years in orthopedic surgery . Today K-wire is commonly used as a kind of temporary fixation device in clinic, however it can also been used as definitive fixator in displaced metacarpal shaft fractures, clavicle fractures and paediatric tibial shaft fractures [ 32 – 34 ]. The bone marrow cavity of fibula is narrow and irregular in shape, so the K-wire can be used to fix fibula fracture according to the principle of multi-point fixation . Its advantages are as follows: first, no reamed medulla cavity, no peeling of periosteum, no destruction of the original hematoma at the fracture end, no aggravation of secondary damage to the skin, soft tissue and blood supply at the fracture site. It reduces complications of skin and soft tissue effectively and reflects the concept of minimally invasive treatment of fractures. Secondly, K-wire intramedullary fixation is easy to operate and does not require special equipment, it can be removed out at clinic without hospitalization. Thirdly, K-wire had lower economic cost but higher cost-effectiveness ratio when compared with locked plate and elastic intramedullary nail. Fibular K-wire intramedullary fixation conforms to the concept of biological fixation (BO) , whose core idea was to protect the blood supply of the fracture end, it didn’t emphasize anatomical reduction, but to seek a balance between the stability of the fracture and the blood supply of local soft tissue. This fixation method belongs to elastic fixation, which didn’t require very strong fixation, but can reduce the stress shielding of tibial healing. In addition, micromotion in elastic fixation of fracture ends can promote revascularization, rapid calcification of callus and the formation of related osteogenic factors, thus promoting the healing of fibular fractures. External fixator combined with K-wire had an excellent fixation effect in fixing comminuted distal tibial fracture. It can restore the continuity of fibula by K-wire and reduce the weight of tibia. Percutaneous k-wire fixation is a minimally invasive method and far away from the fracture end, thus it can maximize the protection of periosteum and soft tissue blood supply at the fracture site, and avoid the destruction of intramedullary nail fixation on the blood supply of the medullary cavity, which conforms to the concept of damage control orthopedics (DCO) . More important, combined fixation increased the stability of tibial fixation, reduced the excessive stress damage of fracture end, and improved the healing rate of tibia fracture. In conclusion, the importance of fibular fixation in the treatment of open fracture of distal third tibia and fibula has been accepted by more and more surgeons, but the method of fixation has not reached a consensus. Proper fibular internal fixation can promote the healing of tibial fracture and maintain the stability of lower tibiofibular joint and ankle joint. Compared with simple external fixation and external fixation combined with plate-screw osteosynthesis, external fixation combined with K-wire has less trauma, shorter operation time, lower costs, faster fracture healing and better healing quality of fracture in the treatment of open fracture of distal tibia and fibula. This study also has some limitations, it is a retrospective case study with small sample size, lack of prospective cohort study and randomized controlled study. The results need to be further confirmed by large sample clinical studies. Compared with simple external fixator fixation and external fixator combined with plate-screw osteosynthesis, external fixator combined with K-wire intramedullary fixation shorten the operative time and fracture healing time, reduced costs and complications of fracture healing, while the blood loss, infection complications and ankle function recovery showed no difference with the other two groups. External fixator combined with plate-screw osteosynthesis had no advantage in treating extra-articular open fractures of distal tibia and fibula when compared with simple external fixation.
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Other
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biomedical
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en
| 0.999997
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33466220
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Mycoplasma pneumoniae (MP), also known as an atypical bacterium, is 1 of the most frequent pathogens involved in the etiology of lower respiratory tract infections. Up to 40% of community-acquired pneumonia cases in children are due to this pathogen, being more prevalent in school-age children. Moreover, it seems that the prevalence of this infection differs also by geographic area because the reported cases in Taiwan and Japan described increased antibiotic resistance rate and complicated pneumonia accounting for up to 30% of intensive care unit admissions as compared to United States, where complicated cases were rarely reported. MP commonly occurs among children above the age of 6 years and it has been reported that in American children with community acquired-pneumonia requiring admission, MP infection was encountered in 19% above 6 years of age as compared to only 3% in those below this age. Thus, the scarcity of information regarding MP infection in children younger than 6 years of age is due to its rarity in this age group. The few reports on small children are contradictory since some of them underlined that younger children might express a worse evolution of this infection, while others revealed a milder course within this age range. The wide clinical spectrum of MP infection varies from asymptomatic defining a carrier state to severe cases of complicated pneumonia. Extrapulmonary manifestations represent another important face of MP infection since multiple organs were reported to be afflicted by this pathogen despite the multiple uncertainties related to the pathogenic mechanism. Nevertheless, 3 possible mechanisms are acknowledged: a direct type consisting of the essential role of inflammatory cytokines induced by the bacterium which is present at the inflammation site; an indirect type when the bacterium cannot be found at the site of inflammation, but it implies immune modulation consisting of autoimmunity or immune complexes formation expressing a major role; and vascular occlusion as the third possible pathogenic mechanism induced directly or indirectly by the bacterium. [ 10 – 12 ] Most often these manifestations occur concomitantly with respiratory tract disease, but they were also reported as single manifestations. MP is a particular bacterium since its cell membrane contains only lipoproteins which seem to be involved in triggering the extrapulmonary manifestations. Arthritis is 1 of the least common extrapulmonary manifestations in children and therefore it is usually overlooked. The few reports on MP induced arthritis stated an incidence of this manifestation ranging between 2.1% and 0.9%. Moreover, the early detection of MP infection is essential in the evolution and prognosis of patients with extrapulmonary manifestations of MP taking into account that this infection is usually not considered in infants and antibiotics like macrolides are not commonly used. Thus, a delay in establishing a proper diagnosis along with the specific immunological immaturity for this age group might represent the main contributors of MP induced arthritis mechanism in infants. We report the case of a 2-year-old female child admitted in our clinic for prolonged fever (maximum 39°C) with the onset approximately 2 weeks before the admission, for which the general practitioner recommended antibiotic (Amoxicillin) establishing the diagnosis of acute pharyngitis, but the fever persisted and she was further referred to a pediatrician, who changed the antibiotic with Ceftriaxone. On the second day of administration, she developed a generalized rash and the limitations of head movements raising the suspicion of meningitis, which was ruled out by the specialist in infectious diseases, and the patient was admitted in our clinic for further investigations. Her history revealed only a preterm birth (35–36 gestational weeks). The laboratory tests performed on the day of admission revealed leukocytosis (19,830 /μL), with neutrophilia (73.1%), elevated inflammatory biomarkers (C-reactive protein [CRP] 30 mg/L, erythrocyte sedimentation rate, 50 mm/h), liver cytolysis (aspartate amino-transferase 294.5 U/L). The peripheral blood analysis revealed only polymorphonuclear cells with toxic granulations. The blood and urine culture, as well as the serology tests for hepatitis B and C, toxoplasmosis, Epstein Barr virus, Rubella, Herpes virus, and cytomegalovirus were negative. A wide-spectrum double-regimen antibiotic therapy (Ceftriaxone + Amikacin) was initiated on the day of admission, but unfortunately the fever persisted and on the 5 th day of admission, the blood tests showed a mild increase of all laboratory parameters leukocytosis (21,220 /μL), neutrophilia (76.6%), and CRP 38.13 mg/L, but the limitations of neck and head movements disappeared. In spite of the normal respiratory sound at clinical exam, the chest radiography revealed an opacity in the right lung. Moreover, on the 2 nd week of admission the patient started to experience gait difficulties, complaining of hip and ankle pain and edema, with functional impotence of the inferior right limb. The cardiology consult revealed no pathological findings. Thus, we decided to change the antibiotics with Meropenem and Clindamycin based on the consult of the specialist in infectious diseases, who raised the suspicion of secondary infectious arthritis of the right knee. We also performed a pneumology consult, which ruled out possible tuberculosis. The fever spikes persisted for approximately 2 weeks after the admission each morning, but no more than 38°C. The leukocyte count remained above the normal limits as well as the CRP, which varied between 20 to 40 mg/L. We repeatedly assessed anti-nuclear antibodies, and they were initially elevated, but after approximately 2 weeks they became normal. Thus, we raised the suspicion of bacteriemia due to an infection with an atypical bacterium, and we introduced Levofloxacin with outstandingly favorable clinical course proved by the remission of fever. Nevertheless, gait difficulties persisted especially in the morning. Thus, we performed an inferior limb computed tomography, but it showed no pathological findings. Nevertheless, on the 5th day of Levofloxacin, she developed a severe hepatitis . The parents decided to go to center specialized in infectious diseases, where an MP infection was detected (immunoglobulin M [IgM] anti-MP >200 U/ml, immunoglobulin G anti-MP 43.7 U/ml) as we already suspected, and clarithromycin orally was initiated for 2 weeks. Moreover, we repeated the hip and ankle ultrasound and we identified a mild effusion within the right hip joint. Thus, based on the clinical and ultrasound findings, we established the diagnosis of MP-related arthritis. After approximately 1 month, the gait difficulties worsened and a rheumatology consult was performed, who recommended only non-steroid anti-inflammatory drugs. The titer of IgM anti-MP antibodies started to decrease (177.2 U/ml). Repeated ultrasound of the hip and knee revealed intraarticular fluid collection with spontaneous remission. The gait difficulties persisted for approximately 5 months from the initial diagnosis, they improved once the titer of IgM anti-MP antibodies lowered considerably (<80 U/mL). After more than 8 months, the patient is completely asymptomatic and the IgM anti-MP are almost within normal ranges (28 U/mL), whereas immunoglobulin G anti-MP increased considerably (>200 U/ml). MP infection is more common during winter as most respiratory pathogens and it may affect people of any age despite the fact that it is frequently reported in young people. Our patient was diagnosed with MP infection during winter. Multiple extrapulmonary manifestations are reported in patients with MP. Joint impairment in patients with MP infection is rare and 3 possible patterns are hypothesized: the first 1 is thought to appear during acute phase of this infection and it is migratory, polyarticular, affecting large joints; the second 1 follows the acute phase implying morning stiffness, hyperemia and joint edema of multiple medium-sized joints that might persist up to 1 year; while third is commonly seen in hypogammaglobulinemia patients in whom MP results in septic arthritis. The findings in our patient belong to the second pattern since she presented morning stiffness and joint edema that followed the acute phase and lasted approximately 5 months. Nevertheless, MP induced arthritis in children might fit also 1 of the other 2 pattern as in the case of a 7-year-old boy with hip impairment described by Ali et al. In a more recent study performed by Azumagawa et al, out of 348 patients diagnosed with MP infection, only 4 male children presented arthritis: 1 of 2 year-old, 2 of 4 years and 1 of 8 years. Nevertheless, our patient was a 2-year-old female. The 2-year-old boy described by Azumagawa et al presented with a history of fever and urticaria and developed right hip joint pain further migrating to the left hip and the ultrasound showed fluid collection around the hip joint. Similarly, our patient also presented with fever and rash before the admission. Moreover, the findings of Azumagawa et al suggest that the rash in our patient might have been misinterpreted as an allergic reaction to the antibiotic. Therefore, edema, erythema, pain and functional impotence must raise the suspicion of MP-related arthritis. The laboratory tests in the patients mentioned above revealed leukocytosis and a CRP of 29 mg/L, similar results to those encountered in our patient. Only 1 of the 4 patients described in the above-mentioned series, a 4-year-old boy presented pneumonia. In terms of our patient, in spite of no respiratory symptoms, the chest radiography revealed right pneumonia. Another study identified 13 cases with arthritis out of 1259 patients diagnosed with MP infection, but only 5 in children. These children diagnosed were between 1 and 7 years of age, and only 1 of them (a 1-year-old female) manifested impairment of multiple joints, the other 4 were monoarticular types. The fever in these pediatric patients lasted between 1 and 70 days, while arthritis lasted up to 4 weeks. In the case described by us, the fever lasted for approximately 1 month, while joint impairment almost 5 months. Hepatitis caused by MP infection is a rare manifestation and it was firstly described in1975. In the series of Ali et al., only 1 patient, a 55-year-old man presented hepatitis. This finding might be misinterpreted as allergic manifestation, poisoning, drug toxicity or as a secondary manifestations due to other conditions, before establishing the diagnosis of MP infection similar to our case who also presented liver dysfunction with a severe increase in transaminase levels during the clinical course, but whose evolution was outstandingly favorable. In spite of their doubtless importance, clinical findings must be confirmed by imagistic methods, such as ultrasound, computer tomography or even magnetic resonance imaging. Nevertheless, taking into account the migratory pattern, it is possible that imagistic changes could be missed during the routine examination. Thus, seriate ultrasound exams might be needed for detecting joint impairment. Cardiovascular system involvement as a result of MP infection consists of intracardiac or intravascular thrombi, Kawasaki disease and, rarely, myocardial damage. MP seems to be associated with the presence of antiphospholipid antibodies in the human blood most likely due to a molecular mimicry between human phospholipids and bacterial components, this mechanism being incriminated in the development of thrombi. Dermatological manifestations associated to MP infection include erythema nodosum, cutaneous leukocytoclastic vasculitis, and rarely, Stevens-Johnson syndrome, Fuchs syndrome, toxic epidermal necrolysis or erythema multiforme major. The most common digestive manifestations due to this infection reported in the literature are liver dysfunction and necrotizing pancreatitis, while the neurological disorders consist of opsoclonus-myoclonus syndrome, striatal necrosis, disseminated encephalomyelitis, transient Parkinsonism, cerebellitis, acute cerebellar ataxia, and most recently described ‘mycoplasmal cerebral vasculopathy’. The last entity presents a slowly progressive clinical evolution consisting of episodic encephalopathy and movement disorders, being a true manifestation of MP infection since MP antigens were identified in the cytoplasm of cerebral microvascular endothelial cells and in microvascular lumina through histological studies. Other types of extrapulmonary manifestations involve hematopoietic system (splenic artery embolism), musculoskeletal system (rhabdomyolysis, arthritis), respiratory manifestations (pulmonary embolism) or urogenital ones (glomerulonephritis, glomerulonephritis with interstitial nephritis, renal artery embolism, pediatric priapism). Most of this information is provided in case reports due to their rarity and the relatively frequent rate of misdiagnosis. Taking into account that many of the aforementioned extrapulmonary manifestations occur in the absence of pneumonia, the most reliable diagnostic tool for these manifestations are serological methods. The treatment of extrapulmonary manifestations due to MP infection is complex involving immunomodulators like corticosteroids or immunoglobulins for the most severe cases, i.e. encephalitis or Stevens-Johnson syndrome; anticoagulant therapy manifestations implying vascular occlusion; and effective antibiotics against MP in order to reduce the excess of antigenic stimuli. Fortunately, no other extrapulmonary manifestations were identified in our case, except for arthritis, rash and hepatitis. MP infection responds well to macrolides and fluoroquinolones, but these are not commonly used in pediatric patients, and thus a proper timely diagnosis is mandatory for a favorable evolution. Certain cases, especially those with severe extrapulmonary manifestations might benefit from corticosteroids administration. Of the 4 cases reported by Azumagawa et al, 3 were treated only with antibiotics, azithromycin or midecamycin, and one received betamethasone associated with azithromycin. Our patient received levofloxacin initially since we suspected a sepsis with an atypical bacterium, and as it is well-known that sepsis in infant might be a life-threatening condition. We further continued with clarithromycin orally once MP infection was serologically confirmed. We can conclude that MP bacteremia can result in a wide-spectrum of extrapulmonary manifestations. MP infection in infants is usually overlooked and it might result in complications if left untreated. MP-induced arthritis is probably the least common extrapulmonary manifestation and frequently leads to delays in the diagnosis. Our case emphasizes once more the importance of MP related extrapulmonary manifestations in infants even in the absence of respiratory symptoms. The awareness of MP-induced arthritis in children represents the cornerstone in preventing diagnosis delays and initiating the proper treatment.
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Review
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biomedical
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en
| 0.999997
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33498766
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Capillaria aerophila (syn. Eucoleus aerophilus ) and Capillaria boehmi (syn. Eucoleus boehmi ) are capillarid nematodes affecting wild and domestic carnivores. While C. aerophila may parasitize different animal species (e.g. dogs, foxes, cats, mustelids) and occasionally humans, C. boehmi has a narrow host range and infects mainly wild canids and domestic dogs . Capillaria aerophila and C. boehmi inhabit the respiratory system of their hosts, i.e., they live beneath the epithelium of bronchi and trachea and in the nasal cavities and sinuses respectively . Their biology is yet to be elucidated. Animals become infected by C. aerophila via the inadvertent ingestion of embryonated eggs from the environment, although earthworms could be somehow (e.g., as facultative intermediate hosts or paratenic hosts) implicated in the life cycle . The biological cycle of C. boehmi is practically unknown but there is no sound reason to consider it different from that of C. aerophila . Capillaria aerophila and C. boehmi commonly infect wildlife, especially foxes that are frequently co-infected by both parasites . However, in the last years, they have been recorded in domestic dogs from Europe, North America and Australia, both in monospecific and mixed infections, that are relatively common, and with varying degrees of clinical relevance . Dogs infected by C. aerophila and C. boehmi could be either subclinically infected or display respiratory clinical signs, in both mixed and monospecific infections . In particular, pulmonary capillariosis of dogs by C. aerophila is a verminous bronchopneumonia characterized by general clinical signs, distress, coughing, sneezing and occasionally airway obstruction . The nasal infection caused by C. boehmi may cause sneezing, itching, mucopurulent nasal discharge, epistaxis, gagging, hypo-/anosmia, that can be severe in the case of heavy parasite burdens . A case of meningoencephalitis with neurological signs caused by the direct migration of C. boehmi through the cribriform plate has also been described . To date, there is no evidence of more severe clinical pictures in dogs co-infected by C. aerophila and C. boehmi compared to monospecific infections. The factual impact of respiratory capillarioses in canine clinical practice is still underestimated because of the non-specificity of clinical signs and hindrances inherent to the diagnosis . Given the rise of records of respiratory capillarioses in domestic animals and the merit in improving knowledge on these parasitoses, the present report describes an unusual clinical presentation of a life-threatening mixed infection by C. aerophila and C. boehmi in a dog, and discusses epizootiological and clinic-pathological implications. In September 2020, a privately owned 14-year old intact male Pointer, weighing ~27 kg, was presented to a veterinary clinic located in Bari municipality (Apulia region of southern Italy) for an acute onset of coughing, sneezing and dyspnea, alongside intermittent neurological signs, i.e., seizure-like focal and generalized crisis with paddling. The dog lived in a house located in a small fishermen town , with a garden, where it had free and continuous access. The animal was kept as a pet, and had travelled only once, in 2016, in a mountainous area of northern Italy (Valtellina, Lombardy region). The dog was not regularly treated with parasiticides nor was subjected to routine copromicroscopic examinations. The physical examination revealed tachypnea (40 breaths/minute), a heart rate of 100 beats per minute, and diffuse pulmonary crackles at the lung auscultation. The examination of the nares and the rostral nasal cavities performed with an otoscope showed hypertrophic and hyperemic nasal mucosae. Thoracic radiology, echocardiography and abdominal ultrasound were performed, and faeces and nasal swabs were collected for parasitological examinations. The blood collected for a complete blood count and serum biochemistry analysis showed values within reference intervals with the exception of a mild left shift (570 band neutrophils/µL; reference interval: 0–300 band neutrophils/µL). A serum aliquot was subjected to the Angio Detect™ test (IDEXX) for the detection of the circulating antigen of Angiostrongylus vasorum . Thoracic radiographs showed bronchial pattern along with diffuse and severe interstitial and alveolar patterns . Echocardiography findings were normal. The abdominal ultrasound showed findings compatible with pancreatitis, i.e. pancreas diffusely enlarged with a hyperechoic echo-texture and hyperechoic surrounding mesentery. The prostate was enlarged and showed diffused anechoic areas of heterogeneous size. The liver parenchyma was inhomogeneous, with irregular mixed-echogenic areas within the right lobe. The size of the liver was mildly reduced. A classical floatation performed using zinc sulfate solution with 1.350 specific gravity as previously described , revealed barrel-shaped nematode eggs with overlapping shape and appearance, but slight microscopic differences. The eggs were subjected to a thorough morphological and morphometric analysis based on size and features of polar plugs, wall, and morulae inside the eggs and identified to be C. aerophila and C. boehmi . In particular, the size of the eggs of C. aerophila were within known ranges of 60–65 × 25–40 μm, with morulae filling the eggs and anastomosing ridges and bridges. The eggs of C. boehmi also complied with key morphometric features (i.e., 50–60 × 30–35 μm) and presented a space between the morula and the wall and an outer shell presenting fine pitting. Eggs of C. boehmi were found also at the microscopic examination of a nasal swab , performed after the floatation. The Baermann’s examination was negative for nematode larvae, as also the Angio Detect™ test scored negative. A wide range of tissue samples, including the brain and the above described gross lesions, were fixed in 10% neutral buffered formalin, embedded in paraffin and routinely processed for histopathological investigations (hematoxylin and eosin stain). Microscopically, pulmonary and renal lesions both consisted of a thick fibrotic capsule, surrounding a central core of necrotic and calcified cellular debris. A severe and diffuse membranous-proliferative glomerulonephritis was also observed, mainly characterized by the marked thickening of the Bowman’s capsule. In the liver, diffuse swelling and vacuolar changes affected the hepatocytes. Scattered perivascular and lymphomonocytic inflammatory foci were observed in the brain, along with a granulomatous lesion in the frontal cortex level . Eggs from the floatation and the nasal swab, fragments of the two worms broken at necropsy, and two tissue portions from the olfactory bulbs and the frontal cortex, were subjected to DNA-based assays specific for C. aerophila and C. boehmi . PCR-positive samples were purified using a QIAquick ® Gel Extraction Kit (Qiagen, GmbH, Hilden, Germany) and sequenced by a commercial laboratory (BMR—Genomics, Padova, Italy). Sequences were determined in both strands, aligned and then compared with each other and with those available in GenBank using the Basic Local Alignment Search Tool (BLAST; http://www.ncbi.nlm.nih.gov/BLAST ). Respiratory parasites were included in the first differentials although history, signalment and anamnesis of the dog could have led to an erroneous exclusion of these infections; in fact, the animal had always lived in the garden of a house located in a fishermen town with no relevant movements nor hunting activities which could have put the dog at risk of extra-intestinal parasitoses originating from wild reservoirs. Nevertheless, the combination of lack of routine anthelmintic treatments and compatible respiratory and neurological signs led the veterinarian to include canine angiostrongylosis in the differential diagnosis. A floatation assay was included in the laboratory procedures for a comprehensive evaluation of the parasitological status of the dog, along with Baermann’s and antigenic detection tests. The absence of A. vasorum fist-stage larvae (L1) and adults in the faeces and pulmonary arteries, respectively, and the negative Angio Detect test indicate that the respiratory disorders were instead caused by the two respiratory capillarioses. This scenario is compatible with the presence of parasitic worms in the airways of the dog, even though such a clinical severity is infrequent in dogs infected by these parasites . Pulmonary capillariosis in dogs is often subclinical, as suggested by studies performed in the last decade where some infected dogs, i.e., 9/12 and 13/21 , had no apparent signs. The lower respiratory clinical signs and the radiographic findings here described are compatible with pulmonary capillariosis, though the abnormalities detected at X-ray imaging of dogs infected with C. aerophila are often non-specific . To date, anatomopathological information on C. aerophila infections is scant, probably due to the often subclinical nature of this parasitosis . Additionally, the areas of lung consolidation found at necropsy in the present case are compatible with C. aerophila -induced inflammation , although alternative disease conditions (i.e., chronic necrotic foci after bacterial infections) cannot be ruled out. The hypertrophia and hyperemia of nasal mucosae of the dog here presented were due to the infection by C. boehmi . Conversely, neurological signs can hardly be put in relation with Capillaria spp. in dogs. However, there is a single described case of C. boehmi -associated meningoencephalitis, where the infected dog showed generalized convulsive seizures. In this latter case, a cerebral mass was removed via image-guided stereotactic craniotomy and the histopathological diagnosis was severe, locally extensive, meningoencephalitis with a granuloma containing an intra-lesional C. boehmi egg. Therefore, an aberrant migration into the cranial cavity of the parasite was the presumed cause of the lesion . In the present case, parasitic stages were not found in the histological analysis of the brain. However, inflammatory foci and granulomatous lesions in the frontal cortex are compatible with an immunity response to the presence of parasites, in accordance with previous findings . Furthermore, the DNA of C. boehmi was found within the olfactory bulbs and prefrontal cortex, further supporting an intracranial migration of the parasite leading to the onset of severe neurological signs. It can be argued that the granuloma found in the present case could have been triggered by C. boehmi eggs, other parasitic stages or parasite metabolites, though unidentified. The lack of the detection of parasitic elements in the histological examination of brain sections could be explained by the activation of the local immune response, which is highly specialized in removing foreign bodies or parasite through the phagocytic activity. During their co-evolution process with the host some parasites (e.g., Taenia solium , Toxoplasma gondii , roundworms) have developed evasion strategies to survive in the central nervous system , but it is unlikely that C. boehmi modulates or escapes from the inflammatory response as the brain is a rare and an aberrant localization of this nematode. It is also possible that these lesions were caused by a temporary and erroneous migration of the parasites but, if this is the case, it is impossible to determine which stage (e.g., female adults laying eggs or larval stages) migrated through the cribriform plate. The life cycle of C. boehmi has not been described in detail thus far and, interestingly, possible endogenous auto re-infections have been suggested based on eggs containing fully developed motile larvae in the upper airways of dogs which were kept infected by C. boehmi for years . According to this hypothesis, the eggs could develop to an infective stage while still infecting the host, hatch and re-infect the dog . Although this needs further confirmations, the auto re-infection could contribute to explain the ability of the parasite to persist for years in the host and the records of intracranial localizations of C. boehmi as consequences of the direct migration of the larvae through the cribriform plate after their hatching in the upper airways. At present, it is unknown if the tendency of C. boehmi to invade the cerebral tissue of dogs could depend on the genetic make-up of the parasite, if brain migrations occur only in cases of heavy parasitic burdens, or if it is a random event. Under a clinical standpoint, causes of neurological diseases other than C. boehmi infection could be reasonably excluded. The dog had ultrasound findings suggestive of pancreatitis but the clinical scenario was not compatible with a pancreatic encephalopathy, as no typical signs of pancreatitis such as vomit, abdominal pain, dehydration, diarrhea, hypocalcemia, hypo/hyperglycemia, hyperlipidemia, were present . Although described in Pointers, idiopathic granulomatous meningoencephalomyelitis (GME) and pyogranulomatous meningoencephalomyelitis could be also ruled out, as typical pathological features, i.e. lesions widely disseminated in the brain and histologically visible dense aggregates of inflammatory cells surrounding the brain vessels (i.e. perivascular cuffs), were here absent . Mycotic infections were ruled out, as no fungi were evidenced by the Periodic Acid-Schiff (PAS) staining. On the whole, based on (i) the past record published by Clark et al. , (ii) the detection of C. boehmi DNA in two sites of the brain, (iii) the lack of other noxae explaining the clinical picture, and (iv) the anatomopathological findings, it can be presumed that C. boehmi was responsible for the neurological condition in the case here presented. The source of infection in the present case is unknown. It is reported that C. boehmi may persist for years , thus the dog could have become infected during his last travel of the dog in 2016. Foxes are major reservoirs of Capillaria spp. affecting companion animals and prevalence is high in this wildlife from northern Italy and bordering countries . As the dog was not subjected to routine copromicroscopic examinations nor did it received routine parasiticide treatments, this possibility cannot be ruled out, albeit no history of respiratory distress in the last few years was reported by the owners. It is also plausible that the dog had acquired both infections, even in different time points, due to a possible contamination of the house garden with fox faeces. Accordingly, fox populations are numerous in the region ( https://discovermammals.org/what-you-can-do/learn-more/countries/italy/ ) where the dog originated from . Infections by C. aerophila and C. boehmi are increasingly reported in dogs, especially in those areas where foxes are present . In Italy, C. aerophila is enzootic in dogs and cats living in southern regions and, recently, also C. boehmi was identified for the first time in dogs from southern Italy, including the region where the dog lived . Therefore, capillarioses should be included in the differential diagnosis in dogs with respiratory alterations or in the presence of unusual clinical scenarios, e.g. severe respiratory distress, extra-respiratory signs, also in areas where these parasites are unexpected. Respiratory capillarioses can be more severe than believed and more attention should be given in canine clinical practice to C. aerophila and C. boehmi for several reasons. First, their geographic distribution is appearing in expansion especially as a result of bridging infections from wild reservoirs which are fostered by conurbation to share habitats with domestic animals . Second, C. aerophila has a zoonotic potential and its eggs can contaminate green public areas : since it may mimic respiratory tumors it is plausible that the incidence of lung capillariosis in humans is overlooked to a certain extent. Finally, nasal capillariosis may cause relevant clinical signs in infected dogs, including partial or total loss of scent and cerebral damages, with an important impact on infected animals .
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Study
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biomedical
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en
| 0.999999
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33579269
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One possible way to effectively share genetic information related to their own health with the general public, is to have local health care providers (LHPs) provide the information to them . Using direct contact with local people through a health care program, LHPs can play a vital role in addressing gaps in the public’s knowledge on genetics . In particular, LHP public health nurses (PHNs), who usually contribute to health maintenance activities for local people through face-to-face consultations, will be best placed to provide genetics knowledge. In previous research, interviews were conducted with PHNs to assess their activities and duties related to human genetics and genetic medicine . For example, some PHNs consider knowledge of genetics helps improve the health of targeted populations, and that makes them support genetics education and related healthcare services . This indicates the possibility that PHNs could effectively provide genetic knowledge to a target population (i.e., contribute to “public health genetics”). However, at the same time, results of the investigation revealed an issue: PHNs rarely have opportunities to consider genetics in their daily operations. This situation means that while PHNs in principle have the potential to help others gain scientific knowledge about genetics, in practice, they do not often do it. The structure of the training course is described in Fig. 1 . The training was conducted so that municipal PHNs could learn the knowledge and skills needed to promote genetic literacy. The criteria for inclusion and exclusion were as follows: we included PHNs who work at the municipality office in Kagoshima Prefecture; however, we excluded the person who was in charge of providing genetic related healthcare services. Though we set the criteria above, the PHNs working at the municipality office are not usually responsible for providing the public with support for genetic diseases in the current Japanese healthcare system . In fact, the participants did not include any PHNs who were involved in genetic diseases. The training was designed based on a similar trial, which aimed to support the decision-making process of local people through consultation on their genetics-related issues . The main results were obtained by the measurement of the participants’ cognition, affect, and psychomotor characteristics, (described later) before the training (pre-test) and again after the training (post-test). In addition, participant’s thoughts on the role of PHNs in genetics consultation, based on the description in the summary sheets provided in their discussions, were analyzed. Details of the intervention are given in “Training for PHN participants.” Fig. 1 Flow of the training program and data collection First, a workshop with a case study was held to measure whether the knowledge of human genetics and related disorders was linked to the daily consultation of PHNs. In this workshop, familial hypercholesterolemia (FH) was selected as a topic of consultation from a simulated client (i.e., the PHN was asked whether hypercholesterolemia is hereditary, see “Details of Case Study”). FH is an inherited autosomal disorder of lipid metabolisms. When the gene encoding the low-density lipoprotein (LDL) receptor in chromosome 19 has double abnormal copies (homozygote), the rate of atherosclerosis accelerates from childhood. Although the prevalence of homozygous FH is not very high (about one in a million), it is a “designated intractable disease” in Japan . Although the proportion of patients with FH is small, such patients are entitled to various forms of public support, and the disease is important for PHNs because support is typically provided by prefectural PHNs through consultation with patients and confirmation of diagnostic evidence such as a genetic test. It is the role of the PHN of the municipality to support the residents until they are connected to the PHN of the prefecture. In addition, in cases where the gene related to FH has only one abnormal copy (heterozygote), it still presents a genetic risk for the onset of atherosclerosis . Though the incidence of the atherosclerosis in heterozygous FH patients is similar to those of dietary or age-related dyslipidemia, knowing the genetic information of the patient and his/her family will be important for PHNs. Specifically, it provides an opportunity for PHNs to help guide the patient to improve his/her life at an early stage. The attainment goals of the training were set according to each of the three domains of learning defined by Benjamin Bloom—the cognitive domain, the affective domain, and the psychomotor domain . In our genetics education program, the target for the cognitive domain was set as the participants become able to explain genomic diseases; for the affective domain, the participants become interested in human genetics; and for the psychomotor domain, the participants become able to address the needs of community members by using their knowledge of genetics. To quantify the degree of achievement, we extracted the data from the worksheet and the survey forms through the following processes. An ID was assigned to each participant and used throughout the training session, written on the survey forms. Survey results from before and after the training were linked at the individual level and then compared using the assigned IDs. By extracting personal responses from the worksheets and corresponding post-discussion feedback, we were able to examine the degree to which participants achieved their goals in genetics literacy. The effect of training was evaluated by comparing survey scores from before and after the training session. The items were rated using a 5-point Likert-type scale. A Wilcoxon signed-rank test was performed to compare the significance in differences of scores between the pre-test (before the lecture and the workshop) and post-test (after the lecture and the workshop). To evaluate the difference in attitudes toward human genetics by PHNs in the current situation (i.e., under the absence of genetics education), associations between age groups and scores in pre-test and post-test, and between years of experience and scores in pre-test and post-test, results were quantified by Spearman’s ρ. The statistical analyses were carried out using SPSS (v. 25) and R (ver. 3.6.2) , with a significance level consistently set as 0.05. The PHNs’ responses and reactions to the simulation were extracted from the descriptions given in the worksheets during the workshop. Descriptive and qualitative analyses were performed. Specifically. we adopted the thematic analysis method recommended in the literature . For all analyses, we extracted specific phrases corresponding to each learning domain. Hereafter, the extracted phrases are indicated in square brackets (i.e., []), and the original texts and codes are shown in single quotation marks (i.e., “). The specific phrases were classified into categories based on their semantic content. The achievement of the goal was verified for each category. In the pre-test, we found a significant negative correlation ( ρ = − 0.461, p = 0.027) between participants’ age group and the first cognitive question, ‘I am familiar with the term “human genomics”.’ Answers to all the remaining questions were correlated with years of experience. For the relationships between age group and the score on each domain (cognitive, affective, psychomotor), and the sum of scores of the three domains (total score), the results of the correlation analyses are shown in Table 2 . All the coefficients show significantly negative associations except for the psychomotor score. These results show that younger PHNs have more frequently heard the word “genome” and have higher cognition, psychomotor, and total scores than older PHNs. On the other hand, there was no significant association found between the age group and questions, scores, and sum of scores on the three domains in the post-test. Table 2 Correlation between age group and scores before learning about human genetics Domains Age group coefficients p -values Cognition −0.397* 0.021 Affective −0.225 0.193 Psychomotor −0.384* 0.035 Total −0.342* 0.042 * p < 0.05 Participants wrote their thoughts on genetics, which were then extracted from the worksheets. Regarding their roles in genetics education to the community, [providing advice thought to be potentially required for individual life] and [providing people with accurate information about genetics] were found often (Table 3 ). Table 3 Participants’ responses during the consultation Categories Code of responses during consultation Extract problems with genetic disorders Summarize the anxiety Check the facts about genetic disorders Organize by listening to the necessary narratives of the person Share your concerns about heredity disorders Ask why they thought they inherited the disorder Gather information for identifying the genetic disorder Determine if the person’s troubles are hidden Confirm the fact that you thought it was inherited Confirm knowledge about illness Listen to their understanding of the disease Pay attention to their family background and life Accept anxiety about getting the same disease Ask about their lifestyle Ask about their life Pay attention to and manage previous living conditions Indicate the problem Make sure that you express you are very worried a Identify problems from statements and appearances Determine issues based on information and prioritize Ask what the person wants to do in the future Promote awareness of other causes of health deterioration Pay attention to medical condition/treatment Check the process until the start of treatment Paying attention to the treatment status and changes toward problem solving Collect information about their health Providing advice and thoughts potentially required for individual life Suggest a countermeasure Thinking together while advising the person on what they think is necessary Do not get preoccupied with hereditary conditions Lead a safe life Check what can be advised Health guidance for life improvement Health guidance closely related to daily life Provide information about what you can do Promote health behaviors such as undergoing regular medical checkups Create an opportunity to appraise your lifestyle Appraise lifestyle habits other than heredity-related aspects Create an opportunity to appraise patient’s lifestyle Thinking together about ways to improve the situation Encourage the patient to notice the problem Notice the problem b Suggest a solution based on what you can do Suggest what could be improved Providing people with accurate information about genetics Assess the risk of onset Thinking about ways to reduce the risk of onset Providing the correct information Providing expert knowledge to reduce anxiety Explain the relationship between lifestyle and heredity Tell the possibility of inheritance Respect the will of the other person Explain potential genetic effects Explain environmental factors Suggest preventive lifestyle behaviors Explain precautions in daily life and help prevent onset Informing the person of potential genetic risks Suggest what can be improved to delay the onset Give an explanation that can be understood by the other person Introducing the person to an appropriate specialized organization Introduce them to a specialized institution Introduce the person to doctors and other necessary healthcare institutions and healthcare professionals Introduce the person to a professional consultation agency a The consultant was asked to express that they are very worried b The consultant was asked to identify the problem In our qualitative interpretation of extracted phrases, we found that a phrase ‘testing is needed to determine if your disease is inherited, let me introduce you to an expert on human genetics’ was reflected on the PHN’s role of [introducing the person to an appropriate special organization]. Moreover, the phrase ‘although the body constitution is inherited, you will not necessarily become ill’ indicated that the participants recognized that the onset of the disease is related not only to physical constitution as a manifestation of personal genetic traits, but also to their lifestyle; therefore, an ‘explanation of environmental factors is needed’; that is, [providing people with accurate information about genetics]. This extracted phrase includes ‘tell the possibility of inheritance’ and ‘explain the risk of development of diseases.’ Participants had a deeper understanding of their role of providing care for genetic disorders as PHNs. We implemented a short-term pilot education program with an aim of helping PHNs working for local municipalities enhance their knowledge of human genetic disorders and provide better genetics-related advice and services to community members, as this is an important role bestowed upon them. Bearing in mind that the effectiveness of our genetics education was measured in a self-report style by the participants, their cognitive, affective, and psychomotor domains related to the learning of public health genetics were significantly improved by the training program; that is, the program was at least effective in the short term for learning about public health genetics by PHNs. In the pre-test, a trend was seen where young, relatively less experienced PHNs scored higher on the cognitive and psychomotor domains, and the sum of all three domains was higher, indicating that the scores may also depend on the content of the educational curriculum. However, this trend disappeared in the post-test. In addition, from a descriptive analysis perspective, the training clarified that the participants’ understanding of the importance of their role in genetics education for local communities has deepened, as seen in the extracted phrases relating to informing about genetic risk provided by inherited bodily constitutions, the existence of genetic testing, and expert persons. Previous studies have indicated that PHNs working for local municipalities do not perceive hereditary diseases as genetic disorders caused by defective genes, but as a phenomenon caused by environmental and social factors shared among members of the community and family . In fact, many previous studies have found that risk of cardiometabolic diseases (e.g., obesity, hypertension) varies depending on the geographical area , socioeconomic status , and environment ; in other words, members from the same community may be exposed to the same environmental and/or socioeconomic factors due to living in the same area and abiding by the same culture and lifestyle, and may even develop the same diseases. Consequently, even if concerns are potentially related to genetics (i.e., heredity and family history), PHNs might not perceive consulted symptoms as genetic disorders per se, but rather as products of complex environmental and socioeconomic conditions. Regardless, through the present study, the need for genetic knowledge and subsequent genetic consultation by PHNs was clarified; some young PHNs stated they had experienced consultations regarding genetic concerns from members of their target population. As seen in the responses after the discussion, not only among younger PHNs, participants have noticed that the genetic aspects of healthcare advice need to be covered in addition to environmental and socioeconomic factors; furthermore, that this will provide a clearer and more reasonable explanation of disease risks than that provided at current consultations. This was similar to an expected phenomenon described by Tonkin et al. : deepening knowledge of genetic disorders will help in understanding why certain people are more likely to develop certain diseases . Their awareness shows that, as we expected, the training was effective. This educational program was considered, to some extent, effective in PHNs for the understanding of genetic disorders as causes of diseases and also for increasing motivation to learn about them. While there are many online resources for learning about human genomics and genetic disorders , PHNs seem to be facing difficulty allocating the time to study the subject . This was seen in their comparably low scores on cognitions and affect domains in the pre-test, and possibly resulted in the current situation where they have had limited opportunities to learn about human genetics in their daily occupational life. It is well known that adults’ motivation to learn new skills or attain new knowledge generally needs to be strongly related to their interests or profession . To address this problem, we propose that introductory learning in genomics must be incorporated into work-related training. It means that cases of genetic disorders are used as teaching materials to develop the PHN’s standard “career ladder” for local governments . We suggest conducting routine training courses of introductory-level genetics, such as the pilot programs used in the present study, and continuously providing follow-up education programs utilizing accessible sources, such as web-based material . If it is organized by professional decision-making bodies (e.g., local, prefectural, and national government, or associations and/or organizations related to PHN) and widely recognized as a required professional skill, we think it will assist PHNs in trying to develop essential technical skills. The scores of all three domains increased in the post-test. In particular, there was an increase in the number of PHNs who indicated that they could handle a consultation with a member of the community (as seen in the third question of the psychomotor domain). Participants’ responses during consultation indicated that the consultation on genetics has also changed to activities based on the duties of a PHN. There is a need to apply counseling techniques to identify problems related to genetic disorders, conduct health assessments, and provide appropriate advice to manage identified problems. The goals of the psychomotor domain can be achieved by incorporating them into PHNs’ regular duties. For some genetic disorders, the risk of onset can be assessed by genetic testing. Further, onset of symptoms can be delayed and managed by lifestyle changes. The utilization of knowledge relating to human genetics is desired in public health services for disease prevention and health management, and may enable reduction of healthcare costs ; good effects have already been seen as a result of screening of some genetic disorders and genetic testing for Alzheimer’s disease . The results of our short-term education program suggested that it may also indirectly contribute to those ethical aspects. Certainly, these conclusions may be inflated because we only assessed short-term enhancement of the responses of PHN for public health genetics. The study has a few limitations: (i) we could not measure the long-term effect of our education program, (ii) the number of participants was limited to 23, and (iii) the effect of education was measured only by self-reported questionnaires. For (i) and (ii), in future research, we should design a program that will give us the capability to assess long-term effects. Considering the effect of training for radiation education, Japanese PHNs who were not in charge of the consultation regarding radiation hazards maintained the education effect 1 month after the training . It was suggested that PHNs who recognize the relationship between their duties and the problems (i.e., here, the radiation hazard) are easily motivated to learn about the problems [ 46 – 48 ]. Moreover, PHNs in multiple locations and with different cultural backgrounds should be recruited. For (iii), the development of methodologies that objectively measure knowledge level, the capability of consultation, and the motivation of participants relating to public health genetics are required. Perhaps, knowledge tests, role-play, and evaluation from third party members will be helpful tools. By implementing a simple case study, we provided an opportunity for PHNs to consider their role relating the informing and education of genetic disorders to local communities. PHNs who participated in our study described their role in public health genetics as “providing advice and accurate information to targeted individuals, and referral to a specialized organization.” The target population of this study was only a limited number of PHNs from a limited number of local municipalities. However, as mentioned above, we think this program should be tried by many on-site PHNs working within different cultural backgrounds. Depending on local characteristics, the familiar cases of genetic disorders used in the teaching material may change. Nevertheless, we believe this type of training will motivate PHNs to learn more about human genomics and genetic disorders, increase their genetic literacy, and thereby also improve public literacy. This will contribute to the effective implementation of genetic testing for the early detection of disease risk. A short-term pilot education program regarding human genetics was conducted for PHNs at a local municipality in Japan. The results of our program demonstrated the achievement of the following goals: first, helping PHNs gain basic knowledge and develop a deeper interest in human genomics and associated genetic disorders; and second, helping PHNs understand their role and the possible opportunities for providing local people with accurate knowledge of human genetics. Bearing in mind that this is a short-term program with a limited sample size, future research should consider implementing this program over the long-term, among PHNs working with people of different cultural backgrounds. Certainly, political amendments by lobbying healthcare and political leaders are needed to change the current situation of nursing practice. This training could potentially motivate more PHNs to learn more about genetics, which may enhance their knowledge and thought process related to genetics, and thereby prepare them to provide care for target residents. Thus, we believe this program can contribute to the enhancement of the use of genetic testing and subsequent early detection of disease risk by improving the genetic literacy of local communities through the services provided by local PHNs.
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Extracorporeal photopheresis (ECP) is an alternative therapy for aGVHD with a well-established clinical efficacy and safety profile . ECP involves collection of peripheral blood mononuclear cells (PBMC) by apheresis, exposure to 8-methoxypsoralen, and ultraviolet A radiation, followed by re-infusion of photoactivated cells into the patient. Uniquely, there are no systemic immunosuppressive effects and ECP facilitates weaning of immunosuppressive medications; therefore, ECP does not increase infection or disease relapse risk . Exactly how ECP exerts its therapeutic effects is not completely understood, but several mechanisms contributing to antigen-specific immunomodulation have been proposed including apoptosis of exposed lymphocytes, differentiation of monocytes into dendritic cells (DC) stimulated by physical interactions within the ECP chamber, promotion of a tolerogenic DC phenotype and increased regulatory T cells (Treg) although many studies incorporate in vitro ECP models or animal models [ 11 – 15 ]. Retrospective studies also suggest that ECP can promote thymic-dependent T cell recovery post-HSCT . We previously observed that ECP-treated patients demonstrated limited thymic recovery, although ECP was commenced late in the course of aGVHD and earlier initiation may further improve thymic output . We aimed to prospectively examine the impact of ECP on thymic-dependent T cell recovery in a pediatric cohort by quantitative (naive T cell and TREC enumeration) and qualitative (T cell receptor (TCR) repertoire diversity) analyses. IL-7, a cytokine produced by thymic epithelial cells in response to lymphopenia , was measured as an indicator of functioning thymic stroma. We hypothesized that patients who respond to ECP have successful return of quantitative and qualitative thymic function. We aimed to explore ECP mechanisms in promoting immunotolerance by analysis of Tregs and DCs throughout treatment and T cell transcriptome analysis before and after treatment. We hypothesized that we would observe alterations in Tregs and DCs (consistent with increased peripheral tolerance) and the T cell transcriptome in patients with treatment progression and we would identify differences between those who respond successfully to ECP and those who fail to respond. This was an observational exploratory study involving allogeneic HSCT pediatric patients who received ECP treatment for aGVHD, following initial corticosteroid treatment. In addition, two control groups were recruited; pediatric allogeneic HSCT patients who did not develop aGVHD (“no aGVHD” group) and pediatric allogeneic HSCT patients with aGVHD treated with systemic corticosteroids but who did not receive ECP (“aGVHD corticosteroid” group). Patients were excluded from recruitment to the “no aGVHD” group if they received corticosteroids for another clinical indication. Decision to treat with ECP and weaning of immunosuppression was a physician-led clinical judgment. Patients were recruited from June 2016–January 2018. All patients attended the Great North Children’s Hospital, Newcastle upon Tyne, UK. Clinical data recorded included demographics, underlying diagnosis, details regarding the HSCT and conditioning regimen, immunosuppressive agents used, type of GVHD, stage, and response to ECP. Grade of aGVHD was determined using the modified Glucksberg criteria. The NIH Consensus scoring system was used for ECP patient 5 with lung involvement . Ethical approval was granted by the South Eastern Scotland Research Ethics Committee . Written informed consent was obtained from all patients or their legal guardians. ECP was administered on 2 consecutive days weekly for the first 9 weeks, then every 2 weeks for 7 weeks, every 3 weeks for 4 weeks and monthly thereafter until treatment cessation, although some patients deviated from this protocol based on judgment of the attending physician. One ECP cycle was defined as two ECP procedures over two consecutive days. ECP was delivered using the CELLEX® System (Mallinckrodt Pharmaceuticals, NJ, USA). Patients were designated “ECP responders” if they completed ECP treatment with GVHD resolution and weaning of immunosuppression. Patients were designated “ECP partial responders” if they remained on ECP with partial clinical improvement. For the ECP group, blood was taken on day 1 of each cycle, and at 4, 8, and 12 months post-HSCT. For the control groups, blood samples were taken at 4, 8, and 12 months post-HSCT. There were two missing samples at 8 months and two at 12 months follow-up in the “no aGVHD” group. In the “aGVHD corticosteroid” group, there was one missing sample at 8 months follow-up. There were no missing samples in the ECP group. Due to more limited sample volumes from the control groups, analyses were confined to naïve T cells, DCs, and Tregs. For enumeration of cell absolute counts and frequencies, whole blood was stained with fluorochrome-conjugated antibodies in Trucount® tubes (BD Biosciences) and incubated for 20 min before adding 900 μl of red blood cell lysis buffer. For enumeration of naive T cells (CD3 + CD4 + CD45RA + CD31 + ), Tregs (CD3 + CD4 + CD25 hi CD127 lo ), and activated T cells (CD3 + CD4 + HLA-DR + ), the following antibodies were used (BD Biosciences): CD45-APC (HI30), CD3-Pe-Cy7 (SK7), CD4-PE (RPA-T4), CD45RA-BUV737 (HI100), CD31-APC Cy7 (WM59), HLA-DR-BUV395 (G46-6), CD127-BV421 (HIL-7R-M2), and CD25-FITC (M-A251) . For DC enumeration (conventional DCs, cDCs; CD45 + CD3 − CD34 − CD14 − DR + CD4 + CD16 − CD11c + and CD11c − CD123 + plasmacytoid DCs, pDCs), the following antibodies were used (BD Biosciences unless otherwise stated): CD3-FITC (UCHT1), CD4-PE (RPA-T4), CD16-PE-Dazzle (3G8, Biolegend), CD123-PerCP-Cy5.5 (7G3), CD45-AF700 (H130, Biolegend), CD34-APC-Cy7 (581, Biolegend), CD11c-BV421 (B-ly6), HLA-DR-V500 (G46-6), CD14-BV650 (M5E2) . Data were collected using the Fortessa X-20 flow cytometer (BD Biosciences). For DC phenotype analysis, PBMCs were prepared by density-gradient centrifugation using Lymphoprep® solution (STEMCELL Technologies) and incubated with the following antibodies (Biolegend unless otherwise stated): CD3-AF700 (SK7), CD19-AF-700 (HIB19), CD20-AF700 (2H7), CD14-BV650 (M5E2), CD11c-BV711 (3.9), HLA-DR-BUV395 (G46-6, BD Biosciences), CD16-PECF594 (3G8), CD123-BV785 (6H6), CD80-PE (L307.4, BD Biosciences), CD83-BV421 (HB15e, BD Biosciences), CD86-FITC , and DAPI viability dye . Data were collected using the BD FACSymphony flow cytometer (BD Biosciences). Median fluorescence intensity (MFI) was measured for CD80, CD83, and CD86 expression and the median value of the ECP responders ( n = 4) and control groups ( n = 3 in each) was calculated. Flow cytometry data were analyzed using the FlowJo software (BD Biosciences). Patient PBMCs were stained with CD4-PE (RPA-T4), CD14-BV650 (M5E2), CD127-BV421 (HIL-7R-M21), CD25-FITC (M-A251), and DAPI, and CD25 hi CD127 lo Tregs were sorted using the FACS-Fusion Sorter (BD Biosciences). Monocytes were isolated from healthy control PBMCs using a MACS separation system (Miltenyi Biotec) according to the manufacturer’s instructions. DCs were then generated by incubation of the isolated monocytes in RF-10 media with IL-4 and GM-CSF for 6 days followed by a further 24-h culture with 0.1 μg/ml LPS. Treg suppression capacity was measured in a co-culture system in which a CellTrace Violet™ (CTV) (ThermoFisher)–labeled effector T cells (Teffs) were cultured with allogeneic DCs (10:1 Teff to DC ratio, both from healthy controls) in the presence of ECP patient Tregs (4:1 Teff to Treg ratio). After 5 days, the frequency of proliferating Teff cells (CTV low) was detected using flow cytometry (BD Biosciences) at 3 time points of ECP treatment (early, mid, and late/end). Co-culture without Tregs served as control. T cell receptor excision circle (TREC) quantification was performed using a real-time PCR instrument as previously described . A standard curve was generated by cloning of plasmid TREC/TRAC DNA kindly supplied by Sottini et al DNA was purified from 5 × 10 6 PBMCs using the QIAamp® DNA Blood Mini Kit (Qiagen). The following primers and probes were used (Integrated DNA Technologies): TREC forward primer 5′-CAC ATC CCT TTC AAC CAT GCT-3′, TREC reverse primer 5′-TGC AGG TGC CTA TGC ATC A-3′, TREC probe 5′-FAM-ACA CCT CTG GTT TTT GTA AAG GTG CCC ACT-TAMRA-3′, TRAC forward primer 5′ TGG CCT AAC CCT GAT CCT CTT-3′, TRAC reverse primer 5′-GGA TTT AGA GCT TCT CAG CTG GTA CAC-3′ and TRAC probe 5′-FAM-TCC CAC AGA TAT CCA GAA CCC TGA CCC-TAMRA-3′. Data were analyzed using Sequence Detection Systems software version 2.4 (Applied Biosystems) and results were recorded as the number of TRECs per 1 ml of blood. T cell receptor (TCR) diversity was evaluated using complementarity-determining region 3 (CDR3) spectratyping. RNA was extracted from PBMCs using the RNeasy® Mini Kit (Qiagen), quantified using a NanoDrop® ND-1000 spectrophotometer (LabTech), and converted to cDNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems). The TCRβ variable region was amplified using twenty-three Vβ primers followed by a run-off reaction with FAM-labeled Cβ primer and CDR3 fragment length analysis by capillary electrophoresis using the 3130 Genetic Analyzer (ThermoFisher). Data were analyzed using Peak Scanner (Applied Biosystems). Using healthy control samples, a scoring system was developed to define electropherograms as normal, abnormal, or highly abnormal . Gaussian distributions were a subjective description of each Vβ family to demonstrate the visual change in the TCR repertoire, rather than a statistical description. Transcriptional analysis was performed on three ECP responders (patients 1, 2, and 4) and two partial responders (patients 5 and 6) pre- and post-ECP. Patients’ CD3 + T cells were purified by magnetic positive selection (Miltenyi Biotec), followed by RNA isolation with the RNeasy Micro Kit (Qiagen). cDNA was synthesized from 10 ng of total RNA using SuperScript™ VILO™ cDNA Synthesis Kit (ThermoFisher). The Ion AmpliSeq Transcriptome Human Gene Expression Kit was utilized to generate barcoded libraries per the manufacturer’s protocol and sequenced using an Ion S5TM system. Differential gene expression analysis was performed using the ampliSeqRNA plugin (ThermoFisher). Pathway analysis was done using Ingenuity Pathway Analysis (Qiagen). Sixteen pediatric patients were recruited. There were 6 patients in the ECP group with steroid-refractory aGVHD and 5 patients in each of the “no aGVHD” and “aGVHD corticosteroid” control groups. A summary of the clinical characteristics and details of aGVHD diagnoses and management are provided in Tables 1 and 2 respectively. Table 1 Summary of patient characteristics. Conditioning was described as myeloablative (MA) if cyclophosphamide was used in combination with busulfan or with total body and cranial irradiation, reduced toxicity MA if cyclophosphamide was used in combination with fludarabine, and reduced intensity conditioning (RIC) if fludarabine and treosulfan were used, with or without additional thiotepa ECP group, N = 6 No aGVHD group, N = 5 aGVHD corticosteroid group, N = 5 Age at HSCT (years) Median 7.7 4.3 6.6 Range 4.1–13 0.6–17.8 1.5–15 Gender Male 4 (66.7%) 2 (40%) 2 (40%) Female 2 (33.3%) 3 (60%) 3 (60%) Underlying diagnosis Immune deficiency 2 (33.3%), STAT3 GOF, CTLA4 deficiency 3 (60%), Nijmegen-breakage syndrome, CGD, SCID 3 (60%), hyper IgD syndrome, STAT3 GOF, CGD Malignancy/hematological 4 (66.7%), relapsed AML × 2, relapsed ALL, high-risk AML 2 (40%), severe congenital neutropenia, severe aplastic anemia 2 (40%), high-risk ALL, AML HSCT source BM 4 (66.7%) 4 (80%) 2 (40%) PBSC 2 (33.3%) 1 (20%) 3 (60%) HSCT donor Sibling/MFD 3 (50%) 3 (60%) 0 MUD 3 (50%) 1 (20%) 4 (80%) Haploidentical 0 1 (20%) 1 (20%) HLA Matching 10/10 6 (100%) 4 (80%) 2 (40%) <10/10 0 1 (20%) 3 (60%) Conditioning MA 4 (66.7%) 0 2 (40%) Reduced toxicity MA 0 1 (20%) 0 RIC 2 (33.3%) 4 (80%) 3 (60%) TBI 1 (16.7%) 0 1 (20%) Serotherapy 4 (66.7%) 4 (80%) 5 (100%) GVHD prophylaxis CSA/MMF 2 (33.3%) 3 (60%) 2 (40%) CSA alone 4 (66.7%) 1 (20%) 2 (40%) None 0 1 (20%) 1 (20%) BM bone marrow, PBSC peripheral blood stem cells, MFD matched family donor, MUD matched unrelated donor, CSA cyclosporin, MMF mycophenolate mofetil, TBI total body irradiation, STAT3 GOF signal transducer and activator of transcription 3 gain-of-function, CGD chronic granulomatous disease, CTLA4 cytotoxic T lymphocyte antigen 4, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia Table 2 Details of patients with aGVHD treated with ECP. Overall grade of aGVHD was determined using the modified Glucksberg criteria. Therapies in italics denote continued aGVHD prophylaxis ECP group Patient GVHD organ involvement (max stage) Max aGVHD grade Treatment (excluding ECP) Reason for ECP Time from HSCT -ECP (days) ECP outcome, number of ECP cycles P1 GIT (3), skin (2) 3 CS, CSA , IFX CS refractory 55 Complete response, 24 P2 GIT (3), skin (2) 3 CS, CSA , IFX CS refractory 39 Complete response, 21 P3 GIT (3) 3 CS, CSA*, MMF , IFX CS refractory 124 Complete response, 20 P4 Skin (3) 2 CS, CSA*, MMF , IFX CS refractory, CMV viraemia 40 Complete response, 16 P5 Skin (3), liver (2), Lung (NIH score 3) 3 CS, CSA, MMF , IFX, BUD CS refractory 173 Normalization of bilirubin, stable respiratory status (PFTs: FEV1 34%, FEV1/FVC 0.63), persistent exertional dyspnea, 44 (ongoing) P6 Lung - CS, CSA , BUD CS dependency 142 Improvement in PFTs; FEV1 35%, FEV1/FVC 0.91 pre-ECP to FEV1 69%, FEV1/FVC 0.98, persistent exertional dyspnea, 21 (ongoing) aGVHD corticosteroid group Patient aGVHD organ involvement (max stage) Max grade Treatment Outcome P1 Skin (3) 2 Topical + systemic CS, CSA Complete response P2 Skin (3) 2 Topical + systemic CS Complete response P3 Skin (3) 2 Topical + systemic CS, CSA, MMFs Complete response P4 Skin (3) 2 Topical + systemic CS, CSA Complete response P5 Skin (3) 2 Topical + systemic CS, CSA, MMF Complete response BUD budesonide (inhaled), CMV cytomegalovirus, CS corticosteroids, CSA cyclosporin, CSA * CSA later changed to tacrolimus, FEV1 forced expiratory volume in one second, FVC forced vital capacity, IFX infliximab, MMF mycophenolate mofetil, PFT pulmonary function tests This was the first HSCT for all patients and none received donor lymphocyte infusions. Median age at HSCT was lowest in the no aGVHD group (4.3 years) and highest in the ECP group (7.7 years). The majority of patients in each group received serotherapy and one patient from the ECP group and one from the aGVHD corticosteroid group received total body irradiation (14 Gy). Patients in the aGVHD corticosteroid group had grade 2 skin aGVHD and received treatment with topical and systemic corticosteroids, along with continuation of aGVHD prophylaxis. Patients 5 and 6 demonstrated partial clinical improvement. Patient 5 initially developed corticosteroid-responsive skin aGVHD, followed by pneumonitis, which partially improved with corticosteroids and infliximab, alongside antimicrobial, and antifungal therapies. Thoracic computerized tomography (CT) demonstrated bronchiolitis obliterans with an obstructive pulmonary function test (PFT) pattern (FEV1 33%, FEV1/FVC 0.63). Lung biopsy was not performed due to poor clinical condition and ECP was started leading to initial clinical improvement. Upon weaning of ECP to four weekly and corticosteroids to 0.1 mg/kg at cycle 30, patient 5 developed liver aGVHD (biopsy confirmed). Weekly ECP and high dose corticosteroids were re-initiated and sirolimus was started, leading to normalization of bilirubin, and respiratory status remained stable (FEV1 34%, FEV1/FVC 0.63, persistent exertional dyspnea). Patient 5 was considered to have overlap syndrome, with features of aGVHD present but lung involvement distinctive of chronic GVHD (cGVHD) (NIH score 3), although no other cGVHD features were present. Patient 6 developed cough and dyspnea with a restrictive PFT pattern (FEV1 35%, FEV1/FVC 0.91) day +39 post-HSCT. Chest CT demonstrated diffuse pulmonary nodularity and lung biopsy identified active mild CD3 + lymphocytic bronchiolitis, consistent with partially treated aGVHD. No infectious causes were identified. Due to steroid dependency, ECP was commenced leading to PFT improvement (FEV1 69%, FEV1/FVC 0.98). Patient 6 had no other aGVHD organ involvement and no features of cGVHD. All patients exhibited low naive T cells and TRECs, and abnormal TCR repertoires at commencement of ECP regardless of timing post-HSCT, indicating poor thymic output. Increased naive T cells and TRECs, and an inverse relationship with IL-7, was observed with treatment progression in ECP responders. . This coincided with resolution of clinical aGVHD, weaning of immunosuppression, and decreased activated T cell frequency . Improvement in TCR diversity illustrated qualitative T cell improvement . These results indicate thymic-dependent T cell recovery during ECP treatment. In contrast, partial responders 5 and 6 demonstrated no thymic-dependent T cell recovery 2 years post-HSCT and 44 ECP cycles, and 1 year post-HSCT and 21 ECP cycles respectively. An inverse relationship with IL-7 was not observed . Fig. 1 In the ECP responders (example shown is patient 3), a increased frequency (dotted line) and number (continuous line) of CD4 + CD45RA + CD31 + -naive T cells and b TRECs (dashed line represents the upper end of the normal range for age) were observed. c An inverse relationship between serum IL-7 (dotted black line) and naive T cells (continuous line) was seen. d , e Evaluation of the TCR repertoire indicates qualitative T cell improvement post-ECP as demonstrated by all TCR Vβ families present with a normal Gaussian distribution, compared to pre-ECP when several non-Gaussian families were seen with multiple monoclonal peaks. Partial responder 5 demonstrated f ongoing negligible number (continuous line) and frequency (dotted line) of naive T cells and g TRECs. h Increased IL-7 (dotted line) was not sustained and an inverse relationship with naive T cells (continuous line) was not evident. i , j Qualitative T cell improvement was not observed with a persistently abnormal TCR repertoire later in the course of ECP. k Comparison of median numbers (with range) of naive T cells at 4, 8, and 12 months post-HSCT demonstrate fastest thymic-dependent T cell recovery in patients with no aGVHD or additional immune suppression. Median naive T cell number was superior in the ECP responder group compared to the aGVHD corticosteroid group at 8 and 12 months post-HSCT. Differences between the groups were not statistically significant ( p value = 0.25). l – n Mean numbers of naive T cells (error bars indicating SEM) at 4, 8, and 12-months post-HSCT respectively demonstrate a similar pattern with highest numbers in patients with no aGVHD To examine how thymic-dependent T cell recovery in the ECP responders compared with the normal trajectory post-HSCT, results were compared with the no aGVHD and aGVHD corticosteroid groups at 4, 8, and 12 months following HSCT . Thymic-dependent T cell recovery was superior in the no aGVHD group at each time point measured. At 4 months post-HSCT, naive T cell numbers were similar between ECP responders and the aGVHD corticosteroid group; however, at 8 and 12 months thymic-dependent T cell recovery was superior in the ECP responder group. These results highlight the negative impact of aGVHD and corticosteroids on thymic recovery. We next sought to understand mechanisms by which ECP mitigates aGVHD activity. Plasmacytoid DC numbers increased with treatment in responders , with an overall decline in cDC/pDC ratio indicating a relatively higher increase in pDCs compared to cDCs , a population shown to mediate aGVHD tolerance and facilitate engraftment . In contrast, the cDC/pDC ratio increased with treatment in partial responder 5 and remained persistently low in partial responder 6 . Fig. 2 a A decline in the cDC/pDC ratio was observed with treatment among ECP responders ( p value = 0.13 using linear regression analysis). Black dots shown represent cDC/pDC values in all responders during ECP treatment. b An incline in the cDC/pDC ratio was seen in partial responder 5. c cDC/pDC ratio was low throughout treatment in partial responder 6. d Compared to the control groups at 4, 8, and 12 months post-HSCT, the median (with range) cDC/pDC ratio was highest in the aGVHD corticosteroid group at each time point measured. Differences between the groups were not statistically significant ( p value = 0.07). e A similar pattern was observed in the mean cDC/pDC ratios (error bars indicating SEM) of each group. f , g Median MFI of CD80, CD86, and CD83 expression of the ECP responders ( n = 4) at 3 time points during treatment (early, middle, and end) was lower compared to that measured in three patients from each control group at 4 months post-HSCT To decipher the potential influence of aGVHD and corticosteroids on this cDC/pDC pattern, we compared ECP responder cDC/pDC ratios at 4, 8, and 12 months post-HSCT with the control groups . Median cDC/pDC ratio was highest in the aGVHD corticosteroid group at each timepoint post-HSCT. Although the range of values and lack of statistical significance indicate the need for analysis in additional patients to ascertain the validity of these findings, lower cDC/pDC values in the ECP responders, particularly at 4 (all ECP responders on treatment) and 8 months (3 ECP responders on treatment and one recently completed treatment) post-HSCT, support an ECP-induced effect, rather than a consequence of corticosteroid use or aGVHD. Conventional DC and pDC expression of co-stimulatory markers CD80, CD86, and CD83 was measured to examine the stage of DC maturation, an important determinant of DC immune regulatory or stimulatory capacity. We observed reduced expression of co-stimulatory markers in the ECP responders in comparison to expression in 3 patients from each control group at 4 months post-HSCT, indicating a more immature or tolerogenic DC phenotype at the time points measured. In contrast, co-stimulatory marker expression was higher with occasional high MFI peaks in partial responder 5 . Tregs increased steadily in the ECP responders from approximately cycle 10 onwards . Responder Treg frequency increased during treatment; however, this fluctuated, without a consistent trend . Partial responder 5 demonstrated a decline in Treg number and frequency and partial responder 6 demonstrated low Treg numbers throughout and frequency mostly within the normal range . Fig. 3 a Responding ECP patients demonstrated increased Treg numbers in the latter half of treatment. b Treg frequency intermittently increased in the responding ECP patients, but with no upward or downward trend (normal range shaded in gray). c Partial responder 5 demonstrated a decrease in Tregs during treatment. Partial responder 6 had low Treg numbers throughout. d A decline in Treg frequency was observed in partial responder 5 and remained largely within the normal range for patient 6. e Median numbers of Tregs (with range) were highest in the no aGVHD group followed by the ECP responders at 12 months post-HSCT. Differences between the groups were not statistically significant ( p value = 0.49). f Median (with range) Treg frequency was highest in the aGVHD corticosteroid group at each time point measured. Mean values with error bars demonstrated a similar pattern . g In the ECP responders, Teff proliferation decreased mid-ECP treatment indicating increased Treg suppression compared to early in the treatment course. The arrows indicate the change (increase or decrease) from the measurement at the previous time point Having identified differences in thymopoiesis and DC and Treg patterns, we explored differences in the CD3 + T cell transcriptional signature following treatment. Compared to the partial responders, ECP responders had 26 downregulated and 24 upregulated genes (>1.5-fold difference in expression, FDR < 0.05) with significant enrichment of genes in pathways important in Teff metabolism . Specifically, expression of genes important for lipid metabolism and localization, lipid-protein complex remodeling, and glycolysis were downregulated in responder T cells compared to partial responders after treatment . To identify pathways most affected by ECP treatment, we performed whole transcriptome analysis on CD3 + T cells from ECP responders before and after ECP treatment. CD3 + T cells after treatment had 3333 downregulated and 364 upregulated genes with at least a 2-fold difference in expression compared to before treatment , enriched in pathways related to estrogen-related receptor alpha (ERRα) signaling, GαS signaling, cytokines, and cellular adhesion and diapedesis . ERRα and GαS signaling pathways are involved in Teff activation and function. Downregulated cytokine genes included those associated with aGVHD pathogenesis . Downregulation of genes involved in cellular adhesion and diapedesis corresponds to the clinical resolution of inflammation observed in the ECP responders at the end of treatment. Fig. 4 a Comparison of the CD3+ T cell transcriptional signature between ECP responders and partial responders after treatment identified 26 significantly downregulated genes (blue) and 24 upregulated genes (red) with a fold change of at least 1.5 times (FDR p value <0.1). b – d Significant enrichment of genes involved in Teff metabolism was identified, including genes important in lipid metabolism and localization, lipid-protein complex remodeling, and glycolysis. e T cell whole transcriptome analysis pre- and post-treatment in ECP responders identified 3333 significantly downregulated genes (blue) and 364 upregulated genes (red) with at least a two-fold difference in expression. f – j Alterations in gene expression were seen in pathways associated with cytokines, cellular adhesion, and diapedesis, and T cell activation including estrogen-related receptor alpha (ERRα) signaling and GαS signaling We show that ECP responding patients exhibit qualitative and quantitative thymic-dependent T cell recovery, likely due to reduced aGVHD activity and immunosuppression, reinforcing previous observations , and supporting the use of ECP as a “thymic-sparing” therapeutic strategy in aGVHD to facilitate T cell reconstitution. In addition, the slower rate of thymic-dependent T cell recovery in the aGVHD corticosteroid group highlights the negative influence of prolonged corticosteroids and the need to develop alternative “thymic-sparing” approaches. Importantly, partial ECP responders did not demonstrate thymic recovery, at least in the time frame post-HSCT analyzed in this study. Increased IL-7 production in response to lymphopenia suggests the presence of functioning thymic epithelial cells; failure to mount IL-7 production as observed in patients 5 and 6 suggests thymic dysfunction which may reflect ongoing active thymic aGVHD and/or irreparable thymic damage. Although unclear if this is a permanent immune outcome, it raises the important question of whether multiple/prolonged insults to the thymus can cause irreversible damage. Contributing factors may include longer corticosteroid exposure, slower weaning of immunosuppression, and later ECP initiation. Patients 5 and 6 commenced ECP 173 and 142 days after HSCT respectively, in contrast to a median of 48 days in the responders, supporting previous reports that earlier ECP may produce better outcomes and suggesting that limiting insult exposure may permit faster recovery of thymic function. Investigation in additional patients is needed, and in adult patients who exhibit continued but reduced thymopoiesis associated with aging . Previous studies indicate a key role played by DCs and Tregs in the immunomodulating mechanisms of ECP. We demonstrate changes in DC subsets and phenotype in ECP responders supporting an immunotolerant environment and identified differences with partial responders. Comparison with control groups provide insight into the potential mechanisms of ECP independent of the impact of corticosteroids and aGVHD, but analysis in additional patients from all groups is required to confirm the findings from this small cohort. A decline in the cDC/pDC ratio in aGVHD treatment with ECP was described by Shiue et al although how this shift to encourage pDC development occurs is not yet known. Reduced co-stimulatory molecule expression indicates an immature tolerogenic DC phenotype shown to be protective against aGVHD and may contribute to reduced aGVHD activity due to inadequate co-stimulatory help . While these results support a potential effect of ECP on DCs, gaps remain in our knowledge regarding their function and further examination should include functional testing such as cytokine production and T cell proliferative response. Our data demonstrate increasing Treg numbers and increased Treg suppressive capacity mid-ECP treatment in responders. Increasing Tregs coinciding with renewed naive T cell output and without a corresponding increase in frequency suggest this incline is attributable to immune reconstitution and egress of thymic-derived Tregs. However, activated Tregs may be primarily located in sites of tissue inflammation, particularly in the early stage of ECP treatment. Examination of Tregs in aGVHD-affected tissue and specifically measuring CD45RA + CD31 + Tregs would be valuable to elucidate Treg patterns and origin . Certain Treg subpopulations are associated with greater suppressive capacity, which could account for the increased Treg suppressive function observed; a more detailed Treg analysis is needed to identify if expansion of certain subsets occurs in ECP such as IL-10-producing Tr1 Tregs. Higher Treg frequencies in the aGVHD corticosteroid group and partial responder 5 may be related to longer corticosteroid exposure . However, partial responder 6, who was also exposed to prolonged corticosteroids, did not demonstrate elevated Treg frequencies suggesting involvement of other factors. Further examination of the impact of corticosteroids on Tregs would help to understand the independent effect of ECP. ECP responders exhibited significant downregulation in gene pathways important in Teff metabolism compared to partial responders, pathways essential for allogeneic Teffs driving aGVHD [ 29 – 31 ]. Although partial responders demonstrated some clinical progress, these data indicate that their T cells retain transcriptional characteristics known to be important for aGVHD. Further evaluation in ECP responders before and after treatment displayed significant changes in ERRα and GαS signaling pathways which have not been highlighted in prior studies of T cells from patients or animal models with aGVHD. ERRα, a transcriptional regulator of cellular metabolism, increases Teff activation and proliferation by increasing expression of genes important for glycolysis and mitochondrial function . ERRα deficiency reduces Teff proliferation and function in experimental autoimmune encephalitis and ERRα downregulation in the setting of ECP therapy may reduce activated Teff generation. GαS signaling is important for Th1 and Th17 differentiation and function but dispensable in Treg generation . Deletion of GαS in CD4 + T cells results in reduced generation of cAMP, decreased calcium flux, and the inability to induce colitis in an adoptive transfer model , underscoring the importance of this pathway in CD4 + T cell–driven inflammation. Reduced T cell activation via these pathways may indirectly promote naive T cells and Tregs by reducing inflammation and facilitating immune reconstitution, and directly promote T cell differentiation towards a Treg phenotype. Further investigation is needed in additional patients to validate these findings and their functional consequences and to determine if this transcriptional signature is unique to ECP therapy. The known importance of T cell chemotaxis in aGVHD pathogenesis [ 35 – 38 ] supports our observation of reduced gene expression in pathways involved in T cell migration, adhesion, and diapedesis in parallel with aGVHD resolution post-ECP. Reduced cytokine gene expression included type 1 interferons which may contribute to reduced alloreactive CD8 + responses. Type 1 interferon signaling is known to increase alloreactive cytotoxic T cell expansion, cross-present host antigens to CD8 + T cells, and activate bystander cells . Further investigation at protein and functional levels, including correlation with T cell cytokine secretion and quantitative cellular adhesion assay would be valuable to validate these transcriptomic findings. Study limitations include the small size and heterogeneity of the cohort. Examination of additional patients and further investigations, as outlined, are needed. Investigation of larger patient and control cohorts is essential to adjust for differences in characteristics between these clinically heterogenous groups and permit clearer interpretation of results. Limited blood volumes from control groups precluded the ability to perform all analyses on these patients, which is needed for comprehensive comparison with the ECP patients. In conclusion, these data indicate that successful ECP associates with thymopoietic recovery in children with aGVHD and can be used as a strategy to promote immune reconstitution, especially when used early. Correlation with reconstitution of other immune cell groups and long-term follow-up is important. We demonstrate, for the first time, differences at a cellular and transcriptional level in patients with a partial ECP response. Alterations in DCs and Tregs suggest that peripheral tolerance is augmented in ECP responders and, as these patterns were not observed in partial responders, lack of upregulation could contribute to an incomplete response. We observed distinct T cell transcriptome changes in responders, with decreased expression of genes important for T cell activation, even in the absence of immunosuppression. As ECP is expensive, time-consuming, and requires central venous access in children, identifying those who will benefit from treatment is an important goal. Due to the nature of this therapy and population, investigation in large numbers is challenging. These data will direct further investigation in additional patients to validate findings and allow statistical inference. In addition, extension of investigations to include detailed Treg phenotyping, DC functional testing, and analysis of functional downstream consequences of T cell transcriptome changes is needed, as well as further longitudinal analysis to explore the longevity of cellular and transcriptomic alterations observed. Confirmation of specific biomarkers will assist clinical decision-making to determine who can benefit from ECP treatment.
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Study
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biomedical
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en
| 0.999995
|
33777437
|
Patients with GLA usually present with dyspnoea, dysphasia and thromboembolic events. The current patient complained of dyspnoea on minimal exertion, but there was no dysphagia. Although the risk of thromboembolism increases with LA dimensions and is independent of anticoagulants’ administration, the published evidence of large thrombus formation in patients with LA size of >8 cm is very scarce. There was a large LA thrombus formation in the current case despite having therapeutic INR with standard vitamin K antagonist therapy. There is a therapeutic dilemma when managing such patients. It is unknown whether the increase in the INR therapeutic range of ≥3.0 will resolve GLA patients’ clot. Contrary to current American Heart Association (AHA) guidelines that do not recommend using novel oral anticoagulants (NOAC) in patients with intracardiac thrombus and valvular AF, several reports are published on the use of off-label NOACs resulting in resolution of thrombus in patients with enlarged LA. 3 , 4 In a case report by Masarova et al ., recurrent thrombus formation with therapeutic INR of 2.89 was observed in their patient with GLA after surgical removal of the thrombus. A combination of rivaroxaban and clopidogrel resulted in partial thrombus regression in their patient. 4 Left atrial volume reduction surgery in AF patients with enlarged LA have shown superior freedom rates from AF up to five years compared with patients in the non-reduction group. 5 AF plays a vital role in LA thrombus formation along with an increase in left ventricular (LV) volume overload and enlargement. Freedom from AF with LV volume reduction surgery may play an essential role in managing patients with GLA and large thrombus formation. The current patient was offered MVR, LA volume reduction surgery and thrombus removal, but he refused and was lost to follow-up.
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Study
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biomedical
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en
| 0.999998
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33992104
|
Bone defects in the extremities caused by severe trauma, infection and tumor resection are common in clinical practice. Bone defects greater than two cm cannot heal spontaneously, and reconstruction surgery is necessary . The induced membrane technique (IMT) is a recently developed effective strategy to repair bone defects [ 3 – 5 ]. Standard IMT includes a two-stage set of surgical procedures. The first stage involves insertion of a polymethylmethacrylate (PMMA) cement spacer after radical debridement of bone and soft tissue. A membrane around the spacer formed as a foreign body reaction is known as an induced membrane (IM). The second stage is bone grafting within the membrane after removal of the cement spacer . The mechanisms of IMT mainly include the following: (i) the IM acts as a barrier to prevent the soft tissue from growing into the fracture site, and plays a role as a wrapping device to prevent loosening and absorption of the bone graft; (ii) the IM secretes osteogenic factors and contains mesenchymal stem cells (MSCs), which express bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β); (iii) the surface of the IM has rich micro-vessels to increase the blood supply . Therefore, the IM has intrinsic osteogenic activity . However, bone defects repaired completely by intrinsic osteogenic activity of the IM alone are rare in clinical practice. We report a case of infected fractures with ulnar and radial bone defects that were repaired completely by osteogenic activity of the IM and review the literature on spontaneous osteogenesis of the IM. A previously fit and healthy 44-year-old female with no history of hypertrophic ossifications was admitted with a complaint of pain and limited movement of the left upper limb following an accident in which her arm was entangled and twisted injury in a machine. Physical examinations and X-rays demonstrated that the patient had fractures of the left humerus, ulna and radius (AO classification: 12-A3, 13-B1, 22-A3) with a forearm skin contusion . Open reduction and definitive stabilization using plates and screws of the fractures of the left humerus, ulna and radius were performed immediately on admission . She was discharged after the incisions healed. Six weeks following internal fixation, her left forearm became red, swollen and painful. A small hole was made, and pus began to exude. Pseudomonas aeruginosa was cultured from the secretion. X-rays showed obvious bone resorption and slight periosteal reactions on the left ulna and radius . A deep incision infection after internal fixation of the ulna and radius fractures was confirmed. Because conservative treatment is invalid, surgical intervention was required. Following radical debridement including removal of the hardware, 0.7 cm segmental defects of the fracture ends, and 4–5 cm partial defects of the ulna and radius were noted. External fixators were used for fixation and maintaining the length of the ulna and radius, then PMMA bone cement beads loaded with vancomycin (40:4) were inserted into and around the defects . Cefmetazole was administered intravenously for 2 weeks, followed by oral rifampin for 4 weeks. The wound healed uneventfully, and she was encouraged to perform early postoperative rehabilitation activities. Follow-up X-rays two and 4 months after the first stage displayed a continuing process of new bone regeneration in the bone defects . The ulnar and radial fractures and defects were healed by clinical evaluation by 4.5 months, and the external fixators were removed in the clinic at 5.5 months. The second stage of the IMT (bone grafting) was not necessary. The bone cement spacers were removed 6 months after filling with PMMA . Intraoperative exploration revealed that parts of the spacers were wrapped by new callus. No additional surgeries were between the two surgeries. The humeral fracture healed by 3 months postoperatively. The patient recovered the normal length of her humerus, ulna and radius, as well as most of the function of her left upper limb. One year postoperatively, there was no recurrence of infection, her hand grip strength recovered to 80% of the contralateral side, her range of motion: wrist flexion recovered to 56°, wrist extension recovered to 53°, pronation of the forearm recovered to 69°, supination recovered to 73°, elbow flexion recovered to 95°, and elbow extension recovered to 0°. FIG. 1 AP radiograph of fractures showing the left humerus, ulna and radius on admission FIG. 2 Lateral radiograph showing fractures of the left humerus, ulna and radius after open reduction and internal fixation using plates and screws FIG. 3 AP and lateral radiographs showing obvious bone resorption and a slight periosteal reaction FIG. 4 AP and lateral radiographs showing bone cement beads inserted into and around the defects and the bone defect fixed externally after the first stage of the IMT for the infected ulnar and radial fractures FIG. 5 AP and lateral radiographs showing less new callus developed 2 months after the first stage procedure of the IMT FIG. 6 AP and lateral radiographs showing new callus continuing to develop and connecting the defects 4 months after insertion of PMMA FIG. 7 AP and lateral radiographs showing clinical healing of the fractures and defects and removal of spacers 6 months after insertion of PMMA There were only two case reports of bone defects repaired by IMT, in which new bone was found with detailed clinical and follow-up data. One of these patients was a 42-year-old male with severe femoral fractures and defects accompanied by traumatic brain injury (TBI). The interval from filling with PMMA to clinical healing was 48 days . The other was a 7-year-old male boy with mandibular Ewing’s sarcoma treated by a combination of neoadjuvant chemotherapy, resection surgery, and adjuvant radiochemotherapy. A macroplate and a PMMA cement spacer were used for the reconstruction. The spacer was removed after 17 days. X-ray films 2 months postoperatively showed that a small amount of new bone had formed along the macroplate; however, bone grafting was performed in a second stage of surgery . In 2009, Klaue et al. first found in an animal model that the IM is spontaneously osteogenic. They designed a reproducible animal model producing a stable 3 cm mid-diaphyseal bone resection and periosteal defects on sheep femurs and created a foreign-body membrane. After removal of the spacer, radiographs in the group without bone grafts at 16–18 weeks demonstrated that a small amount of woven bone formed at the proximal junction of the bone end and the IM. However, the spontaneous osteogenesis of the IM was weak. No constant osteogenesis was observed in other studies, so it did not attract attention. The rapid callus formation in the case of femoral fractures and defects accompanying TBI reported by Hotchen et al. was attributed to the dual effects of the TBI and the IM, especially the TBI. The exact mechanisms of fracture that accompany TBI to increase callus formation are not yet completely understood. Potential mechanisms may include: (i) Bone fracture triggers the release of cytokines including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6) in both the serum and the cerebrospinal fluid that attract MSCs to the fracture site and generate an osteogenic effect . (ii) The enhanced inflammatory response caused by TBI creates a receptive environment for the occurrence of heterotopic ossification (HO), and the upregulation of some inflammatory factors in the body fluids accelerates bone formation. (iii) Leptin is increased in the circulation following TBI and is also released in the stress response to cytokines and hormonal factors. Leptin is positively correlated with the amount of callus formation at a fracture site . (iv) Patients who suffer from TBI are typically in a coma and require mechanical ventilation. The combination of these factors promotes the incidence of HO and rapid bone formation in TBI patients. The case presented in the current study involved a situation in which the infected bone defects healed spontaneously by osteogenic activity of the IM alone. This case differed from that of Hotchen et al. which was based on the presence of TBI, and from that of Sorin et al. based on the amount of osteogenesis. The possible reasons for spontaneous healing of the bone defects are: (i) the local inflammatory responses increase the release of inflammatory factors, which increase the thickness of the IM and the level of vascularization as well as recruitment of pro-osteogenic cytokines [ 10 – 12 ] and (ii) some fracture fragments or periosteum are present near the cement spacer, which can provide seed cells and enhance the osteogenic activity of the IM [ 13 – 15 ]. Catros et al. conducted an in vivo experiment to investigate the osteoinductive properties of the IM on a macroporous hydroxyapatite-tricalcium phosphate (HA-TCP) scaffold in a non-osseous subcutaneous site in rabbits. The results showed that the IM placed in a non-osseous site had no osteoinductive properties. In this current case, callus growth was observed only on the side near the bone defects, but not on the side near the subcutaneous tissue, consistent with the results of Catros et al. and Klaue et al. . In view of the local associated inflammatory responses, fracture fragments or periosteum around the cement spacer may improve the osteogenic activity of the IM, causing spontaneous healing of the bone defects. Therefore, we assume that filling with PMMA beads as a spacer for partial bone defects or adding a small amount of bone graft for segmental bone defects around the beads may stimulate spontaneous osteogenesis. Of course, this hypothesis needs to be tested experimentally. It is a slow process to completely repair bone defects by the osteogenic activity of IM alone. This is especially true in the long bones of the lower limb because it may lead to stiffness of adjacent joints and other sequelae; it is not a preferred method at present. The infection of the incision after internal fixation of the ulnar and radial fractures was related to improper surgery for a complex severe injury of the upper extremity (floating elbow) combined with a forearm skin contusion, or to improper aseptic conditions. The lesson of this case is that for a complex severe injury with a skin contusion, multiple site incisions, especially large incisions, for open reduction and internal fixation should not be performed emergently at the same time. We present a case of infected bone defects of the ulnar and radial bone. After the first stage of the IMT using PMMA beads, X-rays showed that new callus developed and the defects healed by 5 months. This finding most likely can be attributed to local associated inflammatory reactions and bone tissue, which enhance the osteogenic activity of the IM, causing spontaneous healing of the bone defects. This case differed from those reported in the literature. It appears to be the first such case reported in the literature.
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Clinical case
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biomedical
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en
| 0.999997
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34082747
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Antipsychotic augmentation is not a rare strategy in the pharmacological treatment of depression in older adults. Τhe prevalence of clinically relevant depressive symptoms in seniors is higher than 15%, while the prevalence of major depression exceeds 5% . Antipsychotics augment antidepressants in 12–32% of older adults with depression [ 3 – 6 ], albeit in most cases in an off-label manner . Antipsychotics contribute not only to treating psychotic symptoms in severe depression with psychotic features , but also to depressive symptom improvement, since they enhance monoaminergic neurotransmission . Seniors are particularly vulnerable to side effects of antipsychotic agents, such as parkinsonian symptoms. Both typical antipsychotics, which mainly block D2 receptors, and to a lesser degree atypical ones, blocking both D2 and serotonin 5-HT2A receptors, can lead to parkinsonian symptoms . The annual prevalence of drug-induced parkinsonian symptoms approximates 3% and the annual incidence rate is higher than 3 per 100,00 person-years . Seniors are more vulnerable to parkinsonian symptoms compared to younger patients due to age- related changes in the brain’s response to antipsychotics, diminished drug metabolizing capacity, alterations in blood-brain barrier, as well as drug-drug interactions in an age group burdened by polypharmacy . In addition, age- related, still presymptomatic, neurodegenerative (e.g. Lewy-bodies, nigral cell degeneration) and/or vascular brain changes should be considered as factors crucially implicated in the high susceptibility of seniors treated with antipsychotics to develop severe and persistent parkinsonian symptoms which cannot be unambiguously classified into diagnostic categories. Structural imaging and Ioflupane (I-123) dopamine transporter (DAT) single photon emission computerized tomography (DaTSAN) are useful tools in shedding light on such brain changes and assisting the differential diagnosis . Normal DaTSCAN-imaging supports diagnosis of a condition not involving nigrostriatal neurodegeneration such as Alzheimer’s disease, essential tremor or drug-induced parkinsonism and hence a different therapeutic approach . DaTSCAN sensitivity is estimated to be 78–100% and specificity 70–100% for differentiating neurodegenerative versus non-neurodegenerative parkinsonism . The case series consists of five women and three men older than 59 years who were admitted between 2012 and 2017 to the old age psychiatry division of the Eginition Hospital in Athens because of severe depressive symptoms and consecutively agreed to undergo brain SPECT with 123I-FP-CIT (DaTSCAN, GE Healthcare). The brief, focused neurological examination on admission revealed parkinsonian symptoms, which had been developed during exposure to antipsychotic treatment (Table 1 ). On admission, each patient was on antipsychotic medication that had not been changed in the twelve months prior to his/her hospital admission (Table 1 ). Five patients were on atypical and three on typical antipsychotics; four were on serotonin and norepinephrine reuptake inhibitors, two on selective serotonin reuptake inhibitor and four were treated with mirtazapine. Except for one patient, who had received the diagnosis of bipolar disorder many years before current hospital admission, all others had been diagnosed with unipolar depression. Of note, depression had occurred among four patients for the first time at an age greater than or equal to 65 years with no previous history of depression. Table 1 Demographic and clinical data, mental disorder history and medication of older adults with depression and parkinsonian symptoms on hospital admission Case No Age range Education (in years) Neuropsychological assessment at admission Duration of current depressive syndrome (in years) Past mental disorder diagnoses Age of onset of the first mental disorder episode Medication on admission (in mg/day) Comorbidities Geriatric depression scale score Mini mental state examination score 1 71–85 12 12 21 1 Μajor depression 69 Amisulpiride (100), venlafaxine (75), mirtazapine (30), ferrous sulfate, nifedipine (40) Anaemia, hypertension 2 71–85 14 14 27 1 Severe depressive episode with psychotic symptoms 72 Risperidone (3), sertraline (200 mg), mirtazapine (30), lorazepam (2.5), irbesartan (150), metoprolol (100) Hypertension, hypothyreroidism 3 56–70 14 14 28 1 Severe depressive episode with psychotic symptoms 57 Olanzapine (5), mirtazapine (45), alprazolam (3), flunitrazepam (1), biperiden (4) None 4 56–70 14 15 20 1 Moderate to severe depressive episode 36 Haloperidol (10), venlafaxine (150), lorazepam (7.5), biperiden (6), pindolol (5), rosuvastatin (10), atorvastatin (10) Hypertension, dislipidemia 5 71–85 8 12 27 1 Moderate to severe depressive episode with psychotic symptoms 77 Haloperidol (10), sertraline (100), bromazepam (3), amiloride hydrochloride/hydrochlorothiazide (5/50) Hypertension 6 71–85 12 14 23 1 Bipolar disorder 54 Risperidone (3), mirtazapine (45), gabapentin (600), clonazepam (2), baclofen (20), metformin , rosuvastin (20), bisoprolol fumarate (5), Levothyroxine sodium (125 μg) Hypertension, diabetes mellitus, coronary heart disease, dyslipidemia, hypothyroidism 7 71–85 6 15 27 1 Severe depressive episode with psychotic symptoms 76 Haloperidol (20), venlafaxine (150), pramipexol (0.18), quinapril (20), rabeprazole (10) Hypertension 8 56–70 12 13 19 1 Moderate to severe depressive episodes 55 Quetiapine (100), duloxetine (30), pregabalin (75), levodopa/benserazide (200/50) Hypertension The diagnostic workup of depressive symptoms included a history from the patient and from an informant; psychiatric examination; laboratory screening and the administration of the 30-point Mini-Mental State Examination (MMSE) and the Geriatric depression scale-15 . Geriatric depression scale score was in all cases higher than 11, highlighting the severity of depressive symptoms (Table 1 ). In four patients MMSE score was lower than 24 points, pointing to major neurocognitive disorder , even though the magnitude of the detected cognitive deficits was supposed to be at least partially potentiated by the depressive syndrome . Patients were diagnosed with antipsychotic- induced parkinsonism according to the International Statistical Classification of Diseases and Related Health Problems version 10 (ICD-10) diagnostic criteria . Severity of parkinsonian symptoms was graded with the Simpson-Angus scale (SAS), being an established instrument of neuroleptic-induced parkinsonism . The instrument is a 10-item rating scale that measures gait (hypokinesia) with one item, rigidity with six items, whilst three additional items assess glabella tap, tremor and salivation, respectively. Items are rated from 0 to 4 points, yielding a total body score divided by 10, and considered normal up to 0.3. It was performed in all cases by the same psychiatrist (KS). Apart from one case, in all other patients total scores on SAS exceeded 0.5 (Table 2 ). Table 2 Parkinsonian symptoms of depressed older adults Case No Detected movement disturbances on admission Simpson-Angus Scale Total score Gait Arm dropping Shoulder shaking Elbow rigidity Wrist rigidity Leg pendulousness Head dropping Glabella tap Tremor Salivation 1 Parkinsonism 0.7 1 1 0 1 2 0 1 0 1 0 2 Parkinsonism 0.9 2 1 0 0 2 1 0 1 2 0 3 Parkinsonism 0.6 1 1 1 0 1 1 0 0 1 0 4 Parkinsonism 1.4 1 1 1 1 2 1 1 1 3 1 5 Parkinsonism 1.6 2 2 2 2 1 2 1 1 3 0 6 Parkinsonism 1.3 2 2 1 2 2 1 1 1 1 0 7 Parkinsonism 0.3 0 1 0 0 1 0 0 0 1 0 8 Parkinsonism 1.1 1 1 1 1 2 1 1 1 2 0 Brain MRI (3 T) was performed during the hospitalization period. It included T1 weighted sequences on coronal, sagittal and axial planes (or isotropic T1 images), T2 weighted sequences, T2 Fluid Attenuation Inversion Recovery (FLAIR) images and Diffusion Weighted Imaging (DWI). All MRI scans were evaluated by an experienced neuroradiologist (PT). White matter lesions and vascular disease were evaluated using the Fazekas scale on T2-FLAIR sequences . This scale ranges from 0 (no white matter lesions) to 3 (large confluent areas of white matter lesions) . Based on the Medial Temporal Lobe Atrophy (MTA) -Scheltens Score, MTA was classified using a scale from 0 (no atrophy) to 4 (maximum atrophy) . Unfortunately, MRI imaging was not conducted in two cases due to MRI contraindications (Table 3 ). Slightly increased signal in T2-weighted images in white matter was observed in four cases and beginning confluent lesions were detected in one case, while in case 8 basal ganglia ischemic lesions were bilaterally observed in addition to large confluent white matter lesions . Mild or moderate MTA was detected in all cases with available MRI data (Table 3 ). Table 3 Brain imaging findings of older adults with depression and parkinsonian symptoms Case No Structural brain MR imaging DaT scan* MTA-Scheltens Score** White matter lesions/Fazekas Score*** Specific Binding Index right Benamer’s criteria**** Right Left Rater 1 Rater 2 1 2 1 2.17 2.10 0 0 2 1 2 2.05 2.12 1 1 3 1 0 2.04 2.03 0 0 4 No atrophy / Computerized tomography (CT) scan 2.03 2.02 0 1 5 2 1 2.02 2.06 0 0 6 No atrophy / Computerized tomography (CT) scan 2.00 1.88 2 3 7 2 1 1.85 2.07 1 1 8 2 Bilateral basal ganglia ischemic lesions/3 1.51 1.67 1 1 * iofluropane iodine-123 (DAT) single-photon emission computed tomography imaging (SPECT) **Medial Temporal Lobe Atrophy (MTA) -Scheltens Score ranging from 0 (no atrophy) to 4 (severe atrophy) ***The 4-point Fazekas score is a whole brain scale: 0: No lesion or a single punctuate white matter lesion; 1: multiple punctuate lesions; 2: Beginning confluent lesions; 3: large confluent lesions **** Benamer’s criteria: 0: preserved and largely symmetrical striatal tracer uptake; 1: asymmetric uptake with normal or almost normal putamen activity in one hemisphere, and with a more marked reduction in the contralateral putamen; 2: significant bilateral reduction in putamen uptake with activity confined to the caudate nuclei; 3: virtually absent uptake bilaterally affecting both putamen and caudate nuclei Fig. 1 Brain MRI (3 T) of case 8. Lacunar lesions in superior-anterior-medial surface of right thalamus in the proximity inferior surface of caudal nucleus (arrows) ( A : coronal T2* weighted image and B : axial T2 weighted image). Microvascular leukoencephalopathy (Fazekas grade 3). No hemosiderin accumulation in basal ganglia in T2* weighted images. No medial temporal lobe atrophy ( C and D : coronal and axial T1 weighted images) Due to the severity and persistence of parkinsonian symptoms, despite cessation of antipsychotic medication in four cases or switching to other antipsychotic agents in the rest of cases, the assessment of the basal ganglia’s presynaptic dopamine function was recommended. Patients agreed and underwent DaTSCAN. DaTSCAN scintigraphy acquisition and processing methodology as well as the analysis method of the striatal uptake ratios of DaTSCAN images have been previously depicted in detail . Visual analysis of the data was performed by two nuclear medicine specialists who were blind to patients’ clinical status. Tracer uptake patterns were classified according to the Benamer’s criteria as normal (preserved and largely symmetrical striatal tracer uptake), or abnormal grade 1 in case of asymmetric uptake with normal or almost normal putamen activity in one hemisphere, and with a more marked reduction in the contralateral putamen, or abnormal grade 2, if significant bilateral reduction in putamen uptake with activity confined to the caudate nuclei was detected, or abnormal grade 3 in cases with virtually absent uptake bilaterally affecting both putamen and caudate nuclei . The semi-quantitative analysis and calculation (cnts/pixel) of striatal uptake was based on manually drawn, irregular (almost ellipsoid) regions of interest (ROIs), encompassing the entire corpus striatum, and square ROIs in areas corresponding to the occipital cortex in the three consecutive ‘best’ subsets of a transaxial slice through the central striatum of the DaTSCAN image. The specific radiotracer binding ratios of the striatum were calculated from its mean counts per pixel vs those of the occipital cortex as reference [specific binding index in the striatum (S.B.I. ≥ 2.0)] = value for the striatum divided to the value for the occipital cortex reference . According to the visual analysis three patients had a normal study; οne had a marginally asymmetrical tracer uptake; three patients had an abnormal tracer uptake with moderately asymmetric dopaminergic loss and one patient exhibited a significant bilateral reduction in tracer uptake. Consistent with previous reports, the clinical agreement between the two raters was 75% . The specific radiotracer binding indexes point to one case with symmetrically abnormal radiotracer uptake and to two cases with unilateral abnormal uptake, whilst in all other patients the uptake was within the normal range (Table 3 ) . For the sake of clarity of presentation, the eight cases are presented in all tables in a descending order regarding the semi-quantitative calculation of tracer uptake in right striatum. Fig. 2 123 I-Ioflupane SPECT imaging, a measure of dopamine transporter density, demonstrates in case 2 normal radiotracer uptake or very mild hypoactivity in right caudate ( A ); in case 3 normal radiotracer uptake bilaterally ( B ); in case 6 bilateral striatal hypoactivity ( C ) and in case 8 bilateral hypoactivity with a more marked reduction in right striatum( D ) Based on clinical data, GDS- and MMSE results and imaging findings and in accordance with ICD-10 diagnostic criteria mental disorder- and neurological diagnoses were established . Depressive syndromes were classified as organic mood disorder in four cases and as severe depressive episode of recurrent depressive disorder in the other four. Based on neurological consultation, the diagnosis of Parkinson’s disease was established only in one case, whilst one patient with normal striatal tracer uptake was diagnosed with idiopathic tremor and case 8 with vascular parkinsonism. In all other cases parkinsonian symptoms were attributed to the administration of antipsychotics. Mild cognitive impairment due to Alzheimer’s disease was diagnosed in two cases. On discharge, no patient was treated with typical antipsychotics, while in four cases no antipsychotics were administered at all. Antiparkinsonian drugs were initiated during hospitalization or continued in six patients (Table 4 ). Interestingly, apart from one case, the number of prescribed drugs on discharge was lower in five cases or in two cases equal to that of agents with which patients were treated on admission. Table 4 Neurological and mental disorder diagnoses and medication on discharge and 12-month post-discharge follow-up outcome regarding movement disturbances and mental disorder- and neurological diagnoses Case No Hospitalization duration (in days) Discharge neurological diagnosis Discharge mental disorder diagnosis Medication at discharge 12-month post-discharge follow-up outcome 1 45 Drug-induced parkinsonism Mild Cognitive Impairment due to Alzheimer’s disease Organic mood disorder Duloxetine (90), donepezil (5) No movement disturbances Dementia due to Alzheimer’s disease 2 40 Idiopathic tremor Severe depressive episode of recurrent depressive disorder Quetapine (25), duloxetine (60), clonazepam (2), levothyroxine sodium (100 μg) Idiopathic tremor 3 90 Drug-induced parkinsonism Severe depressive episode of recurrent depressive disorder Risperidone (4), paroxetine (20), mirtazapine (60), alprazolam (4), biperiden (4) No movement disturbances 4 120 Drug-induced parkinsonism Tardive dyskinesia Mild Cognitive Impairment due to Alzheimer’s disease Severe depressive episode of recurrent depressive disorder Quetiapine (150), trazodone (50), mirtazapine (45), lorazepam (7.5), biperiden (2), pindolol (5) Tardive dyskinesia Dementia due to Alzheimer’s disease 5 60 Drug-induced parkinsonism Organic mood disorder Quetiapine (50), duloxetine (90), lorazepam (0.5), levodopa/benserazide (100/25), amiloride, hydrochloride/hydrochlorothiazide (5/50) Parkinsonism Persistent psychotic symptoms 6 35 Parkinson’s disease Organic mood disorder Escitalopram (40), lorazepam (1), levodopa/benserazide (600/150), amantadine (100) Parkinsonism 7 100 Drug-induced parkinsonism Severe depressive episode of recurrent depressive disorder Duloxetine (60), mirtazapine (45), lorazepam (1), levodopa/benserazide (200/50) No movement disturbances Dementia due to Alzheimer’s disease 8 40 Vascular parkinsonism Microvascular ischemic brain disease Organic mood disorder Duloxetine (30), rivastigmine (4.6), levodopa/benserazide (200/50), ilbesartan (150) Parkinsonism Vascular dementia For the 12-month post-discharge follow-up outcome assessment, a caregiver-based telephone interview format was employed. The interview was based on questions about movement disturbances and mental disorder- and neurological diagnoses. The individuals diagnosed on discharge with Parkinson’s disease, idiopathic tremor and vascular parkinsonism, respectively, still suffered from movement disturbances, as expected. In a patient who had been diagnosed on discharge with drug-induced parkinsonism, persistent movement disturbances were reported, despite the discontinuation of antipsychotic agents during hospitalization. In all other patients no parkinsonian symptoms were reported, in line with the discharge diagnosis of drug- induced parkinsonism. The two patients who received on discharge the diagnosis of mild cognitive impairment due to Alzheimer’s disease progressed to dementia and faced at follow-up difficulties with both complex and basic activities of daily living. Treatment with antipsychotics can induce parkinsonian symptoms, uncover subclinical degenerative and/or vascular striatal brain pathologies, or lead to the exacerbation of previously mildly manifest parkinsonian symptoms . Drug-induced parkinsonism is conceptualized as parkinsonism that occurs during drug exposure and resolves within six months after the withdrawal of the implicated agent , even though symptoms can persist beyond six to nine months cessation of the drug without evidence of impaired striatal dopamine transporter density . Drug-induced parkinsonism may be distinguished from Parkinson’s disease, since contrary to the latter, drug-induced parkinsonism is characterized by bilateral and symmetric parkinsonism, with more prominent bradykinesia and rigidity. Nonetheless, relying exclusively on the clinical manifestation of parkinsonian symptoms in order to differentiate between drug-induced parkinsonism and other causes is not a reliable and feasible strategy particularly in seniors who commonly develop atypical symptom phenotypes . Ιndeed, more than 30% of patients with drug-induced parkinsonism show asymmetric parkinsonism and tremor at rest . In older adults treated with antipsychotics, the puzzle of the genesis and clinical manifestation of parkinsonian symptoms are further perplexed by the heavy burden of coexisting brain pathologies (e.g. amyloidosis, cerebrovascular alterations, mitochondrial abnormalities) . The clinical expression of such brain pathologies may be potentiated or masked by a complex, dynamic interplay between the interacting co-pathologies and harmful and protective environmental factors (e.g. diet and lifestyle parameters, motor reserve) . Exposure to antipsychotic agents influences this interplay and may trigger the development of clinically evident parkinsonian symptoms. This dynamic equilibrium is mirrored in the complex relationships between DaTSCAN- and MRI- findings, clinical diagnoses and 12-month follow-up outcome (resolution vs. persistence of parkinsonian symptoms) in the presented eight cases. For instance, bilateral basal ganglia ischemic lesions seem to have increased the vulnerability of case 8 to the development of parkinsonian symptoms, even though he/she was treated with quetiapine, i.e. an atypical antipsychotic with low risk of aggravation of parkinsonism . Deciphering the cause of parkinsonian symptoms in seniors treated with antipsychotics is crucial for designing the proper, individualized therapeutic plan. Prescribing antiparkinsonian drugs without an established diagnosis of Parkinson’s disease or even of a Parkinson-plus syndrome, which albeit responds in most cases poorly to current therapies compared to Parkinson’s disease , is not justifiable. Antiparkinsonian agents can lead to further exacerbation of psychotic symptoms (dopaminergic agents) or induce cognitive impairment or delirium (anticholinergic agents), whilst polypharmacy is related to adverse outcomes, including adverse drug events and disability in this age group . On the other hand, cessation of the assumed causative agent in order to shed light on the cause of the parkinsonian symptoms and distinguish between drug-induced parkinsonian symptoms and a movement disorder may not be practical in many cases, since depression in late life tends to be a persistent or recurrent and not rarely a therapy resistant condition , while persistence or paradoxical progressive deterioration of parkinsonism upon antipsychotic withdrawal have been described . Thus, a rigorous and comprehensive diagnostic workup of parkinsonian symptoms, including structural brain imaging and DaTSCAN, seems to be in cases with atypical, severe and/or persistent parkinsonian symptoms inevitable, in order to design justifiable, individualized treatment plans. In addition, such a diagnostic workup can be prospectively conducted in patients thought to be at high risk for parkinsonism because of age, family history or subthreshold parkinsonian symptoms , so that a vulnerable degenerated nigrostriatal tract is identified and considered in decision making about the treatment plan. Despite the phenotypic homogeneity and the thorough and rigorous diagnostic workup of the considered patients, the presented case series has a number of limitations. Even though all patients suffered from severe depressive symptoms on admission, four were diagnosed at discharge with recurrent depressive disorder and four with organic mood disorder, while in one case the diagnosis of bipolar disorder had been established prior hospital admission. Moreover, the age of onset of the first mood disorder episode as well as performance on MMSE varied across the cases. Only four cases can be classified as suffering from late-onset depression. In four cases MMSE scores pointed to clinically significant abnormalities in cognitive function . Taking into account the differences in symptoms and pathogenesis of late-onset depression compared to other forms of depression , the complex relationship between depression and cognitive impairment in seniors , as well as the higher vulnerability of older adults to side effects of antipsychotics, studies on parkinsonian symptoms with homogenous samples with regard to mental disorder diagnosis, age at symptom onset, cognitive status and antipsychotic medication are needed. In the present cases series, the follow-up assessment was conducted twelve months after hospital discharge, although drug-induced parkinsonian symptoms can persist longer than twelve months after cessation of the offending drug . However, in general they resolve in six to nine months and 70% of patients usually recover within a few months after withdrawal of the causative drug . In addition, the diagnostic tools employed in the eight presented cases are characterized by shortcomings. For instance, the SAS has been criticized for overemphasizing body rigidity and DaTSCAN interrater variability and inconsistencies between visual interpretation and classification based on quantitative radiotracer uptake calculation , which were also observed in cases presented here (Table 3 ), are further sources of uncertainty. Regarding the impact of DaTSCAN, the diagnosis itself is not exclusively driven by imaging findings, although physicians reported previously that DaTSCAN influences their final diagnosis, confidence in their diagnosis and management of the patient . Of note, a case series including eight individuals does not suffice to generalize conclusions. Nonetheless, the observed differences in cause and 12-month follow-up outcome in this limited number of depressed older adults treated with antipsychotics point to the uncertainties related to the pathogenesis and development of parkinsonian symptoms in this clinical phenotype and age group and may fuel future research aiming to shed more light on a diagnostic riddle with therapeutic and prognostic implications. In conclusion, detecting the cause of parkinsonian symptoms in seniors who are exposed to antipsychotics and subsequently taking appropriate action is a challenging task. Indeed, parkinsonian symptoms cannot be straightforwardly classified as drug-induced in older adults treated with antipsychotics. Age-related neurodegenerative and vascular brain changes may underlie parkinsonism and shape a terrain of unreliable clinical characteristics, ambiguous exam findings and in many cases hardly justifiable therapeutic choices. Comprehensive diagnostic workup is in cases with atypical, severe and/or persistent parkinsonian symptoms the only feasible strategy for developing proper treatment plans. The field of deciphering the cause of parkinsonian symptoms in seniors treated with antipsychotics merits a systematic and thorough study of possible clinical, imaging and outcome endophenotypes of such symptoms, so that in the future personalized and efficient therapeutic strategies can be designed. Familiarizing clinical psychiatrists with effective ways to cope with inconsistent and/or ambiguous imaging and clinical data and make good diagnostic and therapeutic decisions is another step towards this direction.
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Upon presentation, the patient reported three weeks of diffuse muscle aches with stiffness in his lower extremities. His medical history was also notable for depression with psychotic features, treated with risperidone as well as cocaine use, and HIV/AIDS (prior CD4 nadir was 419 cells/mm 3 ), diagnosed 20 years ago. He had been off ART for the past three years (last regimen was tenofovir/emtricitabine, atazanavir, and ritonavir) and lost to follow up. Physical exam was notable for hypertrophied biceps and calf muscles. Labs demonstrated a CD4 count of 185 cells/mm 3 , a HIV viral load of 54,900 copies/mL, and elevated creatine kinase (CK) of 1667 U/L with normal kidney function. The cause of his muscle weakness was attributed to rhabdomyolysis from recent adjustment of his risperidone dosing and active cocaine use. Risperidone was stopped, and he was given diphenhydramine and benztropine with some improvement in his symptoms. Further infectious workup, including blood cultures, hepatitis B and C serologies, and QuantiFERON-TB gold, was negative. The patient was left against medical advice prior to ART reinitiation. He returned to the hospital 1 week later with worsening muscle pain, particularly in his calves and forearms. At this point, a broad workup for primary and secondary myopathies was performed. ANA, anti-Jo-1, and myasthenia gravis antibodies were negative; thyroid and cortisol levels were normal. An electromyogram (EMG) showed myotonic discharges and was consistent with a myopathy and a disorder of muscle membrane instability. A muscle biopsy of the left calf was performed, and pathology revealed central nuclear migration within the majority of myofibers and a significant inflammatory infiltrate, highly suggestive of myotonic dystrophy and HIV myopathy (Figures 1(a) and 1(b) ). He later revealed similar muscular complaints in other family members on the maternal side. Confirmatory genetic testing was planned in the outpatient setting, but the patient was unfortunately lost to follow up after discharge. HIV-PM is clinically and pathologically similar to autoimmune polymyositis in HIV-negative individuals [ 1 – 3 , 6 ]. On histopathology, HIV-associated inflammatory myopathy manifests as an inflammatory infiltrate within the muscle tissue, predominantly comprised of CD8+ T lymphocytes and macrophages. In a series of 15 patients with HIV-PM, histologic features were identical to those seen in polymyositis in non-HIV affected individuals . In our patient, the diagnosis of HIV-PM was made, in accordance with the 2017 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for polymyositis, based on absence of skin manifestations, the presence of muscle weakness in his legs, and findings on muscle biopsy . The pathogenesis of HIV-PM remains largely unknown, as the direct role of HIV has not been well defined [ 1 , 5 – 7 , 9 ]. One hypothesis is that inflammatory cell-derived cytokines or lymphokines lead to muscle fiber damage, precipitating muscle antigen exposure and a process where muscle fibers themselves act as antigen presenting cells, triggering an autoimmune response . Notably, the severity of inflammatory infiltrate has not been shown to correlate with a patient's symptoms or stage of HIV infection [ 1 , 5 – 7 , 9 ]. The presence of significant fiber variability and internalized nuclei in majority of the myofibers in our patient, coupled with the patient's family history and EMG findings, strongly suggested a concurrent myotonic dystrophy. Genetic testing is typically confirmatory for the diagnosis of myotonic dystrophy; however, in instances where it is unavailable like in our patient, the diagnosis can be made using clinical history and exam, EMG, and muscle biopsy findings . The histopathology findings of myotonic dystrophy are often sufficient for the diagnosis in the appropriate clinical context [ 11 – 13 ].
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Although distinct conditions, TSC and ADPKD association is described and known as a contiguous gene syndrome involving deletion of all or part of the TSC2 and PKD1 genes. ADPKD is genetically heterogeneous, with two major genes, PKD1 (Chr. 16.p13.3; approximately 78% families) and PKD2 (4p21; approximately 15%), and a rare third locus, GANAB (11q12.3; approximately 0.3%), discovered in 2018 5 . This syndrome is characterized by clinical signs of both conditions, early-onset of renal failure in their second or third decades of life, and greater risk of malignancy 2 , 4 . Angiomyolipomas (AML) are renal tumors composed of smooth muscle cells, fat, and vascular tissue in varying quantities, most being benign and asymptomatic. Although incidentally found in 0.3% of healthy adults, AMLs are strongly associated with TSC presenting an incidence of up to 80% depending on age. As they enlarge, these lesions frequently develop micro- and macro-aneurysms due to abnormal elastin-poor vascular structures, which can rupture and lead to retroperitoneal bleeding and hematuria 4 , 6 , 7 . Treatment of AMLs in TSC is still controversial. Nephrectomy and partial nephrectomy are invasive procedures and preserving nephrons is difficult. Laparoscopy, cryoablation, or radiofrequency are minimally invasive surgical techniques and have gained popularity 8 . More recently, selective arterial embolization has also been offered as an effective parenchymal sparing technique and preferred for treatment of AML in TSC patients. Herein, we report a case of embolization of a patient with ADPKD and TSC-related renal AMLs bleeding using an elastic polymer comprised of ethylene-vinyl alcohol copolymer (EVOH) dissolved in dimethyl sulfoxide (DMSO) with micronized tantalum powder ( Onyx ® , ev3, Irvine, CA , USA). Informed consent was obtained from the patient for publication of the case report and accompanying images. He was admitted to our service as hematuria became persistent and more severe, requiring blood transfusion, but hemodynamically stable. Abdominal computed tomography showed enlarged kidneys with innumerable bilateral cysts consistent with ADPKD, small fat-containing masses in the lower pole of the right kidney consistent with AMLs and hyper-attenuating material filling the right renal pelvis due to bleeding . Arterial phase evidenced multiple saccular dilatations within the inferior interlobar branches of the right renal artery, suggestive of aneurysms/pseudoaneurysms . Figure 1 a) Non-enhanced CT evidencing multiple small masses with fat attenuation in the right kidney lower pole consistent with AMLs (arrow). Hyperattenuating material filling the dilated renal pelvis and calyces due to hematuria (arrowhead). b) Maximum intensity projection arterial phase CT evidencing pseudo-aneurysms/intrarenal aneurysms in the right kidney lower pole (arrows) and bilateral cortical cysts (arrowhead). c) Coronal T2-weighted fat-suppressed magnetic resonance image shows multiple bilateral simple cysts with thin regular walls (arrows). Renal parenchyma is shown in the lower pole of the right kidney (arrowhead). Figure 2 A: Arterial phase evidenced multiple saccular dilatations (aneurysms) within the inferior interlobar branches of the right renal artery (white arrow). B: Selective arteriography of the lower pole branch with multiple saccular dilations (White arrow). C: Cone beam CT was performed to assess the remaining kidney segments. In the reconstruction, a suspicious area of active bleeding was identified in the lower pole (white arrow). D: Superselective embolization of microaneurysms with Onix-18 and control arteriography with devascularization of the lower pole branches (white arrow). We chose to perform a right renal arteriography with a 5F Cobra catheter in which multiple microaneurysms were identified in the lower pole without signs of macrofistulas or blush . Cone beam CT was performed to assess the remaining kidney segments. In the reconstruction, a suspicious area of active bleeding was identified in the lower pole . We proceeded with superselective catheterization of the branches that irrigated the lower pole with a Progreat 2.4 microcatheter (Terumo) and a Fathom-16 guidewire (Boston). Superselective embolization was performed with Onix-18 (Covidien) . Post-embolization angiography evidenced complete devascularization of the lesions in the lower pole while the remaining renal parenchyma was preserved. Serum creatinine before treatment was 1.9 mg/dL, rose to 2.6 mg/dL in the following day of embolization, and returned to baseline in 72 hours after hydration. Hemogram results remained stable and the patient no longer required blood transfusion. No complication occurred. TSC is associated with a variable spectrum of disorders including epilepsy, intellectual disability, autistic spectrum disorder, and other neuropsychiatric problems as well as skin, heart, lung, and kidney lesions 3 . Renal complications are the second cause of death in TSC patients after neurological ones and encompasses renal cysts, angiomyolipomas, impaired kidney function and, less frequently, renal cell carcinoma 7 , 9 . Around 80% of TSC patients have renal angiomyolipomas that can lead to life-threatening bleeding in 25% of cases while cysts are present in approximately 30-45% of patients and may be associated with kidney failure and hypertension. 7 In order to prevent renal complications, some authors recommend a baseline renal ultrasound before 5 years of age and a repeat every 2-3 years if results are normal, or annually if angiomyolipomas or cysts are present 9 . In summary, early molecular diagnosis of tuberous sclerosis polycystic kidney disease contiguous gene syndrome (PKDTS) may be crucial for providing appropriate disease-related surveillance and therapeutic options in patients, as well as appropriate genetic counseling for the family. ADPKD is usually inherited, but new mutations without a family history occur in approximately 10% of the cases 10 . AMLs in TSC patients usually behave differently than in the general population as they are typically larger, bilateral, rapidly grow during childhood and adolescence, and are often associated with micro and macro-aneurysms that predispose this population to hemorrhage 8 . In fact, the most severe complication of AMLs is tumor rupture, which presents as hemodynamic shock in up to 20% of cases at the time of initial presentation. AMLs rupture is related to tumor size >4 cm, tumor growth, and aneurysm formation >5mm, the latter presenting higher specificity and sensitivity in predicting this complication 6 . Besides, lesions >4 cm are more likely to grow and to require surgical intervention 11 . The stronger relationship to aneurysm formation is represented in our case as the AMLs were small but multiple micro-aneurysms lead to hemorrhage. Everolimus is approved for the treatment of TSC after failed tyrosine kinase inhibitor treatment. The effect of everolimus on TSC-associated AML was investigated in the EXIST-2 and extension studies, in which 6-month everolimus treatment reduced the AML volume by > 50% in 55% of patients (39 of 71) 12 , 13 . In the EXIST-2 extension study, the main adverse events of everolimus were nasopharyngitis (43%), stomatitis (43%), and headache (30%). Grade 3 adverse events developed in 14% (16 of 112) of the patients 13 . Based on these results, the International Tuberous Sclerosis Complex Consensus Conference (ITSCCC) recommended the use of mammalian target of rapamycin (mTOR) inhibitors for first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter 14 . As these patients usually have renal function impairment, nephron-sparing therapies are essential in order to delay the need for renal replacement therapy 7 . In patients with TSC and ADPKD this is even more important as they are at higher risk of renal failure. Superselective renal artery embolization is a minimally invasive alternative to renal resection that was initially reserved for symptomatic cases but has been also used on an elective basis in patients with large growing AMLs to prevent bleeding 15 . On angiography, renal AMLs frequently present hypervascular tumor with enlarged interlobar and interlobular arteries, tortuous, irregular and dilated intratumoral arteries, focal aneurysms or pseudoaneurysms, "sunburst" appearance of capillary nephrogram, "onion peel" appearance of peripheral vessels in venous phase, and no arteriovenous shunting 16 . Numerous embolic agents have already been used including particles, coils, vascular plugs, absolute ethanol, N-butyl 2-cyanoacrylate. and Onyx ® (Covidien, Mansfield, MA, USA) 17 , 18 . Coils should be avoided because they only provide proximal vessel occlusion, which may form collaterals around or at the distal level of occlusion, making further embolization difficult or impossible. Our team's preference in these cases is a liquid agent, as it closes the distal circulation and microaneurysms avoiding recanalization and refilling by collateral circulation. Due to the variety of composition of AMLs, the response to embolization will also be different. Fat-rich AMLs have a lower response because the tissue is hypovascular and those with higher angiomyogenic component tend to respond better to embolization 16 .
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The total global volume of surgical operations performed in 2012 was estimated at almost 313 million procedures, 1 and the rate is undoubtedly increasing as the burden of disease requiring interventional surgery increases. 2 In the same year, the International Surgical Outcomes Study Group estimated an in-hospital surgical complication rate of 16.8%. 3 From this, we can extrapolate that over 50 million patients will suffer from a surgical complication in their lifetime. Comparatively, the incidence of in-hospital surgical complication in Australia and New Zealand was reported to be 20% in 2013, 4 , 5 which was higher than the international average. More recently, a New Zealand study found that 40% of patients reported experiencing a surgical complication, 6 another indication that surgical complication rates may be rising. Although surgical complications seem ubiquitous, adverse events, which result in harm to a person receiving care, are potentially preventable. One such adverse event is when a surgical item is unintentionally left behind in the patient after surgery, also known as a retained surgical item (RSI). In most jurisdictions around the world, an RSI is a reportable adverse event. We previously reported findings from this review in our analysis of the key legal issues arising from RSI claims for compensation and the phenomenon of the vanishing trial in Australia. 7 In this paper, we focus our attention on understanding the risks, antecedents, and human costs of living with a retained surgical item and make recommendations to improve detection, responses and reporting. Over the last decade, common risk factors for RSIs have been reported in the international literature, 8–14 and the list is growing. For example, in 2018, Steelman et al examined 319 event reports of retained surgical sponges submitted to the Joint Commission in the United States of America (USA) and identified more than 1400 contributing factors across eight broad categories, with most relating to human factors (interaction between humans, such as staff orientation and supervision; medical staff credentialing and peer review; staffing levels and skill mix), leadership (eg policies and procedures and compliance; nursing and medical leadership; and organisational culture) and communication (eg oral, written and electronic; and with doctors, with administration, and among staff). 15 Prevention strategies are consistent around the world and supported by national professional organisation standards for practice, or local policies and procedures. Strategies range from manual counting of accountable items to reconcile baseline counts (undertaken before incision) with final counts (undertaken before wound closure); methodical wound exploration prior to wound closure; clear processes to be undertaken in the event of an incorrect surgical count, such as searching in the patient, in and around the aseptic field, and in the operating room environment for the missing item; use of radiographs of the operative site to locate the missing item; and effective communication among the surgical team. 16 Surgical teams routinely rely on discrepancies (for example, an incorrect count) in the manual surgical count procedure as a prevention strategy to identify situations of potential or actual RSIs. However, evidence suggests that sole reliance on manual counting procedures and radiographs (x-rays) are inadequate prevention strategies. Large seminal trials estimate that manual counting procedures are only 77% effective in picking up an RSI 17 and intraoperative x-rays are only 67% effective in picking up RSIs. 18 Furthermore, in 62–88% of RSI cases, the count at the end of the procedure was actually reported as correct. 10 , 18 , 19 In the past decade, several adjunctive technologies have been incorporated into prevention strategies, such as radio frequency identification (RFID), bar coding of surgical items or other automated counting technologies; 20–22 however, none of these newer technologies are used consistently across jurisdictions or facilities. Quantifying the incidence and prevalence of RSIs is problematic. The most frequently quoted estimates to date of the incidence of RSIs from the published literature range from 1 in 5500 to 1 in 18,760 in-patient operations. 10 , 17 , 18 Around the world, the true incidence is difficult to accurately quantify due to inconsistencies in reporting criteria and reporting requirements. The Organisation for Economic Co-operation and Development (OECD), an intergovernmental economic organisation of 37 member countries, reports annually on key indicators for population health and health system performance. In 2017, the OECD reported an average rate in 2015 for a foreign body left in during a procedure was 5.4 per 100,000 surgical discharges, ranging from 0.2 per 100,000 (Poland) to 12.3 per 100,000 (Switzerland). 23 In the 2019 data, the average rate had decreased slightly to 5.2 per 100,000 separations. 24 Attempts to quantify incidence or prevalence of RSIs have historically been drawn mainly from studies of incident reports and, in some cases, medical insurance claims. It has long been established that adverse events are underreported and studies in the last decade continue to support this finding. A retrospective study 25 of 5375 patient records in 14 hospitals in the Netherlands compared adverse events found in the patient records against the four main mechanisms of reporting: informal patient complaints, formal patient complaints, incident reports submitted by health professionals, and medico-legal claims filed by patients. Of the 498 adverse events identified in the patient records, only 18 (3.6%) were found in one or more of the four reporting systems. 25 In 2004, Australian Health Ministers agreed on a national core set of eight sentinel events requiring mandatory reporting by all Australian public hospitals, 26 with RSIs being one of the eight. Comparatively, the incidence of RSIs in Australia is higher than the international OECD average, with a reported rate in Australia in 2015 of 8.8 per 100,000 surgical admissions, 23 decreasing to 8.2 per 100,000 surgical admissions in 2017. 24 In the ten years between 2005/2006 and 2015/2016, 322 incidents of RSIs requiring re-operation or a further surgical procedure were reported by Australian hospitals. 27 In Australia, the true incidence and prevalence is also difficult to accurately quantify due not only to inconsistencies in national reporting requirements but also inconsistencies in the types of organisations that are required to report. For instance, mandatory reporting does not apply to private facilities in all states (see Supplementary Materials Table S1 ). Individual state and territory government reports detail events and circumstances, usually explored by root-cause analysis, as possible contributors to retention in specific cases. While these reports provide a useful snapshot of actual reported incidents, they contain limited detail on antecedents for retention or on the longer-term impacts on patients. This approach to legal doctrine review was strengthened by using a narrative synthesis approach, which relies mainly on the use of words and text to summarise and explain the findings from the included cases. Although originally described for use with systematic reviews of intervention effectiveness or factors influencing the implementation of interventions, we adopted the general framework for narrative synthesis described by Popay et al 30 to “tell the story” of the findings from the included cases. The four main elements of the narrative synthesis framework were: (1) developing a theory of how, why and for whom the prevention interventions work (or in the case of RSIs, did not work), (2) developing a preliminary synthesis of findings, (3) exploring relationships in the data, and (4) assessing the robustness of the synthesis for drawing and generalising conclusions. As depicted in Figure 1 , from a search pool of 5728 case records (after two duplicates were removed), only 11 decisions reporting on 10 cases 33–43 were found concerning incidents of RSIs and meeting the inclusion criteria, including one coronial case, 43 three civil appeal cases, 33 , 34 , 39 and six civil first instance cases, 35 , 38 , 40–42 including two decisions referring to the same legal matter. 36 , 37 Despite the small sample of cases available, it is possible to derive a number of observations about how RSI claims are considered in the Australian legal system. It should be noted that the majority of the 10 cases located are unreported, with only two involving a final consideration of liability and damages. 33 , 39 Figure 1 Australian case law flow diagram (diagram adapted from Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med . 2009;6(7):e1000097). 44 A brief summary of the findings of key characteristics from each of the 10 included cases are presented in Table 1 . A more detailed summary of findings table, including the material factual circumstances of the cases, antecedents for risk, and long-term impacts, can be found in the Supplementary Materials Tables S6 and S7 . Table 1 Summary of Key Findings Table (Abbreviated) Case Citation [Date, State] Type of Hospital Date of Retention (ie, Date of Surgery) Type of Surgery Item (s) Retained Means of Discovery Date of Discovery [Disclosure] Time from Retention to Discovery/Removal Elliott v Bickerstaff [1999, ACT] 33 Private 13 Jun 1991 Total hysterectomy and colpo-suspension Sponge Patient complained of “physical problems” “about six weeks later” “about six weeks” Gaynor v Milton; Ulladulla Hospital [1981, NSW] 34 Public 10 Jun 1975 Appendicectomy Piece of forceps Item known to be retained; confirmed with x-ray [Authors Note: Date of discovery unclear] [Authors Note: Details missing from record] Hughes v Minister for Health East Pilbara Health Service [1999, WA] 35 Public 20 Dec 1994 Insertion drainage tubes Drainage tube Patient complained of physical symptoms (severe central abdominal pain, nausea, vomiting, constipation, fatigue); item found by x-ray and ultrasound scan 21/22 Dec 1994 - item missing; 19 January 1995 - retention of item in abdominal wall discovered 28 days Ives v Australian Capital Territory and Anor [1995, ACT] 36 / The Australian Capital Territory v Ives [1996, ACT] 37 Public “On or around 12 Mar 1974” Securing/removing drainage tube in connection with hysterectomy Straight needle Patient had chest and spinal x-rays for unrelated condition; item revealed 11 Oct 1994 20 years, 7 months [Authors Note: item not removed due to greater perceived risk] Kenjar v Australian Capital Territory [2014, ACT] 38 Public 26 Aug 2008 Open reduction, multiple K-wire fixation of right hand Piece of K-wire Patient had pain, swelling, necrotic tissue, abscess in right hand; x-ray taken days after debridement surgery revealed item 2 Oct 2008 [Authors Note: Patient not informed of retention after initial surgery] 16 days Langley & Warren v Glandore Pty Ltd & Thomson [1997, QLD] 39 Private 22 Feb 1990 Total abdominal hysterectomy Sponge Patient had “painful symptoms” following surgery; subsequent surgery revealed item “some ten months later” “some 10 months later” Miller v Broadbent [1999, QLD] 40 Private Oct 1992 Laparoscopy stomach banding Silicon tubing Patient had ongoing abdominal pain; item revealed during exploratory surgery to identify cause of pain 5 June 1996 3 years, 8 months O’Hagan v Sakker [2011, NSW] 41 Private 10 Aug 1992 Hemi-colectomy/ sigmoid colectomy Sponge Patient admitted following fall; complained of abdominal pain; x-ray taken; item revealed 2 Oct 2007 [Authors Note: Patient only became aware of RSI after removal] 15 years, 1 month Smith v Marcus [1989, NSW] 42 Public 24 Nov 1977 Hysterectomy and insertion of drainage tube Drainage tube Patient had persistent pain and discomfort in the stomach and pelvic area exacerbated by walking. Eventually, had IVP examination, item present on film but not in report; IVP film later re-examined by GP, item confirmed by ultrasound and CT scan 24 Nov 1987 [Authors Note: Patient not aware of RSI previously] 10 years Investigation into Death of James Stirling McKinlay [2013, TAS] 43 Public 2 Jun 2012 Follow up surgery for internal bleeding post pancreaticoduodenectomy Sponge Multiple surgeries: item intentionally retained to be removed at subsequent surgery; item not found; x-ray and later CT scan taken; item visible on both films but not in either report; item revealed during subsequent surgery 14 June 2012 12 days The legal cases revealed little uniformity in the items retained as presented in Table 1 : silicon tubing in the abdominal cavity retained during a laparoscopy stomach banding operation, 40 Kirschner-wire (K-wire) fragment retained in the right hand after an open reduction and multiple K-wire fixation, 38 one instance of a drainage tube retained after a recurrent umbilical hernia, 35 and another after a hysterectomy, 42 a straight needle, which had migrated into the heart after being retained during a hysterectomy 36 , 37 a broken piece of forceps retained in the body after an appendicectomy, 34 one instance of a surgical sponge being retained in the patient’s abdominal cavity at the conclusion of a colectomy, 41 two instances of a sponge being retained after the patient underwent a hysterectomy, 33 , 39 and a final instance of a sponge being accidentally retained after being initially left in situ deliberately to stem intra-abdominal bleeding. 43 While the majority of cases involved open abdominal or pelvic surgical procedures (n = 8), one case was a minimally invasive abdominal surgical procedure, and one case was an orthopaedic upper limb procedure. The most frequently retained item was the surgical sponge, which occurred in 4 of the 10 cases. Time from retention to discovery of RSIs ranged from 12 days to 20 years with significant disparity in the manner of discovery of the retained item across the cases (see Table 1 ). In most cases, the discovery came after the patient presented with physical symptoms. In one case, 36 , 37 a retained straight surgical needle was discovered incidentally after a chest x-ray for an unrelated condition; and in another, a retained surgical sponge was discovered after presentation to the emergency room following a fall. 41 In two other cases, the RSIs were device fragments that were known to be retained at the time of the surgery; a broken forceps tip in Gaynor v Milton 34 and a broken piece of a K-wire in Kenjar v Australian Capital Territory . 38 A notable feature in three of the reviewed cases was a failure to identify a retained item that was visible on postoperative x-ray scans taken at the time of the suspected missing item. In Kenjar v Australian Capital Territory , 38 the patient underwent day surgery for an open reduction and multiple K-wire fixation to his right hand on 26 August 2008, and a later surgery on 16 September 2008 to remove the K-wires. Images taken during the earlier surgery revealed a fragment of K-wire retained in his right hand, but no action was taken to remedy this until the patient returned to hospital with pain and swelling in his right hand, necrotic skin, and an abscess on 30 September 2008, 14 days later. In O’Hagan v Sakker , 41 the patient, who suffered from longstanding abdominal and pelvic problems, underwent a partial removal of her colon on 10 August 1992 and consequently experienced fevers, abdominal cramps and loss of bowel control. She had an abdominal x-ray on 7 June 2003 in anticipation of a planned colonoscopy procedure. This x-ray film showed the retained surgical pack in the patient’s abdominal cavity; however, the Court accepted that she was not informed of this x-ray finding in 2003, when it was initially examined. The patient underwent an abdominoplasty in February 2005 and a further colonoscopy in February 2007; however, there was no evidence that x-rays were taken or viewed for these surgeries. The foreign body, which by the time of its removal was “about the size of a grapefruit”, was only discovered in late September 2007 when the patient was admitted to hospital suffering from abdominal pain after falling several days earlier. In the Tasmanian Coroners Court matter of the Investigation into Death of James Stirling McKinlay , 43 the retained pack was visible on an x-ray taken on 6 June 2012, but the radiologist did not report it, and managing doctors did not see it. The retained pack was visible in a CT scan of the abdomen on 7 June 2012, but again it was not noted. The retained pack, which was tightly compressed and separately located from the other packs, was discovered and removed during another operation on 14 June 2012. In Hughes v Minister of Health , 35 the discovery of a retained object was hindered by postoperative care failures. The patient underwent surgery in September 1993 to repair a recurrent umbilical hernia. In a later surgery, two drainage tubes were inserted to drain fluid build-up. These drainage tubes protruded from the patient’s abdomen and were connected to a fluid suction apparatus. On 20 December 1994, the drainage suction apparatus was removed, as were stitches that held the drainage tubes in place. The drainage tubes remained in place, extending approximately 20 mm from the patient’s abdomen. On 22 December 1994, the left-side drainage tube was found to be missing. Despite this discovery, the plaintiff was discharged from the hospital after the removal of the right-side drainage tube. After discharge, the patient suffered from “severe central abdominal pain, nausea, vomiting, constipation and fatigue and was incapable of working”. 35 X-rays and an ultrasound scan taken in early 1995 located the lost drainage tube within the anterior abdominal wall. The review considered whether operating room staff involved in the litigated procedures had performed appropriate procedural steps and checks in relation to the management and accountability of surgical supplies and equipment. Deviation from established protocols regarding counts and record-keeping was implicated in five cases. Only five case reports discussed counts and contemporaneous record-keeping in any detail. In four cases reporting on count status, the count was deemed correct at the end of surgery (see Table 2 ). Table 2 Count Status at Key Timepoints in the Counting Procedure Case Citation/Date Item (s) Retained Initial Count Wound Closure Count Skin Closure Count Xray Taken Elliott v Bickerstaff [1999, ACT] Sponge Not recorded in case note Not recorded in case note Correct Unable to determine if x-ray was taken Gaynor v Milton ; Ulladulla Hospital [1981, NSW] Piece of forceps Not recorded in case note Item known to be missing Item known to be missing Yes, later (+) Hughes v Minister for Health East Pilbara Health Service [1999, WA] Drainage tube Not recorded in case note Not recorded in case note Not recorded in case note [Authors'Note: tube known to be missing day after stitches removed] Yes, later (+) Ives v Australian Capital Territory and Anor [1995, ACT] Straight needle Not recorded in case note Not recorded in case note Correct Yes, much later and unrelated (+) Kenjar v Australian Capital Territory [2014, ACT] Piece of k-wire Not recorded in case note Not recorded in case note Not recorded in case note Yes, later (DOS) (+) Langley & Warren v Glandore Pty Ltd & Thomson [1997, QLD] Sponge Not recorded in case note Not recorded in case note Correct Unable to determine if x-ray was taken Miller v Broadbent [1999, QLD] Silicon tubing Not recorded in case note Not recorded in case note Not recorded in case note Yes, later (-); later exploratory surgery (+) O’Hagan v Sakker [2011, NSW] Sponge Not recorded in case note Not recorded in case note Correct Yes, 2003 xray (+) but reported (-); 2003 xray re-examined later (+) Investigation into Death of James Stirling McKinlay [2013, TAS] Sponge Not recorded in case note Item intentionally retained Incorrect - intentional retention Yes, later, misread (-); later CT scan misread (-); later exploratory surgery (+) Smith v Marcus [1989, NSW] Drainage tube Not recorded in case note Not recorded in case note Not recorded in case note Yes, later, several xray reported (-); xrays and IVP re-examined later (+) Notes: (+) Retained item found on x-ray; (–) Retained item not found on x-ray. Abbreviations: DOS, day of surgery; IVP, intravenous pyelogram. The fifth case concerning a retained surgical sponge, the Tasmanian Coroners Court inquiry into the death of James Stirling McKinlay 43 specifically discusses the importance of easily accessible and consistent documentation. The court found that the deceased underwent a lengthy and complicated “Whipples procedure” on 15 May 2012 to remove a cancer of the bile duct. Between the date of surgery and 1 June 2012, he underwent multiple surgeries, which unsuccessfully sought to address internal bleeding. The operating room nurse’s report for a further surgery on 2 June 2012 recorded that one large pack and six small packs were deliberately left in position to stem intra-abdominal bleeding. After surgery, the patient was transferred, with his medical records and notes, to the Royal Hobart Hospital. Surgery was undertaken on 4 June 2012 and six packs were removed, but one pack was accidentally retained. While Coroner Pearce found that the retained pack did not contribute to the patient’s death, he found that the deceased was transferred to the Royal Hobart Hospital with an incomplete medical record, which failed to formally communicate the number of packs left in situ on the handover. The Coroner recommended that because the count procedure is used as a risk mitigation strategy, it requires due diligence and care to ensure that the recording of the count is accurate, consistent between nursing and medical team members, and easily accessible as a communication tool, not only between clinicians but also between facilities when patients are transferred. 43 The Coroner also made the following recommendation: Each hospital should also consider whether a practice of abdominal x-ray following emergency abdominal surgery to identify and reduce the risk of retained packs might be appropriate. 43 Judgments in many cases linked deviations from the protocol closely to either inadequate verbal communication or written communication in the patient records. In two of the four cases concerning a retained surgical sponge, the count was communicated and documented (according to medical records) to be correct at the end of the surgery. 33 , 39 In one case, the correct count was implied from the trial transcripts, despite a lack of written records confirming this. 41 In either case, the presence or absence of written records impacted on the success of the plaintiffs’ or defendant’s case. For example, in O’Hagan v Sakker , 41 the judge commented on the expectation of certain documents contained in the medical record to be able to provide evidence … whether or not the relevant items were counted at the conclusion of the operation, and whether such counting was the subject of the signing off, in conformity with the usual practice. 41 Eight out of ten records reported harm suffered by the patient as a consequence of a retained surgical item. Physical harm was described in two cases. 39 , 40 In five cases, a range of both physical harms and psychosocial harms were described; 33 , 35 , 38 , 40 , 41 although in one of these the physical symptoms were masked due to multiple existing co-morbidities and were re-investigated after the patient presented to the emergency department for an unrelated fall. 41 In one case, there was no mention of physical harm prior to discovery; however, psychosocial symptoms manifested after the retained item was discovered on a chest x-ray taken for an unrelated reason. 36 , 37 It is well accepted in the academic and popular literature that reported incidents of RSIs are considered the “tip of the iceberg” when looking at the true extent of the problem in hospitals around the world. This may be due to the current absence of mandatory reporting of “near misses” and failures or delays in discovering RSIs due to patients who may be asymptomatic or suffering from non-specific symptoms; 46 that is, symptoms not initially linked to a prior surgical procedure. Furthermore, the number of incident reports for a specific event may not be a reliable reflection of the frequency of that event nor of the true risk of the event occurring. For example, following their study of a falls prevention program, Abujudeh et al warned that the prevalence of incident reports may be more a reflection of a particular organisational focus on reporting of particular incidents at that point in time. 47 More concerning is the Grattan Institute Report on Strengthening Safety Statistics, 48 which concluded that incident reports cannot be relied upon to benchmark performance over time or across organisations, or to help understand what types of adverse events or harm to patients are most prevalent. This may be because incident reporting is mostly voluntary; and, where mandatory, reporting criteria and definitions (such as “end of surgery”) are not always clear or consistent, resulting in inconsistency in measurement indicators. This therefore contributes to the possible underestimation of the actual risk of a patient leaving the operating room with an RSI. The National Hospital Morbidity Database, published by the Australian Institute of Health and Welfare, 27 provides a useful overview of the incidence of RSI retention, while a number of state government reports detailed circumstances that contributed to the retention of surgical items in specific cases. The range of factors at different levels of the process leading up to an RSI, from unsafe individual actions to latent hazard conditions within the organisational system, demonstrate the application of Reason’s accident causation model. 31 , 32 Some of these incidents arose from procedural failures (eg operating staff’s non-adherence to the use of the instrument count sheet; reliance on memory to remove a surgical gauze at the end of a procedure; performance of an organ closure despite incorrect swab count; commencement of wound closure prior to the completion of the first surgical count), and some from communication failures (eg a failure to report a missing swab after the initial swab tally was found to be incorrect; failure to confirm removal of a pack inserted by the anaesthetist). Retention also arose from issues with surgical instruments or equipment (eg use of equipment with easily removable parts, equipment failure) and use of other ancillary equipment (eg incorrect reading of intraoperative or postoperative x-rays or other scans). Government reports provide a useful glimpse of RSI incidents; however, findings from government reports of mandatory reporting are typically based on root cause analysis, which is inherently subject to human biases of the investigators, such as hindsight bias or attribution error, as they attempt to determine causal factors of an adverse event. 49 The aim of our study was not to find the one cause, per se, of the RSI or to attribute blame. We took the stance recommended by Henriksen et al 49 “to be fair and yield new knowledge” (p71). As such, our efforts were directed at the antecedent circumstances that existed for the operating room personnel before the item was retained to make sense of the previously unknown factors contributing to the retention. This study sought to examine the antecedent circumstances leading up to, and the human costs arising from, the retention of surgical items through the lens of Australian case law reports of legal proceedings relating to RSIs. From these cases, it is evident that retention of surgical items (which encompasses a diverse range of items) is a widespread phenomenon that cannot be attributed to a particular surgical practice or type of surgery. As discussed above, retention may be impacted by a number of human factors including failure to adhere to established risk mitigation processes, deficient communication and record-keeping, 50 and issues surrounding postoperative care practices including omissions in clinical handover information or mis-reading or misinterpretations of postoperative diagnostic x-rays, where in some cases, retained items later determined to be visible on postoperative scans were not identified at the time of the scan. The human factors implicated in the reviewed cases were referred to by the judges in their decisions and recommendations to address failures in the system that enabled human factors failures. The cases also revealed physical and psychosocial harms allegedly experienced by patients due to retention of the surgical item. Some of these harms were exacerbated by a lengthy delay before discovery, and most were certainly not known or expected at the time of transfer from the operating room or even prior to discharge from hospital. Clark and Oakley 51 , 52 argued that patients should be provided with comparative information about surgeons’ performance as part of the informed consent process (which is a universal pre-requisite for elective surgery) and quality assurance processes. The identified cases illustrate that operating room staff work as a team with shared responsibility and accountability for patient safety; 7 therefore, surgeon performance data alone may not necessarily be useful in the case of minimising RSIs, particularly in cases of prolonged retention. We did find, though, that current team-based risk mitigation strategies, including counting, communicating, and documenting items used during surgery, are not always effective. 7 The cases analysed in our study highlight the importance of shared responsibility, particularly for communication and documentation, and for compliance with established processes to reduce the risk of harm. The cases also highlight varying outcomes in judicial determinations of alleged negligence in the advent of an RSI. However, as such, it appears that the “elaborate ritual” 33 of manual counting and management of accountable items prescribed by ACORN in the national standards for the profession is not sufficient to prevent all incidents of RSIs from occurring. In all included case reports that explicitly discuss the count procedure, the procedures described correspond with current ACORN Standards for Perioperative Nursing in Australia. 16 As such, the fact that these procedures were not sufficient to avoid the retention of surgical items is a relevant consideration for contemporary prevention and protective strategies. Our findings in this context align with the recent findings by Gunnar et al 54 in their study of root cause analysis of RSI events, which found that a majority of incidents (64%) involved human factors issues (eg, staffing changes during shifts, staff fatigue), policy/procedure failures (eg, failure to perform methodical wound sweep) or communication errors. 54 In addition, standard and usual processes outlined in ACORN Standards for locating missing items in the event of a discrepancy in the count, including immediately notifying the surgeon, requesting a thorough re-exploration of the wound, search of environmental surroundings and intra-operative imaging, do not provide a completely effective prevention strategy. This conclusion, derived from an analysis of case law, is supported not only by the literature but also by state government patient safety reports that point to procedural non-compliance as a key contributing factor to surgical item retention. This naturally leads us to consider the need to adopt newer, technologically advanced adjunctive strategies, particularly those with evidence of effectiveness. 20 , 21 , 54 This strategy to improve detection and supplement counts, and the need for an evidence base in this area, was also highlighted by Hibbert et al. 50 The continued persistence of RSIs across the world, including Australia, highlights the shortcomings of current prevention strategies in totally preventing this sentinel event and at the same time questions the assumption that an RSI is a never-event. The occurrence of never events, such as RSIs, undermines the trust and confidence that the public has in a healthcare system. Most facilities follow-up patients for signs and symptoms of infection. A survey of 462 internal medicine patients across five university hospitals in Finland 55 found that when patients have positive health care service experiences, they participate more in ensuring their own safety during hospital care. This premise could naturally extend to post-hospitalisation patient safety practices. It is worth considering a longer postoperative follow-up period and investigation of all patient-reported outcome measures (PROMs), regardless of whether the symptoms reflect “usual” postoperative complaints (like surgical pain or surgical site infection) or are non-specific. Of course, the patient may not tell us at the time that something had been left behind. However, healthcare professionals need to improve the information and encouragement we give to patients, so patients can be more pro-active in their own postoperative safety practices, 55 such as reporting signs and symptoms some of which could assist in identifying RSIs earlier in the post-discharge period. The true incidence and prevalence of RSIs is difficult to accurately quantify due to the nature of reporting as well as the inconsistency in operational definitions and measurement indicators. For example, inconsistency in reporting near misses, that is, situations of an incorrect count where the RSI is subsequently located prior to wound closure or prior to the patient leaving the operating room. Furthermore, there are very little data on miscounts, that is, situations where the count is deemed correct at the end of the procedure, yet an RSI is identified later after the wound is closed and the patient has left the operating room, and in many cases, the hospital. By contrast, in the USA, the current Joint Commission definition is that “an unintended retained foreign object (URFO) [is] an object that is retained after skin closure has occurred following an invasive procedure”, 57 that is, the definition is not limited to cases where the retention results in serious harm or death and does not specify that the patient has left the operating room. Contrary to this, the definition from the National Quality Forum, also in the United States, states, “ … the patient has been taken from the operating/procedure room” (pB-4). In the United Kingdom, the 2009 never event was called “retained surgical instrument postoperation”, then “retained instrument”, and finally in 2011, “retained foreign body postoperation”. 58 The definitional inconsistency around the world has the potential to impact on the accuracy of indicators not only of actual RSIs but also of the true risk, making benchmarking problematic and contributing to the underestimation of the extent of the problem. Standardised data collection is important for accurately interpreting outcomes data. 59 What is needed is a globally standardised ontology and taxonomy including operational definitions and clearly demarcated measurement indicators, and mandatory reporting based on these standard indicators. Once accurate data are captured, the data need to be stored and made accessible. Changes in healthcare and developments in information systems have seen an increase in the use of big data sets captured in large national databases, particularly in surgical research. 60 Establishing a national or international registry for the tracking and surveillance of patients identified as having an RSI and those with a differential diagnosis of RSI would provide the opportunity for accurate estimates of the problem and of the risk; and may lead to global collaborative efforts to address this never event. Donabedian’s model of quality improvement posits that structure measures have an effect on process measures, which have an effect on outcome measures. 61 Thus, registry data that include structure, process and outcome indicators would allow a more complete evaluation of current strategies for preventing RSIs as well as how we have moved forward to any sustainable improvements in reducing incidence and prevalence, which technically, should be zero. The case law related to RSIs to date is very limited, with only nine civil cases and one coronial case dealing with this issue since the early 1980s, which is explained by the small number of claims that proceed to publicly available judicial determination. Further research could extend to reviewing trial transcripts, as well as de-identified insurance claims and settlement documents (if not subject to a confidentiality agreement). Nevertheless, our review of the decided cases indicates that current forms of risk management to minimise or eliminate the incidence of this sentinel event, including standards-based professional perioperative practice and mandatory reporting of adverse events, are not always effective in preventing retention. Additional measures, including newer technologies for detection, should be explored, and those with clear evidence of effectiveness should be deployed where resources permit. In addition, estimates of the true risk of RSI in Australia can be improved by more standardised and consistent reporting of risk of RSIs; not just reporting of actual events but also near misses; and consistency across jurisdictions about the definition of RSIs, including whether it is limited to cases involving serious harm or death, and the timing of when an item is considered retained (for example, before or after wound closure; before or after leaving the operating room). Finally, this study has presented a starting point for a call to action for a consistent methodology, ontology and taxonomy for mining data from case law to inform better understanding of RSIs that can contribute to better estimates of the global nature and extent of the risk, as well as the problem.
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Laterality defects (LDs) are a group of developmental diseases that affect internal organ positioning in the body. In general, human LDs can be divided into three categories: (1) situs solitus (SS) with normally expected organ arrangement; (2) situs inversus (SI) characterised by complete mirror image of organs; and (3) situs ambiguus (SA) with organ arrangement falling along a spectrum of various anomalies between SS and SI, including congenital heart defects (CHDs). Within SA, a subgroup of patients presents a severe and complex form of congenital heart disease, which is commonly known as heterotaxy ( 1 ). Defective left–right (LR) patterning of internal organs is associated with multiple congenital diseases affecting the cardiovascular system, kidneys, liver, and biliary tract ( 2 , 3 ). According to the National Birth Defects Prevention Study ( 4 ), the estimated prevalence of LD is 1.1 per 10,000 in the United States. Despite the rare likelihood of LD, its incidence is excepted to be higher among the Arab population due to their high rate of consanguinity and genetic disorders ( 5 ). The aetiology of LD is complex and includes both environment ( 5 – 7 ) and genetic factors ( 8 , 9 ). Disease-causing genetic variations are found in <20% of LD cases; and the remaining 80% of cases are due to unidentifiable causes ( 10 , 11 ). Up to now, known LD genes were mostly associated with NODAL/TGFβ signalling ( NODAL, CFC1, ACVR2B, LEFTYB, GDF1, TGFBR2 , and FOXH1 ), SHH signalling ( ZIC3 and LZTFL1 ), and monocilia function ( NPHP2, NPHP3, NPHP4, PKD2 , and TTC8 ) ( 10 ). Other genetic alterations associated with early cardiac development ( NKX2-5, CRELD1, MMP2 1, and PKD1L1 ) were also implicated in LD development ( 10 ). The main functional roles of these genes were demonstrated in LR axis determination, controlling cardiac looping direction, nodal activity regulation in embryogenesis, protein interaction of primary cilia, and signalling involved in morphogenesis cascade ( 12 – 19 ). Hence, LDs occur in a variety of different diseases, affecting various cardiac, respiratory, and gastrointestinal organs, reflecting the complex genes involved in signalling pathways of organogenesis and ciliary function. Genetic testing and molecular diagnostics are now regarded as an useful approach to discover molecular causes underlying the LD development. Whole-exome sequencing (WES) analysis proved to be a successful method to uncover novel candidate genes or novel variants in known candidate genes ( 10 ). To this end, there is an increasing need to study the rare developmental disorders across different ethnic populations due to its potential in expanding the genetic spectrum of the disease. However, literature searches reveal sparse data on the Arab LD patients. We hypothesise that genetically investigating LD patients from a consanguineous Arab society will offer new insights into disease pathogenesis by identifying novel genes or novel variants in known genes, as demonstrated in other complex diseases ( 20 ). Therefore, the objective of the present study was to identify the genetic cause of LD in Arab patients, using WES and multilevel bioinformatics-based structural (protein variant structural modelling, divergence, and stability) and functional (gene expression and knockout mouse model) analysis approaches. The ethical approval for the present study was obtained from the institutional ethics committee of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia. Informed consent forms were collected from both adult parents and their children (parental consent and children's assent for those <18 years old) prior to blood sample collection and genetic testing. As per the National Birth Defects Prevention Study, LD participants were selected based on the following clinical criteria: situs inversus , CHDs (heterotaxy), isomerism of the lungs (bilateral two lobes/left-sidedness and bilateral three lobes/right-sidedness), abdominal situs abnormality ( abdominal situs inversus and SA), and spleen abnormality (asplenia and polysplenia) ( 4 ). One LD index family composed of the proband (affected child) and both parents was recruited to paediatric cardiology, surgery, and pulmonology clinics in KAUH. Clinical, laboratory, and radiological results were independently assessed by both paediatric cardiology and pulmonology consultants. Family pedigree was drawn by interviewing the parents. Samples from two other LD families were screened for the presence of the identified candidate variants. The DNA library was prepared using Agilent Sure Select Target Enrichment Kit. DNA library was captured using ultralong 120 mer biotinylated cRNA baits. The library was sequenced using HiSeq2000 Next Generation Sequencer (Illumina, San Diego, CA, USA). The FASTQ format sequence was obtained, and reads were aligned using Burrows-Wheeler Aligner (BWA) software (Version bwa-0.7.12) against human genome reference sequence build 38 (GRCH38.p12). Variant calling was conducted using the genome analysis tool kit (GATK). The filtration pipeline was applied as follows: all coding variants that passed quality control (phred > 30 score) were included. All variants with a minor allele frequency (MAF) <0.015% were included. Known candidate gene variants were filtered based on the function of the gene and their role in LD development. Genes that are related to LD disease were collected through the Coremine Medical™ tool, National Center for Biotechnology Information (NCBI), OMIM, and literature review. The functional relevance of LD candidate genetic variant on candidate proteins was predicted by searching the nucleotide and amino acid sequences against the functional domains of concerned protein as per the listing available in Conserved Domain Database (CDD). To estimate the sequence conservation characteristics of the functional domains in the candidate protein, CDD tool uses RPS-BLAST, which rapidly scans the query protein for pre-computed position-specific scoring matrices (PSSMs). The output file demonstrates the links between protein domains with annotations against the query input sequence together with imagining choices ( 21 ). The pathogenic effects of amino acid variants on disease candidate proteins can be best understood when they are studied at the structural level. Therefore, the potential effect of LD variant on the tertiary structural features was explored through 3D simulation of the candidate protein. Based on the availability of the X-ray crystallographic structure of the query protein, either a combination of ab initio approaches or homology modelling approaches were followed ( 22 , 23 ). The 3D simulated structure of the native protein was then used to construct the mutated version of candidate protein, which was then energy minimised and then analysed for structural deformities like amino acid or whole structure level deviations using YASARA software ( 24 ). The impact of candidate variant on the stability of protein structure was estimated using DUET webserver, which contains Protein Data Bank (PDB) structures of query proteins to predict the Gibbs free energy (G) values ( 25 ). The Human Protein Atlas (HPA) ( https://www.proteinatlas.org/ ) database was used to determine the RNA expression status of the LD candidate gene. This database provides the expression profile of the query gene or protein based on primary antibody staining data in a series of immunohistochemistry pictures of clinical specimens. The functional enrichment analysis of the potential LD candidate gene was done using gene ontology (GO) webtool hosted in Ensembl web browser. Moreover, Mouse Genome Informatics (MGI) database ( http://www.informatics.jax.org/ ) was used to better understand the functional role of potential LD gene on phenotype characteristics of knockout mouse models. The MGI resource provides a comprehensive set of data, tools, and analysis designed specifically for use in mouse laboratory model. It accepts input data in the form of a gene symbol and provides output corresponding to the physiological condition of knockout mice. The proband aged 4 years 6 months at the time of clinical diagnosis was born to an apparently healthy consanguineous parents of Arab origin . The proband exhibited a spectrum of phenotypes including visceral heterotaxy (abnormal arrangements of thoracoabdominal organs) , congenital cyanotic heart disease in the form of single ventricle physiology, left isomerism with polysplenia syndrome, double inlet atrioventricular connection (a heart defect that affects the valves and chambers), pulmonary atresia, interrupted inferior vena cava with absent supra-renal segment, and azygos continuation (a rare congenital abnormality often combined with cardiovascular and visceral malformations). At the age of 10 months, the proband underwent thorough palliative cardiac procedures in the form of ductal stenting in the neonatal period followed by Kawashima cavo-pulmonary shunt (a palliative surgical procedure performed in cases of left isomerism and azygos continuation of the inferior vena cava, and common atrioventricular valve with or without regurgitation and pulmonary stenosis) in addition to left pulmonary artery (LPA) balloon dilatation procedure. At 3 years of age, Fontan completion was performed via incorporation of hepatic veins to pulmonary artery correcting thereby blood flow from the lower body parts directly to the lungs. The sequencing of the index case generated approximately 98,000 variants, including 12,150 synonymous variants, 13,000 missense variants, and 11,500 indels. Variant filtration was based on its rare frequency, deleterious potential, autosomal recessive mode of inheritance, and functional relevance to disease (LD, primary ciliary dyskinesia (PCD), congenital heart disease, and heterotaxy). Nine genetic variants were identified as potential candidates ( Table 1 ). Among these variants, only one missense variant in MYO1D novel gene has survived our variant filtration criteria. This allele is absent in local databases like GME (Greater Middle East) ( http://igm.ucsd.edu/gme/ ), DALIA (Disease Alleles in Arabs) ( http://clingen.igib.res.in/dalia/index ), and Saudi Human Genome Program (SHGP) ( https://shgp.kacst.edu.sa/index.en.html#home ). The MAF of this variant in international databases like 1,000 Genomes and gnomAD databases is 0.005 and 0.002, respectively. Although it has an allele frequency of 0.013 in the African population, only eight individuals are reported as homozygous for this variant in the gnomAD. But their clinical details are not provided in the gnomAD database. In the index family studied here, both parents were heterozygous and do not have any symptoms associated with LD, confirming the autosomal recessive inheritance pattern as we initially deduced from their pedigree analysis. Moreover, more than 80% (5/6; 83.34) of the computational prediction methods like CADD, FATHMM, MetaLR, Mutation Taster, PROVEAN, and REVEL have attributed pathogenicity scores to this MYO1D (p.Pro765Ser) variant ( Table 2 ). Functional biology data available from model organisms like Drosophila , zebrafish, and frog have proved the functional role of MYO1D gene in LDs. The PDB database search revealed the availability of partial 707 aa (between 10 and 717 of 1,006 AA long MYO1D protein) X-ray crystal protein model (4L79) with 2.3-Å resolution. Hence, the remaining 306 aa long chain was simulated with iterative threading assembly modification (I-TASSER) webserver following an ab initio approach. From the I-TASSER output, the best MYO1D model was chosen based on its polypeptide prediction quality scores like confidence score (C = −1.52), template modelling (TM = 0.53 ± 0.15), and root-mean-square deviation (RMSD) (12.7 ± 4.3 Å) scores. These quality metrics indicate the very good structural similarity between the query and template proteins . The stereochemical evaluation of the energy-minimised MYO1D protein model revealed that 96.2% of the amino acids are in the allowed portion of the protein, whereas 3.8% are in the non-allowed region. As per the above outlined processes, the native MYO1D model was used as a template to create a mutant variant by manually substituting proline for serine at the 765th position. PyMOL was used to depict native and mutant proteins. We have used YASARA tool to analyze Cα-atom coordinates of native and mutant MYO1D 3D structures to evaluate their structural drifts (in terms of RMSD) at residue and whole structure levels. RMSD value is used to quantitatively measure the structural similarity between two atomic coordinates when superimposed on each other. The impact of substitution mutations on amino acid structures can be calculated when there is a divergence at the polypeptide chain level. We noticed minor structural drifts in MYO1D structure only at 765th residue position due to the RMSD value difference (2.28) induced by the substitution of proline with serine . The DUET analysis of the MYO1D (P765S) variant predicted Gibbs free energy (ΔΔG) alterations shifting the energy equilibrium to negative value, i.e., −0.959 kcal/mol, suggesting that the queried variant is potentially deleterious to the protein stability owing to its destabilising behaviour. The HPA shows the positive expression status of MYO1D gene in different tissues and organs of the human body like the colon, lungs, and thyroid gland. In particular, the highest expression was seen in the digestive system with the colon, where the 274 transverse colon samples showed a maximum of 221.5 protein transcripts per million (pTPM) and 233 sigmoid colon samples showed a maximum of 97.8 pTPM. The RNA-Seq analysis of immunohistochemistry tissue specimens from three control specimens showed that glandular cells showed the highest pTPM status of MYO1D gene when compared with smooth muscle cells and other cell types in the colon . The Ensembl GO analysis of MYO1D gene showed its involvement in 43 GO terms, including those connected to biological processes (seven GO terms), molecular functions (11 GO terms), and cellular component (25 GO terms) ( Supplementary Table 1 ). All the annotations collectively highlight that MYO1D is localised in the cytoplasm (cellular component) and plays an important role in actin filament organisation (biological process) as well as microfilament motor activity function (molecular function). Supplementary Table 2 shows details of disease phenotypes corresponding to the MYO1D genetic background in different knockout mice models. Recent evolution and easy accessibility of next-generation sequencing resulted in accurate molecular diagnosis of variety of genetic diseases from around the globe ( 39 , 40 ). Owing to the genetic heterogeneity, identification of specific molecular cause of LD is very challenging in up to 80% of the cases. Majority of known LD causative genes are structural proteins of the cilia and are known for their involvement in NODAL/TGFβ or SHH signalling pathways. During embryonic development, these genes play an important role in symmetrical LR positioning of the organs ( 10 ). MYO1D gene consists of 27 exons mapped to chromosome 17q11.2. Myosin heavy chain class 1 is a member of the myosin superfamily, playing essential roles in cytoskeletal structure, mechanical signal-transduction membrane dynamics ( 41 ), and endosome processing ( 42 ). In the present study, we identified the first case of a homozygous missense mutation in MYO1D gene causing LD in the proband of an Arab consanguineous family. Further screening of LD participants from two additional Arab families did not reveal any mutations in this gene. In Middle Eastern Arab databases (with more than 10,000 exome data combined) such as SHGP, GMC, and DALIA, not a single case was recorded for this variant. Also, this variant was extremely rare (<0.005) in 1,000 Genomes and 0.013 in gnomAD across all ethnic groups. In gnomAD, only eight individuals were reported as homozygous (six males and two females), but no clinical data were available. Various studies suggested the role of MYO1D gene in laterality disease in Drosophila , zebrafish, and frog ( 43 – 47 ). MYO1D has a role in organ asymmetry in Drosophila , which lacks cilia and nodal pathway while developing LD by using polar cell polarity (PCP), MYO1D , and HOX gene Abd-B ( 48 , 49 ). Another study demonstrated the function of MYO1D in Xenopus laevis and influence the orientation of the cilia on the LR organiser (LRO) through planar cell polarity pathway as implicated in Drosophila ( 45 ). In zebrafish, MYO1D plays a fundamental role in the LR organisation ( 43 , 50 ). Aside from the above initial reports, our understanding of MYO1D function in the context of human LR patterning remains largely unexplored. The situs inversus (SI) phenotype is reported in approximately 50% of PCD cases with congenital cardiac defects ( 51 , 52 ). Approximately 3–7% of LD patients have CHDs ( 53 ). Many studies ( 54 , 55 ) in a variety of species failed to identify a unifying mechanism for LR patterning. However, recent studies ( 43 , 50 ) provided the first evidence of a shared origin of laterality in both arthropods and chordates through MYO1D gene. The clinical features are consistent with previous observations in zebrafish and Drosophila , indicating that MYO1D has an important role in LR patterning during embryogenesis. Moreover, asymmetric clustering of cilia was disrupted in ependymal cells of MYO1D KO rat models, consistent with LD ( 56 ). MYO1D gene knockout in different mouse strains (seven different strains) is shown to demonstrate a variety of phenotypes like decreased body fat amount (adipose tissue), decreased startle reflex (behaviour/neurological), increased susceptibility to colitis (digestive/alimentary), decreased bone mineral content (skeleton), and increased susceptibility to weight loss (growth size/body weight and immune system and mortality or ageing) . Our study is the first one to report the association of defective MYO1D to LD in humans, confirming that the function is evolutionarily conserved from Drosophila , to zebrafish, to frog, to humans. Thus, MYO1D gene can be considered as the new causal gene for LD in humans. Though the Drosophila and zebrafish models clearly showed the visceral heterotaxy, mouse KO phenotypes were surprisingly not showing any LD-related phenotypes. Extensive computational analysis of the protein structure and function adds the supporting evidence for MYO1D in LD. MYO1D protein is 1,006 aa long with a molecular weight of 116 kDa. It consists of a large, highly conserved Myocin Motor Domain (671 aa), short calmodulin-binding motif (20 aa), and a basic C-terminal tail homology-1 (TH1) domain (197 aa). The amino acid residue level structural deviation observed with the variant serine (Pro765Ser) in MYO1D is likely to disturb the primary, secondary, tertiary, and quaternary structural features in the protein. Numerous studies have shown the strong correlation between deviations in residue level RMSD score and structural properties for the disease-causing variants ( 23 , 57 – 59 ). Disease causative pathogenic mutations have often changed the energy equilibrium, which is required to maintain the protein stability ( 60 ). Given the close physical proximity of P765S variant between calmodulin-binding motif and TH1 domains, the conformational and stability changes in MYO1D protein are likely to impact its main biological functions such as calmodulin binding, actin-dependent ATPase activity, calcium-dependent protein binding, and microfilament motor activities ( 61 ). LD is a complex disease, and its clinical phenotype presentations often overlap with PCD symptoms. A recent study from Saudi Arabia reported the overlapping clinical symptoms between PCD and LD patients ( 26 ). This report investigated a total of 81 patients, including 58 patients with sinopulmonary infections (SPIs), 15 patients with combined LD with SPIs, and six patients with LD alone. They reported mutations in the known PCD genes as follows: RSPH9, CCNO , DNAAF5, RSPH4A, MCIDAS , and CCDC40 gene mutations in PCD patients with SPIs; CCDC151, DNAH11, CCDC40, DNAH5 , and CCDC39 gene mutations in LD patients with SPIs; PKD1L1 and DNAAF5 gene mutations in LD patients; and RSPH9 and MCIDAS gene mutations in neonatal respiratory distress. Additionally, they have also identified gene mutations in ITCH and CEP164 in two patients, demonstrating ITCH-related syndrome and Bardet–Biedl syndrome. Sparrow et al. ( 29 ) reported HES7 as a cause of spondylocostal dysostosis with SI and dextrocardia. Molecular diagnosis of LD and PCD in Arab patients has revealed a spectrum of mutations in many genes with variable clinical presentations ( 35 ), which is summarised in Table 3 . In conclusion, we discovered missense mutation in MYO1D gene in an Arab patient presenting with visceral heterotaxy and left isomerism with polysplenia syndrome by using higher-throughput WES technology. This is the first report to establish the relationship between MYO1D variants and LD, supporting the previous findings in Drosophila zebrafish , and frog. This exciting finding may support the critical role of MYO1D gene for LR patterning in humans. This study has some sincere limitations, as this is the first case identified with MYO1D mutation potentially contributing to LD phenotypes, and there are no reported cases with MYO1D variants to compare our data with. Therefore, testing MYO1D variants for LD patients in large cohort studies is recommended to verify our findings. Future functional studies are also recommended to investigate the specific molecular role and therapeutic prospects of targeting MYO1D genetic variants in patients demonstrating LD phenotypes.
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Superior plating of midshaft clavicle fractures is a procedure that has been performed frequently in the past with good functional results and low non-union rates 2 , 3 , 16 . Compared to anteroinferior plating, superior plating has been described as the easier technique resulting in shorter operation times 8 , 17 . Biomechanical studies have demonstrated high stability of superior plating constructs with superior stiffness in axial compression, torsion, and bending loads to failure compared to anteroinferior plates 18 – 20 . Although many authors see a potential benefit in using anteroinferior plates for the aforementioned reasons, thus far, the literature does not delineate clear indications 4 , 7 , 8 . Furthermore, the currently available literature is relatively limited and primarily looks at only short-term follow-up of less than 4 years 8 , 11 , 21 , 22 . Longer-term follow-up is especially relevant for determining the rates of implant removal. It is usually recommended to leave the plate for at least 1 year following fracture fixation; thus, studies with short-term follow-up may underestimate implant removal rates. Ethics committee approval was obtained prior to data collection and informed consent was obtained from all patients included. In this retrospective cohort study, all patients with acute, displaced midshaft clavicle fractures were operatively treated at a level-1-trauma center between May 2009 and November 2014 were included if they met the following inclusion criteria: displaced clavicle fractures type 2B according to Robinson 23 , treatment within 4 weeks after trauma 22 , patient age at time of surgery ≥ 18 and ≤ 80 years, operative treatment with either superior or anteroinferior locking compression plates (LCP), and were at least 2-year postoperatively. Patients were excluded if they had an open fracture, a prior ipsilateral clavicular fracture, and if they were not able to adhere with the postoperative protocol. This led to a total of 79 included patients. Patients treated with superior plating (group A) were compared to those with anteroinferior plating (group B). All surgeries were performed by one out of four board certified orthopedic trauma surgeons with extensive experience with this procedure. Until early April 2010, the standard plate configuration at our institution was superior plating. In late April 2010 the standard plate configuration was changed to anteroinferior plating as this was believed to result in less implant removal rates without compromising healing and stability. Figure 1 Radiographic anteroposterior images (right shoulder) of a 30-year-old female following a motorcycle accident demonstrating a midshaft clavicle fracture and fracture fixation with a superior plate. ( A ) Displaced midshaft clavicle fracture, ( B ) plate fixation with a superior plate. The approach to anteroinferior plating only differed from that of superior plating in that the incision was made slightly anterior to the clavicle and the locking compression plate (LCP, DePuy Synthes, MA, USA) was positioned onto the anteroinferior aspect of the clavicle . This plate position allowed for the placement of long screws from anteroinferior to posterosuperior, especially in the lateral aspect of the clavicle. Figure 2 Radiographic anteroposterior images (right shoulder) of an 18-year-old male following a fall while playing soccer demonstrating a midshaft clavicle fracture and fracture fixation with an anteroinferior plate. ( A ) Displaced midshaft clavicle fracture, ( B ) plate fixation with an anteroinferior plate. At a minimum 2-year follow-up, patient-reported outcome scores were collected including the age and gender adjusted Constant score (aCS) 24 , Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, and Visual Analog Scale (VAS) at rest and under stress. The aCS was chosen as the primary outcome measure. Bony healing was assessed on the most recently obtained radiographs and was defined as an invisible fracture line or bridging callus across the fracture line. In addition to the aforementioned scores, patients completed questionnaires regarding implant removal, time to implant removal, and return to work/previous workplace. Statistical analysis was performed with PRISM version 8.4.0 (GraphPad, San Diego, CA, USA). Categorical data are presented as number and percentages. For continuous data, mean and standard deviation (SD) were used if the data was normally distributed, and median and interquartile range (IQR) if the data was non-normally distributed. The independent t test was used for univariate analysis for normally distributed data and the Mann–Whitney test for nonparametric data. Bivariate data was analyzed with the Fisher exact test. Subgroup analyses were performed for implant removal rates of male and female patients. The level of significance was set at P < 0.05. Patient demographics for each study group are summarized in Table 1 . The groups did not differ significantly in age, injured side, hand dominance, dominant-sided injury, polytrauma, and time to surgery; however, there was a significant difference between groups regarding gender (group A: 18 (64.3%) vs. group B: 45 (88.2%); P = 0.018). Table 1 Demographics of the patient cohort. Demographics Total Superior Anteroinferior P value Age, mean ± SD, y 48.5 ± 13.0 47.4 ± 13.8 49.2 ± 12.6 0.567* Gender, n (%) Male 63 (79.7) 18 (64.3) 45 (88.2) 0.018 † Female 16 (20.3) 10 (35.7) 6 (11.8) Injured side, n (%) Right 32 (40.5) 9 (32.1) 23 (45.1) 0.339 † Left 47 (59.5) 19 (67.9) 28 (54.9) Dominant side, n (%) Right 70 (88.6) 27 (96.4) 43 (84.3) 0.147 † Left 9 (11.4) 1 (3.6) 8 (15.7) Dominant side injured, n (%) Yes 39 (49.4) 11 (39.3) 28 (54.9) 0.241 † No 40 (50.6) 17 (60.7) 23 (45.1) Polytrauma, n (%) Yes 22 (27.8) 10 (35.7) 12 (23.5) 0.298 † No 57 (72.2) 18 (64.3) 39 (76.5) Time to surgery, median (IQR), d 6 (4–9) 6.0 (3.0–8.8) 6.0 (4.0–10.0) 0.479 # Significant values are written in bold text. IQR: Interquartile range, SD: standard deviation, *: Independent t test, † : Fisher exact test, # : Mann–Whitney test. Injury mechanisms are summarized in Table 2 . The most common mechanisms of injury were bicycle accidents (40.5%), followed by motor vehicle accidents (25.3%). Table 2 Injury mechanisms. Injury mechanism Total Superior Anteroinferior Bicycle accident, n (%) 32 (40.5) 10 (35.7) 22 (43.1) Motor vehicle accident, n (%) 20 (25.3) 9 (32.1) 11 (21.6) Sport accident, n (%) 9 (11.4) 3 (10.7) 6 (11.8) Falls from ≤ 1.5 m, n (%) 9 (11.4) 2 (7.1) 7 (13.7) Falls from > 1.5 m, n (%) 7 (8.9) 3 (10.7) 4 (7.8) Other, n (%) 2 (2.5) 1 (3.6) 1 (2.0) Time to follow-up and outcome scores are summarized in Table 3 . Time to follow-up differed significantly between groups (group A: 5.7 (4.7–7.1) years vs. group B: 4.3 (3.0–5.9) years; P = 0.001). When comparing the aCS between groups, group B showed a significantly higher score compared to group A (group A: 90 (85.0–91.0) vs. group B: 91 (90.0–93.0); ( P = 0.037)). There was no significant difference in the QuickDASH score ( P = 0.384), VAS at rest ( P = 0.283), and VAS under stress ( P = 0.286) between the two groups (Table 3 ). Table 3 Outcome variables. Outcome Variables Total Superior Anteroinferior P value Time to follow-up, median (IQR), y 4.9 (3.7–6.1) 5.7 (4.7–7.1) 4.3 (3.0–5.9) 0.001 # aCS, median (IQR) 91 (86.0–93.0) 90 (85.0–91.0) 91 (90.0–93.0) 0.037 # QuickDASH, median (IQR) 2.9 (0.6–11.9) 4.6 (0.8–18.5) 2.1 (0–11.3) 0.384 # VAS at rest, median (IQR) 0 (0–1) 0 (0–1) 0 (0–2) 0.283 # VAS under stress, median (IQR) 1 (0–3) 0 (0–2) 1 (0–3) 0.286 # Implant removal, n (%) Yes 51 (64.6) 17 (60.7) 34 (66.7) 0.630 † No 28 (35.4) 11 (39.3) 17 (33.3) Time to implant removal, median (IQR), m 14.5 (11–17.6) 17.0 (11.0–23.0) 14.0 (11.0–16.5) 0.154 # Bone union, n (%) Yes 76 (96.2) 27 (96.4) 49 (96.1) > 0.999 † No 3 (3.8) 1 (3.6) 2 (3.9) Return to work, n (%) Yes 75 (94.9) 27 (96.4) 48 (94.1) > 0.999 † No 4 (5.1) 1 (3.6) 3 (5.9) Return to previous workplace, n (%) Yes 63 (91.3) 21 (87.5) 42 (93.3) 0.412 † No 6 (8.7) 3 (12.5) 3 (6.7) Significant values are written in bold text. aCS: adjusted Constant score, DASH: Disability of the Arm, Shoulder and Hand, IQR: Interquartile range, VAS: Visual Analog Scale, † : Fisher exact test, # : Mann–Whitney test. Both groups showed similar implant removal rates without significant differences (group A: 60.7% versus group B: 66.7%; P = 0.630) (Table 3 ). There were no differences in overall implant removal rates between males and females (63.5% vs. 68.8%; P = 0.78) and no difference between removal rates for males and females in group A (55.6% vs. 70%; P = 0.69) or group B (66.7% vs. 66.7%; P = > 0.99) (Table 4 ). Additionally, time to implant removal did not differ significantly between groups ( P = 0.154). Table 4 Implant removal rates by gender and plate position. Plate position Male Female P value Removed Not removed Removed Not removed Superior, n (%) 10 (55.6) 8 (44.4) 7 (70.0) 3 (30.0) 0.69 † Anteroinferior, n (%) 30 (66.7) 15 (33.3) 4 (66.7) 2 (33.3) > 0.99 † Total, n (%) 40 (63.5) 23 (36.5) 11 (68.8) 5 (31.2) 0.78 † † : Fisher exact test. A total of 76 out of 79 patients (96.2%) had healed at final follow-up. Of those, one patient in group B had a non-union and was revised 412 days after primary surgery, and two patients (one in each group) suffered re-fracture shortly after implant removal in the absence of excessive trauma and were revised 755 and 380 days following the primary surgery, respectively. Demographic data of these patients are demonstrated in Table 5 . Table 5 Demographic data of the patients with compromised bony healing. Group Sex Age, y Comorbidity Complication Revision Time to revision, d Follow-up, y Healing Outcome A Male 51 – Refracture following implant removal LCP + iliac crest autograft 755 4.8 Yes DASH 0 aCS 91 VAS at rest 0 VAS under stress 0 B Female 57 Hashimoto Refracture following implant removal LCP + iliac crest autograft 380 3.8 Yes DASH 5 aCS 82 VAS at rest 0 VAS under stress 0 B Male 40 – Non-union LCP + iliac crest autograft 412 5.7 Yes DASH 24.2 aCS 75 VAS at rest 2 VAS under stress 6 aCS: adjusted Constant score, DASH: Disability of the Arm, Shoulder and Hand, IQR: Interquartile range, LCP: locking compression plate, VAS: Visual Analog Scale. Table 6 summarizes complication and revision rates. A total of 13 plate-related complications were found in group A (46.4%) compared to 16 plate-related complications in group B (31.4%); but there was no significant difference between groups ( P = 0.226). No significant difference was found with regard to revision surgery; a total of seven patients in group A (25%) and five patients in group B (9.8%) underwent revision surgery due to plate related complications ( P = 0.102). At final follow-up, pain was the most common recorded complication (2 in group A, 7 in group B) followed by postoperative paresthesia (4 in group A and 2 in group B). Table 6 Complications and revisions. Complications and revisions Total Superior Anteroinferior P value Plate-related complications, n (%) Yes 29 (36.7) 13 (46.4) 16 (31.4) 0.226 † No 50 (63.3) 15 (53.6) 35 (68.6) Pain 9 (11.4) 2 (7.1) 7 (12.1) Paresthesia 6 (7.6) 4 (14.3) 2 (3.4) Infection 3 (3.8) 1 (3.6) 2 (3.4) Implant failure 3 (3.8) 2 (7.1) 1 (1.7) Soft-tissue compromise 2 (2.5) 1 (3.6) 1 (1.7) Refracture after implant removal 2 (2.5) 1 (3.6) 1 (1.7) Hematoma 2 (2.5) 2 (7.1) 0 (0) Exostosis 1 (1.3) 0 (0) 1 (1.7) Non-union 1 (1.3) 0 (0) 1 (1.7) Revision surgery, n (%) Yes 12 (15.2) 7 (25.0) 5 (9.8) 0.102 † No 67 (84.8) 21 (75.0) 46 (90.2) Re-osteosynthesis and iliac crest autograft 3 (3.8) 1 (3.6) 2 (3.4) Re-osteosynthesis 3 (3.8) 2 (7.1) 1 (1.7) Superficial wound revision 2 (2.5) 1 (3.6) 1 (1.7) Hemostasis 2 (2.5) 2 (7.1) 0 (0) Deep wound revision 1 (1.3) 1 (3.6) 0 (0) Debridement of exostosis 1 (1.3) 0 (0) 1 (1.7) † : Fisher exact test. Prior clinical studies demonstrated higher numbers of implant removal following superior plating, mostly due to symptomatic hardware 8 , 11 or cosmetic issues 4 , 8 , 9 . In contrast, we found no significant difference in the implant removal rate, and even a trend towards a higher rate in the anteroinferior group. However, our findings are in line with those of Hulsman et al. 22 who demonstrated a similar removal rate for superior and anteroinferior plates and found that plate positioning was not associated with implant-related irritation. Also, the common assumption, that female patients desire implant removal more frequently was not verified by our study. The overall removal rate, as well as the rates for the superior and anteroinferior group did not show significant differences in female patients when compared to male patients. In the present study, the anteroinferior plating group reached a significantly higher aCS compared to the superior plating group ( P = 0.037). However, the minimal clinically important difference (MCID) for the Constant score for patients undergoing rotator cuff repair has been demonstrated to be 10.4 points, thus questioning the clinical significance of this result 25 . This is further emphasized by the fact that no significant differences between anteroinferior and superior plating were found in the other assessed clinical outcome scores. Although the MCID for the Constant score of 10.4 points was established for rotator cuff repair, we are not aware of any studies investigating the MCID for clavicle fractures. Formaini et al. 8 evaluated the clinical outcome based on the VAS and the Oxford Shoulder Score. Patients with anteroinferior plating reached a significantly higher score in the OSS ( P = 0.008), but no differences were found in VAS. This is consistent with our finding of a significantly higher aCS in the anteroinferior group compared to the superior group, but no statistical differences in the VAS. Controversial results were presented by Sohn et al. 21 who performed a prospective randomized controlled trial to compare minimally invasive plating in the superior versus the anteroinferior position. No differences in CS, pain, strength, range of motion or activities of daily living were observed between the two groups 21 . In this study, high bone union rates in excess of 95% for both groups were demonstrated. A total of three non-unions where observed, with no significant differences between superior compared to anteroinferior plating. One patient in the anteroinferior group had an obvious non-union that was revised 412 days following primary surgery. The other two patients (one in each group) had their plates removed at an external clinic and sustained a refracture within 1 month following implant removal without adequate trauma. Clinically, this is highly suspicious for non-union as well, although radiographs prior to the hardware removal were not available. For this reason, they were also considered to be a non-union. Overall, these findings are supported by other groups who demonstrated comparable bone union rates for anteroinferior compared to superior plating 8 , 11 , 21 . We observed similar numbers of plate-related complications and revisions in both groups without significant differences. However, a trend towards higher numbers was seen for the superior group. Whereas in the superior group 46.4% of patients had a complication, only 31.4% in the anteroinferior group had a complication. Admittedly, these numbers are high for both groups and the reason may be that our definition for complications was relatively strict (e.g. pain, paresthesia). Consistent with the number of complications, there were also more revisions performed in the superior group (25% vs. 9.8%). Of note, there were two patients in the superior group and one patient in the anteroinferior group that had an implant failure. This may be considered a sign of non-union; however, in these cases implant failure occurred within the first month after surgery and is likely due to patient compliance. Since our results demonstrated similar outcomes for both groups, we have to reject our hypothesis. In consequence, we recommend choosing the plate position based on patient specific factors and by taking into account surgeon preference. For individuals with limited soft-tissue coverage, the anteroinferior plate position may be advantageous, whereas patients with high physical demands, such as manual laborers or athletes, may benefit from the superior biomechanical stability that has been shown for superior plating 18 – 20 . This study is subject to several limitations. First, this study contains bias that is inherent to its retrospective design. The time periods were of different length subsequently leading to the limitation of unequal group sizes. With larger and more similar groups sizes, the observed trends in some outcome parameters may have reached statistical significance. Second, the follow-up period for the superior plate group was longer, thereby subjecting this group to a higher chance of failure. Third, although performed at a single center and thus reducing variability in approach and technique, surgeries were performed by four surgeons. However, all surgeons exclusively performed superior plating in the first period of time, and anteroinferior plating in the second period of time.
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Other
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biomedical
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en
| 0.999997
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34881252
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Sudden visual loss is an ophthalmologic emergency. Central retinal artery occlusion (CRAO), one of the common etiological factors, can lead to sudden visual loss ( 1 , 2 ). Systemic conditions play an important role in the development of CRAO ( 3 ). Bee sting may lead to local and systemic reactions due to sensitization of the patient. A symptomatic spectrum of a bee sting ranges from mild local reaction to death ( 4 ). Inflammation caused by bee stings, such as keratopathy and endophthalmitis, has been well-reported ( 5 – 8 ). Recently, Pujari et al. described a patient with CRAO after bee sting; this patient was treated with systemic steroids and his systemic workup was normal at 1 week following the incidence, the exact pathogenesis of CRAO in this case is not clear ( 9 ). In this study, we present another case of visual loss caused by CRAO after bee sting, which was accompanied with hypersensitivity, hypercoagulable state, myocardial damage, and hepatic damage. Forty-eight hours later, visual loss in left eye was observed by an ophthalmologist. She was referred to our Eye Center. On presentation, the visual acuity was 20/32 in right eye and no light perception (NLP) in left eye. The intraocular pressure was 16 mmHg in right eye and 19.5 mmHg in left eye. Examination of left eye revealed eyelid edema, conjunctiva congestion, a 6-mm fixed pupil , scattered retinal hemorrhage, and white-appearing ischemic retina with one small area of the normal-appearing retina temporal to the optic disk . The CRAO with one cilioretinal artery sparing was identified by fundus fluorescein angiography . Except for mild cortical cataract, the ocular examination was unremarkable in right eye. She was admitted to the emergency department of our hospital and systemic workup was performed. Increased total immunoglobulin E 910 IU/ml (reference 0–100 IU/ml) indicated hypersensitivity. Decreased activated partial thromboplastin time 25 s (reference 30–45 s) and increased D-dimer 590 ug/L (reference 0–500 μg/L) indicated a hypercoagulable state. Increased creatine kinase 3,340 U/L (reference 0–145 U/L) and creatine kinase-MB 68 U/L (reference 0–24 U/L), decreased left ventricular diastolic function by cardiac Doppler ultrasound and T wave change in the left anterior wall by ECG were observed, which revealed myocardial damage. Increased alanine aminotransferase 97 U/L (reference 0–34 U/L) and aspartate aminotransferase 200 U/L (reference 0–34 U/L) indicated hepatic damage. Increased lactate dehydrogenase 507 U/L (reference 140–271 U/L) may be associated with the myocardial damage and hepatic damage. Other systemic workups including blood test (routine, C reactive protein, erythrocyte sedimentation rate, electrolyte routine, procalcitonin, B-type natriuretic peptide, immunoglobulin, complement, and renal function), color Doppler ultrasound (bilateral thyroid and cervical lymph nodes, liver, gallbladder, pancreas, spleen, bilateral kidney, ureter, and bladder), cranial MRI, and high-resolution CT (orbital and chest) were within normal limits. The patient received treatments including dilation of the central retinal artery (sublingual isosorbide nitrite), reduction of intraocular pressure (intravenous mannitol), topical eye drops (Tobramycin and Dexamethasone eye drops, Pranoprofen eye drops, and Olopatadine eye drops), and systemic treatment (methylprednisolone, compound glycyrrhizin, ceftriaxone sodium, and glutathione). After 5 days of treatment, the visual acuity was still NLP in left eye with mildly decreased activated partial thromboplastin time 28.8 s (reference 30–45 s) and mildly increased D-dimer 510 ug/L (reference 0–500 ug/L), normal creatine kinase 37 U/L (reference 0–145 U/L) and creatine inase-MB 20 U/L (reference 0–24 U/L), normal aspartate aminotransferase 26 U/L (reference 0–34 U/L), mildly increased alanine aminotransferase 46 U/L (reference 0–34 U/L), and lactate dehydrogenase 351 U/L (reference 140–271 U/L). Bee stings are common environmental injuries, generally resulting in some limited discomfort and swelling at the site of the sting with minimal residual effect. Occasionally they cause severe adverse reactions such as anaphylaxis, cardiovascular collapse, and death ( 10 ). Bee venom contains a complex mixture of biogenic amines, enzymes, and polypeptide toxins ( 11 ). A sudden release of highly concentrated biogenic amines, such as histamine in the venom, produces vasodilatation and increase in capillary permeability and an immunologic reaction to high molecular weight enzymes in the venom-induced type 1 hypersensitivity response mediated by immunoglobulin E ( 12 – 14 ). The patient was in coma for 2 h after bumble bee sting. When she woke up, left eyelid edema and blurred vision of the left eye were reported, following dizziness, headache, nausea and vomiting, multiple diarrhea, which indicated that the bee venom caused serious systemic symptoms. Ansotegui et al. suggest that immunoglobulin E testing is the basis for the diagnosis and evaluation of suspected allergic diseases ( 15 ); significantly increased total immunoglobulin E was observed in this patient, which provided evidence for the allergic reaction in this patient. As bee venom activates some inflammatory and vascular events resulting in occlusion in vessels or diseases in the electrical system of the heart, it may cause myocardial infarction or atrial fibrillation ( 16 ). Decreased activated partial thromboplastin time and increased D-dimer, which indicated hypercoagulable state, may attribute to the myocardial damage that was revealed by increased creatine kinase and creatine kinase-MB, ECG, and cardiac Doppler ultrasound. Local reactions, such as pain, wheal, flare, edema, and swelling, are common and generally self-limiting. The lesions of the eye after bee stings may be caused by toxic and allergic reactions ( 17 ). Ocular features after bee sting include conjunctivitis, corneal infiltrates, cataract formation, acute iritis with keratic precipitates, hyphema, lens subluxation, and rarely retinal damage ( 12 – 14 , 18 ). In this patient, blurred vision and visual loss in left eye were reported 2 and 48 h, respectively, after being stung, which were consistent with the fundus fluorescein angiography examination showing CRAO with one cilioretinal artery sparing. Recently, one study reported the first case of CRAO following multiple bee stings ( 9 ). The exact pathogenesis of CRAO in this case is not clear, because the systemic workup including blood investigations, carotid Doppler, and echocardiography was within normal range at 1 week following the incidence, which might be attributed to steroid-induced resolution of allergic and toxic reactions. A transient vasospasm of the central retinal artery via the Kounis reaction following bee stings appears as the most likely mechanism of CRAO. A transient hypercoagulable state caused by large-dose envenomation is another possible mechanism. Thrombotic events either due to direct toxin effect or toxic vasculitis may also be responsible for this vascular complication ( 8 ). In our case, hypersensitivity, hypercoagulable state, myocardial damage, and hepatic damage were observed 2 days after bee sting. After 5 days of systemic treatment, her systemic workup was within normal range 1 week after the bee sting.
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Clinical case
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biomedical
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en
| 0.999997
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35001200
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The novel 2019 coronavirus disease (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly around the world and has caused many deaths . Although efforts to recognize and manage COVID-19 have been focused on elucidating the respiratory complications, it has now become clear that COVID-19 infection occasionally involves atypical presentations, such as gastrointestinal manifestation and thromboembolic complications . COVID-19 may predispose to both venous and arterial thromboembolism including stroke, myocardial infarction, acute limb ischemia, mesenteric ischemia, deep venous thrombosis, and pulmonary embolism, due to excessive inflammation, hypoxia, immobilization and diffuse intravascular coagulation [ 2 – 7 ]. Acute mesenteric ischemia, especially superior mesenteric artery (SMA) occlusion, is a critical condition with a high mortality rate of 60–80% which requires urgent diagnosis and treatment . COVID-19 and acute SMA occlusion seem to be a very deadly combination knowing the destructive nature of both alone . To date, limited cases of these lethal patient subgroup have been reported in the world. Herein, we report a first case of SMA occlusion in patient with COVID-19 pneumonia successfully treated by surgical intervention in East Asia. A 70-year-old man, who had been taking with aspirin, dabigatran and other medication for atrial fibrillation, hypertension, type 2 diabetes mellitus and dyslipidemia, presented to his local physician with a 3-day history of cough and diarrhea. A real-time reverse transcriptase-polymerase chain reaction test of his nasopharyngeal swab specimen showed positive for SARS-CoV-2 nucleic acid, and he was admitted to the source hospital with the diagnosis of moderate COVID-19 pneumonia. He had been administered one liter of supplemental oxygen via nasal cannula and treated by remdesivir and dexamethasone. Antithrombotic therapy with dabigatran and aspirin for comorbidities was continued after his admission. Eight days later, acute onset of severe abdominal pain appeared, and he was diagnosed as right renal infarction by contrast computed tomography (CT) at that time. Although heparinization was administered immediately, his clinical course was complicated with worsening abdominal pain and respiratory condition. On the next day, he was transferred to our hospital with severe general condition, and intubated immediately. Contrast CT in our hospital showed that bilateral lower lobe/middle lobe and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonia and right renal infarction. In addition, it demonstrated SMA occlusion with intestinal ischemia suggesting extensive necrosis from the jejunum to the transverse colon . A retrospective re-review of the CT at the previous hospital showed SMA occlusion was already presented at that time. After consultation with surgery departments, the patient underwent an emergency exploratory laparotomy. During operation, institutional COVID-19 precaution guideline was implemented with appropriate personal protective equipment. Upon exploration, the intestine from jejunum at 100 cm from Treitz ligament to middle of transverse colon appeared clearly necrotic. We resected necrotic bowel and evaluated the blood flow in the preserved intestine by utilizing an indocyanine green fluorescence imaging device, photodynamic eye camera. Although intestinal blood flow was confirmed by the system, considering severe general condition of the patient, we constructed jejunostomy and transverse colon mucous fistula without primary anastomosis. Fig. 1 Contrast computed tomography (CT). Contrast CT revealed ground glass opacification with distribution suggestive of COVID-19 pneumonia ( a ), right renal infarction ( b , white arrow), and superior mesenteric artery occlusion (yellow arrow) with intestinal ischemia suggesting extensive necrosis from the jejunum to the transverse colon ( c ) He was extubated the next day of the surgery and out of intensive care unit on postoperative day 2. The jejunostomy and transverse colon mucous fistula had revealed favorable color with no signs of necrosis. After surgery, the patient was continued on heparinization, and then transitioned to apixaban on postoperative day 11. We performed second surgery to close the jejunostomy and transverse colon mucous fistula with end-to-end anastomosis on postoperative day 22. The postoperative course was uneventful and he required no nutritional treatment despite having only 100 cm small bowel. He moved to another hospital for rehabilitation to improve activities of daily living (ADLs) on postoperative day 45. As of 6 months after the surgery, his ADLs have completely improved and he has returned to social life without any intravenous nutritional supports for short bowel syndrome. SARS-CoV-2 infection and its disease, COVID-19, have spread rapidly and led the pandemic around the world. COVID-19 has been known a respiratory disease, mainly pneumonia, but also it causes a variety of organ damage . It has been reported worldwide that COVID-19 causes abnormal coagulation from a systemic inflammatory immune response and induces thrombosis-related complications, which is mostly venous thrombosis . Arterial occlusion is less common complication of this disease, but it can involve fatal prognosis . In our literature review on PubMed, total 17 cases (including our case) of SMA occlusion in COVID-19 have been reported from over the world (Table 1 ) [ 3 , 7 , 9 – 22 ]. Out of the 14 cases with a description about detailed prognosis in the papers, 5 had died in hospital. Table 1 Literature review: summary of the case reports of SMA thrombosis with COVID-19 infection Case no. Authors Year Country Age Sex Medical history Preventive anti-thrombotic therapy Treatment Outcomes 1 Amaravathi et al. 2020 India 45 M None Missing Thrombectomy and laparotomy Unknown 2 Azouz et al. 2020 France 56 M Missing Missing Endovascular thrombectomy/laparotomy Unknown 3 Bannazadeh et al. 2020 USA 55 M HT, hyperthyroidism Heparin Laparotomy Alive 4 Barry et al. 2020 France 79 F None None Thrombectomy and laparotomy Dead 5 Beccara et al. 2020 Italy 52 M Missing Heparin Thrombectomy and laparotomy Alive 6 Cheung et al. 2020 USA 55 M HT Missing Thrombectomy and laparotomy Alive 7 Karna et al. 2020 India 61 F DM, HT Enoxaparin Laparotomy Dead 8 Krothapalli et al. 2020 USA 76 F Af, CAD, DM, HF, HT Apixaban Conservative management Dead 9 Ucpinar et al. 2020 Turkey 82 F Af, CKD, HT Enoxaparin Conservative management Dead 10 Vulliamy et al. 2020 UK 75 M None None Thrombectomy and laparotomy Unknown 11 Balani et al. 2021 India 37 M None None Thrombolysis and thrombectomy Alive 12 Chaubal et al. 2021 India 9 M Missing Missing Laparotomy Alive 13 Dinoto et al. 2021 Italy 84 F CKD, DM, HT Aspirin Endovascular thrombectomy Dead 14 Hanif et al. 2021 Pakistan 20 F None None Laparotomy Alive 15 Mahrugi et al. 2021 Oman 51 M Missing Missing Thrombectomy and laparotomy Alive 16 Mitchell et al. 2021 USA 69 M Missing None Thrombectomy and laparotomy Alive 17 Current case 2021 Japan 71 M Af, DM, HT Dabigatran + aspirin Laparotomy Alive SMA superior mesenteric artery , USA United States of America , UK United Kingdom, Af atrial fibrillation, CAD coronary artery disease , CKD chronic kidney disease , DM diabetes mellitus , HF heart failure, HT hypertension This present case is a first report from East Asia about acute SMA occlusion associated with COVID-19 pneumonia. This is presumably because the distribution of COVID-19 epidemics varies among regions in the world, and the situation of the pandemic revealed relatively stable in East Asia, including Japan, compared to other regions. It suggests that if patients with COVID-19 will increase from the current level, it will be necessary to pay attention to this lethal complication even in areas where the pandemic situation has been currently stable. Acute mesenteric arterial occlusion most commonly results from thrombosis based on atherosclerotic disease, or embolism where the embolus originates from the left atrium as a consequence of atrial fibrillation . Interestingly, in our literature review, SMA occlusion also occurred in COVID-19 patients who had no risk factors for thromboembolic diseases, which is consistent with previous review . The mechanisms of arterial occlusion in patients with COVID-19 are still unclear. Emerging evidence suggests that COVID-19 is associated with (1) endotheliitis by diffuse endothelial damage and infiltration of inflammatory cells, and (2) a systemic hypercoagulable state caused by hyperinflammation and hypercytokinemia [ 25 – 27 ]. These factors of COVID-19 patients can provide a plausible explanation for the mechanisms of arterial occlusion; highlighting the impact of COVID-19 infection on both thrombosis and embolism. Further fundamental researches to elucidate the mechanism are essential to establish anticoagulation/antiplatelet therapy for preventing this lethal complication. In our case, due to his medical history of atrial fibrillation, he had been managed with dabigatran since before the thromboembolic complication developed. However, he had multi-site thromboembolism, SMA occlusion and renal infarction. In our literature review, 3 out of 12 patients with a detailed description of their medical history had atrial fibrillation (Table 1 ). Recently, anticoagulation therapy with heparin and low molecular weight heparin has been reported to be useful for prevention of thrombotic complication with COVID-19 infection . Importantly, despite 7 patients (6 of them had high risk factors for thromboembolic diseases such as atrial fibrillation, diabetes mellitus, hypertension, and dyslipidemia) were maintained with preventive anticoagulation therapy by heparin/low molecular weight heparin or direct oral anticoagulants, they developed SMA occlusion. These results suggest that COVID-19 patients with thromboembolic risk factors are categorized as a high-risk subgroup for SMA occlusion, and stronger anticoagulation, possibly including antiplatelet therapies, may be necessary for those patients, as in our case. In order to establish the preventive strategies for arterial occlusion in COVID-19, further clinical/basic studies using large patient cohorts are required. Necrotic bowel resection is essential for saving lives in most cases of SMA occlusion. In our literature review, 13 cases underwent laparotomy with necrotic bowel resection. It had described the detail of surgical procedures in 9 cased, 4 out of 9 patients were reconstructed with primary anastomosis, and another 5 were constructed intestinal stomas. There were no reports that cases underwent second surgery for intestinal stoma closure. In our case, since the patient's general condition including respiratory function was stable after first surgery, we performed jejuno-transverse colon anastomosis on postoperative day 22. As a result, it was possible to discharge the patient on independent ADLs without intestinal stomas. The decision of whether to perform primary or secondary anastomosis and the optimal timing of secondary anastomosis should be determined, based on the intestinal and general condition, as well as the severity of COVID-19 pneumonia. We have reported a first case of SMA occlusion in a patient with COVID-19 pneumonia in East Asia. Intensive treatment including surgical procedures allowed the patient to return to social life with completely independent ADLs. Although treatment for COVID-19 involves many challenges, including securing medical resources and controlling the spread of infection, when severe abdominal pain occurs in patients with COVID-19, physicians should consider SMA occlusion and treat promptly for life-saving from this deadly combination.
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Review
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biomedical
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en
| 0.999995
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35038044
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Breast cancer remains the most lethal malignancy in women worldwide . Mortality from breast cancer is associated with metastatic spread. The sites of metastasis vary, and the most common sites are lymph nodes, bone, lung, brain, and liver . However, the number of breast cancer survivors increases with advances in diagnosis and treatment, the development of secondary malignancies and unusual metastatic patterns is being frequently recognized . Microscopic metastases of primary breast cancer to the kidney are commonly found at autopsy with an incidence of 12.6% . Yet clinically apparent renal metastasis from breast cancer is rare and there are several case reports describing the radiologic findings and symptoms of kidney metastasis from breast cancer . In addition, to the best of our knowledge, there are no prior reports of kidney metastasis from breast cancer presenting with a thrombus in the inferior vena cava. It is sometimes difficult to tell the differences on imaging between primary cancer of the renal pelvis and a metastatic lesion. Herein, we showed a breast cancer patient with metastases of kidney and tumor thrombus in inferior vena cava and the necessity of biopsy before treatment for presumed renal cancer. A Japanese woman in her forties visited a nearby clinic because of lower abdominal pain. Thirteen years prior, she had undergone a left mastectomy with sentinel lymph node biopsy for breast cancer; the pathological diagnosis was invasive ductal carcinoma, pT1aN0M0, stage IA. Her tumor was positive for ER and PgR, and negative for HER2. She received tamoxifen plus goserelin for 2 years as adjuvant therapy. Contrast-enhanced CT showed masses in her left lung and a mass in her right kidney, with an apparent tumor thrombus in the inferior vena cava. The renal tumor displayed hypovascular features in both the early and late phases, exhibited diffuse and invasive growth, and occupied the entire right kidney . She was diagnosed with primary kidney cancer. Based on the imaging findings, we suspected papillary renal cell carcinoma or chromophobe renal cell carcinoma more strongly than clear cell renal cell carcinoma because of the hypovascular and homogeneous features present in our patient’s lesion. The tumor thrombus in the vena cava reached to the height of the diaphragm, so it was impossible to insert a venous filter. Although surgical resection was considered, the lesion was too large. Instead, molecular targeted therapy consisting of nivolumab and ipilimumab for renal cell carcinoma was started. Unfortunately, the tumors did not shrink after 3 months of therapy. The patient underwent a CT-guided needle biopsy of the kidney and lung lesions; pathological examination revealed that both organs contained lesions resembling primary breast cancer that were ER positive, PgR positive and HER2 negative . Other immunohistological examinations such as TTF-1 showed that her tumors were breast cancer metastasis and she was referred to our department. Considering that a pulmonary thrombus could be lethal if the patient’s tumor collapsed as a result of systemic chemotherapy, we selected endocrine therapy consisting of tamoxifen, leuprorelin, and abemaciclib. After a few months of treatment, her hepatic and renal dysfunction worsened, and she was unable to continue systemic therapy. She died 6 months after starting systemic treatment. Fig. 1 Contrast-enhanced CT. A right renal tumor is occupying the entire right kidney and protruding outside the cortex. There is a tumor thrombus visible in the inferior vena cava on early phase ( a ) and late-phase ( b ) imaging. Positron emission tomography–CT shows kidney metastasis with a tumor thrombus in the inferior vena cava (arrows) and lung metastases (dashed arrow) ( c ). Plain CT shows a tumor in the left lung ( d ) Fig. 2 Pathological findings. Almost of all breast cancer lesions had intraductal cribriform structures. There was small invasive lesions with mucus representing stromal infiltration ( a , HE ×200). ER positive ( b ), PgR positive ( c ) and HER2 negative (1+) ( d ). Renal tumor had proliferative tumor cells with ductal and cribriform structures, and the tumor cells are similar to those of breast cancer ( e , HE ×400). ER positive ( f ), PgR positive ( g ) and HER2 negative (2+, FISH negative) ( h ) for renal tumor. Cells in lung tumor were also similar to those of breast cancer ( i , HE ×400). ER positive ( j ), PgR positive ( k ) and HER2 negative (2+, FISH negative) ( l ) for lung tumor. Both TTF-1 and Napsin-A were negative (not shown) Metastases to the kidney are often diffusely invasive and form small, multiple, bilateral, circular- or wedge-shaped lesions that rarely protrude outside the kidney capsule . The most common form of kidney cancer, clear cell carcinoma, has smooth edges and a uniform internal structure. However, when the tumor grows, it sometimes forms irregular edges, developing an uneven internal structure and cystic features . Contrast-enhanced CT shows a hypervascular lesion with a high degree of contrast effect in the early phase, and lower absorption than the surrounding normal renal parenchyma in the late phase. In contrast, papillary renal cell carcinoma and chromophobe cell carcinoma, which are atypical renal cancers, have hypovascular characteristics on contrast-enhanced CT . Our patient had a kidney lesion that formed a diffusely invasive, large, single mass that protruded outside the cortex. While invasion into the inferior vena cava from a renal metastasis of breast cancer has not been previously reported, tumor thrombus in the renal vein and inferior vena cava reportedly occurs up to 10% of patients with renal cell carcinoma . Therefore, renal lesion was initially diagnosed as renal cell carcinoma in this case. Recently, the use of renal tumor biopsy has been rapidly increasing due to improvements in safety and accuracy of diagnosis. However, traditionally, renal tumor biopsy is only performed for selected patients in whom pathological information is needed for treatment decisions . Renal biopsy is recommended when kidney masses are suspicious for metastatic disease in the presence of a known extrarenal malignancy . In our patient, her early breast cancer was 13 years prior, so she was considered to have no known current extrarenal malignancy. It is our opinion that kidney biopsy is required for a definitive diagnosis in patients with a kidney lesion and a tumor thrombus in the inferior vena cava, even though this is a very rare presentation in a patient who had early stage breast cancer 13 years prior.
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Clinical case
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biomedical
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en
| 0.999999
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35199642
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Galvanic current applied using a percutaneous needle is an emerging and minimally invasive technique that seeks to regenerate damaged tissues . The needle used to apply galvanic current is guided, using ultrasound equipment, into affected soft tissues by direct visualization and therefore is able to stimulate locally the cells in the damaged area. Percutaneous needle electrolysis consists of applying a galvanic current through an acupuncture needle and thus combining mechanical and electrical stimulation of the tissue that results in a local controlled microtrauma. This microtrauma in turn generates a local inflammatory response that makes possible and fosters the repair of the affected tissue . Galvanic current has been successfully used to repair chronic non-resolving lesions, such as tendinopathies developed after prolonged extreme exercise, which often establish a degenerative condition of the tissue that impairs healing and complicates clinical management . In randomized trials, anti-inflammatory therapies have shown to be ineffectual at treating these types of lesion and application of galvanic currents by percutaneous needle alone has been found sufficient when it comes to regenerating the tissue . Resolving inflammation promotes a response that recovers homeostasis by repairing tissues . However, chronic non-resolving inflammation can induce continuous tissue regeneration and excessive accumulation of extracellular matrix components, which in turn leads to fibrosis of soft tissues . Therefore, a balanced inflammatory response is required to recover homeostasis and successfully heal tissue . In response to tissue damage, the nucleotide-binding oligomerization domain with leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome is specifically activated over other inflammatory pathways and coordinates an inflammatory response . NLRP3 inflammasome is a multiprotein complex induced in myeloid cells after the detection of damage- or pathogen-associated molecular patterns, including elevated concentrations of extracellular ATP, changes in extracellular osmolarity or detection of insoluble particles and crystals, such as uric acid crystals or amyloid deposition . These triggers specifically induce NLRP3 activation over other inflammasomes as they decrease intracellular K + concentration resulting in conformational change of NLRP3 structure and, therefore, active NLRP3 oligomers . Active NLRP3 oligomers recruit the accessory apoptosis-speck-like protein with a caspase recruitment and activation domain (ASC) that favors the activation of the inflammatory caspase-1 . Caspase-1 proteolytically processes immature pro-inflammatory cytokines of the interleukin (IL)–1 family to produce the bioactive form of IL-1β and IL-18 . Caspase-1 also processes gasdermin D protein (GSDMD), and its amino-terminal fragment (GSDMD NT ) oligomerizes in the plasma membrane forming pores, thus releasing IL-1β and IL-18 cytokines, as well as other intracellular content, including inflammasome oligomers . Prolonged NLRP3 activation occurs in different chronic inflammatory, metabolic and degenerative diseases such as gout, type 2 diabetes or Alzheimer , therefore selective small molecules that block NLRP3 are emerging as novel anti-inflammatory therapies . However, in some pathological circumstances, a boost, rather than an inhibition, of NLRP3 would be more beneficial for reducing clinical complications, such as in immunosuppressed septic patients, who have high mortality rates due to secondary infections associated with a profound deactivation of the NLRP3 inflammasome . The detailed molecular mechanism behind percutaneous needle electrolysis inducing an inflammatory response has not been yet described, so we studied if NLRP3 inflammasome could be activated via galvanic currents and if doing so would lead to tissue regeneration. We found that applying galvanic current via percutaneous needle electrolysis activated the NLRP3 inflammasome and induced the release of IL-1β and IL-18 from macrophages. Mice deficient in NLRP3 failed to increase IL-1β in tendons after percutaneous needle electrolysis and ended up with reduced TGF-β and type I collagen deposition with high dispersion of collagen fibers, which in turn resulted in tendons with decreased resistance. All this indicates that the NLRP3 inflammasome plays an important role in the regenerative response of the tendon after application of therapeutically percutaneous needle electrolysis. We initially designed and produced a device to apply galvanic current to adherent cultured cells in six-well cell-culture plates , this device allowed us to explore the effect of galvanic currents in mouse macrophages derived from bone marrow. Applying 12 mA of galvanic current twice for 6 s each time to LPS stimulated macrophages increase the expression of Cox2 and Il6 genes . However, it did not affect LPS-induced Il1b or Tnfa pro-inflammatory gene expression . Interestingly, meanwhile Tnfa expression was upregulated with galvanic current alone , galvanic currents did not induce the expression of Cox2 , Il6 or Il1b genes on non-LPS-treated macrophages, or over IL-4-treated macrophages . When macrophages were polarized to M2 by IL-4, galvanic currents decreased the expression of the M2 markers Arg1 , Fizz1, and Mrc1 ; however, this decrease was small and non-significant for the M2 marker Ym1 . These data suggest that galvanic current could enhance the pro-inflammatory signature of M1 macrophages whilst decreasing M2 polarization. We next studied the concentration of released pro-inflammatory cytokines from macrophages, and found that galvanic current did not increase the concentration of IL-6 or TNF-α released after LPS stimulation , but that it did significantly augment the release of IL-1β in an intensity-dependent manner . These data indicate that the increase in Il6 and Tnfa gene expression detected at mRNA level does not transcribe to higher release of IL-6 and TNF-α over LPS treatment, but that galvanic current could potentially activate an inflammasome that induces the release of IL-1β. Given that IL-1β release is increased by the activation of caspase-1 after the canonical or non-canonical formation of inflammasome , we next studied the release of IL-1β induced by galvanic current in macrophages deficient in caspase-1 and –11 to avoid both the canonical and non-canonical inflammasome signaling. We found that Casp1/11 -/- macrophages fail to release IL-1β induced by galvanic current . We then found that applying galvanic current to Pycard -/- macrophages also failed to induce the release of IL-1β, which indicated that the inflammasome adaptor protein ASC is also needed to activate the inflammasome . Since applying current could be considered a sterile danger signal, we next assessed the role of NLRP3 as an inflammasome sensor important for eliciting an immune response in sterile dangerous situations . Nlrp3 -/- and the use of the specific NLRP3 inhibitor MCC950 impaired the release of IL-1β induced by galvanic current , demonstrating that the NLRP3 inflammasome is activated when galvanic current is applied. Similarly, galvanic current was also able to induce the release of IL-18 , another cytokine dependent on the activation of the inflammasome. The use of MCC950 or macrophages deficient in NLRP3 failed to release IL-18 after galvanic current was applied , which confirms that galvanic current stimulates NLRP3 to induce the release of both IL-1β and IL-18. Similar results were obtained with controls using the specific NLRP3 activator nigericin . Mechanistically, the use of an extracellular buffer with 40 mM of KCl decreased IL-1β release induced by nigericin and galvanic current application, but not the release of IL-1β induced by Clostridium difficile toxin B, which activates the Pyrin inflammasome, which is a K + -efflux independent inflammasome . However, two pulses of 12 mA of galvanic current for 6 s failed to decrease intracellular K + , but increasing the number of pulses of galvanic current to eight did result in a significant decrease of intracellular K + . These data suggest that galvanic current slightly decreases intracellular K + when compared to the application of the K + ionophore nigericin and this explains the smaller concentration of IL-1β that is released by galvanic current compared to nigericin application . After applying galvanic current we were able to detect the generation of the active p20 caspase-1 fragment, and processed IL-1β and GSDMD NT . MCC950 was able to abrogate caspase-1 activation and the processed forms of IL-1β and GSDMD NT , which suggests functional activation of caspase-1 and downstream signaling because of the activation of canonical NLRP3 and rules out the non-canonical NLRP3 activation that would result in GSDMD processing in the presence of MCC950. To ensure that the galvanic current was activating NLRP3, we used HEK293T cells that were stably expressing NLRP3-YFP protein, a method widely used to assess NLRP3 activation . Fluorescence microscopy showed that 2 impacts of 12 mA of galvanic current for 6 s induced the formation of an intracellular NLRP3–YFP punctum, which was inhibited by the application of MCC950 . All these data confirm that galvanic current activates the NLRP3 inflammasome, and since NLRP3-deficient macrophages failed to release IL-1β or IL-18, that no other inflammasome expressed in the macrophages was being activated. Given that GSDMD was processed and the N-terminus was detected after the application of galvanic current, we next assessed pyroptosis by means of Yo-Pro-1 uptake in cells to measure plasma membrane pore formation and cell viability, and LDH leakage from the cell to determine plasma membrane damage. Two impacts of galvanic currents of different intensities (3, 6, 12 mA) for a period of 6 s only induced a slight increase in cell death . This increase in cell death was not associated with the activation of the inflammasome given that it was also present in macrophages deficient in NLRP3, ASC or caspase-1/11 , which in turn suggests that it occurred independently of inflammasome-mediated pyroptosis. Increasing the number or the length of time of 12 mA impacts of galvanic current on macrophages, resulted in a time-dependent increase in cell death , which correlates with higher concentrations of IL-1β and IL-18 release . However, whereas IL-1β and IL-18 release was blocked by MCC950 , LDH release was not dependent on NLRP3 activation . This further corroborates the fact that the NLRP3 activation is dependent on the intensity and time of galvanic current application. Similarly, two impacts of 12 mA for a period of 6 s were unable to induce plasma membrane permeabilization measured in terms of Yo-Pro-1 uptake during a period of 3 h . Yo-Pro uptake increased over 3 h in an intensity dependent manner (3, 6, 12 mA) when eight impacts were applied for 6 s . This increase in plasma membrane permeabilization was not reversed after NLRP3 was blocked with MCC950 or when ASC-deficient macrophages were used . All these results demonstrate that doses of 3 or 6 mA of galvanic current for impacts of 6 s do not compromise cell viability but are still able to induce an inflammatory response dependent on NLRP3 activation, in contrast to current intensities of 12 mA which, if prolonged cause significant cell death independently of the inflammasome. When studying the effect of galvanic current in vivo, we found that application of 3 impacts of 3 mA of galvanic current for 3 s in the calcaneal tendon of mice increased the number of polymorphonuclear cells after 3 days when compared with tendons treated with needling alone . This increase returned to basal after 7 days and stayed low up to 21 days after galvanic current application . Similarly, the number of F4/80 + macrophages increased 3 days after the application of galvanic current when compared to needling alone and returned to basal levels after 7 days . Other immune cell types detected in the tendon, such as mastocytes, were not significantly increased by galvanic current when compared to needling alone . Given that polymorphonuclear cells increased in a similar manner to macrophages, we then aimed to investigate if galvanic current might also induce the release of IL-1β from neutrophils. However, the application of galvanic current to LPS-primed neutrophils failed to release IL-1β or LDH . Other histological features of the tendon (general structure of the tendon, number of tenocytes, shape and area of tenocyte nuclei or neo-vascularization) were also unaffected by the application of galvanic currents compared to needling alone . We next assessed the expression of different pro-inflammatory cytokines in the calcaneal tendon 3 days after 3 impacts of 3 mA of galvanic current application for 3 s to characterize the molecular inflammatory response in the tendon. Expression of Il6 , Il1a, and Il1b , as well as the IL-1 receptor antagonist ( Il1rn ) and the chemokine Cxcl10 all increased after percutaneous electrolysis when compared to needling alone . However, as shown in Figure 1 the increase in Il6 cytokine gene expression induced by galvanic current in macrophages did not correlate with an increase in IL-6 cytokine secretion in vitro. Different NLRP3 inflammasome genes also exhibit an increase in expression ( Nlrp3 , Pycard , Casp1 ) when galvanic current was applied, but this increase was not significant when compared to needling . Gsdmd expression was not upregulated in the tendons after galvanic current application . These data suggest that galvanic current induces an inflammatory response driven by the infiltration of polymorphonuclear cells and macrophages, together with an increase in the expression of several cytokines and chemokines. In order to evaluate if the NLRP3 inflammasome mediates the inflammatory response in tendons after percutaneous electrolysis, we applied galvanic currents to the calcaneal tendon of Nlrp3 -/- mice. Application of 3 impacts of 3 mA of galvanic current for 3 s in the calcaneal tendon of Nlrp3 -/- mice resulted in a significant reduction of Il1b , Il1rn and Cxcl10 expression after 3 days when compared to wild type mice . Specific inflammasome associated genes, such as Pycard , Casp1, or Gsdmd (except for Nlrp3 ) did not affect their expression in the calcaneal tendon of Nlrp3 -/- mice 3 days after the application of galvanic current when compared to wild type mice . Surprisingly, galvanic current tended to increase both the expression of Il6 in the tendons of Nlrp3 -/- after 3 days and the number of polymorphonuclear cells . However, the number of macrophages was not affected in the Nlrp3 -/- calcaneal tendon when galvanic current was applied . We also confirmed a decrease in Il1b and Cxcl10 expression in the tendons of Pycard -/- mice 3 days after the application of galvanic current , which suggests that the NLRP3 inflammasome is important in modulating part of the inflammatory response after the application of galvanic current. Galvanic current application has been widely used to resolve chronic tendinopathies in different tendons , and as an example we present here a case where lateral epicondylitis was resolved in 6 weeks after four sessions of percutaneous electrolysis through the application of 3 mA of galvanic current for 3 periods of 3 seconds (3:3:3) , in accordance with the clinical protocol previously described by Valera-Garrido and Minaya-Muñoz . During tissue regeneration, the production of new extracellular matrix through collagen deposition is a key process . In order to determine if the inflammatory response mediated by the NLRP3 inflammasome after galvanic current application is important for tissue regeneration, we measured Tgfb1 expression as a key factor in inducing collagen production. We found that in vivo the expression of Tgfb1 3 days after the application of galvanic current in the calcaneal tendon of mice was dependent on NLRP3 . Likewise, after 7 days of percutaneous electrolysis the levels of type III collagen were decreased, with a parallel increase in type I collagen when compared to needling alone . However, percutaneous electrolysis did not affect collagen fiber properties (width or length) when compared to needling alone . The increase in type I collagen 7 days after galvanic current application was reduced in Nlrp3 -/- mice . NLRP3 also controlled the structural dispersion of collagen fibers, which was decreased by galvanic current application in wild type mice, but increased in Nlrp3 -/- mice . All these results suggest that the NLRP3 inflammasome controls the response of galvanic current thus inducing type I collagen production and arranging the collagen fibers. This controlled deposition of collagen fibers induced by galvanic current increased tendon stiffness and decreased the maximum tension supported by the tendon . NLRP3 inflammasome was responsible for increased tendon stiffness after galvanic current application . Overall, we found that the application of galvanic current is able to activate the NLRP3 inflammasome and induce the release of IL-1β, thus initiating an inflammatory response that regenerates the tendon by increasing type I collagen, arranging the collagen fibers and increasing the resistance of the tendon to changes in length . In this study, we demonstrate how the application of galvanic current induces in macrophages a pro-inflammatory signature, mainly characterized by the activation of the NLRP3 inflammasome and the release of mature IL-1β and IL-18. This is in agreement with the fact that the NLRP3 inflammasome is a key pathway for controlling inflammation in the absence of pathogenic microorganisms (in sterile conditions) by executing a pro-inflammatory type of cell death called pyroptosis . Here, we found that galvanic current application, a technique that has been widely used to resolve chronic lesions in humans , was able to activate the NLRP3 inflammasome and induce IL-1β and IL-18 release, but with very little associated pyroptotic cell death. This could be due to two potentially different mechanisms: ( i ) that after galvanic current application an alternative means of processing GSDMD occurs which is independent of NLRP3 and which could inactivate its N-terminal lytic domain, as has been previously found for caspase-3 processing GSDMD ; and/or ( ii ) that the small amounts of GSDMD NT found could create a small number of pores in the plasma membrane, thus facilitating their repair by the endosomal sorting complexes required for transport machinery, which in turn leads to an hyperactive state of the macrophage . During this state of the macrophage, IL-1β is released in the absence of cell death . However, an increase in the intensity and the time of galvanic current application leads to an increase in cell death that was independent of the inflammasome and could be related to the technique per se. Therefore, clinical application of current intensities above 6 mA would probably lead to necrosis of the tissue and not to an efficient reparative process. Galvanic currents of 3 and 6 mA for 2 impacts of 6 s are both able to induce NLRP3 inflammasome activation in vitro and lead to phenotypic changes in the tendon in vivo. This is in line with the fact that 3 mA of galvanic current is able to induce a clinically significant regeneration of lesions . High-intensity doses for long periods of time or repeated impacts could induce massive tissue necrosis and are therefore not recommended for clinical practice. The activation of the NLRP3 inflammasome induced by galvanic currents was found to be dependent on K + efflux, because extracellular high concentrations of K + were able to block IL-1β release, and high intensities of galvanic current decreased intracellular K + . This is similar to the effect of the well-studied K + ionophore nigericin, which dramatically decreases intracellular K + and releases IL-1β . In fact, the amount of IL-1β released from galvanic current activated macrophages was lower than when macrophages were activated with nigericin, which suggests that the NLRP3 activation is correlated with the decrease in intracellular K + . The low NLRP3 activation induced by galvanic current application could result in a moderate inflammatory response in vivo that is beneficial for tissue regeneration. In fact, NLRP3 was important for inducing an inflammatory response in vivo with increased quantities of different cytokines including Il1b or Cxcl10 , that conditioned the structure and functions of the treated tendons. However, NLRP3 deficiency does not affect Il6 production or the infiltration of polymorphonuclear cells when galvanic currents are applied in vivo. This shows that NLRP3 induced by galvanic current is able to control a specific inflammatory program in vivo, but it probably do not affect the IL-6-mediated infiltration of polymorphonuclear cells in tendons. Exacerbated NLRP3 activation could led to fibrosis , which suggests that NLRP3 could control collagen deposition. The mild activation of NLRP3 found after galvanic current application was associated with increased production of Tgfb1 , increased in collagen type I vs type III in tendons, and reduced structural dispersion of collagen fibers. This is associated with an increase in tendon stiffness, which is related to the resistance of the tendon to changes in length. Tendon stiffness is reduced during ageing and results in weaker tendons . This could explain previous clinical findings related to galvanic current therapy, such as the fact that almost all patients treated with galvanic current in tendon lesions had no relapses at long term and the fact that application of galvanic current in human tendon lesions in combination with exercise therapy achieved greater functional recovery compared to exercise alone , and also compared to the combination of exercise with other rehabilitation interventions such as electrotherapy or mechanical intervention . Thus, our findings could help professionals to choose and combine rehabilitative and orthopedic treatments. However, a limitation of our study is that using animals restricts us to employing the ultrasound-guided puncture when applying galvanic current to the calcaneal tendon of mice, because it is the largest accessible tendon, whereas in humans galvanic current has been applied supraspinatus , patellar and lateral epicondyle tendons. In all tendons, applying galvanic current was found to have a similar clinical benefit, but we cannot rule out the fact that the calcaneal tendon of mice would present a different response to galvanic current. In fact, different species have been reported to have different inflammatory tenocyte responses , and although mice and humans present high overall similarities in their tenocyte responses , it is necessary to apply galvanic current in the presence of specific NLRP3 blockers, such as MCC950, in additional animal models with species other than mice. All experimental protocols for animal handling were refined and approved by the local animal research ethical committee and the Animal Health Service of the General Directorate of Fishing and Farming of the Council of Murcia . C57/BL6 mice (wild type) were obtained from Jackson Laboratories. NLRP3-deficient mice ( Nlrp3 -/- ) and Caspase-1/11-deficient mice ( Casp-1/11 -/- ) in C57/BL6 background were a generous gift of I. Coullin. For all experiments, mice between 8 and 10 weeks of age were used. Mice were bred in specific pathogen-free conditions with a 12:12 h light-dark cycle and used in accordance with the animal experimentation guidelines of the Hospital Clínico Universitario Vírgen de la Arrixaca , and the Spanish national and EU legislation. Percutaneous needle puncture was performed with 0.2 x 16 mm needles (Agupunt) in the calcaneal tendon in isoflurane (Zoetis) anesthetized mice; galvanic current was applied using Physio Invasiva equipment (Prim) delivering three impacts of 3 mA for 3 s and compared to a puncture without current application. Paws without puncture were also used as controls. 3, 7, 14, and 21 days after puncture, animals were euthanized and paws were collected for histopathology or gene expression. Only calcaneal tendon was dissected for gene expression and the zone between gastrocnemius and calcaneus, including tendon, adipose tissue, tibia, and peroneus, was dissected for histopathology. A male patient, 36 years old with lateral epicondylalgia in the right elbow for 6 months, with pain and functional impairment. Resistant to conventional treatments (physiotherapy, oral non-steroidal anti-inflammatory and local corticoid infiltrations). Ultrasound analysis showed extensor joint tendon degeneration correlating with positive orthopedic tests. The patient was subjected to four sessions of percutaneous electrolysis with an intensity of 3 mA of galvanic current for 3 s, 3 times (3:3:3), according to the protocol by Valera-Garrido and Minaya-Muñoz, 2016 . Bone-marrow-derived macrophages (BMDMs) were obtained from wild type, Casp1/11 -/- , Nlrp3 -/- and Pycard -/- mice. Cells were differentiated for 7 days in DMEM (Lonza) supplemented with 25% L929 medium, 15% fetal bovine serum (FCS, Life Technologies), 100 U/ml penicillin/streptomycin (Lonza), and 1% L-glutamine (Lonza). After differentiation, cells were primed for 2 h with 1 µg/ml E. coli lipopolysaccharide (LPS) serotype O55:B5 at (Sigma-Aldrich) or for 4 h with 20 ng/ml recombinant mouse IL-4 (BD Pharmigen). Cells were then washed twice with isotonic buffer composed of 147 mM NaCl, 10 mM HEPES, 13 mM glucose, 2 mM CaCl 2 , 1 mM MgCl 2 , and 2 mM KCl, pH 7.4, and then treated in OptiMEM (Lonza) with different intensities and time of galvanic current using an ad hoc adaptor for six well plates , and then cultured for 6 h. Alternatively and as a positive control, after LPS-priming macrophages were treated for 6 h in OptiMEM with 1.5 µM nigericin (Sigma-Aldrich) or 1 µg/ml Clostridium difficile toxin B (Enzo Life Sciences) to activate NLRP3 and Pyrin inflammasomes respectively. In some experiments, cells were treated with 10 µM of the NLRP3 inflammasome inhibitor MCC950 after LPS priming and during inflammasome activation. The presence of lactate dehydrogenase (LDH) in cell culture supernatants was measured using the Cytotoxicity Detection kit (Roche), following manufacturer’s instructions. It was expressed as the percentage of the total amount of LDH present in the cells. For Yo-Pro uptake, macrophages were preincubated for 5 min at 37 °C with 2.5 µM of Yo-Pro-1 iodide (Life Technologies) after galvanic current application or 1% triton X100 (Sigma-Aldrich) application. Yo-Pro-1 fluorescence was measured after the treatments every 5 min for the first 30 min and then every 30 min for the following 3 h with an excitation wavelength of 478 ± 20 nm and emission of 519 ± 20 nm in a Synergy neo2 multi-mode plate reader (BioTek). Intracellular K + was quantified using macrophages lysates, as has already been reported , and measured by indirect potentiometry on a Cobas 6000 with ISE module (Roche). After cell stimulation, cells extracts were prepared in cold lysis buffer and incubated at 4 °C for 30 min and then centrifuged at 12,856 x g for 10 min at 4 °C. Cells supernatants were centrifuged at 12,856 x g for 30 s at 4 °C and concentrated by centrifugation at 11,000 x g for 30 min at 4 °C through a column with a 10 kDa cut-off (Merk-Millipore). Cell lysates and concentrated supernatants were mixed with loading buffer (Sigma), boiled at 95 °C for 5 min, resolved in 15% polyacrylamide gels and transferred to nitrocellulose membranes (BioRad). Different primary antibodies were used for the detection of interest proteins: anti-IL-1β rabbit polyclonal , anti-caspase-1 (p20) mouse monoclonal , anti-gasdermin D rabbit monoclonal and anti-β-Actin mouse monoclonal (1:10,000, Santa Cruz). Appropriate secondary antibody conjugated with HRP was used at 1:5000 dilution (Sigma) and developed with ECL plus (Amhershan Biosciences) in a ChemiDoc HDR (BioRad). Uncropped western blots are shown in Figure 2—source data 1 and 2 . The concentration of IL-1β, IL-18, TNF-α, and IL-6 in cell supernatants was determined by ELISA following the manufacturer’s instructions. ELISA were purchased from R&D Systems or Thermo Fisher Scientific (see Key Resources Table). Results were read in a Synergy Mx plate reader (BioTek). Total RNA extraction was performed using macrophages or mice tendons dissected as described above. Macrophage total RNA extraction was performed using the RNeasy Mini Kit (Qiagen) following the manufacturer’s instructions. Total RNA extraction from mice tendons was performed using Qiazol lysis reagent (Qiagen) and samples were homogenized using an Omni THQ homogenizer. After homogenization, samples were incubated for 5 min at room temperature and centrifuged at 12,000 xg for 15 min at 4 °C. After centrifugation, the upper phase was collected and one volume of 70% ethanol was added. Samples were loaded in RNeasey Mini Kit columns and total RNA isolation was performed following manufacturer’s instructions. In both cases a step with a treatment with 10 U/μl DNase I (Qiagen) was added during 30 min. Reverse transcription was performed using iScript cDNA Synthesis kit (BioRad). The mix SYBR Green Premix ExTaq (Takara) was used for quantitative PCR in an iCyclerMyiQ thermocycler (BioRad). Specific primers were purchased from Sigma (KiCqStart SYBR Green Primers) for the detection of the different genes. Relative expression of genes was normalized to the housekeeping gene Actb using the 2 -ΔCt method and for the expression in tendon then normalized to mean Ct value of non-treated samples using the 2 -ΔΔCt method . When expression in non-treated samples was below threshold and was non detected (ND), 2 -ΔCt values are shown in the Figures. To compare gene expression between wild type and knock-out mice, the fold change of 2 -ΔΔCt values of the knock-out mice was calculated with respect to the average of the 2 -ΔΔCt values of the wild type mice. Mice paws were fixed using 4% p -formaldehyde (Sigma-Aldrich) for at least 24 h, processed, paraffin-embedded, and sectioned in 4 μm slides. Hematoxylin and eosin stained slices were initially evaluated in a 0–3 qualitative scale, with 0 being control (healthy tendon) conditions, 1 mild, 2 medium, and 3 severe, for inflammatory infiltration, tendon cellularity and neo-vascularization grade . The number of polymorphonuclear cells was quantified by counting three different fields for each sample, and these cells were identified by their nuclear morphology. The number and area of tenocytes nuclei was evaluated using the FIJI macro based on a manual threshold to select nuclei and evaluating the different parameters measured with the ‘Analyze particles’ tool. Sirius red staining was performed in the slides using the Picro Sirius red stain kit (Abcam) following the manufacturer’s instructions and polarized light pictures were used to quantify the type of collagen by converting pictures to SHG color and then using either a script based on the number of pixels of each color and calculating the percentage of type I or III collagen or the CT-Fire algorithm to calculate width, length, straightness and angle of collagen fibers in these pictures . Toluidine blue staining was performed using a toluidine blue polychrome solution (Bio-Optica) for metachromatic staining of acid substances, and this staining was used for the mastocytes count. Immunohistochemistry with anti-F4/80 rat monoclonal antibody (MCA497GA, BioRad) was used to quantify macrophages by counting three different fields for each sample. All slides were examined with a Zeiss Axio Scope AX10 microscope with 20 x and 40 x objectives (Carl Zeiss) and pictures were taken with an AxioCam 506 Color (Carl Zeiss). Achilles tendons were dissected following the protocol described in Rigozzi et al., 2009 . In brief, tendons were dissected maintaining intact the calcaneus and the gastrocnemius/soleus muscles. The tendon sheaths were also maintained in order to preserve the natural anatomical structure and relative orientation of the individual tendon bundles . Gastrocnemius/soleus muscle fibers were then cautiously removed to expose the intramuscular tendon fibers . All mechanical tests were performed with an Autograph AG-X plus 50 N-5KN machine (Shimadzu) with a speed of 0.1 mm/s and 1 kN load head. Specimens were clamped for testing with the calcaneus mounted to approximate a neutral anatomical position . Tendon area was calculated measuring tendon width in two segments, frontal and lateral. Tendon area and length were then used to calculate stiffness of tendons. Other parameters such as maximum force and maximum tension were also obtained. Elastic module was calculated as the slope of the curve generated representing force vs displacement. The slope was calculated taking into account the curve generated only between 1–2 N of force. All parameters were obtained using Trapezium X software (Shimadzu). A detailed description of the second harmonic generation microscope used can be found in Skorsetz et al., 2016 , a non-lineal optical tool . Unstained collagen molecules are able to generate second harmonic signal due to their natural structure with lack of a center of inversion symmetry . The imaging instrument used combines a Ti:Sapphire femtosecond laser source and an inverted microscope. The laser system emits light pulses of 800 nm of wavelength at a repetition rate of 76 MHz. An XY scanning unit and a Z-motor attached to the microscope objective allow the sample to be scanned across the plane and depth location of interest. The second harmonic generation signal from the sample propagates back through the same objective used for excitation (dry long-working distance, 20 x, 0.8 N.A.), is isolated by a short-wave pass filter (400 ± 5 nm), and finally detected by a photon counting photomultiplier module. A home-made LabView software controlled the entire system. The average power at the sample’s plane was always below 100 mW. Second harmonic generation images were acquired at 2 Hz. To analyze the structural organization of the collagen fibers in the tendon, an algorithm based on the Hough transform was used . The Hough transform is a mathematical procedure able to detect aligned segments of collagen fibers within an image, and provide quantitative information on the degree of organization of the spatially resolved structures. On the basis of a pixel-by-pixel calculation, when a straight line is found, the corresponding polar coordinates are filed in the so-called 2D accumulator matrix. For each new detected straight line, the accumulator increases one unit. The local peaks (i.e. maximum values) in this accumulator space determine the preferential orientations found across the image. The standard deviation of these orientations is defined as the structural dispersion. A previously developed Matlab script was used for image processing . Statistical analyses were performed using GraphPad Prism 7 (Graph-Pad Software, Inc). A Shapiro-Wilk normality test was initially performed on all groups to decide the analysis type to be used. For two-group comparisons, nonparametric Mann-Whitney U test (without making the assumption that values are normally distributed) or the parametric unpaired t -test (for normal distributed data) were used to determine the statistical significance. For more than two group comparisons, one-way ANOVA test (for normal distributed data) or nonparametric Krustal-Wallis test (without making the assumption that values are normally distributed) were used to determine the statistical significance. Data are shown as mean values and error bars represent standard error from the number of independent assays indicated in the figure legend, which are also overlaid in the histograms as dot-plotting. p Value is indicated as *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001; p> 0.05 not significant ( ns ).
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Evaluation of anatomical variations around the pancreas is important in pancreatoduodenectomy (PD) because an arterial anomaly is a risk factor for morbidity . Previous studies have reported celiac axis stenosis on angiography in 12.5–49% of cases , . It is usually asymptomatic because of collateral circulation such as the arterial arcade of the pancreatic head. However, dividing these important collaterals via the gastroduodenal artery (GDA) during PD can lead to ischemic complications in the upper abdominal organs , . On the other hand, anatomical variations of the hepatic artery system are occasionally observed in 25–40% of cases; nonetheless, a replaced common hepatic artery (rCHA) is rare, with an incidence ranging from 1.5% to 3% , , . Such arterial variations may be problematic in PD because of the route of the replaced artery near the resection margin, particularly the superior mesenteric artery (SMA) margin. Intraoperative damage to the rCHA may lead to refractory bile leakage from bile duct jejunal anastomosis, liver abscesses , . Herein, we report a rare case of PD for lower bile duct cancer in which celiac axis stenosis and rCHA coexisted. An 84-year-old woman with a 1-week history of epigastric pain presented to our district general hospital. She had a medical history of hyperlipidemia. Physical examination revealed no fever or jaundice. Laboratory findings indicated a slightly elevated white blood cell count and liver dysfunction. Magnetic resonance cholangiopancreatography showed obstruction of the lower bile duct and dilation of the upper bile duct ( Fig. 1 (a)). Obstruction due to bile duct cancer was suspected; hence, emergency endoscopic retrograde cholangiopancreatography was performed. An endoscopic nasobiliary drainage tube was placed, and the results of bile duct biopsy indicated adenocarcinoma in the lower bile duct. Contrast-enhanced computed tomography (CT) showed wall thickening of the lower bile duct; however, there was no suspicion of distant metastasis or lymph node metastasis. Stenosis of the origin of the celiac artery was observed, and the deformed celiac artery had a “hooked appearance,” suggesting compression by the median arcuate ligament (MAL) ( Fig. 2 (a, b)). The common hepatic artery directly branched from the SMA. The rCHA passed through the dorsal side of the portal vein and pancreatic head and branched into the left and right hepatic arteries within the hepatoduodenal mesentery. The GDA diverged from the rCHA, forming a developed arterial arcade of the pancreatic head, which was the collateral pathway between the SMA and celiac artery systems ( Fig. 2 (a, c)). Fig. 1 Preoperative imaging findings. (a) Magnetic resonance cholangiopancreatography shows lower bile duct obstruction (arrow) and dilation of the upper bile duct. (b) CT scan after placement of the ENBD tube shows the collateral artery (arrowhead) around the pancreatic head runs in contact with the bile duct in which the ENBD tube was placed (arrow). CT: computed tomography, ENBD: endoscopic nasobiliary drainage. Fig. 1 Fig. 2 Preoperative CT angiography findings. (a) Front view. Stenosis of the origin of the CA is observed (arrow). The rCHA arises from the SMA and the GDA branches from the rCHA. The collateral pathway of the pancreatic head is developed (arrowhead). (b) Lateral view. Focal stenosis in the proximal celiac axis is described as having a “hooked appearance” (arrow). (c) Three-dimensional CT shows the rCHA passing behind the PV (allow), and the collateral artery runs around the head of the pancreas (arrowhead). CT: computed tomography; CA: celiac artery, rCHA: replaced common hepatic artery, SMA: superior mesenteric artery, GDA: gastroduodenal artery, SA: splenic artery, PHA: proper hepatic artery, LGA: left gastric artery, PV: portal vein. Fig. 2 We performed PD with her consent after her liver function was improved by bile duct drainage. Intraoperative exploration ruled out latent peritoneal or liver metastasis and showed arterial anomalies similar to those indicated by preoperative findings. There was an oncological safety margin between the rCHA and common bile duct; however, a part of the collateral artery was close to the common bile duct ( Fig. 1 (b)). Therefore, we planned to preserve the rCHA and resect the GDA to form collateral circulation ( Fig. 3 (a–c)). The collateral artery passed the pancreas posteriorly, and joined the celiac artery ( Fig. 2 (c)). The collateral artery was resected at the root of the celiac artery. Pulsations of the celiac and splenic arteries were attenuated by dissection of the collateral circulation. As the MAL was suspected to be the cause of celiac axis stenosis, division of the MAL was performed. To evaluate blood flow of the left upper abdominal organs, including the stomach, remnant of the pancreas, and spleen, indocyanine green (ICG) fluorescence imaging with a near-infrared camera system was performed. A bolus injection of 5 mg of ICG (Diagnogreen; Dai-Ichi Pharm, Tokyo, Japan) was delivered from a peripheral vein, and blood perfusion was confirmed ( Fig. 3 (d)). Therefore, PD was performed without vessel reconstruction. The duration of surgery was 493 min, blood loss was 600 mL, and blood transfusion was unnecessary. Pathological findings indicated moderately to poorly differentiated adenocarcinoma of the lower bile duct (T2N0M0, stage IIA, according to the UICC classification). Fig. 3 Intraoperative pictures. (a) The GDA branches from the rCHA, which runs behind the PV. (b) Schema of (a). (c) After removal of the duodenum and head of the pancreas. The rCHA arising from the SMA is preserved, and the GDA, which forms collateral circulation, is resected. (d) Indocyanine green fluorescence imaging reveals that the blood supply of stomach is preserved (arrowhead). GDA, gastroduodenal artery, rCHA: replaced common hepatic artery, PV: portal vein, PHA: proper hepatic artery, RGA: right gastric artery, panc: pancreas, SMA: superior mesenteric artery. Fig. 3 She developed a postoperative pancreatic fistula (grade B, as defined by the International Study Group on Pancreatic Fistula), which improved with antibiotic administration. Contrast-enhanced CT performed at 1 postoperative week showed that the contrast effect of the stomach, spleen, and remnant pancreas was preserved and no ischemic change was detected . The patient was discharged on postoperative day 28, and no signs of recurrent cancer were identified at 3 years postoperatively. Fig. 4 Contrast-enhanced computerized tomography at 1 week after the operation. The contrast effect of the remnant of pancreas, stomach (allow) and spleen (allow head) were preserved. Fig. 4 PD is an important surgical treatment for tumors located in the head of pancreas, lower bile duct, and duodenum, although morbidity and mortality remain high. Insufficient understanding of anomalies in the celiac artery and SMA systems can lead to intra- and postoperative complications. This is a very rare case in which celiac axis stenosis and a rCHA were recognized on preoperative CT angiography, where a careful intraoperative assessment was required because the coexistence of these anomalies made the procedure of PD more complicated. It is reported that preoperative CT before PD showed stenosis in 11% of cases . Generally, ischemic symptoms with celiac axis stenosis rarely become a clinical problem, because collateral circulation via the arterial arcade of the pancreatic head develops between the SMA and celiac artery systems. However, dividing these important collaterals during PD can lead to ischemia in the liver, stomach, spleen, and remnant of the pancreas, thereby increasing the risk of complications such as hepatic abscess, bile leakage, residual pancreatic necrosis, pancreatic fistula, and anastomotic leakage at the site of gastrointestinal anastomosis and splenic abscess . Celiac axis compression by the MAL is the most common cause of celiac axis stenosis (55–88%), followed by arteriosclerosis (11–12%), and these two causes account for the majority of cases , . The CT angiography finding of characteristic focal narrowing of the proximal celiac axis noted as a “hooked appearance” can help distinguish celiac axis stenosis by the MAL from other causes of celiac axis stenosis, such as atherosclerotic disease , . Interventions for celiac axis stenosis have been reported, including division of the MAL, vessel reconstruction, and preservation of collateral circulation , , . If celiac axis stenosis is due to MAL compression, division of the MAL is considered the primary procedure for surgical treatment. If the arterial flow cannot be resolved because of severe stenosis, revascularization of the celiac artery or preservation of the collateral circulation of the pancreatic head should be considered . Through an extensive search of PubMed, we identified only one case report concerning PD in a patient with celiac axis stenosis and a rCHA. PD with preservation of the rCHA and collateral circulation of the pancreatic head was performed for intraductal papillary mucinous neoplasia in the pancreatic head . In our case, the rCHA ran through the dorsal side of the portal vein and pancreatic head, and no invasion of the bile duct cancer was observed, but the collateral artery ran close to the common bile duct, as visible in preoperative CT. Consequently, we selected to preserve the rCHA and considered the need for resection of the GDA to form collateral circulation for oncologic cure. After the MAL was divided for celiac axis stenosis, we evaluated the blood flow of the organs by ICG fluorescence imaging to determine the necessity for vessel reconstruction. Recent reports have suggested the use of ICG fluorescence imaging for evaluating the perfusion of various organs, such as in cases of ischemic gastropathy which is a major complication after distal pancreatectomy with celiac axis resection or distal pancreatectomy with distal gastrectomy , . In our case, we confirmed that the blood flow of the organs was preserved by ICG fluorescence imaging, which could help us to omit unnecessary vessel reconstruction. Although ICG fluorescence imaging can be easily performed and is noninvasive and valuable, there is concern that ICG fluorescence imaging largely depends on the subjectivity of the operator, and the intensity of fluorescence emitted on the screen is not quantified. The criteria for determining ischemia have not yet been established, and further consideration of cases evaluating blood flow by ICG fluorescence imaging is necessary.
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Clinical case
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biomedical
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en
| 0.999996
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35505624
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An 81‐year‐old woman, affected by Horton disease and with previous history of rheumatic fever, was hospitalized for acute chest pain. Physical examination and EKG were not significant. Chest X‐ray showed a diffuse hypodense lobulated area in the left ventricle . The echocardiogram revealed diffuse aortic and mitral calcifications with mild stenosis, marked septum, and antero‐lateral asymmetric hypertrophy, with extensive antero‐lateral calcifications . Non‐contrast computed‐tomography (CT) highlighted widespread amorphous confluent calcifications in the left ventricular wall, with septal sparing, extended to the mitral‐aortic annulus and both coronary arteries . Cardiac magnetic resonance (CMR) 3,0 T presented the following: septal hypertrophy, antero‐lateral wall thickening with areas of intra‐myocardial signal‐alteration, surrounded by normal myocardium matching the CT calcifications. Areas of low‐signal were shown in multiple sequences: SSFP‐cine in 4‐chambers (4C) and in short‐axis (SAX) ; T1‐weighted‐spin‐echo in 4C and SAX ; STIR in 4C . T1‐native‐mapping in 4C focused on diffuse septum and lateral fibrosis with low‐signal compatible with calcifications . After contrast‐gadolinium injection, PSIR‐sequence showed intra‐myocardial hypersignal in the lateral wall both in 4C and SAX, Figure 2H‐H1 , respectively). Coronary angiography documented significant disease that required revascularization. Extensive intra‐myocardial calcifications are extremely rare. 1 In our case the diagnostic pathway excluded previous myocardial infarction, myocarditis and calcium‐phosphate disorders. A dystrophic etiology has been supposed. The pathological mechanism for dystrophic calcifications is related to calcium deposition in any dead and dying myocardial tissues. Methastatic calcification are otherwise related to any disturbance in calcium metabolism and can occur with abnormal calcium‐phosphorous homeostasis. There are no standardized imaging features available to classify specific subtypes of intra‐myocardial calcifications. 2 CT scan is the gold standard examination for the noninvasive detection of myocardial calcifications. CMR with late‐ gadolinium enhancement and native T1/T2 mapping has the unique ability to provide a differential diagnosis in the whole spectrum of myocardial diseases, allowing tissue characterization and hemodynamic assessment. The combination of imaging pattern and potential etiology plays a key role in characterizing calcifications and deriving its clinical impact.
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Clinical case
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biomedical
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en
| 0.999996
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35586679
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An 87-year-old woman had presented with nausea and emesis, followed by retrosternal chest pain of 1 day duration. Her medical history was significant for coronary artery disease, hypertension, atrial fibrillation, congestive heart failure, and grade IIIb follicular lymphoma. She had been previously treated with rituximab induction weekly for 4 weeks, followed by maintenance therapy for 2 years, and had completed treatment in January 2018. Her lymphoma had slowly progressed since 2019, with significant local progression in the same retroperitoneal region as the site of origin. The patient provided written informed consent for the report of her case details and imaging studies. On presentation to the emergency room, on April 5, 2021, she was hypertensive with significant pain. Computed tomography angiography demonstrated a 6.5 × 5.7-cm infrarenal pseudoaneurysm in the region of previously seen adenopathy that was concerning for a contained aortic rupture secondary to the lymphoma . The patient was emergently taken to the operating room for endovascular repair of the aorta. Fig 1 Computed tomography angiograms before rupture from 2019 with evidence of mild lymphadenopathy, in transverse ( Ia ; arrow ) and coronal ( Ib ; arrow ) views. Computed tomography angiograms after rupture showing evidence of significant lymphadenopathy with infrarenal aortic pseudoaneurysm and active bleeding, in both transverse ( IIa ; arrow ) and coronal (IIb) views. Lymphoma ( arrow ) can be differentiated from rupture in IIa . Percutaneous access was established via the left common femoral artery, and aortography confirmed an aortic rupture at the midportion of the infrarenal aorta . A 20-mm × 4.5-cm Excluder conformable abdominal aortic aneurysm endoprosthesis aortic extender (W.L. Gore & Associates, Flagstaff, AZ) was deployed at the rupture site just above the aortic bifurcation. To obtain an adequate seal and protect the infrarenal aorta, an additional 20-mm × 4.5-cm cuff was deployed proximally, followed by a 23-mm × 4.5-cm cuff up to the level of the renal arteries. Completion angiography confirmed adequate placement of the endoprosthesis without evidence of an endoleak . Aortic duplex ultrasound on postoperative day 1 demonstrated no evidence of endoleak with an avascular mass present between the inferior vena cava and aorta, likely the lymphoma. The patient’s postoperative course was uneventful, and she was discharged on postoperative day 3. At 1 month of follow-up, the patient was doing well, and a repeat duplex ultrasound scan had demonstrated resolving retroperitoneal hematoma. In addition, the patient had undergone post-stenting radiation therapy to the periaortic lymphoma and tolerated it well without any issues. Fig 2 Three-dimensional reconstruction of computed tomography angiogram demonstrating infrarenal aortic pseudoaneurysm with a focus of active bleeding ( arrow ). Fig 3 Intraoperative fluoroscopic views demonstrating the point of active bleeding ( arrow ) before graft deployment (a) and resolution of bleeding after covered stent placement (b) . Prior treatment with chemotherapeutic agents is also thought to affect vessel wall strength. In a 2017 study by Leopardi et al, 10 patients with aortic aneurysms diagnosed during computed tomography for oncologic follow-up were analyzed retrospectively according to the oncologic treatment they had received. Those undergoing chemotherapy were found to have significant aneurysmal growth and a higher rate of rupture compared with those not undergoing oncologic treatment. 10 Chemotherapy regimens that specifically include rituximab have also been reported to contribute to abdominal aortic wall stress. 11 In the present case, the patient had a known malignant adenopathy present within the periaortic window and the aortocaval window without a history of an aortic aneurysm. The combination of malignant lymphocytic infiltration in an already weakened vessel wall secondary to oncologic treatment might have been responsible for the contained aortic rupture in our patient. For our patient, we chose to treat the pseudoaneurysm using Excluder conformable abdominal aortic aneurysm endoprosthesis aortic extender cuffs (W.L. Gore & Associates). Deployment of three separate devices was performed to adequately cover the entire area affected by the lymphoma, which was the total length of the infrarenal aorta. The advantage of using aortic extension cuffs, instead of a thoracic endograft, was the shorter length of the graft. This allowed us to precisely cover the weakened surface area of the vessel. In addition, the novel Food and Drug Administration–approved conformable device has the ability to angulate, or “conform,” the proximal end of the graft before deployment. This allows for use of the entire surface area of the available proximal sealing zone. Furthermore, its independent sealing zones eliminate the need for extensive graft overlapping, without concern for an increased risk of endoleaks. 15
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Clinical case
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clinical
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en
| 0.999996
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35842891
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Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders of cortisol biosynthesis with varying levels of severity . Indeed, the clinical phenotype is typically classified as a classic form (the most severe one), and non-classic that is mild or late onset. Disorders of sex development (DSD) depend on the affected gene that cause CAH but also on sex proband. The presence of salt-wasting, postnatal virilization, sex steroid deficiency, hypertension, and other features, such as skeletal defects, are caused by the specific gene that is mutated . Among the long-term complications of CAH, infertility is frequent in both female and male patients [ 2 – 8 ]. Male patients may experience the growth of testicular adrenal rest tumors (TARTs), which can cause intra-testicular compression of efferent seminiferous tubules in turn affecting spermatogenesis . CAHs have a specific hormonal pattern based on the enzymatic dysfunction that causes it. The CYP21A2 genotype is the main, but not the only, determinant of the phenotype in patients with 21α-hydroxylase deficiency (21α-OHD) . In some patients suspected of having a 21α-OHD, no pathogenic variants were found in one or both alleles even after complete sequencing of the CYP21A2 gene . Other patients have pathogenetic variants of the CYP21A2 gene, but the genotype does not fully match the phenotype. These apparent discrepancies between genotype and phenotype suggest the presence of other genetic factors including modifier genes that can modulate the clinical expression of some aspects of 21α-OHD . In humans, P450 oxidoreductase (POR) deficiency (PORD) causes an unusual and rare form of CAH, whose exact incidence is not known . POR is an 82-kDa membrane-bound protein containing 680 residues encoded by a 32-kb gene containing 15 exons mapping on chromosome 7q11.2 . It is necessary for the metabolic activity of P450 cytochrome enzymes including CYP17A1, CYP21A2, CYP19A1, and CYP51A1 . Consequently, PORD can affect the function of these enzymes with different phenotype based on the residual enzymatic activity. As an example, studies on the CYP17A1, the steroidogenic enzyme that catalyzes both 17α-hydroxylase and 17,20 lyase activities , show that the levels of some P450 activities are determined, at least in part, by the stereochemistry of the interaction of POR with the cytochrome P450 . In the case of CYP17A1, the 17,20 lyase reaction, but not the 17α-hydroxylase reaction, is very sensitive to this stereochemistry, as shown by three lines of evidence . First, variants of basic residues in the redox-partner binding site of CYP17A1 selectively reduce the 17,20 lyase activity . Second, cytochrome b5 acts as an allosteric factor to promote the interaction of P450c17 with POR, selectively increasing 17,20 lyase activity [ 17 – 19 ]. Third, phosphorylation of CYP17A1 selectively increases the 17,20 lyase activity of CYP17A1 [ 19 – 21 ]. PORD phenotype is characterized by DSD in both sexes and is often associated with skeletal defects . The latter, known as Antley–Bixler syndrome (ABS), is characterized by craniosynostosis, brachycephaly, radio-ulnar or radio-humeral synostosis, bowed femora, arachnodactyly, midface hypoplasia, proptosis, and choanal stenosis. ABS is transmitted with an autosomal recessive mechanism by POR pathogenic variants and with an autosomal dominant mechanism by gain-of-function variants of the fibroblast growth factor receptor 2 ( FGFR2 ) gene . No definitive data are available on TARTs and fertility in male patients with recessive PORD. Data for the systematic review were independently extracted by C.G. and R.C. A systematic search was performed through PubMed, MEDLINE, Cochrane, Academic One Files, Google Scholar, and Scopus databases, from the beginning of each database through May 22, 2021. The search strategy was based on the combination of the following Medical Subjects Headings (MeSH) terms and keywords, using “AND” between each MeSH search term: “P450 oxidoreductase” AND “congenital adrenal hyperplasia”, “P450 oxidoreductase” AND “DSD”, “P450 oxidoreductase” AND “homozygosity”, “P450 oxidoreductase” AND “heterozygosity”, “P450 oxidoreductase” AND “pregnancy”. Additional manual searches were made using the reference lists of relevant studies. Only articles available in English full-text have been included. We added to our database the case of a patient not previously described in the literature who resulted in a carrier of compound heterozygous c.1891G > A, p. (Val631Ile) and c.516G > A variant. He had classical salt-wasting CAH, TARTs , infertility, abnormal sperm parameters (oligoasthenoteratozoospermia, OAT), and extremely elevated ACTH serum levels. He achieved spontaneous paternity after adding dexamethasone 0.25 mg/day to his daily cortisol replacement therapy. This therapeutic arrangement led to the normalization of ACTH serum levels. Fig. 1 Ultrasound pictures of the testicular adrenal rest tumors. Upper panels: longitudinal ( A ) and transversal ( B ) scans of the right testis. Lower panels: longitudinal ( C ) and transversal ( D ) scans of the left testis Using the above-mentioned search terms, we found 246 articles. After the exclusion of 34 duplicated records, 212 articles were screened. Thirty-one articles were excluded because the English full-text was not available. Of the remaining articles, 119 were excluded after having read their title and abstract, since they did not satisfy the inclusion criteria. In particular, 10 studies were excluded because performed in vitro and/or on animals, and 24 were excluded because they were reviews. The remaining 62 full-texts were carefully read. Finally, 48 articles matched the inclusion criteria [ 14 , 22 , 24 – 69 ]. These studies included 119 patients (46 males and 73 females) with PORD . They had homozygous, combined, or heterozygous POR gene variants in 58.0% (69/119), 32.8% (39/119), and 9.2% (11/119), respectively. These patients are worldwide distributed. The main features of the included studies are summarized in Table 1 . Fig. 2 Flowchart of the included studies Table 1 Summary of the studies included in this systematic review Authors Study design Sample size (M/F) Age of patients (years) POR genotype CAH DSD TARTs Fertility Arlt et al. Case series and in-vitro study 1/2 2–14 Compound Het. (the authors did not indicate patient-specific mutations): c.531 T > G/p.Tyr178Asp c.849G > C/p.Ala284Pro c.1360G > A/p.Arg454His c.1696G > A/Cys566Tyr Y (XX) Y (XY) Y (XX) Y N Y NR N NR Unsearched NR NR Fluck et al . Case series and in-vitro study 2/2 XX XY XY XX 5 4.5 1.9 23 Het: c.1370G > A(p.R457H)/731 + 1G > A Het: c.1475 T > A(p.V492E) Homo: c.859G > C (p.A287P) Het: c.1706G > A(p.C569Y)/c.1822G > T(V608F) Y Y Y Y Y Y Y N NR N N NR Unsearched (all) Adachi et al . Case series 1/1 XY XX 14 11 Het: 1329insC/R457H Het:1698insC/R454H Y Y N Y N NR Unsearched (all) Wudy et al. Case report 1/0 18 Homo: exon 8, GCT > CCT /p.Ala284Pro Y N N Unsearched Shackleton et al . Case series 1/1 XX XY At birth At birth Het: p.Y178D/p.C566Y Het: p.Y178D/p.C566Y Y Y Y N NR N Unsearched (all) Huang et al . Cohort study (18/19 excluded for lack of data) and in-vitro 0/1 XX (patient 16) NR Het: c.859G > C (p.A287P)/- Y Y NR Unsearched Fukami et al. Case series 4/6 XY XY XX XY XY XX XX XX XX XX 26 29 10.9 17.9 17.5 2 6.7 9.5 13.2 15 Het: c.1370G > A(p.R457H)/c.1835-1858del(p.L612_W620delinsR) Het: c.1370G > A(p.R457H)/c.1835-1858del(p.L612_W620delinsR) Het: c.1329_1330insC(I444fsX449)/c.1733A > G(p.Y578C) Het: c.1329_1330insC(I444fsX449)/c.1733A > G(p.Y578C) Het: c.15A > G(p.G5G)/c.1370G > A(p.R457H) Homo: c.1370G > A(p.R457H)/ c.1370G > A(p.R457H) Het: c.1370G > A(p.R457H)/- Homo: c.1370G > A(p.R457H)/c.1370G > A(p.R457H) Het: c.1329_1330insC(p.I444fsX449)/c.1370G > A(p.R457H) Homo: c.1370G > A(p.R457H)/c.1370G > A(p.R457H) Y Y Y Y Y Y Y Y Y Y Y Y Y N N Y Y Y Y Y N N NR N N NR NR NR NR NR Unsearched (all) Fukami et al. Case series 1/2 XY XX XX 10 5 1 Homozygous: R457H/R457H Homozygous: R457H/R457H Homozygous: R457H/R457H Y Y Y N Y Y N NR NR Unsearched (all) Homma et al. Case–control 5/2 XY XY XY XY XY XX XX 22 23 15 16 0.3 0.7 12 Homo: R457H/R457H Homo: R457H/R457H Het: R457H/Q201X Het: R457H/Q201X Het: R457H/A462_S463insIA Het: R457H/E580Q Het: R457H/Q201X Y all N N N N Y Y N N N N N N NR NR Williamson et al . Case report 0/1 NR Het: p.A278P/p.H604P Y Y NR Unsearched Hershkovitz et al . Case series 4/0 XY XY XY XY 21 14.6 16.5 At birth Homo: c.1697G > A(p.G539R) Homo: c.1697G > A(p.G539R) Homo: c.1697G > A(p.G539R) Homo: c.1697G > A(p.G539R) Y Y Y Y Y Y Y Y N N N N Unsearched (all) Nakamura et al . Case series (2/3 duplicated) 0/1 8 Het: p.T228I Y Y NR Unsearched Ko et al. Case report 0/1 0.58 Het: c.1329_1330insC(I444fsX449)/ c.1370G > A (R457H) Y Y NR Unsearched Sahakitrungruang et al. Case series 1/3 XY XX XX XX 3 24 21 3.5 Het: delGGA651-653(delE217)/859G > C(A287P) Het: 555T > A(N185K)/1730T > G(L577R) Het: 1615G > A(G539R)/1363delC Het: 1615G > A(G539R)/697-698insGAAC Y Y Y Y Y N Y Y N NR NR NR Unsearched Infertile Unsearched Unsearched Fukami et al. Cohort study (23/35 duplicated, 11/12 lack of data) 1/0 13.1 Het: c.1370G > A(p.R457H)/(-)(DeltaExons 2–13) Y Y N Unsearched Iijima et al. Case report 0/1 2.5 Het: 348delV/R457H Y N NR Unsearched Idkowiak et al. Case report and in-vitro study 1/0 9 Het:c.32062delG(p.E601fsX12)/ c.32171A > G(p.Y607C) Y Y N Unsearched Tomalik-Scharte et al. Case report 0/1 48 Homo: c.852G > C Y Y NR Unsearched But et al . Case report 0/1 10 Homo:c.1370G > A/p.R457H Y Y NR Unsearched Idkowiak et al . Case series 2/4 XX XX XX XX XY XY 12 23 19 16 16 13.5 Homo: A287P/A287P Homo: A287P/A287P Het: T142A/Y376LfsZ74 Het: A287P/R223X Het: R457H/Y576X Het: A287P/IVS7-dupT Y Y Y Y Y Y Y Y N Y N N NR NR NR N N Unsearched (all) Fluck et al. Case series 0/2 XX XX At birth At birth Homo: c.1196_1204delCCTCGGAGC (p.Pro399_Glu401del) Y Y Y Y NA (all) Unsearched (all) Herkert et al. Case report 0/1 19 Het:c.2640A > G, p.T142A c.30843dupC, p.Y376LfsX74 Y N NR Unsearched Krone et al . Cohort study (6/30 duplicated, 2/24 no POR mutation) 9/13 XX XX XY XY XY XX XX XX XX XY XY XX XY XX XX XY XX XX XY XY XX XX At birth At birth At birth At birth At birth 12 At birth At birth At birth At birth At birth At birth At birth 24 At birth At birth At birth 18 At birth 12 16 31 Het: p.A287/- Het: A287P/ IVS6-2A > T Het: A287P/ IVS6-2A > T Het: A287P/V472AfsX102 Het: Q455RfsX544/IVS7 + 2dupT Homo: A287P/ A287P Het: A287P/DelexU1-1 Het: A287P/IVS8 + 1G > A Homo: A287P/ A287P Homo: A287P/ A287P Het: A287P/G188_V191dup Homo: A287P/ A287P Het: A287P/I444HfsX6 Homo: A287P/ A287P Het: Y87X/ - Het: R457H/Y576X Homo: R498P/R498P Het: Y376LfsX74/T142A Het: A287P/R616X Het: A287P/IVS7 + 2dupT Het: A287P/R223X Het: A287P/Dup ex 2–5 Y (all) Y N Y Y Y Y N Y Y N Y Y Y Y Y Y Y N N N Y Y Unsearched (all) Boia et al. Case report 1/0 3 Homo: c.859G > C Y Y N Unsearched Guaragna-Filho et al. Case report 0/1 9 Het: p.Arg223*/p.Met408Lys Y Y NR Unsearched Sànchez-Garvìn et al . Case report 0/1 7 Het:c.1615G > A (p.Gly539Arg) p.Gly80Arg Y Y NR Unsearched Nakanishi et al. Case report 0/1 At birth Homo:p.R457H/ p.R457H Y Y NR Unsearched Oldani et al. Case report 0/1 IUD Het: c.859G > C(p.Ala287Pro)/c.732A > T Y Y NR NA Koika et al. Case report 1/0 36 Het.:c.1591_1593delGTC(p.del531Val)/G858C,A259G rs1057868(C/TA503V) rs1057870 (G/AS572S) Y Y NR Unsearched Parween et al. Case report and in-vitro study 0/1 At birth Het:p.L374H/c.5 + 4A > G Y Y NR Unsearched Bonamichi et al. Case series 0/1 15 Homo:p.A287P/p.A287P Y Y NR Unsearched Tzetis et al. Case series (2 samples excluded for lack of data) 0/1 Fetus Homo:c.859G > C Y Y NR Unsearched Woo et al. Case report 1/0 7 Het: p.Arg457His/p.Gln555Profs19 Y N N Unsearched Bai et al . Case report 0/1 27 Homo: c.1370G > A(p.R457H)/c.1370G > A(p.R457H) Y Y NR Unsearched Song et al . Case report 0/1 28 Het: c.976 T > G(p.Y326D) Y Y NR Y (ART) Khadilkar et al. Case report 0/1 17 Het: c.430G > A(p.G144S)/c.1265G > A(p.W422X) Y Y NR Unsearched Oh et al. Case report 0/1 21 Het:c.1370G > A (p.Arg457His); c.529G > C (p.Gly177Arg) Y (mild phenotype) Y (hypoplastic uterus) NR Unsearched Fan et al. Case series 5/3 XX XY XY XY XY XX XY XX 4.2 2.2 1 0.5 3.5 17.8 9.8 12.5 Het: c.1370G > A(p.R457H)/c.744C > G(p.Y248X) Het:c.1370G > A(p.R457H)/c.744C > G(p.Y248X) Het:c.1370G > A(p.R457H)/c.1660C > T(p.R554X) Het:c.1370G > T(p.R457L)/c.1820A > G(p.Y607C) Het:c.1370G > A(p.R457H)/c.629A > G(p.D210G) Het:c.1370G > A(p.R457H)/c.517-19_517-10delGGCCCCTGTGinsC Het:c.1370G > A(p.R457H)/c.517-19_517-10delGGCCCCTGTGinsC Homo: c.1370G > A(p.R457H)/c.1370G > A(p.R457H) Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y NR N N N N NR N NR Unsearched (all) Lee et al . Case series (1/4 duplicated) 2/1 XX XY XY 5.3 3.3 2.6 Homo: c.1370G > A(p.R457H)/c.1370G > A(p.R457H) Homo: c.1370G > A(p.R457H)/c.1370G > A(p.R457H) Het:c.1329_1330insC(p.I444Hfs*6)/c.1370G > A(p.R457H) Y Y Y Y Y Y NR N N Unsearched (all) Papadakis et al. Case series 0/5 XX XX XX XX XX 30 36 33 38 19 Het: c.1249-IG > C(p.?)/c.1324C > T(p.Pro442Ser) Het: c.1825C > T(p.Gln609*)/c.1859G > C(p.Trp620Ser) Het: c.1825C > T(p.Gln609*)/c.1859G > C(p.Trp620Ser) Het: c.1648C > T(p.Arg550Trp)/- Homo: c.859G > C(p.Ala287Pro)/c.859G > C(p.Ala287Pro) Y Y Y Y Y N N Y N N NR (all) Y (ART) Y (ART) Unsearched Unsearched Unsearched Parween et al. Case report 0/1 XX 11 Het:c.73_74delCT(p.L25Ffs*93)/c.1648C > T(p.R550W) Y Y NR Unsearched Zhang et al . Case report 0/1 XX 35 Het:c.1195_1203delCCTCGGAGC(p.399_401delPSE)/ IVS14-1G > G/C Y Y NR Y (ART) Aljabri et al. Case report 1/0 XY 2.5 Compound: Homo: nonsense Het c.317A > G(p.His106Arg) Y N N Unsearched Song et al . Case report 0/1 XX 10.5 Compound: Homo c.1370G > A(p.R457H) Het c.2978T > A(p.I993N) Y Y NR Unsearched Unal et al. Case series 1/1 XX XY 8.5 1.25 Homo:c.929_937delTCTCGGACT(p.Ile310-Ser313delinsThr Homo:c.929_937delTCTCGGACT(p.Ile310-Ser313delinsThr Y Y Y N NR N Unsearched (all) Wang et al . Case series 0/1 XX 31 Het: p.Arg223Ter/p.Tyr67Cys Y N NR Infertility Rakover et al. Case series 0/1 XX 11.8 Homo: c.1615G > A(p.G539R) Y Y NR Unsearched Pan et al . ( 69 ) Case report 0/1 XX 29 Het: c.1370G > A(p.Arg457His)/c.1196_1204del(p.Pro399_Glu401del) Y N NR Y (ART) Patient from the present study Case report and literature systematic review 1/0 17 Het: c.1891G > A, p. (Val631Ile); c.516G > A Y N Y Y (spontaneous) ART assisted reproductive technique, CAH congenital adrenal hyperplasia, DSD disorders of sex development, F female, Het heterozygous, Homo homozygous, M male, N no, NR not reported, TARTs testicular adrenal-rest tumors, Y yes, IUD intrauterine death By reviewing data from 48 articles including 119 patients from around the world, the present study aims to show the gender- and genotype-related prevalence of CAH, DSD, TARTs, and infertility in patients with heterozygous or homozygous POR gene variants. Genotype–phenotype correlation is sometimes a complex and attempted association and is still a matter of research, considering the most recent studies that have focused on mutations of the CYP21A2 gene . This review allows a better understanding of the PORD phenotype. Our results show that CAH can be caused by both homozygous and heterozygous POR gene variants. Among 119 patients DSD was found in 85 (71.4%), respectively, in 65.2% (45/69) of patients with compound heterozygous variants, 82.1% (32/39) of patients with homozygous variants (82.1%), and 72.7% (8/11) of those with monoallelic heterozygous variants. Furthermore, DSD had a higher frequency in females affecting 79.5% (58/73) and 58.7% (27/46) male patients ( p < 0.05), indicating that DSD affects both homozygous and heterozygous carrier patients, although with a higher prevalence in the former. Specifically analyzing the individual variants, the most frequent are c.859G > C (p.A287P), typically with a higher prevalence of DSD when the heterozygous mutation is found in association with another monoallelic variant (DSD present in 81% of probands with compound heterozygous variants); c.1370G > A(p.R457H), that shows a higher prevalence of DSD when the homozygous variants are found (79%); c.1697G > A(p.G539R), with no difference between homozygous or heterozygous pathogenic variants (DSD present in 100% of probands) (Table 2 ). All the other detected variants, including the one found in our proband, were found in 1–2 patients (for each variant), so statistical analysis could not be applied (Table 3 ). According to a recent publication on POR polymorphisms, variants of this gene can influence CAH phenotypical expression acting as a genetic modifier of CYP21A2 defects . Although the literature has so far focused on different allelic mutations on a single gene, we should now consider the coexistence of POR variants and polymorphisms in CAH patients carrying CYP21A2, CYP11B1, CYP17A1, HSD3B2, StAR , or CYP11A1 variants. Table 2 Prevalence of disorders of sex development (DSD) in homozygous and heterozygous pathogenetic variants Mutation Homozygous mutations DSD in homozygous (%) Heterozygous mutations DSD in heterozygous (%) Compound heterozygous mutations DSD in compound heterozygous mutations (%) c.859G > C (p.A287P) 12 75 3 66 16 81 c.1370G > A(p.R457H) 14 79 4 25 23 74 c.1697G > A(p.G539R) 5 100 2 100 Table 3 Single pathogenetic variant associations of P 450 oxidoreductase-associated congenital adrenal hyperplasia Mutation Homozygous mutations Heterozygous mutations Composed heterozygous mutations c.1706G > A(p.C569Y)/c.1822G > T(V608F) 1 GCT > CCT (p.Ala284Pro) 1 p.Y178D/p.C566Y 2 c.1733A > G(p.Y578C) 2 p.T228I 1 555T > A(N185K)/1730T > G(L577R) 1 c.32062delG(p.E601fsX12)/ c.32171A > G(p.Y607C) 1 c.852G > C 1 T142A/Y376LfsZ74 1 p.Pro399_Glu401del 2 c.2640A > G, p.T142A 2 Q455RfsX544/IVS7 + 2dupT 1 Y87X 1 R498P 1 p.Arg223Ter 2 c.1615G > A (p.Gly539Arg) 1 p.del531Val/G858C,A259G rs1057868(C/TA503V) rs1057870 (G/AS572S) 1 p.L374H/c.5 + 4A > G 1 c.976T > G(p.Y326D) 1 c.430G > A(p.G144S)/c.1265G > A(p.W422X) 1 c.1249-IG > C(p.?)/c.1324C > T(p.Pro442Ser) 1 c.1825C > T(p.Gln609*)/c.1859G > C(p.Trp620Ser) 2 c.1648C > T(p.Arg550Trp) 1 1 c.1195_1203delCCTCGGAGC(p.399_401delPSE)/IVS14-1G > G/C 1 c.317A > G(p.His106Arg) 1 c.929_937delTCTCGGACT(p.Ile310-Ser313delinsThr 2 p. (Val631Ile); c.516G > A 1 This is the first article reporting the presence of TARTs in a patient with CAH due to PORD. So far, TARTs have been described in patients with 21α-OHD and 11ß-hydroxylase deficiency . It is thought that poor hormonal control, leading to high blood levels of ACTH, is an important factor in the pathogenesis of TARTs by inducing hypertrophy and hyperplasia of these adrenal-like cells within the testis . Accordingly, the case herein reported showed that TARTs tend to grow when ACTH levels are elevated. However, TARTs are also found in properly treated patients, whereas some poorly controlled CAH patients never develop TARTs despite they are chronically exposed to elevated ACTH levels . The most plausible explanation for this observation is that in the embryological period aberrant adrenal cells do not nestle in the testes in all males, so the presence of these aberrant adrenal cells within the testis is a prerequisite for the development of TARTs . This ectopic migration does not seem to be related to a specific genotype as so far described. However, the presence of TARTs in the patients described in this article allows us to speculate that also POR gene variants, can cause TART development. Articles on PORD patients do not report the presence of TARTs in any of the patients described. In conclusion, the unknown incidence of POR gene variants and the poorness of fertility-investigating reports enlighten that it is still unclear whether PORD is associated with human infertility since most of the cases reported so far did not focus on patients’ fertility. Further studies exploring the relationship between POR genotype and fertility are needed. Evidence from the male proband herein reported suggests that spontaneous fatherhood can occur in male patients with PORD but proper management of CAH is needed to reach spontaneous fertility without the need to undergo ART.
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biomedical
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