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UBC Theses and Dissertations
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Oxovanadium(IV) and (V) complexes with naturally-occurring molecules Zhou, Ying 1993
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OXOVANADIUM(IV) AND (V) COMPLEXES WITHNATURALLY-OCCURRING MOLECULESbyYING 7J-10UB.Sc. (Honours), Chengdu University of Science and Technology,Chengdu, Sichuan, People's Republic of China, 1990A THESIS SUBMIllED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinTHE FACULTY OF GRADUATE STUDIES(Department of Chemistry)We accept this thesis as conformingto the required standardThe University of British ColumbiaApril 1993© Ying Zhou, 1993this thesis inUniversity offor referenceIn presentingdegree at thefreely availablepartial fulfilment of the requirements for an advancedBritish Columbia, I agree that the Library shall make itand study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.Department of C4 e The University of British ColumbiaVancouver, CanadaDate 4pi Q 26. I 773DE-6 (2/88)AbstractComplexes with naturally-occurring ligating moieties were prepared and studied aspart of an overall process to understand the coordination chemistry of vanadium.Bis(kojato)oxovanadium(IV), VO(ka)2, bis(3-oxy-1,2-dimethy1-4-pyridinonato)-oxovanadium(IV), VO(dpp)2, bis(2-hydroxymethy1-5-oxy-1-methy1-4-pyridinonato)-oxovanadium(IV), VO(hmp)2, bis[2-(2'-oxypheny1)-2-oxazolinato]oxovanadium(IV),VO(oz)2, bis[2-(2'-oxypheny1)-2-thiazolinato]oxovanadium(IV), VO(thz)2.0.5H20 andbis(benzohydroxamato) oxovanadium(IV), VO(bz)2 were prepared and characterized. Inaddition, two oxovanadium(V) complexes, bis(benzohydroxamato)methoxo-oxovanadium(V), V0(OCH3)(bz)2 and bis(benzohydroxamato)ethoxooxovanadium(V),VO(0C2H5)(bz)2 were also prepared from VO(bz)2. All eight complexes were preparedin one step processes, in particular V0(dpp)2 and V0(hmp)2 which were prepared directlyfrom maltol and kojic acid, respectively, using vanadyl and methylamine in a one-potsynthesis method.All oxovanadium complexes were characterized by infrared spectroscopy, massspectrometry, elemental analyses and room temperature magnetic susceptibilitymeasurements, and whenever possible, by UV-Visible spectrophotometry. 1H and 51VNMR were also used to characterize the two oxovanadium(V) complexes,VO(OCH3)(bz)2 and VO(0C2H5)(bz)2. Single crystal X-ray diffraction studies ofVO(oz)2 and V0(thz)2 were also performed by the departmental facility.Characterization of the oxovanadium(IV) complexes revealed them to be 5-coordinate square pyramidal bis(ligand)oxovanadium(IV) complexes with each ligandbinding in a bidentate fashion to the central vanadium atom. VO(OCH3)(bz)2 andV0(0C2H5)(bz)2 were found to be 6-coordinate bis(ligand)oxovanadium(V) complexes.Comparison of the infrared stretching frequencies of the vanadium-oxo bond revealed thatthe strength of the vanadium-oxo bond in the eight complexes was consistent with bondiiistrength observed in other oxovanadium complexes. Single crystal X-ray diffractionstudies of VO(0z)2 and VO(thz)2 showed them to be isostructural. The bidentate ligandsare bonded to the vanadium center through the phenolate oxygen and the oxazoline orthiazoline ring nitrogen. The two complexes are both regular square pyramids with thebidentate ligands coordinated in a trans fashion. The vanadium atoms in these complexesare elevated by approximately 0.6 A from the basal square planes defined by the fourligand 0 and N donors. The average V=0 bond length is 1.6 A.TABLE OF CONTENTSpageAbstractTable of Contents^ iv^List of Tables vList of Figures ^ viList of Abbreviations viiAcknowledgements^ xChapter 1.^General Introduction^ 1Chapter 2.^Experimental Details 72.1. Synthesis Material and methods^ 72.2. Characterization^ 102.2.1 Infrared Spectroscopy ^ 112.2.2. Elemental Analyses 122.2.3. 1H NMR Spectroscopy 132.2.4. Variable Temperature 1H NMR Spectroscopy ^ 152.2.5. 51V NMR Spectroscopy ^ 152.2.6. Mass Spectrosmetry 162.2.7. UV-Vis Spectrophotometry^ 172.2.8. X-ray Crystallographic Analysis 18Chapter 3.^Results and Discussion ^ 19References 39Appendix A 42Appendix B 49ivLIST OF TABLESpageTable 2.2.1.^Characteristic infrared absorptions ^ 11Table 2.2.2.^Results of elemental analyses of the vanadium complexes ^ 13Table 2.2.3.^1H NMR data for the VO(OR)(bz)2 complexes ^ 14Table 2.2.5.^51V NMR data for the VO(OR)(bz)2 complexes 15Table 2.2.6.1.^FAB mass spectral data (m/z) of the vanadium complexes ^ 16Table 2.2.6.2.^El mass spectral data (m/z) of the vanadium complexes ^ 16Table 2.2.7.^UV-Vis spectral data, X, nm (e, M-1cm-1) ^ 17Table 3.1.^Selected bond lengths for VO(oz)2 and VO(thz)2 ^ 30Table 3.2.^Selected bond angles for VO(oz)2 and VO(thz)2 31Table Al^Selected crystallographic data for VO(oz)2 and VO(thz)2 ^ 42Table A2^Final atomic coordinates (fractional) and Beg for VO(oz)2 ^ 43Table A3^Final atomic coordinates (fractional) and Beg for VO(thz)2 ^ 44Table A4^Bond lengths for VO(oz)2 and VO(thz)2 ^ 45Table A5^Bond angles for VO(oz)2 and VO(thz)2 46Table B1^Comparison of the plasma glucose levels between the acutetime course experiments for VO(ma)2 and VO(ka)2 ^ 51VLIST OF FIGURESpageFigure 1.1.^Ligand precursors chosen for thebis(ligand)oxovanadium(IV) complexes ^ 2Figure 1.2.^Structures of the siderophores mycobactin anddeferriferrioxamine B ^ 4Figure 2.2.3.^VO(OR)(bz)2 complexes atom labelling used in NMR data ^ 14Figure 3.1.^Bis(ligand)oxovanadium(IV) complexes ^ 19Figure 3.2.^Scheme for the one-pot synthesis of bis(3-oxy-4-pyridinonato)-oxovanadium(IV) complexes ^ 20Figure 3.3.^Six possible isomers for VO(OR)(bz)2 complexes ^ 25Figure 3.4.^Structure of bis(benzohydroxamato)chlorooxovanadium(V)complex ^ 26Figure 3.5.^ORTEP view of the VO(oz)2 unit ^ 28Figure 3.6.^ORTEP view of the VO(thz)2 unit 29Figure 3.7.^Molecular orbital scheme for [VO(H20)521 (C4, symmetry)according to Ballhausen and Gray ^ 34Figure 3.8.^Potential "intensity stealing" effect in UV-Visspectrophotometric study of VO(oz)2 and VO(thz)2 ^ 36Figure 3.9.^Splitting of the vanadium d levels ^ 37Figure Bl.^Daily average blood glucose levels for the ten STZ-diabeticrats following chronic administration of VO(ka)2 in thedrinking water. ^ 52Scheme I 32viLIST OF ABBREVIATIONSAbbreviation^ Meaninga^length of the unit cell along the a axisA angstroma^interaxial angle between unit cell edges b and cb length of the unit cell along the b axis13^interaxial angle between unit cell edges a and cBM Bohr magnetonc^length of the unit cell along the c axis°C degrees Celsiuscm-i^wave number8 chemical shiftDcalc^calculated densitydeg degreese^molar extinction coefficientEl electron-impact ionizationEIMS^electron-impact ionization mass spectrometry+FAB positive ion fast atom bombardment+FABMS^positive ion fast atom bombardment mass spectrometryfw formula weightg^gramsY interaxial angle between unit cell edges a and b67Ga^gallium-67iH protonHbz^benzohydroxamic acidH3DFB deferriferrioxamine BviiviiiHdpp^3-hydroxy-1,2-dimethy1-4-pyridinoneHhmp 2-hydroxymethy1-5-hydroxy-1-methyl-4-pyridinoneHka^kojic acid, 2-hydroxymethy1-5-hydroxy-y-pyroneHoz 2-(2'-hydroxypheny1)-2-oxazolineHthz^2-(2'-hydroxypheny1)-2-thiazolineHz hertzI.P.^intraperitonealIR infraredJab^NMR coupling constant between hydrogens a and bK degrees Kelvinkg^kilogramsL literLL^bidentate ligandX, wavelength, nmmaltol^3-hydroxy-2-methyl-4-pyronemL millilitermmol^millimoleVx-y vibrational stretching modenm^nanometer, 10-9mNMR nuclear magnetic resonanceORTEP^Oak Ridge Thermal Ellipsoid PlotR agreement factorRw^weighted agreement factorSTZ streptozotocinT^temperatureUV-Vis^ultraviolet-visbleVO(bz)2 bis(benzohydroxamato)oxovanadium(IV)ixVO(bz)2C1^bis(benzohydroxamato)chlorooxovanadium(V)VO(dpp)2 bis(3-oxy-1,2-dimethy1-4-pyridinonato)oxovanadium(IV)VO(hmP)2^bis(2-hydroxymethy1-5-oxy-1-methyl-4-pyridinonato)oxovanadium(IV)VO(H20)(C204)2^aquobis(oxalato)oxovanadium(IV)VO(ka)2^bis(kojato)oxovanadium(IV)VO(ma)2 bis(maltolato)oxovanadium(IV)VO(OCH3)(bz)2^bis(benzohydroxamato)methoxooxovanadium(V)VO(0C2H5)(bz)2^bis(benzohydroxamato)ethoxooxovanadium(V)VO(OiPr)(ox)2^isopropoxobis(8-hydroxyquinolinato)oxovanadium(V)VO(OR)(bz)2^bis(benzohydroxamato)alkoxooxovanadium(V)VO(oz)2 bis[2-(2'-oxypheny1)-2-oxazolinato]oxovanadium(IV)VO(thz)2^bisf2-(2'-oxypheny1)-2-thiazolinato]oxovanadium(IV)weighting factorWia^peak width at half peak heightnumber of molecules in the unit cell (excluding solventmolecules of crystallization)ACKNOWLEDGEMENTSI would like to thank Dr. Chris Orvig for his guidance and encouragementthroughout this work.Thanks also to the Orvig team members, past and present, from whom I learned alot. I would like to give my special thanks to Dr. Lucio Gelmini and Ernest Wong for theirhelp on my computer techniques and their patience in reading through this thesis and theirvaluable suggestions.I would also like to thank Mr. P. Borda for the elemental analysis of the productsand his patience in their determination; Dr. S. Rettig for his prompt determination of thecrystal structures; the technical staff of the NMR and mass spectroscopy facility and theUBC Chemistry support staff for their expertise.I would like to extend my thanks to Dr. J. McNeill and his group at UBCPharmaceutical Sciences Department for supplying the data of VO(ka)2 in animal studies.Financial support in the form of a Teaching Assistantship is gratefullyacknowledged.To my parents and my sisters who always support me with their love.xi1Chapter 1. General IntroductionVanadium is a widely distributed first row transition metal and is the nineteenthmost abundant element in the earth's crust. Research into the chemistry and biologicalimportance of vanadium has been in progress since its discovery by N. G. Sefstrom in1831,1 however, interest in vanadium intensified after the discovery of the inhibitoryactions of orthovanadate ion (VO43-) in sodium-potassium pump in 19772 and thediscovery of the insulin mimicking properties of vanadate in 1980.3,4 Much progressconcerning the chemistry and biological relevance of vanadium has been made during thepast decade. It is known that the biological role of vanadium encompasses stimulatory,regulatory and inhibitory functions.1 Vanadium has also been recognized as anendogenous component present in trace quantities in tissues of higher animals and issuspected to be essential for growth and development in many organisms. Whethervanadium is essential for humans remains unclear, although mounting evidenceincreasingly suggests that vanadium is most likely an essential trace element.5,6,7Research into this suggestion has led to numerous studies which have examined thebehaviour of vanadium within the human body. For example, the binding of V(IV) andV(V) to human serum transferrin has been well documented.8 In addition, the discoveryof vanadate as a possible insulin mimicking agent has also stimulated research into thesynthesis of new vanadium compounds and the study of their properties in vivo.Vanadium is of course found in numerous other biological systems besides humans.Recently, vanadium has been recognized as a part of the catalytically active center in thenitrogenase system of a special strain of Azotobacter chroococcum9 and in thevanadate(V)-dependent haloperoxidases of several marine algae.10 However, much workis still required before the precise functions of vanadium in these and other biologicalsystems can be fully understood.Although much effort has been expended studying the behaviour and function of2vanadium in naturally-occurring systems, there is also much interest in studying theproperties of synthetic vanadium compounds and their possible applications. For example,the discovery of the insulin mimicking properties of vanadate has accelerated the searchfor vanadium compounds which could replace insulin in the treatment of diabetes.3ADiabetes is a condition in which the level of glucose in the blood plasma of mammals isabnormally high.11 Present diabetic treatment often involves twice daily injections ofinsulin, a hormone which regulates the utilization and storage of basic human nutrients.Since insulin is not orally active, there is tremendous interest in developing an orallyactive vanadium compound as a replacement for insulin.HO00/OHX=0 HozX=S HthzHIcaNHO 'HR2=CH3, R6=H^Hdpp^ HbzR2=H, R6=CH2OH HhmpFigure 1.1. Ligand precursors chosen for the bis(ligand)oxovanadium(IV) complexes.3In order to better understand the biological role of vanadium, the relevantcoordination chemistry of vanadium needs to be thoroughly investigated. Vanadium existsin a number of oxidation states, but only oxidation states +3, +4 and +5 are important inbiological systems.12 Compounds of oxovanadium(IV) are of particular interest to usbecause oxovanadium(IV) compounds are less toxic in the rabbit, rat, mouse, and guineapig than vanadate(V) compounds, and, furthermore, several studies have indicated that theinsulin-like actions of vanadate are also found with the vanadyl form and that theformation of vanadyl from vanadate in vitro coincided with the appearance of effects thatare similar to those observed with insulin.13The V02+ moiety is known to bond effectively to electronegative donor atomssuch as fluorine, chlorine, oxygen and nitrogen. Complexes with fluorine and oxygendonor atoms are known to be especially stable.14 Examples of the V02+ moiety bondingto sulfur and phosphorus atoms are also known.14 In this study of the coordinationchemistry of vanadium, potential bidentate ligands with oxygen-oxygen or oxygen-nitrogen donor atoms were chosen to coordinate to the V02+ moiety. It was our desire toutilize naturally-occurring compounds or ligating moieties as a basis for choosing potentialligands of interest. The ligands in this study of the coordination behaviour ofoxovanadium(IV) are illustrated in Figure 1.1.The coordination of oxovanadium(IV) with benzohydroxamic acid (Hbz), 2-(2'-hydroxypheny1)-2-oxazoline (Hoz) and 2-(T-hydroxypheny1)-2-thiazoline (Hthz) werestudied because the ligating moieties of these ligands can be found in certain classes ofmicrobial iron chelators (i.e. the siderophores). For example, the binding groups in thesiderophore mycobactin consists of two hydroxamic acid residues and a 2-(2'-hydroxypheny1)-2-oxazoline residue. Two examples of siderophores (mycobactins anddeferriferrioxamine B) containing the 2-(2'-hydroxypheny1)-2-oxazoline residue and thehydroxamic acid residues are shown in Figure 1.2.15,16,17 It is of interest to determinehow the ligating moieties in these ligands would bind to oxovanadium(IV).4Mvcobactin R4^4^ Rl, R4 = Me, Et, or long chain0 R1^R2, R3, R5 =H or Me1N .,.,,,"...,,...„. N ....ki^0OHHON11\2^CONH^CONH/^'''), /^".>(CH2)5^(CH2)2 kCH2)5^(CH2)2 (CH2)5^CH3\ /^\ /^\ /N—C N—C N—CI^II^I^II I^IIOHO OHO^OHODeferriferrioxamine B (H3DFB)Figure 1.2. Structure of the siderophores mycobactin and deferriferrioxamine B (H3DFB)Over the past several years, the coordination of the a-hydroxyketone moiety withvarious metal centers has been investigated in this lab. Initial investigation focused onligands containing the a-hydroxyketone moiety derived from 3-hydroxy-4-pyrones and 1-alky1-3-hydroxy-4-pyridinones. Aluminium, gallium, indium, rhenium, and technetiumcomplexes with these pyrone and pyridinone ligands have been prepared and studied.17,18Coordination of these ligands to Al, Ga, and In resulted in 6-coordinate tris(ligand) metalcomplexes. For Tc and Re, 6-coordinate bis(ligand) complexes containing a metal oxobond were formed. As a continuation of this work, the coordination of the a-hydroxyketone moiety to oxovanadium(IV) was studied. Kojic acid (Hka), a naturally-occurring compound which contains the a-hydroxyketone moiety was chosen as one of thepotential ligands for this study. In addition, 3-hydroxy-1,2-dimethy1-4-pyridinone (Hdpp)5and 2-hydroxymethy1-5-hydroxy-1-methyl-4-pyridinone (Hhmp), which also contain thea-hydroxyketone unit, also were chosen as potential ligands for coordination withoxovanadium(IV).A unique combination of biologically relevant properties (water solubility,hydrolytic stability and lipophilicity) has made pyrone and pyridinone complexesparticularly interesting with respect to their possible medical application. For example,the tris(maltolato)aluminium complex has been used widely in the study of Alneurotoxicity.19 Another example is the 67Ga complex tris(1-p-methoxypheny1-2-methyl-3-oxy-4-pyridinonato)gallium(III), which is a potential heart imaging agent.20 Thesepyrone and pyridinone ligands are non-toxic, naturally-occurring or easily synthesized andthe properties of their complexes can be altered by changing the substituents on theligands. With such favorable ligand properties, oxovanadium(IV) complexes of theseligands may prove to have interesting potential medical applications considering theinsulin mimicking properties of some vanadium compounds.Coordination of six different bidentate ligands to oxovanadium(IV) were studied.For each ligand, 5-coordinate bis(ligand) complexes with a V02+ core were synthesizedand characterized. The characterization of these complexes involved the use of infraredspectroscopy, mass spectrometry, elemental analyses, magnetic susceptibilitymeasurements and ultraviolet-visible spectrophotometry when possible. X-raycrystallographic analyses of bis[2-(2'-oxypheny1)-2-oxazolinato]oxovanadium(IV),VO(oz)2, and bis[2-(2'-oxypheny1)-2-thiazolinatoloxovanadium(IV), VO(thz)2, were alsoobtained. Besides the oxovanadium(IV) complexes, two V(V) derivatives of VO(bz)2,VO(OCH3)(bz)2 and VO(0C2H5)(bz)2 which are 6-coordinate oxovanadium(V)complexes were also synthesized. In addition to the techniques used to characterized thesix oxovanadium(IV) complexes, 1H and 51V NMR were also used to studyVO(OCH3)(bz)2 and VO(0C2H5)(bz)2. The preparation and characterization of the eightvanadium complexes are summarized in Chapter 2. It is the belief that by studying the6coordination of vanadium with ligating moieties of biological or medical significance, abetter understanding of the general roles or behaviour of vanadium in nature can beachieved. As a secondary objective, some of these oxovanadium complexes could also beevaluated as potential replacement for insulin in the treatment of diabetes (see AppendixB).7Chapter 2. Experimental Details2.1 synthesis Material and MethodsAll chemicals were reagent grade and were used as received without furtherpurification: kojic acid (2-hydroxymethy1-5-hydroxy-y—pyrone), maltol (3-hydroxy-2-methy1-4-pyrone) and benzohydroxamic acid (Hbz, Sigma), VOSO4-5H20 andVOSO4•3H20 (Aldrich), Na0Ac-3H20 (Fisher). 2-(2'-Hydroxypheny1)-2-oxazoline(Hoz)21, and 2-(2'-hydroxypheny1)-2-thiazoline (Hthz)22 were prepared according to theliterature and were used without further purification. Water was deionized (BarnsteadD8902 and D8904 cartridges) and distilled (Corning MP-1 Megapure still). The yields arefor analytically pure compounds and they are calculated based on vanadium. The meltingpoints were measured with a Mel-Temp aparatus; however, all the vanadium complexeswere non-volatile, charring and decomposing above 120°C. Room temperature (293.5 K)magnetic susceptibilities were measured on a Johnson Matthey magnetic susceptibilitybalance, using Hg[Co(NCS)41 as the susceptibility standard. Diamagnetic correctionswere estimated by using Pascal's constants23.8Bis(kojato)oxovanadium(IV), VO(ka)z. VOSO4.5H20 (2.50 g, 9.88 mmol) was dissolvedin 10 mL hot water and the solution was degassed with As for 10 minutes. The solutionwas then added to 10 mL of a degassed aqueous solution of kojic acid (2.88 g, 20.3 mmol)and Na0Ac.3H20 (2.97 g, 21.8 mmol). After refluxing under Ar overnight, a blue solidwas collected by vacuum filtration using a Schlenk filtering funnel and dried overnight invacuo. The yield was 2.69 g (78%). The solid state magnetic moment was 1.76 BM.Bis(3-oxy-1.2-dimethy1-4-pyridinonato)oxovanadium(IV). VOldpgq To a solution ofmaltol (2.10 g, 16.7 mmol) and V0SO4-5H20 (2.01 g, 8.0 mmol) in 20 mL hot water wasadded 20 mL 40% methylamine in water (26 mmol) and the pH of the solution wasdecreased from 11.7 to 9.9 by addition of 2 N H2SO4. The solution was refluxed for 8hours. A gray blue solid was collected by filtration and washed several times with hotwater. The yield was 2.56 g (94%). The solid state magnetic moment was 1.77 BM.Bis(2-hydroxymethy1-5-oxy- 1 -methyl-4-pyridinonato)oxovanadium(IV). VO(hmpla. Toa solution of kojic acid (2.80 g, 19.7 mmol) in 40 mL hot water was added 20 mL 40%methylamine in water (26 mmol) and V0SO4-5H20 (2..47 g, 9.8 mmol) in 20 mL hotwater. The pH of the solution was decreased from 12.8 to 11.0 by addition of 2 N H2SO4.The solution was refluxed under Ar for 8 hours. A blue solid was collected by filtrationand washed several times with hot water. The yield was 2.45 g (67%). The solid statemagnetic moment was 1.74 BM.Bis12-(2'-oxypheny1)-2-oxazolinatoloxovanadium(IV), VO(oz)z. To a solution of Hoz(0.31 g, 1.90 mmol) and Na0Ac.3H20 (0.27 g, 1.95 mmol) in CH3OH (10 mL) was addedV0SO4.3H20 (0.20 g, 0.92 mmol) in 11 mL of CH3OH:H20 (10:1) solution. A gray-bluesolid immediately precipitated and was collected by filtration. Recrystallization of the9solid from CH2C12 yielded large blue crystals. The yield was 0.27 g (75%). The solidstate magnetic moment was 1.84 BM.B is12-(2'-oxypheny1)-2- thiazolin atol oxovanadium(IV), VO(thz)224L5..tiz11. Thepreparation was as for VO(oz)2. V0SO4.3H20 (0.20 g, 0.92 mmol), Hthz (0.34 g, 1.90mmol) and Na0Ac-3H20 (0.27 g, 1.95 mmol) were employed. Recrystallization fromCH2C12 yielded large yellow-green crystals. The yield was 0.32 g (82%). The solid statemagnetic moment was 1.80 BM.Bis(benzohydroxamato)oxovanadium(IV). VO(bz). VOSO4.3H20 (0.20 g, 0.92 mmol)in 10 mL water was added dropwise to a solution of benzohydroxamic acid (0.26 g, 1.90mmol) in 20 mL hot water. A purple solid precipitated. The pH of the suspension wasraised from 1.7 to 7.4 by the slow addition of 0.5 N NaOH. The suspension was thenstirred for 1.5 hours. The purple solid was collected by filtration yielding 0.22 g (71%) ofthe product. The solid state magnetic moment was 1.72 BM.Bis(benzohydroxamato)methoxooxovanadium(V). VO(OCH2)(bz)z. VO(bz)2 (0.11 g,0.32 mmol) was dissolved in 10 mL -35°C methanol and then stirred for 2 hours. Abrick-red microcrystalline solid precipitated after the addition of 10 mL water. Theproduct was collected by filtration and washed several times with water. The yield was0.065 g (54%).Bis(benzohydroxamato)ethoxooxovanadium(V). V0(0C21_1.5.1.(1L)z. VO(bz)2 (0.10 g,0.30 mmol) was dissolved in 10 mL hot ethanol and stirred for 2 hours. A golden-redsolid precipitated upon slow evaporation of solvent. The product was collected byfiltration and washed several times with water. The yield was 0.058 g (52%).102.2. CharacterizationThe bis(ligand)oxovanadium(IV) complexes were characterized by infrared (IR)spectroscopy, positive ion fast atom bombardment mass spectrometry (+FABMS) orelectron-impact ionization mass spectrometry (EIMS), UV-visible spectrophotometry(UV-Vis), elemental analyses, and in some cases, X-ray crystallograghy. In addition to theabove methods, the six-coordinate bis(ligand)alkoxooxovanadium(V) complexes were alsocharacterized by 1H NMR and 51V NMR.IR spectra were recorded as KBr disk in the range 4000-400 cm-1 on a Perkin-Elmer PE783 spectrophotometer and were referenced to polystyrene. The mass spectrawere obtained with an AEI MS9 (FABMS) spectrometer, or a Kratos MS50 (EIMS)instrument by the UBC mass spectrometry service. Elemental analyses were performed byMr. Peter Borda of the Microanalytical Laboratory of this department. 1H NMR spectra,recorded on a Varian XL-300 instrument, are reported in ppm downfield oftetramethylsilane (TMS) as the internal standard. 51V NMR spectra were recorded on aVarian XL-300 instrument and are referenced to external VOC13. The UV-Vis spectrawere recorded from 900-200 nm with a Shimadzu UV-2100 spectrophotometer. Bothcrystal structures reported in this thesis were determined with a Rigaku AFC6Sdiffractometer by Dr. Steven J. Rettig of the UBC Structural Chemistry Laboratory.112.2.1 Infrared SpectroscopyThe relevant IR data is summarized in Table 2.2.1. All compounds exhibit a strongV=0 stretching frequency in the region from 960 to 995 cm-1.Table 2.2.1 Characteristic IR absorptions (cm-1).All bands are sharp and strong except where noted.*Assignment VO(ka)2 VO(dpp)2 VO(hmp)21610 1605 1610(m)vc.0 and 1550 1550 1560(m)vc.c(ring) 1500 1490 15101470 1450 14501430(w)vv.o 980 965 970VC-N(ring) 1300Assignment VO(0z)2 VO(thz)2VC.N 1620 1600VC=C(aroma tic) 1595(w) 15701540vv.° 990 98012Assignment^VO(bz)2^VO(OCH3)(bz)2^VO(0C2H5)(bz)21600^1600^1600vc.0 and^1570 1520(b)^1550(b)Vc.C(aromatic)^1510^ 1520(b)1480 1480^14901440^1440 1450vv.o^995^960^970VN-H 3200(b)^3200(b)^3200(b)* w, weak; m, medium; b, broad.2.2.2. Elemental AnalysesSatisfactory elemental analyses were obtained for all complexes (refer to Table2.2.2). Prior to analysis, each sample was purified by recrystallization when possible anddried at —65°C in vacuo for at least 24 hours.13Table 2.2.2Results of elemental analyses of the vanadium complexes(Calculated[Found])Compound^Formula %C %H %NyO(ka)2 C12111009\1 41.28[41.06] 2.89[2.89]VO(dpp)2 C141116N205V 48.99[48.56] 4.70[4.65] 8.16[8.38]VO(hmp)2 C141116N207V 44.81[45.00] 4.30[4.39] 7.47[7.47]VO(oz)2 C181-1 16N205V 55.25[55.12] 4.12[4.17] 7.16[7.08]VO(thz)2.0.5H20 C181-117N203.5S2V 50.00[50.42] 3.98[3.83] 6.48[6.47]VO(bz)2 C141112N205V 49.57[49.37] 3.57[3.66] 8.26[8.02]VO(OCH3)(bz)2 C151115N206V 48.66[48.46] 4.08[4.03] 7.57[7.54]VO(0C2H5)(bz)2 C161117N206V 50.01[50.32] 4.46[4.54] 7.29[7.16]2.2.3. 11-1 NMR Spectroscopy1H NMR spectral data of the two vanadium(V) complexes are listed in Table 2.2.3.Both spectra exhibit a doublet and two triplets for the phenyl hydrogens and characteristicsignals for the alkoxy hydrogens.214R=CH3f^VO(OCH3)(bz)2R=CH2gCH3h VO(0C2H5)(bz)2Figure 2.2.3. VO(OR)(bz)2 complexes atom labelling used in NMR data.Table 2.2.3. 111 NMR chemical shifts (8) for the VO(OR)(bz)2 complexes (PPn1).aRefer to Figure 2.2.3. for atom labelling.VO(OCH3)(bz)2 VO(0C2H5)(bz)2Ha,e (d) 7.73(2H, J=7.1 Hz) 7.78(2H, J=7.2 Hz)Hb,d (t) 7.40(2H, J=7.5 Hz) 7.43(2H, J=7.5 Hz)He (t) 7.49(1H, J=7.5 Hz) 7.52(1H, J=7.4 Hz)CH3f (s) 3.34(3H)CH2g (q) 3.60(2H, J=7.1 Hz)CH3h 1.17(3H, J=7.1 Hz)a in CD3ODAbbreviations: s=singlet d=doublet t=triplet q=quartet152.2.4. Variable Temperature 1H NMR SpectroscopyThe variable low temperature 1H NMR spectra for VO(OCH3)(bz)2 andVO(0C2H5)(bz)2 in CD3OD were recorded over the range -80°C to 25°C. The lowtemperature 111 NMR spectra did not differ significantly from the spectrum obtained atroom temperature except for a slight broadening of the signals.2.2.5. 51V NMR Spectroscopy51V NMR data for VO(OCH3)(bz)2 and VO(0C2H5)(bz)2, recorded in CH2C12and C2H5OH respectively, are given in Table 2.2.5. Both complexes yielded one sharpsingle resonance, as expected for single species.Table 2.2.5. 51V NMR chemical shifts (8) for the VO(OR)(bz)2 complexes (Ppm).complex^chemical shift. (ppm)^line width (W112, Hz)VO(OCH3)(bz)2a^-425^ 222VO(0C2H5)(bz)2b -411 543a in CH2C12, b in C2H5OH162.2.6. Mass SpectrometryThe mass spectra of the complexes showed the HVOL2+, and/or VOL2+ fragmentswhen recorded in the positive ion FAB mode, or the VOL2+, VOL+, and L+ fragments inthe El mode. The results are listed in Table 2.2.6.1. for positive ion FAB mode and inTable 2.2.6.2. for the El mode.Table 2.2.6.1. FAB mass spectral data (m/z) of the vanadium complexes.HVOL2+ VOL2+VO(ka)2 350* 349VO(bz)2 340 339*VO(dpp)2 344* 343VO(hmp)2 376* 375VO(OCH3)(bz)2 339VO(0C2H5)(bz)2 339* indicates the base peak.Table 2.2.6.2. El mass spectral data (m/z) of the vanadium complexes.The relative intensities of the peaks are included in the parentheses.VOL2+^VOL+^L+VO (0z)2 391(100) 229(17.9) 163(88.9)v0(thz)2 423(100) 245(11.4) 179(5.2)172.2.7. UV-Vis ^m tr .The UV-Visible spectral data which were obtained at room temperature aresummarized in Table 2.2.7. Data for VO(dpp)2, VO(hmp)2 and VO(bz)2 were notobtained either due to their very limited solubility in various solvents or due to the reactionof the complexes with the solvents.Table 2.2.7. UV-Vis spectral data, X, nm (c, M-1cm-1).complex^solvent Amax (E)1 II In otherv0(ka)2^H20 842(30) 612(15) 223(34200)VO(oz)2^CH2C12 597(47) 543(45) 409(sh*, 111) 331(12000)239(63700)VO(thz)2^CH2C12 595(53) 537(66) 437(sh, 179) 346(11200)242(56500)VO(OCH3)(bz)2 CH3OH 441(2000)222(22200)203(25600)VO(0C2H5)(bz)2 C2H5OH 446(2400)222(25600)204(29700)* sh=shoulder182.2.8. X-ray Crystallographic AnalysesThe solid state structures of VO(oz)2, and VO(thz)2 were established by singlecrystal X-ray diffraction studies at 21°C. Single crystals of thebis(ligand)oxovanadium(IV) complexes were grown by slow evaporation from saturatedmethylene chloride solution. Crystallographic data, final atomic coordinates andequivalent isotropic thermal parameters Beg for VO(oz)2 and VO(thz)2 are given inAppendix A as Tables Al, A2 and A3. The complete list of bond lengths and bond anglesare summarized in Tables A4 and A5 in Appendix A.x=o vo(oz)2X=S VO(thz)22vo(ka)2•I■0IIV\,1-/ CH3 12019Chapter 3. Results and DiscussionThe coordination chemistry of oxovanadium(IV) was studied with kojic acid(Hka), 3-hydroxy-1,2-dimethy1-4-pyridinone (Hdpp), 2-hydroxymethy1-5-hydroxy-1-methyl-4-pyridinone (Hhmp), 2-(2'-hydroxypheny1)-2-oxazoline (Hoz), 2-(2'-hydroxypheny1)-2-thiazoline (Hthz) and benzohydroxamic acid (Hbz) as potential ligandsfor binding to the V02+ moiety. The ligands used in this study were chosen because theyall possess qualities which are desirable for bonding to oxovanadium(IV). All of these2 R2=CH3, R6=H VO(dpp)2R2=H, R6=CH2OH VO(hmp)2 VO(bz)2Figure 3.1. Bis(ligand)oxovanadium(IV) complexes.1 12CH3NH2-2H202 _R62R2V02+OH -2H+ _11VIMP20potential ligands when deprotonated behave as bidentate Lewis bases.24,25 The V02+cation is classified as a hard Lewis acid,26 therefore, according to hard soft acid basetheory,26 the V02+ cation should bind favorably to donor atoms which are hard Lewisbases. In the case of Inca, Hdpp, Hhmp and Hbz, the deprotonated hydroxy oxygen andthe carbonyl oxygen act as donor atoms, each donating an electron pair to theoxovanadium(IV) center. For Hoz and Hthz, the donor atoms are the deprotonatedhydroxy oxygen and the oxazoline or thiazoline ring nitrogen. The hydroxy oxygen, thecarbonyl oxygen and the ring nitrogen within these ligands can be classified as relativelyhard bases.25 Binding of the hard Lewis acid, V02+, to the hard Lewis base donor atomsresulted in bis(ligand) metal complexes of neutral charge. Each ligand binds to the centralvanadium atom to form 5 or 6-membered chelate rings (refer to Figure 3.1.). The chelateeffect contributes to the overall thermodynamic stability of these bis(ligand)oxovanadium(IV) complexes.R2=CH3, R6=H maltolR2=H, R6=CH2OH kojic acidFigure 3.2. Scheme for the one-pot synthesis of bis(3-oxy-4-pyridinonato)oxovanadium(IV)complexesThe synthesis of oxovanadium(IV) complexes with the {0, 0} or {0, N} bidentatemonobasic ligands were straightforward and gave relatively high yields (67%-94%). Theratio of ligand precursor to V02+ used was 2:1 with a slight excess of ligand precursor21used to force the reaction to completion. In the synthesis of VO(dpp)2 and VO(hmp)2, aone pot synthetic method was utilized.27 The synthesis involves the conversion of themetal coordinated pyrone precursor to the corresponding coordinated pyridinone metalcomplex. The traditional method of synthesis for 3-hydroxy-4-pyridinone involves theamination of the analogous 3-hydroxy-4-pyrone.27 To carry out this conversion, protectedpyrone precursors are usually utilized in a multistep process. The overall conversion istime consuming and rigorous. On the other hand, one pot synthesis of VO(dpp)2 andVO(hmp)2 took only a single step and gave yields of 94% and 67%, respectively. The onepot synthetic process begins by the in situ formation of the metal-pyrone complex. This isthen followed by the insertion of a primary amine into the pyrone ring to form theappropriate pyridinonate complex. Figure 3.2. outlines the synthetic scheme for the one-pot synthesis of the oxovanadium pyridinonate complexes.Recrystallization of the oxovanadium(IV) complexes was not always possible dueto the limited solubility of some of these complexes in common solvents or due to theoxidation of the complex by oxygen within the solvent. For example, purple VO(bz)2dissolves in methanol to give a light orange solution which quickly changes colour to darkred. Addition of water to this solution yields microcrystalline VO(OCH3)(bz)2, anoxovanadium(V) species. Dissolving VO(bz)2 in ethanol produces similar results; theoxovanadium(V) complex, VO(0C2H5)(bz)2 was obtained.All the oxovanadium(IV) complexes were found to be air stable and exhibit amagnetic moment at room temperature in the solid state. Vanadium(IV) has an electronconfiguration of [Ad3d1 and hence has a single unpaired electron. Assuming that themagnetic moment has contribution from only the spin angular momentum of the unpairedelectron, the spin only formula predicts a magnetic moments of 1.73 for a d1 system. Thesix oxovanadium(IV) complexes possess solid state magnetic moment of 1.72 to 1.84 BMat room temperature. The observed magnetic moment for the six oxovanadium(IV)complexes is within the range of values commonly found for many vanadium(IV)22complexes and indicates the presence of a single unpaired electron.28 VO(OCH3)(bz)2and VO(0C2H5)(bz)2 are oxovanadium(V) species with an electron configuration of1Arl3d0. The two oxovanadium(V) complexes showed no solid state magnetic momentsince they possess no unpaired electron.Infrared measurements for each of the oxovanadium complexes are summarized inChapter 2, Table 2.2.1. The infrared spectral pattern of the ligands is preserved in thesecomplexes with a general bathochromatic shift upon coordination to the oxovanadiumcenter. In the infrared spectra of the eight oxovanadium complexes, the absorptionassociated with the characteristic V=0 stretching frequency is of particular interest. Thestretching frequencies of the V=0 bond in oxovanadium complexes are generally observedaround 930 cm-1 to 1030 cm-1.14 For the eight oxovanadium complexes synthesized inthis study, vv.() was observed to range from 965 to 995 cm-1.The oxovanadium(V) complexes, VO(OCH3)(bz)2 and VO(0C2H5)(bz)2, showedDv.0 at 960 cm-1 and 970 cm-1 respectively. The Dv.° for VO(OCH3)(bz)2 andVO(0C2H5)(bz)2 were 35 cm-1 and 25 cm-1 lower than Dv.° in the oxovanadium(IV)complex VO(bz)2 (995 cm-1). This indicates that the vanadium oxo bond in theVO(OR)(bz)2 complexes is weaker than the vanadium oxo bond in VO(bz)2. This may beexplained as follows.The V=0 bond is a multiple covalent bond involving pit-dir electron donation fromthe oxygen to the vanadium center which has empty acceptor orbita1.29 This electrondonation through the it bond is superimposed upon a a bond. Changes in the electronaccepting ability of the vanadium center causes changes in the strength of the vanadiumoxo bond, which is reflected in changes in the V=0 stretching frequency. Coordinatedligands which donate electron density to the vanadium center will increase the electrondensity in the vanadium d orbitals. This increased electron density in the vanadium dorbitals reduces the electron accepting ability of the vanadium atom, therefore reducing theV=0 pit-d/c electron donation. The degree of reduction in the V=0 pit-dn electron23donation depends on the electron donating ability of the ligands. It is not unreasonable toassume that the total electron accepting ability of a metal ion in a particular valence state iscertain.30 When a V4+ complex oxidises to a V5+ complex, the vanadium ion increases itselectrophilicity. At this stage, when a monodentate negative group reaches thecoordination zone, it may or may not exactly counterbalance the increased electrophilicitya V5+. If the donor property of the new ligand is greater than the increased acceptorproperty of the metal ion, there will be an overall accumulation of increased electrondensity around the vanadium ion. This would greatly affect V=0 bond, the stretchingfrequency of which would certainly be lowered. This is what is found in the complexesVO(bz)2 and VO(OR)(bz)2 (R=methyl or ethyl).Analyses for carbon, hydrogen and, when appropriate, nitrogen were carried outfor each oxovanadium complex. The results are summarized in Table 2.2.2. The data areconsistent with the formulation of bis(ligand) oxovanadium complexes. With theexception of VO(thz)2, no solvate water was observed in these complexes. Attempts toremove the solvated water in VO(thz)2 by drying at approximately 65°C in vacuo (< 0.3Torr) for a minimum of 24 hours were not successful.The eight synthesized oxovanadium complexes were examined by massspectrometry. The data are summarized in Chapter 2, Tables 2.2.6.1 and 2.2.6.2. Themass spectra of VO(oz)2 and VO(thz)2 were obtained using electron impact ionization (El)while the mass spectra of the other complexes were obtained using positive ion fast atombombardment (+FAB). The spectra of VO(oz)2 and VO(thz)2 showed strong signalscorresponding to VOL2+, VOL+ and L+ fragments. For VO(ka)2, VO(bz)2, VO(dpp)2 andVO(hmp)2, the mass spectra revealed very strong signals corresponding to HVOL2+ andVOL2+ fragments. The results for these complexes are consistent for a VOL2 formulation.In the case of VO(OCH3)(bz)2 and VO(0C2H5)(bz)2 complexes, VO(OR)(bz)2+ andHVO(OR)(bz)2+ fragments were not the dominant fragments. The base peak in theobserved mass spectra corresponds instead to VOL2+. The alkoxy group was lost during24the fragmentation process in the mass spectrometer. This would suggest that the alkoxygroup is bonded less strongly to the vanadium(V) center compared to the other oxygendonor atoms within the complexes.1H NMR data for VO(OCH3)(bz)2 and VO(0C2H5)(bz)2 were recorded inCH3OD and are presented in Table 2.2.3. The assignments and integrations of the Hsignals are consistent with the coordination of two bidentate ligands to the oxovanadiumcore. 1H signals due to the phenyl ring hydrogens of the two benzohydroxamato ligandssuggest that the phenyl rings of the two ligands are in the same chemical environment.Low temperature 1H NMR of both complexes were carried out and the spectra at differenttemperatures show only slight broadening of the signals. No emergence of any additional1 H resonances was observed even at -80°C.Six isomers are possible for the VO(OR)(bz)2 complexes. These possible isomersare illustrated in Figure 3.3. Isomers I and II have the alkoxy group trans to the V=0 bondwhereas isomers III to VI have the alkoxy group cis to the V=0 bond. At roomtemperature, the 1H NMR spectra shows the hydrogens on the two phenyl rings associatedwith the two benzohydroxamate ligands to be in the same chemical environment. Thiswould suggest that the oxovanadium complex has assumed a trans configuration where thehydrogens in the two phenyl rings are chemically equivalent (I or II). However, fastexchange of the two benzohydroxamate ligands in a cis configuration (III to VI) wouldalso show equivalent phenyl ring hydrogens. If such an exchange process is occurring,lowering the temperature might slow down the rate of exchange and allow the observationof two sets of inequivalent hydrogens on each of the benzohydroxamate ligands.However, variable temperature 1H NMR experiments (as low as -80°C) did not produceany significant changes in the H NMR spectra. This may suggest that the oxovanadiumcomplexes are indeed in a trans configuration. However, the possibility of the complexesin a cis configuration can not be ruled out on the basis of the results from the variable0C v^CH N...O/I O NH‘°0RU,,,. II %%0,N0/1^CoNfr. ‘C0,, ll 0....N.11c o-- ,...11,v^IH NI0 /IN0 C' 025IIIII^ IV^RO„,. 11^c^*V*^I0N /'C V^ VIFigure 3.3. Six possible isomers for V0(OR)(bz)2 complexes.26temperature H NMR experiments. It may be that the rate of exchange of thebenzohydroxamate ligands is faster than the NMR time scale; then the stereochemistry atthe vanadium metal center would not be elucidated using H NMR.A crystal structure of bis(benzohydroxamato)chlorooxovanadium(V), VOC1(bz)2(Figure 3.4.) was reported by Raymond et al.3 1 In this crystal structure, theoxovanadium(V) complex assumes a cis configuration cooresponding to the stereoisomerIII in Figure 3.3 with the chlorine atom cis to the vanadium oxo bond. Similar structures0Cl„ II10 C/0NFigure 3.4. Structure of bis(benzohydroxamato)chlorooxovanadium(V) complex.31have been observed in aquobis(oxalato)oxovanadium(IV), VO(H20)(C204)232 andisopropoxobis(8-hydroxyquinolinato)oxovanadium(V), VO(OiPr)(ox)2.33 Theseoxovanadium(V) complexes exhibit the trans influence which refers to the ability of oneligand to lengthen (and apparently weaken) the bond to the ligand trans to it.34 It waspredicted that a multiply bonded ligand (e.g. V=0) will preferentially weaken other ligandbonds in the trans position.34 Thus, ligands that tend to form strong bonds willpreferentially occupy a position cis to the vanadium oxo bond.31 In 6-coordinateoxovanadium complexes with both bidentate and monodentate ligands, it is likely that one27donor atom of the bidentate ligand would occupy the trans position with the monodentateligand occupying the cis position. This could be attributed to the chelate effect of thebidentate ligand, since the extra thermodynamic stability caused by the positive enthalpychange after chelation might overcome the trans influence from the vanadium oxogroup.24 The trans influence of the oxo group within VO(bz)2C1, VO(H20)(C204)2 andVO(OiPr)(ox)2 causes the chlorine, the water and the isopropoxy group to assume aposition cis relative to the vanadium oxo bond. In our example, VO(OR)(bz)2, it issuspected that the trans influence of the oxo group would also cause the alkoxy group totake up a cis position relative to the oxo bond. However, we have been unable to obtainevidence which supports this conclusion in the VO(OR)(bz)2 complexes. Hence, in theabsence of any concrete evidence in solid state or in solution, the possibility of the alkoxygroup being trans to the oxo group cannot be entirely ruled out.Single crystal X-ray diffraction studies of VO(oz)2 and VO(thz)2 were performed.The analyses show unequivocally that the complexes are indeed the expected bis(ligand)oxovanadium(IV) complexes. The crystal structure of VO(oz)2 was found to beisostructural with VO(thz)2. Computer generated ORTEP diagrams of VO(oz)2 andVO(thz)2 are presented in Figures 3.5. and 3.6.. Selected bond lengths and bond anglesare summarized in Tables 3.1. and 3.2. respectively. X-ray diffraction studies revealedboth VO(oz)2 and VO(thz)2 to be 5-coordinate square pyramidal oxovanadium(IV)complexes, with the oxo group in the axial position. This structure is common for manyoxovanadium(IV) complexes.10 The 2-(2'-oxypheny1)-2-oxazolinate and 2-(2'-oxypheny1)-2-thiazolinate ligands are coordinated to the vanadium center via the phenolateoxygen and the oxazoline or thiazoline ring nitrogen. The two oxazolinate or thiazolinateligands are found to be trans to one another and cis to the oxo group.The vanadium oxo bond lengths in VO(oz)2 and VO(thz)2 are observed to be1.594(1) A and 1.591(3) A, respectively, and are typical for V=0 bond lengths inoxovanadium(IV) complexes (1.52 A-1.68 A).29 Within the six-membered chelate ring01H204C14 H13C15H10H728Figure 3.5. ORTEP view of the VO(oz)2 unit.29Figure 3.6. ORTEP view of the VO(thz)2 unit.30Table 3.1.^Selected Bond Lengths (A) for V0(oz)2 and V0(thz)2 with EstimatedStandard Deviations in ParenthesesVO(oz)2 VO(thz)2Atoms Distance Atoms DistanceV(1)-0(2) 1.931(1) V(1)-0(2) 1.903(3)V(1)-0(4) 1.926(1) V(1)-0(4) 1.900(3)V(1)-0(5) 1.594(1) V(1)-0(5) 1.591(3)V(1)-N(1) 2.068(1) V(1)-N(1) 2.083(3)V(1)-N(2) 2.061(1) V(1)-N(2) 2.083(3)0(1)-C(1) 1.347(2) S(1)-C(1) 1.757(4)0(1)-C(2) 1.460(2) S(1)-C(2) 1.790(5)0(2)-C(5) 1.315(2) 0(2)-C(5) 1.330(4)0(3)-C(10) 1.346(2) S(2)-C(10) 1.761(4)0(3)-C(11) 1.458(2) S(2)-C(11) 1.788(5)0(4)-C(14) 1.319(2) 0(4)-C(14) 1.328(4)N(1)-C(1) 1.284(2) N(1)-C(1) 1.295(5)N(1)-C(3) 1.472(2) N(1)-C(3) 1.479(5)N(2)-C(10) 1.287(2) N(2)-C(10) 1.291(4)N(2)-C(12) 1.472(2) N(2)-C(12) 1.474(5)31Table 3.2.^Selected Bond Angles (deg) for VO(oz)2 and VO(thz)2 with EstimatedStandard Deviations in Parentheses.Atoms Anglevo(oz)2 v0(thz)20(2)-V(1)-0(5) 108.41(5) 115.2(1)0(4)-V(1)-0(5) 108.81(5) 114.9(1)0(5)-V(1)-N(1) 104.73(6) 99.1(1)0(5)-V(1)-N(2) 103.79(5) 99.4(1)0(2)-V(1)-N(1) 85.28(5) 86.8(1)0(2)-V(1)-N(2) 85.25(5) 86.4(1)0(4)-V(1)-N(1) 85.23(5) 85.5(1)0(4)-V(1)-N(2) 86.21(5) 85.7(1)0(2)-V(1)-0(4) 142.79(5) 129.9(1)N(1)-V(1)-N(2) 151.47(5) 161.4(1)formed by the coordination of the phenolate oxygen and the ring nitrogen to the vanadiumcenter, the average vanadium phenolate oxygen bond length is 1.928(1) A and 1.901(3) Afor VO(oz)2 and VO(thz)2 respectively. The average vanadium ring nitrogen bond lengthis 2.064(1) A for the oxazolinate complex and is 2.083(3) A for the thiazolinate complex.The V-0 and V-N bond lengths fall in the range of V-0 and V-N bond lengths observedfor many oxovanadium Schiff base complexes.35 The average V-0 bond length in bothcomplexes are shorter than the observed V-N bond lengths. In the complexes M(oz)3(M=A13+, Ga3+ and In3+), the M-0 bonds were also found to be shorter than the M-Nbonds.1732Examination of one of the oxazoline rings in VO(oz)2 (Figure 3.5.) shows theC(1)-0(1) bond length of 1.347(2) A to be significantly shorter than the C(2)-0(1) bondlength of 1.460(2) A. Also the C(1)-N(1) bond length (1.284(2) A) is shorter than theC(3)-N(1) bond length (1.472(2) A). The average bond length of a carbon oxygen singlebond is 1.45 A while a typical carbon oxygen double bond has a bond length of about 1.25A. A typical carbon nitrogen single bond has bond length of about 1.47 A.36 Comparisonof the observed C-N and C-0 bond lengths with typically observed bond lengths suggeststhat some of the C-N and C-0 bonds exhibit double bond character. This can berationalized using resonance structures (see Scheme 0.17,37For the complex VO(thz)2, similar double bond character was observed for the C-N bonds of the thiazoline rings. However, very little double bond character, if any wasobserved for the C-S bonds in the thiazoline rings. Hence no resonance structures like theones in Scheme I can be given for the thiazoline rings of the VO(thz)2 complex. OH OHScheme IIn the structure of both VO(oz)2 and VO(thz)2, the vanadium atom is displacedtoward the oxo group and away from the least-square basal plane defined by the fourligating atoms, Ni, N2, 02 and 04 (refer to Figures 3.5. and 3.6.). This displacement ofthe vanadium atom is observed in many oxovanadium(IV) complexes. The displacementof the vanadium atom was observed to be 0.57 A in VO(oz)2 and 0.60 A in VO(thz)2.These observed displacements are close to those commonly observed in other similar33oxovanadium(IV) complexes.35,38Ultraviolet-visible spectra of VO(ka)2, VO(oz)2, VO(thz)2, VO(OCH3)(bz)2 andVO(0C2H5)(bz)2 were recorded in appropriate solvents. A summary of the observedabsorbances for the oxovanadium(IV) complexes are listed in Chapter 2, Table 2.2.7.Oxovanadium(IV) complexes typically exhibit three d-d or ligand field bands in the UV-Visible spectra.14,39,40,41,42,43 These three bands, band I, band II, and band III areobserved in the regions of 900 to 625 nm, 690 to 520 nm and 470 to 330 nm respectively.The extinction coefficient of the observed bands range from 5 to 100 M-1cm-1. Band IIIwhose absorbance is of the highest energy is frequently obscured by the strong chargetransfer bands in the ultraviolet region of the spectra. When band III is observable, itoften appears as a shoulder on one of the charge transfer bands so that its maximumposition is known with the least accuracy among the three bands.40 Oxovanadium(IV)complexes commonly exhibit coordination numbers of 5 or 6 with observed coordinationgeometries of square pyramid or distorted octahedron.10 However, due to the presence ofa dominant axial field, the energy level diagrams associated with each coordinationgeometry do not differ very much from each other.42 Hence, the bands of both 5-coordinate and 6-coordinate oxovanadium(IV) complexes can be assigned on the basis ofthe same energy level scheme.42Ballhausen and Gray have proposed a energy level diagram for VO(H20 )52+.41The orbital transformation scheme for the C4v species VO(H20)52+ defines: (i) a strong a-bond of al symmetry between the (3dz2+4s) hybrid on vanadium and the spa oxygenhybrid; (ii) two e symmetry 7c-bonds lying between the vanadium dxz and dyz orbitals andthe 2px and 2py orbitals of oxygen; (iii) formation of four a—bonds between the spahybrids (on the equivalent water oxygens) and the vanadium (4s-3d2) (ai symmetry), 4Pxand 4py (e symmetry), and 3d2_2 (bi symmetry) orbitals; (iv) the sixth ligand forming aa—bond with the 4pz vanadium orbital; and (v) a nonbonding b2 symmetry 3dxy orbital ofvanadium.40 Figure 3.6. illustrates the proposed energy level diagram.38•,. ,s„^• ,^ ,*.•., ', ... .. ,.......:-ebEit1:, ......•,. „ • • it (oxide)34Vanadium orbitals^M.O. Levels^Oxygen orbitalsea',• • ••^,•‘ ;. /^,-'.,'...11:1 '.^‘Ia*i ..• 1 .,\ \ ',..b*i \ '‘,......,^',,.'.sse*n',•',s• ',,-' ss,,,,‘^...,.%, • •^,• s;,^*. •, ,• • %,••st^., i3d ^i''..s*-..:" \^b2^':'. ; \•...:,^ro'.^I,. .^rb^..'-re^'.., . ,..^Mal', ,..:\ ,,,eb :,/■,`,,V,.:^..,,•- ,,,,'^'..^a ^.‘ ,^b^/^‘b ^b1 ^nal^.. .1 ____.--....1121%^...."-a (water) a (oxide)Figure 3.6. Molecular orbital scheme for [VO(H20)52+] (C4v symmetry) according toBallhausen and Gray4135With reference to the energy level diagram in Figure 3.7., the three observed bandswere assigned by Ballhausen and Gray as follows: (a) band I, electronic transition from b2to en* or 2B2 to 2E(I) (b) band II, electronic transitions from b2 to bl* or 2B2 to 2Bi (c)band III, electronic transitions from b2 to Iai* or 2B2 to 2A1.41 The second transitionmaximum yeilds the value of 10Dq directly.39 The intense higher energy bands that areobserved out to 200 nm are assumed to be charge transfer in origin.39,40,41 Even thoughin some cases, distortion from C4v symmetry occurred (especially where LL is a bidentateligand in common complexes of the type VO(LL)2), the three observed bands wereassigned in the same way as that for C4v species by the comparison of the energies andintensities with the C4v species.41 However, it should be noted that there is still no realagreement on the ordering of the energy levels.39In our study, the UV-Visible spectrum of the complex VO(ka)2 shows only twobands in the region of 330-900 nm. The lowest energy band observed at 842 nm isassigned to the b2 to en* transition while the band observed at 612 nm is assigned to the b2to 1)1* transition. The band corresponding to the higher energy b2 to Iai* transition (orband III) is obscured by the low energy tail of the intense charge transfer band in the UVregion of the spectra. In the case of VO(oz)2 and VO(thz)2, the higher energy band IIIwhich could be assigned to b2 to Iai* transition was observed as a shoulder of the chargetransfer band at 409 nm and 437 nm, respectively. In addition, band I for these complexeswas observed at approximately 595 nm, which falls slightly out of the region where band Iis commonly observed for previously reported oxovanadium(IV) complexes.The intensity of band I is commonly observed to be greater than the intensity (i.e.extinction coefficient) of band II for many oxovanadium(IV) complexes. For VO(ka)2,band I is observed to have an extinction coefficient of 30 while band II has an extinctioncoefficient of 15. These observed intensities and extinction coefficients are consistentwith the fact that the b2 to en* transition is partially allowed (allowed xy)40 while the36, .-oo000°'ogoo4-c )0o'.8'o^■ ■ a . ■ .... ■ . ■,•■•• . • • • ■ . • .... .......... .,,A4\114. 0o800^900 ooFigure 3.8. Potential "intensity stealing" effect in UV-Vis spectrophotometric study ofVO(oz)2 and VO(thz)2.dz2dx 2 _y 2 (or d„y)1 dxz, dyzdxy (or dx2 _y 2)I.^.4^:^;Ial^I^II^I^.lb I:I 11dxy d2 III id22II37transitions corresponding to the other bands are totally forbidden. However, thisphenomenon of band I having a greater intensity than band II is not found in VO(oz)2 andVO(thz)2. This is particularly true for VO(thz)2 where the intensity of band II isabnormally higher than band I. The greater intensity of band II is probably due to the"intensity stealing" effect of band II. Figure 3.8. illustrates the intensity stealing effect ofband II.C4v symmetry^Low symmetryFigure 3.9. Splitting of the vanadium d levels (b2, e and b1 considered mainly as V orbitals)It should be noted that for some oxovanadium(IV) complexes, four distinct bandsare observed in the UV-Visible spectra. This is attributed to a lowering of the symmetryof the complexes. A lowering of symmetry would result in the lifting of the degeneracy ofthe en* orbital. This would change the molecular orbital diagram to that shown in Figure3.9.14 With this lowering of symmetry, four bands are expected in the UV-Visiblespectrum. Low symmetry oxovanadium(IV) complexes involving tartrate, lactate,mandelate or malate groups have UV-Visible spectra showing four well defined absorptionbands in the region of 1000 to 380 nm.43 For the oxovanadium(IV) complexesinvestigated in our study, the highest possible symmetry of the VOL2 complex (L is a38bidentate ligand) is C2. The symmetry of VO(oz)2 and VO(thz)2, in the solid state, wasshown by single crystal X-ray diffraction studies to be C2 (refer to Figure 3.5. and 3.6.).However, the complexes studied in this thesis all showed less than four bands. It isassumed that the splitting of the eic* level caused by the lowering of symmetry is simplytoo small to be observed experimentally.40Vanadium(V) has a d0 configuration and as such does not exhibit d-d transition.The two oxovanadium(V) complexes, VO(OCH3)(bz)2 and VO(0C2H5)(bz)2 do not showd-d transitions in the UV-Vis spectra. Only high intensity ligand to metal charge transferbands, which are allowed transitions, are observed in the UV portion of the optical spectra.UV-Visible spectra of freshly prepared solutions of VO(bz)2 in methanol or ethanol showno d-d transition bands. This is because the reaction of VO(bz)2 with solvent molecules(methanol or ethanol) produces VO(OCH3)(bz)2 or VO(0C2H5)(bz)2 extremely rapidly.In conclusion, some new oxovanadium complexes have been prepared and therelevant coordination chemistry observed in these complexes is consistent with thatexpected from examining the literature. Naturally-occurring ligating moieties were usedto coordinate to V02+ because of the potential application of their oxovanadiumcomplexes in the treatment of diabetes. An evaluation of VO(ka)2 as a potential insulinmimicking agent has been performed and preliminary data are presented in the appendixB.39REFERENCES1. Rehder, D. Biometals 1992, 5, 3.2. Cantley Jr., L. C.; Cantley, L. G.; Josephson, L. J. Biol. Chem. 1978, 253, 7361.3. Dubyak, G. R.; Kleinzeller, A. J. Biol. Chem. 1980, 255 , 5306.4. Shechter, Y.; Karlish, S.J. D. Nature 1980, 284, 556.5. Post, R. L. 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A., 1987; p. 455, and 488.15. Miller, M. J. J. Am. Chem. Soc. 1983, 105, 240.16. Crumbliss, A. L. Coord. Chem. Rev. 1990, 105,155.17. Hoveyda, H. R.; Karunaratne, V. Rettig, S. J.; Orvig, C. Inorg. Chem. 1992, 31,5408.18. Luo, H.; Rettig, S. J.; Orvig, C. Inorg. Chem. in press.4019. Hewitt, C. D.; Herman, M. M.; Lopes, M. B. S.; Savory, J.; Wills, M. R.Neuropath. App!. Neurobiol. 1991, 17, 47 and references therein.20. Zhang, Z.; Lyster, D. M.; Webb, G. A.; Orvig, C. Nucl. Med. Biol. 1992, 19, 327.21. Black, D.; Wade, M. J. Aust. J. Chem. 1972, 25, 1797.22. Hoveyda, H. R.; Orvig, C. Unpublished results.23. Mabbs, F. E.; Machin, D. J. Magnetism and Transition Metal Complexes,Chapman and Hall: London, Great Britian, 1961; p.5.24. Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, A ComprehensiveText, 4th Ed.; John Wiley and Sons: New York, U. S. A., 1980; p.63 and 7125. Cotton, F. A.; Wilkinson, G. Basic Inorganic Chemistry, John Wiley and Sons:New York, U. S. A., 1976; p.131, 170 and 21126. Huheey, J. E. Inorganic Chemistry, 3rd Ed.; Harper and Row: New York, U. S. A.,1983; p.31427. Zhang, Z.; Hui, T.; Orvig, C. Can. J. Chem. 1989, 67, 1708, and references therein.28. Drago, R. S. Physical Methods in Chemistry, W. B. Saunders Company:Philadelphia, U. S. A., 1977; p.42529. Caira, M. R.; Haigh, J. M.; Nassimbeni, L. R. J. Inorg. Nucl. Chem. 1972, 34,3171.30. Dutta, R. L.; Lahiry, S. Jour. Indian Chem. Soc. 1964, 41, 546.31. Fisher, D. C.; Barclay-Peet, J.; Balfe, C. A.; Raymond, K. N. Inorg. Chem. 1989,28, 4399.32. Oughtred, R. E.; Raper, E. S.; Shearer, H. M. M. Acta Crystallogr. Sect. B 1976,B32, 82.33. Scheidt, W. R. Inorg. Chem. 1973, 12, 1758.34. Nugent, W. A.; Mayer, J. M. Metal-Ligand Multiple Bonds; John Wiley and sons:New York, U. S. A., 1988, p156-157.4135. Carrano, C. J.; Nunn, C. M.; Quan, R.; Bonadies, J. A.; Pecoraro, V. L. Inorg.Chem. 1990, 29, 944.36. Weast, R. C. C.R.C. Handbook of Chemistry and Physics, 54th Ed.; C.R.C. Press:Ohio, U. S. A., 1973; p.F19637. Eng-Wilmot, D. L.; van der Helm, D. J. Am. Chem. Soc. 1980, 102, 7719.38. Cooper, S. R.; Koh, Y. B.; Raymond, K. N. J. Am. Chem. Soc. 1982, 104, 5092.39. Bonadies, J. A.; Carrano, C. J. J. Am. Chem. Soc. 1986, 108, 4088.40. Selbin, J. Chem. Rev. 1965, 65, 153.41. Ballhausen, C. J.; Gray, H. B. Inorg. Chem. 1962, 1, 111.42. Sacconi, L.; Campigli, U. Inorg. Chem. 1965, 5 , 606.43.^Lever, A. B. P. Inorganic Electronic Spectroscopy, 2nd Ed.; Elsevier SciencePublishers B.V.: Amsterdam, 1984, p.385-39242Appendix ATable Al Selected Crystallographic Data for VO(oz)2 and VO(thz)2.complex^VO(oz)2^v0(thz)2formula^C181116N205V^C181116N203S2Vfw 391.28^423.40crystal system^triclinic orthorhombicspace group P1^ Pbcaa,A^10.408(1)^12.331(2)b,A 11.282(1) 26.090(2)c, A^7.666(1)^11.125(2)a, deg 103.78(1)0, deg^109.64(1)7, deg 84.75(1)V, A3^823.3(2)^3579.3(9)Z 2 8Dcalc, g/cm3^1.578^1.571T, °C 21 21radiation (k, A)^Mo Ka (0.71069)^Mo Koc (0.71069)[t(MoKa) cm-1 6.14^ 7.80transmission factor^0.92-1.00 0.82-1.00R^ 0.034^0.035Rw 0.035 0.03043Table A2 Final atomic coordinates (fractional) and Beg (A2) for V0(oz)2.Atom^x^Y^z^BegV(1) 0.27964(3) 0.46204(2) 0.12244(4) 2.351(8)0(1) 0.2143(1) 0.7491(1) 0.5528(2) 3.41(4)0(2) 0.4605(1) 0.5193(1) 0.2775(1) 2.79(3)0(3) 0.4041(1) 0.1095(1) -0.1073(2) 3.42(4)0(4) 0.1376(1) 0.3577(1) 0.1060(2) 3.05(4)0(5) 0.2300(1) 0.5241(1) -0.0560(2) 3.16(4)N(1) 0.2157(1) 0.5813(1) 0.3285(2) 2.62(4)N(2) 0.3771(1) 0.3041(1) 0.0311(2) 2.55(4)C(1) 0.2793(1) 0.6769(1) 0.4406(2) 2.50(5)C(2) 0.0801(2) 0.6965(2) 0.5014(3) 4.18(7)C(3) 0.0860(2) 0.5753(2) 0.3635(3) 3.45(6)C(4) 0.4150(1) 0.7131(1) 0.4626(2) 2.52(5)C(5) 0.5005(1) 0.6279(1) 0.3840(2) 2.45(5)C(6) 0.6357(2) 0.6628(2) 0.4224(2) 3.12(5)C(7) 0.6814(2) 0.7763(2) 0.5293(3) 3.84(7)C(8) 0.5959(2) 0.8606(2) 0.6204(3) 3.80(6)C(9) 0.4645(2) 0.8287(1) 0.5705(2) 3.27(6)C(10) 0.3223(2) 0.1989(1) -0.0510(2) 2.57(5)C(11) 0.5362(2) 0.1640(2) -0.0636(3) 3.44(6)C(12) 0.5210(2) 0.2953(2) 0.0397(2) 2.90(5)C(13) 0.1823(2) 0.1673(1) -0.0884(2) 2.72(5)C(14) 0.0972(2) 0.2502(1) -0.0059(2) 2.60(5)C(15) -0.0380(2) 0.2150(2) -0.0460(3) 3.29(6)44C(16) -0.0859(2)^0.1052(2)^-0.1638(3)^4.28(7)C(17) -0.0022(2)^0.0242(2)^-0.2450(3)^4.57(7)C(18)^0.1306(2)^0.0548(2)^-0.2070(3)^3.71(6)Table A3. Final atomic coordinates (fractional) and Beg (A2) for VO(thz)2.Atom^x^Y^z^BeqV(1) 0.44725(6) 0.35945(2) 0.40706(6) 2.89(3)S(1) 0.53110(11) 0.47063(5) 0.71884(11) 4.95(7)S(2) 0.27819(10) 0.22705(5) 0.19962(12) 4.57(7)0(2) 0.3157(2) 0.39716(10) 0.4207(3) 3.6(1)0(4) 0.4955(2) 0.30099(10) 0.4937(2) 3.5(1)0(5) 0.5296(2) 0.38000(10) 0.3081(2) 3.9(1)N(1) 0.5023(3) 0.40147(13) 0.5541(3) 3.2(2)N(2) 0.3596(2) 0.30771(12) 0.3027(3) 2.9(2)C(1) 0.4587(3) 0.44201(15) 0.6006(4) 3.1(2)C(2) 0.6426(4) 0.4276(2) 0.6984(4) 4.9(3)C(3) 0.6046(4) 0.3859(2) 0.6131(4) 4.3(2)C(4) 0.3560(3) 0.46407(15) 0.5638(4) 3.0(2)C(5) 0.2891(3) 0.4402(2) 0.4778(4) 3.0(2)C(6) 0.1880(4) 0.4621(2) 0.4510(4) 3.5(2)C(7) 0.1551(4) 0.5065(2) 0.5064(5) 4.4(3)C(8) 0.2201(4) 0.5304(2) 0.5904(5) 5.1(3)C(9) 0.3193(4) 0.5097(2) 0.6170(4) 4.1(2)C(10) 0.3619(3) 0.2582(2) 0.3049(4) 3.1(2)C(11) 0.2258(4) 0.2873(2) 0.1495(4) 5.0(3)45C(12) 0.2914(3)^0.3290(2) 0.2060(4) 4.0(2)C(13) 0.4290(2)^0.22764(15) 0.3840(4) 3.1(2)C(14) 0.4925(3)^0.2508(2) 0.4746(4) 3.1(2)C(15) 0.5560(4)^0.2194(2) 0.5486(4) 4.3(2)C(16) 0.5585(4)^0.1673(2) 0.5324(5) 5.2(3)C(17) 0.4972(4)^0.1444(2) 0.4440(5) 5.2(3)C(18) 0.4330(4)^0.1737(2) 0.3714(4) 4.4(3)Table A4. Bond Lengths (A) for VO(oz)2 and VO(thz)2 with Estimated StandardDeviations in ParenthesesVO(oz)2 vO(thz)2Atoms Distance Atoms DistanceV(1)-0(2) 1.931(1) V(1)-0(2) 1.903(3)V(1)-0(4) 1.926(1) V(1)-0(4) 1.900(3)V(1)-0(5) 1.594(1) V(1)-0(5) 1.591(3)V(1)-N(1) 2.068(1) V(1)-N(1) 2.083(3)V(1)-N(2) 2.061(1) V(1)-N(2) 2.083(3)0(1)-C(1) 1.347(2) S(1)-C(1) 1.757(4)0(1)-C(2) 1.460(2) S(1)-C(2) 1.790(5)0(2)-C(5) 1.315(2) 0(2)-C(5) 1.330(4)0(3)-C(10) 1.346(2) S(2)-C(10) 1.761(4)0(3)-C(11) 1.458(2) S(2)-C(11) 1.788(5)0(4)-C(14) 1.319(2) 0(4)-C(14) 1.328(4)N(1)-C(1) 1.284(2) N(1)-C(1) 1.295(5)46N(1)-C(3) 1.472(2) N(1)-C(3) 1.479(5)N(2)-C(10) 1.287(2) N(2)-C(10) 1.291(4)N(2)-C(12) 1.472(2) N(2)-C(12) 1.474(5)C(1)-C(4) 1.451(2) C(1)-C(4) 1.450(5)C(2)-C(3) 1.526(3) C(2)-C(3) 1.518(6)C(4)-C(5) 1.415(2) C(4)-C(5) 1.410(5)C(4)-C(9) 1.405(2) C(4)-C(9) 1.404(5)C(5)-C(6) 1.411(2) C(5)-C(6) 1.404(5)C(6)-C(7) 1.374(2) C(6)-C(7) 1.372(6)C(7)-C(8) 1.391(3) C(7)-C(8) 1.380(6)C(8)-C(9) 1.372(2) C(8)-C(9) 1.370(6)C(10)-C(13) 1.448(2) C(10)-C(13) 1.447(5)C(11)-C(12) 1.526(2) C(11)-C(12) 1.495(6)C(13)-C(14) 1.414(2) C(13)-C(14) 1.411(5)C(13)-C(18) 1.405(2) C(13)-C(18) 1.417(5)C(14)-C(15) 1.409(2) C(14)-C(15) 1.400(5)C(15)-C(16) 1.370(2) C(15)-C(16) 1.373(6)C(16)-C(17) 1.389(3) C(16)-C(17) 1.377(6)C(17)-C(18) 1.372(3) C(17)-C(18) 1.365(6)Table A5. Bond Angles (deg) for VO(oz)2 and VO(thz)2 with Estimated StandardDeviations in Parentheses.VO(Oz)2^ VO(thz)2Atoms^Angle^Atoms^Angle47O(2)-V( 1)-0(5) 108.41(5) 0(2)-V(1)-0(5) 115.2(1)0(4)-V(1)-0(5) 108.81(5) 0(4)-V(1)-0(5) 114.9(1)0(5)-V(1)-N(1) 104.73(6) 0(5)-V(1)-N(1) 99.1(1)0(5)-V(1)-N(2) 103.79(5) 0(5)-V(1)-N(2) 99.4(1)0(2)-V(1)-N(1) 85.28(5) 0(2)-V(1)-N(1) 86.8(1)0(2)-V(1)-N(2) 85.25(5) 0(2)-V(1)-N(2) 86.4(1)0(4)-V(1)-N(1) 85.23(5) 0(4)-V(1)-N(1) 85.5(1)0(4)-V(1)-N(2) 86.21(5) 0(4)-V(1)-N(2) 85.7(1)0(2)-V(1)-0(4) 142.79(5) 0(2)-V(1)-0(4) 129.9(1)N(1)-V(1)-N(2) 151.47(5) N(1)-V(1)-N(2) 161.4(1)C(1)-0(1)-C(2) 106.7(1) C(1)-S(1)-C(2) 91.6(2)V(1)-0(2)-C(5) 129.80(9) V(1)-0(2)-C(5) 133.2(3)C(10)-0(3)-C(11) 107.0(1) C(10)-S(2)-C(11) 90.7(2)V(1)-0(4)-C(14) 130.4(1) V(1)-0(4)-C(14) 134.6(3)V(1)-N(1)-C(1) 125.6(1) V(1)-N(1)-C(1) 127.5V(1)-N(1)-C(3) 125.9(1) V(1)-N(1)-C(3) 118.8(3)C(1)-N(1)-C(3) 108.4(1) C(1)-N(1)-C(3) 113.7(4)V(1)-N(2)-C(10) 126.4(1) V(1)-N(2)-C(10) 128.7(3)V(1)-N(2)-C(12) 125.0(1) V(1)-N(2)-C(12) 117.3(3)C(10)-N(2)-C(12) 108.6(1) C(10)-N(2)-C(12) 113.9(4)0(1)-C(1)-N(1) 116.4(1) S(1)-C(1)-N(1) 115.8(3)0(1)-C(1)-C(4) 116.9(1) S(1)-C(1)-C(4) 119.1(3)N(1)-C(1)-C(4) 126.7(1) N(1)-C(1)-C(4) 125.1(4)0(1)-C(2)-C(3) 104.3(1) S(1)-C(2)-C(3) 107.0(3)N(1)-C(3)-C(2) 103.4(1) N(1)-C(3)-C(2) 110.1(4)C(1)-C(4)-C(5) 119.3(1) C(1)-C(4)-C(5) 121.8(4)C(1)-C(4)-C(9) 120.4(1) C(1)-C(4)-C(9) 120.0(4)C(5)-C(4)-C(9) 120.2(1) C(5)-C(4)-C(9) 118.2(4)0(2)-C(5)-C(4) 123.7(1) 0(2)-C(5)-C(4) 123.6(4)0(2)-C(5)-C(6) 118.7(1) 0(2)-C(5)-C(6) 117.6(4)C(4)-C(5)-C(6) 117.6(1) C(4)-C(5)-C(6) 118.9(4)C(5)-C(6)-C(7) 120.9(2) C(5)-C(6)-C(7) 120.8(4)C(6)-C(7)-C(8) 121.2(2) C(6)-C(7)-C(8) 120.9(4)C(7)-C(8)-C(9) 119.4(2) C(7)-C(8)-C(9) 119.1(4)C(4)-C(9)-C(8) 120.7(2) C(4)-C(9)-C(8) 122.1(4)0(3)-C(10)-N(2) 116.2(1) S(2)-C(10)-N(2) 115.8(3)0(3)-C(10)-C(13) 117.0(1) S(2)-C(10)-C(13) 119.0(3)N(2)-C(10)-C(13) 126.7(1) N(2)-C(10)-C(13) 125.2(4)0(3)-C(11)-C(12) 104.4(1) S(2)-C(11)-C(12) 108.3(3)N(2)-C(12)-C(11) 103.5(1) N(2)-C(12)-C(11) 109.9(4)C(10)-C(13)-C(14) 119.9(1) C(10)-C(13)-C(14) 121.0(4)C(10)-C(13)-C(18) 120.2(1) C(10)-C(13)-C(18) 120.5(4)C(14)-C(13)-C(18) 119.9(1) C(14)-C(13)-C(18) 118.5(4)0(4)-C(14)-C(13) 123.7(1) 0(4)-C(14)-C(13) 123.5(4)0(4)-C(14)-C(15) 118.6(1) 0(4)-C(14)-C(15) 117.7(4)C(13)-C(14)-C(15) 117.8(1) C(13)-C(14)-C(15) 118.7(4)C(14)-C(15)-C(16) 121.0(2) C(14)-C(15)-C(16) 120.9(5)C(15)-C(16)-C(17) 121.1(2) C(15)-C(16)-C(17) 120.8(5)C(16)-C(17)-C(18) 119.4(2) C(16)-C(17)-C(18) 119.9(4)C(13)-C(18)-C(17) 120.8(2) C(13)-C(18)-C(17) 121.2(4)4849Appendix BMillions of people suffer from a mammalian condition known as diabetes. Peoplesuffering from diabetes have an abnormally high level of glucose in their blood plasma.'Diabetes can be life-threatening and can lead to a number of medical complications suchas atheosclerosis, microangiopathy, kidney disorders, renal failure, cardiac disease,diabetic retinopathy and other ocular disorders including blindness.2 There are a variety ofways to control diabetes but the primary method is the daily administering of insulin.Insulin is a hormone that is normally produced naturally in the pancreas and is primarilyresponsible for signaling the utilization or storage of basic nutrients. In general, insulinactivates the enzymes that are involved in intracellular utilization and storage of basicnutrients such as glucose, amino acids and fatty acids.3 It is also involved in the inhibitionof processes which breakdown glycogens, fats and proteins. In diabetic individuals, thereis insufficient insulin present in the body or the body is tolerant to insulin, resulting in thebody requiring an abnormally high dose of insulin to cause the desired effect. The use ofinsulin in treating diabetics involves the daily injection of the hormone. Insulin must beinjected since it is not orally active and is known to decompose before or during passagethrough the gastrointestinal tract.In 1980, it was discovered that vanadate simulated the action of insulin in glucoseoxidation in rat adipocytes.4,5 The years following this discovery revealed that vanadatewas able to mimic nearly all or most of the documented actions of insulin. Interest in theinsulin mimicking action of vanadate rose even higher when McNeill et al reported thatvanadate, administered to diabetic rats through drinking water caused a decrease inelevated blood glucose.6 Unfortunately, vanadate has the disadvantage of being poorlyabsorbed from the gastrointestinal tract. An even greater disadvantage of vanadate is thatit must be administered at near toxic levels before any insulin mimicking effects areobserved. Nevertheless, the work by McNeill et al showed that it may be possible to50utilize orally active vanadium compounds as a substitute for insulin. There has beeninterest in the insulin-mimetic effects of both vanadate and vanadyl since Sakurai et. al.showed that vanadate is reduced in vivo to vanady1.7Recently, our group in collaboration with Dr. McNeill of the Faculty ofPharmceutical Sciences at UBC has been studying the feasibility of usingbis(maltolato)oxovanadium(IV) as an insulin mimicking agent.2 As a continuation of thiswork, the feasibility of bis(kojato)oxovanadium(IV) as an insulin mimic was alsoinvestigated.Bis(kojato)oxovanadium(IV), VO(ka)2, was prepared according to the proceduredescribed in Chapter 2. Initial investigations into the feasibility of using VO(ka)2 asinsulin mimicking agent involved laboratory rats that were made diabetic by the injectionof streptozoticin (STZ). VO(ka)2 was administered by intraperitoneal injection as asuspension in 1% methyl cellulose or orally administered by gavage. Of the diabetic ratswhich were given 0.063 mmol/kg of VO(ka)2 by injection, 60% showed decrease bloodglucose levels within 24 hours. Of the diabetic rats which were given 0.55 mmol/kg ofVO(ka)2 by gavage, 57% showed reduced blood glucose level within 24 hours. Similarexperiments were also carried out using bis(maltolato)oxovanadium(IV), VO(ma)2. Inexperiments involving the administering of VO(ma)2 by injection and by oral gavage, 50%of the rats showed reduced blood glucose level within 24 hours. A higher percentage ofrats responding to the oxovanadium compound was observed with VO(ka)2 compared toVO(ma)2 in both cases when the oxovanadium compound was administered either byinjection or by oral gavage. The results of the studies using VO(ka)2 and VO(ma)2 aresummarized in Table Bl.A drinking water pilot study with VO(ka)2 was also performed on 10 diabetic rats.Administration of VO(ka)2 was done using aqueous solutions in the concentration range of1.43 to 3.58 mM. The rats received doses in the range of 0.41 to 0.91 mmol/kg. Onaverage, a reduced blood glucose level was observed in the diabetic rats. This is51Table B1^Comparison of the plasma glucose levels (mmol/L) between the acute timecourse experiments for bis(maltolato)oxovanadium(IV) (n=8) andbis(kojato)oxovanadium(IV) (n=10)Bis(maltolato)oxovanadium(IV)^Bis(kojato)oxovanadium(IV)I.P. Injection^Oral Gavage^I.P. Injection^Oral Gavage(0.063 mmol/kg) (0.55 mmol/kg)^(0.063 mmol/kg) (0.55 mmoVkg)TIME DTR DTN DTR DTN DTR DTN DTR DTN(Hrs) (50%) (50%) (50%) (50%) (60%) (40%) (57%) (43%)0 17.51 19.42 18.09 19.31 17.94 20.86 15.75 23.08±0.8 ±0.15 ±0.72 ±0.35 ±0.41 ±0.28 ±0.55 ±1.271 14.77 18.82 14.55 18.05 14.75 18.55 12.5 21.18±2.0 ±0.8 ±1.96 ±0.46 ±0.44 ±0.42 ±1.46 ±1.452 12.65 18.51 13.13 17.57 10.17 16.62 10.1 21.51±2.33 ±0.79 ±2.04 ±0.5 ±0.47 ±0.65 ±0.99 ±1.724 10.6 17.94 11.68 16.92 9.26 17.37 7.96 20.57±2.39 ±0.85 ±2.07 ±0.35 ±0.32 ±0.23 ±0.26 ±1.076 10.28 18.08 9.47 16.43 8.73 16.62 6.6 18.2±1.76 ±0.48 ±2.58 ±0.43 ±0.17 ±0.35 ±0.35 ±0.898 9.08 17.77 9.27 15.02 7.4 15.49 6.87 19.06±1.06 ±0.59 ±2.27 ±1.13 ±0.12 ±0.65 ±0.33 ±0.9612 9.38 19.07 7.01 17.17 10.37 18.24 6.01 18.81±0.96 ±0.37 ±0.57 ±0.6 ±0.46 ±0.45 ±0.25 ±00.3324 7.15 19.01 6.31 18.07 13.28 18.77 6.74 25.0±1.51 ±0.21 ±0.57 ±0.74 ±0.83 ±0.49 ±0.05 ±0.4DTR-Diabetic Treated RespondersDTN-Diabetic Treated Non-responder3052.^I^I^15 1 0 1 5Time (Days)120^25Figure Bl. Daily average blood glucose levels for the ten STZ-diabetic rats followingchronic administration of VO(ka)2 in the drinking water. Time 0 is the dayof treatment started.53illustrated in Figure Bl.Initial studies into the feasibility of VO(ka)2 as an orally active insulin mimickingagent have given promising results. It appears that VO(ka)2 gives the same, if not, betterperformance than VO(ma)2 in reducing blood glucose level in diabetic rats. The resultsfrom these preliminary experiments justify more in depth studies into the possibility ofusing VO(ka)2 as an insulin mimicking agent.1) Atkinson, M. A.; Maclaren, N. K. Sci. Am.. 1990, 263, 62-71.2) McNeill, J. H.; Yuen, V. G.; Hoveyda, H. R. ; Orvig, C. J. Med. Chem.. 1992, 35,1489.3) Weyer, R.; Drenn, B. E. Vanadium in Biological Systems Kluwer AcademicPublishers: Norwell, 1990, p. 129.4) Shechter, Y.; Karlish, S. J. D. Nature 1980 , 284, 556-558.5) Dubyak, G. R.; Kleinzeller, A. J. Biol. Chem. 1980, 255 , 5306.6) Heyliger, C. E.; Tahiliani, A. G. ; McNeill, J. H. Science 1985, 227, 1474-1477.7)^Sakurai, H.; Shimomura, S.; Fukuzawa, K.; Ishizu, K. Biochem. Biophys. Res.Commun. 1980, 96, 293-298
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Dataset Information
0
Metabolomics of Hydrazine-Induced Hepatotoxicity in Rats for Discovering Potential Biomarkers.
ABSTRACT: Metabolic pathway disturbances associated with drug-induced liver injury remain unsatisfactorily characterized. Diagnostic biomarkers for hepatotoxicity have been used to minimize drug-induced liver injury and to increase the clinical safety. A metabolomics strategy using rapid-resolution liquid chromatography/tandem mass spectrometry (RRLC-MS/MS) analyses and multivariate statistics was implemented to identify potential biomarkers for hydrazine-induced hepatotoxicity. The global serum and urine metabolomics of 30 hydrazine-treated rats at 24 or 48?h postdosing and 24?healthy rats were characterized by a metabolomics approach. Multivariate statistical data analyses and receiver operating characteristic (ROC) curves were performed to identify the most significantly altered metabolites. The 16 most significant potential biomarkers were identified to be closely related to hydrazine-induced liver injury. The combination of these biomarkers had an area under the curve (AUC)?>?0.85, with 100% specificity and sensitivity, respectively. This high-quality classification group included amino acids and their derivatives, glutathione metabolites, vitamins, fatty acids, intermediates of pyrimidine metabolism, and lipids. Additionally, metabolomics pathway analyses confirmed that phenylalanine, tyrosine, and tryptophan biosynthesis as well as tyrosine metabolism had great interactions with hydrazine-induced liver injury in rats. These discriminating metabolites might be useful in understanding the pathogenesis mechanisms of liver injury and provide good prospects for drug-induced liver injury diagnosis clinically.
SUBMITTER: An Z
PROVIDER: S-EPMC5914126 | BioStudies | 2018-01-01
REPOSITORIES: biostudies
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Expression Analysis of Aquaporin-1 (Aqp-1) in Human Biliary Tract Carcinoma
Journal of Cancer Therapy
Vol.07 No.01(2016), Article ID:62678,7 pages
10.4236/jct.2016.71003
Expression Analysis of Aquaporin-1 (Aqp-1) in Human Biliary Tract Carcinoma
Shinichi Sekine*, Tomoyuki Okumura, Takuya Nagata, Kazuto Shibuya, Isaku Yoshioka, Koshi Matsui, Ryouta Hori, Kazuhiro Tsukada
Department of Surgery and Science, University of Toyama, Toyama, Japan
Copyright © 2016 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Received 23 November 2015; accepted 9 January 2016; published 12 January 2016
ABSTRACT
Background: Aquaporins (AQPs) are important in controlling bile water secretion. AQP is related to the invasion and metastasis of cancer. However, the relationship of biliary tract cancer is not clear. The role of AQP-1 in cancer cell is also unknown. Methhods: We analyzed AQP-1 expression using tissue microarray (TMA) in 99 samples immunohistochemically (50 gallbladder carcinoma, 39 bile duct carcinoma and 10 Papilla Vater carcinoma patients who underwent surgery at our department from 1997 to 2011). Gene expressions were evaluated by the combination of the immunohistological intensity and distribution. The expression level is compared to the clinico-pa- thological data of the patients. Results: In the TMA, depth of tumor invasion and histological type are associated with AQP-1 expression. The group of patients with high AQP-1 expression is associated with higher rates of disease specific survival (log-rank p = 0.013). Cox’s proportional hazard model reveals that AQP-1 expression is an independent prognostic factor (RR, 0.324; p = 0.001) in multivariate analysis. There is a correlation between AQP-1 expression and tumor invasion. Conclusions: These observations of this study suggest that AQP-1 expression may be favorable biomarkers associated with prognosis and tumor invasion in biliary tract carcinoma.
Keywords:
Aquaporin, Biliary Tract Carcinoma, Tissue Microarray, Immunohistochemistry
1. Introduction
Biliary tract carcinoma (BTC) is composed of mutated epithelial cells that originate in the bile ducts, which drain bile from the liver into the small intestine. BTC includes carcinomas of the bile duct, gallbladder, and papilla of Vater. Most patients with BTC present at an advanced disease stage; thus, prognosis remains poor despite the recent development of new diagnostic modalities [1] [2] . Currently, there is no consensus on a universal measure of BTC malignancy; therefore, it is necessary to identify prognostic factors indicating the biological properties of this disease.
Aquaporins (AQPs) are integral membrane proteins that facilitate the movement of water and play important roles in the control of bile formation. However, the exact role of AQPs in human biliary tract carcinogenesis has not been defined [3] - [5] . AQP-1 and AQP-4 have also been implicated in the absorption of water by the intrahepatic bile duct [6] [7] . Epithelial cells of the human and mouse gallbladder express AQP-1 and AQP-8 [8] [9] , with AQP-1 localized on both the apical and basolateral plasma membranes of epithelial cells lining the neck of the organ [8] . In addition, AQPs are reportedly distributed within cells lining the mammalian biliary tract [8] [9] .
2. Methods
We analyzed AQP-1 expression in BTC using tissue microarray (TMA) and identified correlations among the clinicopathological parameters, and patient survival. In this study, we assessed paraffin-embedded tissues of 99 BTC samples (50, 39, and 10 from gall bladders, bile ducts, and papilla of Vater, respectively) collected from patients who had undergone surgery from 1997 to 2011 at Toyama University Hospital (Toyama, Japan). This study was approved by the Ethics Committee, University of Toyama. All samples were histologically diagnosed at the Department of Pathology. The final stage of BTC was pathologically confirmed, according to the TNM classification system of malignant tumors by the Union for International Cancer Control (seventh edition). CEA, CA19-9, tissue type one by each one cases, was not able to confirm the inspection data. Expression profiles of AQP-1 were analyzed using the TMA, as described previously [10] [11] . The protein expression profiles were evaluated by combining immunohistological intensity and distribution. Selected micrographs from the TMAs immunostained with polyclonal antibodies against AQP-1 are shown in Figure 1. The following primary antibodies were used: rabbit polyclonal anti-AQP-1 (H-55: dilution, 1:100; Santa Cruz Biotech, Santa Cruz, CA, USA). Goat anti-rabbit horseradish peroxidase-conjugated immunoglobulin-G was used as a secondary antibody, according to the manufacturer’s instructions. The secondary antibodies were visualized using En Vision™ + Dual Link, Single Reagent (K4061; Dako, Tokyo, Japan), according to the manufacturer’s instructions. The staining intensity of carcinoma cells was scored on a 4-point scale: 0 = no staining of carcinoma cells, 1 = weak staining, 2 = moderate staining, and 3 = marked staining, as compared to the staining of control tissues. The staining distribution within the tumor cells was graded on a 3-point scale: 0: n ≤ 10%; 1: 10% ≤ n < 50%; and 2: n ≥ 50%. AQP-1 expression in the carcinoma tissue was defined as positive when the sum total of the staining intensity and distribution was graded at a score of ≥ 3 (Figure 1). Using the Ki67 (MIB-1)-labeling index, the malignancy grade of BTC was rated on a 2-point scale (≤10 and >10%).
Statistical analysis was performed using the chi-square test and t-tests. Prognostic factors were examined by both univariate and multivariate analyses. Survival curves were estimated using the Kaplan-Meier method and differences between survival curves were analyzed using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model to assess the risk of cancer death. A p value of <0.05 was considered statistically significant. All statistical analyses were performed using JMP software for Windows (SAS Institute Inc., Cary, NC, USA).
3. Results
The clinicopathological backgrounds and univariate analysis of factors related to survival in patients with BTC
Figure 1. Immunohistochemistry of AQP-1.
are shown in Table 1. Depth of tumor invasion, lymph node metastasis, distant metastasis, histological type, CEA and CA19-9 were associated with prognosis. AQP-1 expression was also associated with disease-specific- survival (p = 0.001).
Correlations between patient characteristics and expression patterns of AQP-1 in BTC are shown in Table 2. TMA analysis of the 99 tissue samples showed that AQP-1 expression was significantly associated with depth of tumor invasion and histological type (p = 0.021 and 0.005). Kaplan-Meier analysis revealed that the group of patients with high AQP-1 expression were associated with higher rates of disease specific survival (log-rank test,
Table 1. Univariate analysis of factors related to survival in patients with biliary tract carcinoma.
*: p < 0.05; **: p < 0.01.
Table 2. Relationship between patient characteristics and AQP-1.
*: p < 0.05; **: p < 0.01.
p = 0.013) (Figure 2). Cox’s proportional hazard model revealed that AQP-1 expression was an independent prognostic factor (RR, 0.324; p = 0.001) in multivariate analysis (Table 3). Multivariate analysis showed that Lymph node metastasis, Distant metastasis and CEA (p = 0.035, <0.001 and 0.027) were also associated with survival (Table 3).
4. Discussion
AQP-1 plays an important role in bile formation across cell membranes of the biliary epithelium [5] [12] [13] . Recently, various studies have focused on the association of AQPs with carcinoma and reported that several types of cancer express AQP-1, which may be involved in carcinogenesis and tumor progression [14] -[19] .
Figure 2. Survival rates of BTC patients with the AQP-1 expression.
Table 3. Relationship between patient characteristics and prognosis in biliary tract carcinoma. (Multivariate analysis).
*: p < 0.05; **: p < 0.01.
These observations suggested a potential role of AQP-1 in BTC. There was no difference in AQP-1 expression between carcinomas of the gallbladder, bile duct carcinoma, and papilla of Vater. AQP-1 is expressed in the biliary epithelium and its expression decreases with the degree of invasion of the carcinoma. This conclusion is also evident in the literature [20] .
AQPs are distributed in the pancreas and biliary tract and are essential for secretion and reabsorption of water in the bile and pancreatic juice. AQP-1 is strongly expressed in the intercalated ducts in humans and maintains cellular integrity to protect tissues against cancer cell invasion [6] [13] .
Overexpression of AQP-1 was associated with increased proliferation and migration in colorectal and non- small cell lung carcinomas. The results of this study suggested that AQP-1 plays a different role in BTC, such as facilitation of bile transport and reabsorption. The roles of the biliary epithelium in BTC differ from those in cancers of the colon and lung [17] -[19] . Therefore, AQP-1 expression in BTC may be an indicator of tumor cell invasion and proliferation associated with carcinoma progression.
Epithelium-mesenchyme transition (EMT) is a specialized mechanism in which the character of the tissue is undifferentiated. Previous studies have suggested that EMT through AQPs greatly contributes to regulation of malignancy [21] . Involvement in the invasion and metastasis of a hypercoagulable state of adenocarcinoma through loss of cell-cell adhesion is mediated by the loss of AQP-1 function. The activation of molecules related to epithelial stromal migration and cell proliferation has been suggested. Bordering on this stage, there exists the possibility for acceleration of metastatic potential. Controlling AQP-1 may contribute to prognosis extension in BTC.
5. Conclusion
These observations of this study suggest that AQP-1 expression may be favorable biomarkers associated with prognosis and tumor invasion in biliary tract carcinoma.
Acknowledgements
This study was supported by KAKENHI Grant-in-Aid for Research Activity Start-up from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Cite this paper
ShinichiSekine,TomoyukiOkumura,TakuyaNagata,KazutoShibuya,IsakuYoshioka,KoshiMatsui,RyoutaHori,KazuhiroTsukada, (2016) Expression Analysis of Aquaporin-1 (Aqp-1) in Human Biliary Tract Carcinoma. Journal of Cancer Therapy,07,17-23. doi: 10.4236/jct.2016.71003
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http://dx.doi.org/10.1096/fj.06-5930fje
17. 17. Machida, Y., Ueda, Y., Shimasaki, M., et al. (2011) Relationship of Aquaporin 1, 3, and 5 Expression in Lung Cancer Cells to Cellular Differentiation, Invasive Growth, and Metastasis Potential. Human Pathology, 42, 669-678.
http://dx.doi.org/10.1016/j.humpath.2010.07.022
18. 18. Bin, K. and Zhao, S.-P. (2011) Acetazolamide Inhibits Aquaporin-1 Expression and Colon Cancer Xenograft Tumor Growth. Hepatogastroenterology, 58, 1502-1506.
http://dx.doi.org/10.5754/hge11154
19. 19. Yoshida, T., Hojo, S., Sekine, S., et al. (2013) Expression of Aquaporin-1 Is a Poor Prognostic Factor for Stage II and III Colon Cancer. Molecular and Clinical Oncology, 1, 953-958.
http://dx.doi.org/10.3892/mco.2013.165
20. 20. Aishima, S., Kuroda, Y., Nishihara, Y., et al. (2007) Down-Regulation of Aquaporin-1 in Intrahepatic Cholangiocarcinoma Is Related to Tumor Progression and Mucin Expression. Human Pathology, 38, 1819-1825.
http://dx.doi.org/10.1016/j.humpath.2007.04.016
21. 21. Nath, S. and Mukherjee, P. (2014) MUC1: A Multifaceted Oncoprotein with a Key Role in Cancer Progression. Trends in Molecular Medicine, 20, 332-342.
http://dx.doi.org/10.1016/j.molmed.2014.02.007
NOTES
*Corresponding author.
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Eletriptan Hydrobromide
Class and Category
Pharmacologic Class: Triptan
Therapeutic ClassAntimigraine agent
Indications and Dosages
To relieve acute migraine attacks with or without aura
TABLETS
Adults
Initial: 20 or 40 mg as a single dose. Repeated in 2 hr, as needed and ordered. Maximum: 40 mg as a single dose, 80 mg daily.
Mechanism of Action
May stimulate 5-HT1 receptors, causing selective vasoconstriction of dilated and inflamed cranial blood vessels in carotid circulation, which decreases carotid arterial blood flow and relieves acute migraines.
Contraindications
Bibasilar or hemiplegic migraine, cardiovascular disease (significant), cerebrovascular syndromes (stroke, transient ischemic attack), hepatic impairment (severe), hypersensitivity to eletriptan or components, ischemic bowel disease, ischemic or vasospastic coronary artery disease (CAD), peripheral vascular disease, uncontrolled hypertension, use within 24 hours of another serotonin 5-HT1 receptor agonist or ergot-type drug, use within 72 hours of a potent CYP3A4 inhibitor (clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin), Wolff–Parkinson–White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders
Interactions
DRUGS
1. Clarithromycin, ketoconazole, itraconazole, nefazodone, nelfinavir, ritonavir, troleandomycin, and other potent CYP3A4 inhibitors: Increased blood eletriptan level significantly
2. Ergot-containing drugs, 5-HT1receptor agonists: Possibly additive or prolonged vasoconstrictive effects
3. MAO inhibitors, selective serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants: Increased risk of serotonin syndrome
Adverse Reactions
1. CNS: Asthenia, chills, dizziness, headache, hypertonia, hypesthesia, paresthesia, seizures, somnolence, tiredness, weakness, vertigo
2. CV: Chest tightness, pain, or pressure; coronary artery vasospasm; hypertension, MI, or myocardial ischemia (transient); palpitations; shock; ventricular fibrillation or tachycardia
3. EENT: Dry mouth, pharyngitis, throat tightness
4. GI: Abdominal pain, cramps, discomfort, or pressure; dysphagia; indigestion; nausea, vomiting
5. MS: Back pain
6. SKIN: Diaphoresis, flushing
7. Other: Allergic reaction; angioedema; feeling of warmth, pain, or pressure
Childbearing Considerations
PREGNANCY
• It is not known if the drug causes fetal harm.
• Use with caution only if benefit to mother outweighs potential risk to fetus.
LACTATION
• The drug is present in breast milk.
• Patient should check with prescriber before breastfeeding.
Nursing Considerations
• Ensure that patients who are at risk for CAD undergo a satisfactory CV evaluation before administering the first dose of eletriptan and that they have a periodic reevaluation of their cardiac status during intermittent long-term therapy.
• Obtain an ECG immediately after the first dose of the drug in patients who have CV risk factors but who have had a satisfactory CV evaluation because of the drug’s potential to cause coronary vasospasm.
• Evaluate patient for CV signs and symptoms after administration of eletriptan and notify prescriber if they occur. Expect the drug to be withheld, as ordered, while the patient undergoes an extensive CV workup, and discontinued if abnormalities are detected.
• Monitor patient’s blood pressure during therapy because of the drug’s potential to increase blood pressure.
PATIENT TEACHING
• Advise patient to take eletriptan as soon as possible after the onset of migraine symptoms.
• Urge patient to contact prescriber and avoid taking drug if headache symptoms aren’t typical.
• Advise against exceeding the prescribed dose.
• Instruct patient to seek emergency care for chest, jaw, or neck tightness after taking drug because these may indicate adverse CV reactions; subsequent doses may require ECG monitoring.
• Urge patient to report palpitations.
• Advise patient to avoid hazardous activities until drug’s CNS effects are known.
• Advise yearly ophthalmic examinations during prolonged eletriptan therapy.
• Instruct patient to inform prescriber of all drugs he’s taking, including OTC products and herbal remedies.
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Should smaller implants be used with a lollipop lift? (photo)
When you remove the skin during a lollipop lift, should a smaller size implant be used because you have less skin to fill? I am 5'6" 130 lbs semi athletic build 50 years old. Bra size 36B or 34C. Looking for a more youthful, natural, perky shape and size. But certainly do not want them too big so they are In the way or look heavy chested. Would like to keep my same active lifestyle.
Doctor Answers 20
Lift
Based on the photos, you will need a breast lift or what we call a mastopexy with or without breast augmentation depending on the look you are interested in. Adding an implant will give you some extra superior fullness. Good luck!
Smaller is safer
Patients with breast ptosis have demonstrated that their soft tissue is not supporting the weight of the breasts in an aesthetically adequate fashion causing patients to seek a breast lift. Adding weight of the implant serves to stress the soft tissues more than the natural weight of the breasts.
So yes, the smaller the implant you choose the less the weight of the implant and the less stress the implant will cause your tissues.
In addtion to implant size you may wish to discuss with your surgeon the pros and cons of placing mesh of collagen support in the breast to potentially increas the longevity of the lift.
Possible lift with implants alone
This is what I do to maximize lift with a breast implant alone:
- use silicone cohesive gel implants. The more cohesive the better. I am not sure if these are available yet in the US, but the Allergan Inspira Truform 2 implants are ideal
- use high profile implants. The more projection you have, the more lift you will get
- have the implants placed in the submammary pocket (under the breast itself). You should have a pinch thickness at the top of your breast of at least 2 cm
Please see an experienced board certified plastic surgeon to find out whether you are a suitable candidate. Best of luck.
Avoid lollipop lift
I personally never use the lollipop lift because it leaves ugly vertical scars and newer techniques have replaced it.If you are happy with the volume of your breasts in a bra then you only need a lift.I recommend The Ultimate Breast LiftTM.Your breast tissue is reshaped creating upper pole fullness, elevated higher on the chest wall and more medial to increase your cleavage.Aligning the areola and breast tissue over the bony prominence of the chest wall maximizes anterior projection without the use of implants.If you want to be bigger then implants can be added.At size 34 each 100 cc’s of implant corresponds to 1 cup size change.From this, you can compute the volume required to achieve your desired goal.I always recommend small round textured silicone gel implants placed retro-pectoral since they look and feel more natural, are more stable, less likely to ripple or have complications needing revision.
Best Wishes,
Gary Horndeski, M.D.
Gary M. Horndeski, MD
Texas Plastic Surgeon
4.7 out of 5 stars 208 reviews
Breast Implant Sizing and Mastopexy
There are many factors that are used when determining the size of breast implants for a patient. Some of the factors are breast size, chest measurements, tissues and patient desires. Mastopexy (breast lift) can be performed in conjunction with breast augmentation or as an isolated procedure.
Craig Mezrow, MS, MD, FACS
Philadelphia Plastic Surgeon
5.0 out of 5 stars 15 reviews
Breast implants with lift
Thank you for your breast augmentation question.
I place the implants first - and then do the lift for the very reason you ask about. Skin may be too tight if the lift if done first.
I do not believe it is possible to tell you from photographs the best implant for you.
It requires a face-to-face examination with a Board Certified Plastic Surgeon. The implant depends on your chest measurements, your goals, height and weight, skin looseness and proportions.
All of that said, when combining a lift with an implant, choose the smallest implant that will meet your goals. It will give you your most natural result and place less tension on the lift. I would not suggest anything larger than a 350 and that may be too large for the look you want. Best wishes
Implants
Thank you for the picture.
I would recommend a 350-375 cc high profile implant. This will enhance your breast with a natural look.
Dr. Campos
Jaime Campos Leon, MD
Mexico Plastic Surgeon
4.4 out of 5 stars 241 reviews
Implant Size Selection Accompanying Breast Lift
Thank you for your question. It may be helpful to point out that a lift addresses nipple position and shape, and implants address volume. While they have an impact on one another, they are two separate procedures and can be addressed as such. The type of lift isn't dictated as much by the size of the implant as it is by your anatomy. You aren't "filling skin" with your implant. You create a pocket in underlying tissue that will be the envelope for the implant. After that is complete, the excess skin is removed and the nipple position lifted. Too large an implant can cause tension on the lift incision, but is far from the deciding factor. Make an appointment with a Board Certified Plastic Surgeon to be assessed in person. Best of luck to you.
Mary Lee Peters, MD
Seattle Plastic Surgeon
4.9 out of 5 stars 109 reviews
Breast Augmentation and Breast Lift
Hello,
Breast implants should be considered to only give additional volume and/or more upper pole fullness. The choice to use implants at all or what size implant would be appropriate should not be based on any other issue like breast sagging. Similarly, the type of breast lift to use on a patient should be based on how much vertical and horizontal skin excess is present, and an implant should not be considered to supplement the desired outcome of a lift: to reposition the breast mound and nipple areolar complex. The greater the skin excess in one or both directions, the more likely a 'bigger' lift will be necessary, going from a periareolar to a lollypop to an anchor type breast lift to address this excess. Although it is true that one does affect the other, consideration of implants and lifts should be made separately and not contingent upon one another.
To use you as an example, you desire a modest enhancement in volume, a more youthful breast shape, and you have an active lifestyle. I usually begin with the decision to use implants, and in your case that seems reasonable. A relatively small, low or intermediate profile implant will give you a modest boost in volume and excellent upper pole fullness. Next, I would assess your natural breast tissue envelope. One breast has significantly more vertical and horizontal excess than the other, and that difference may or may not affect my decision to use a particular type of breast lift pattern. In general, I prefer not to rely too much on circumareolar gathering of skin to address skin excess, as it has a detrimental outcome on breast shape and scar appearance. Instead, I would rather use the lollypop or anchor for breasts with too much skin excess.
Augmentation Mastopexy is a complex surgery that has a higher rate of complications than either mastopexy or augmentation alone, at least by national averages. However, surgeons specializing in cosmetic breast surgery do this operation frequently, and get complications no greater than performing the two surgeries separately. Please visit only a few highly qualified surgeons that have great reputations for this surgery, not just implants alone. There credentials should include certification from the ABPS and membership with the ASAPS.
Best of luck!
Gerald Minniti, MD, FACS
Beverly Hills Plastic Surgeon
4.9 out of 5 stars 78 reviews
Should smaller implants be used with a lollipop lift? (photo)
As is the case over the internet we can ONLY GUESS!!! Best is in person opinions to address the concerns of volume vs skin excision...
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.
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Why a Lack of Sleep Can Lead to Weight Gain
Research on Lack of Sleep and Weight Gain Are you trying to manage your weight? Well, you might consider sleeping more. Mounting evidence shows that more sleep may be the missing link for many people who are trying to lose weight. According to the Centers for Disease Control and Prevention (CDC), 35% of US adults are sleeping fewer than 7 hours most nights which is defined as short sleep. Short sleep, or lack of quality sleep, has been repeatedly linked to higher body mass index (BMI) and weight gain. An analysis of 20 studies including 300,000 people found a 41% increase in obesity risk among adults who slept fewer than 7 hours a night. Another study showed that short sleep duration was significantly associated with greater waist circumference, which is an indicator of the accumulation of belly fat. (1, 2) Newer research suggests that an extra hour of sleep every night could help sleep deprived people that are overweight consume between 270-500 fewer calories per day without even trying. This translates to nine pounds of weight loss over a year, according to the researchers behind the study. (3) This is significant for people who are trying to manage their weight and believe … Continue reading Why a Lack of Sleep Can Lead to Weight Gain
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What is the Best Exercise for Your Abs?
by Darin L. Steen
A flat, defined abdominal wall is a universal symbol for sex appeal, virility, power, and youth. At one point in time almost every one of us has wanted a smaller, chiseled mid-section.
Your first inclination may be to think that doing a lot of sit ups will develop the type of abs you see in fitness magazines. Many of you may have given up hope of achieving a tight, toned tummy. Perhaps you’ve bought into the misconceptions myths about fitness, fat loss, and aging. Many people think that it is impossible to have defined abs in your 40’s and 50’s.
This simply is not the case.
Armed with a little information, and some will power, anyone, at any age, can achieve a tight tummy.
A tight, toned mid-section is about more than just looking good. It is also about having a strong, pain-free back. It’s about being able to do functional activities. It’s about being able to remain strong and independent into your 80’s, 90’s, and even 100’s.
It takes more than just doing effective ab exercises to develop a lean ripped midsection.
Everyone wants to know the best exercise for abs, but ironically, the exercise is only part of the formula.
You Must Lower Your Overall Body Fat Percentage with an Effective Fat loss Program That Includes Resistance Training, Interval Cardio, and Nutrition
Most of you already have a complete six pack. The problem is that it is covered up by the fat that lies on top of your muscle, underneath your skin. If you want to see the abs you already have, you need to get your overall body fat percentage between 8-12 percent (for men) and 10-14 percent (for women).
Your abdominal muscles are relatively small in comparison to other skeletal muscles. Seeing them is much more about bringing your body fat level down than it is about building them up.
An effective exercise program should include both resistance training (two or three times per week) and Interval Cardio (two to three times per week).
Resistance training should utilize body weight, and free weight exercises using barbells and dumbbells aimed at increasing the size of your major muscle groups. Your chest, legs, back, shoulders and arms are muscle groups you’ll want to focus on.
One of the best, most time efficient ways to lose body fat is to carry more muscle.
For every pound of additional muscle, your body will burn 50-70 calories more per day. Build 10 lbs. more muscle with an effective resistance training program and your body will burn 500 -700 calories more per day.
Interval cardio is also an effective way to burn extra calories. Interval cardio is short burst (60-90 seconds) of running, jumping, skipping, or body weight exercises that get your heart rate up above 150 beats per minute. Each interval challenge should be slightly more challenging than the last, and followed with a 1-2 minute recovery phase.
Interval cardio is better for fat loss than traditional aerobic type cardio (aka jogging) for several reasons. But the most important is that with interval cardio you get an after-burn of 4-6 hours. That means your engine stays revved up and burns more calories for a long time a after you are done with the interval session.
With aerobic type cardio (jogging), you only burn calories while you are exercising.
Fat loss nutrition is a very important part of a fat loss program. You can work out with the most effective exercise program in the world, but your body will change only minimally until you implement a healthy nutrition plan. The exercise is the spark and the food is the fuel for your metabolic fire. It is the combo together that will make you strong and lean.
Effective Abdominal Exercise Tactics
Most of us initially are taught that sit-ups will create abs. The more sit-ups you can do, the better your abs will look. Or so we think.
I hate to be the bearer of bad news, but sit-ups are not an effective exercise to build up your abs.
The problem with sit ups is that the range of motion is too large and other muscles help out too much, namely your hip flexors.
So ditch the sit-up and use the “crunch”.
The key with the crunch is to slow down the tempo and limit your range of motion. By slowing down the speed of the crunch, it is easier to focus on just your abdominal muscles.
With the crunch, curl your chin toward your chest as you exhale. Focus on pushing the small of your back into the floor during the contraction. The contraction should last about 3 seconds, and just your shoulder blades should come off the floor. Take your head and shoulder blades back to the floor for a 3 count as you inhale. Then repeat.
Variety is the Spice of Life
Your abdominal muscles are slightly different than your other skeletal muscles. They need to work involuntarily 24/7 to help your core support you in order for you to stand and sit upright. Thus, they need even more variety than other skeletal muscles in order to grow.
How, and How Often
There seems to be a common misconception that you can work your abs every day. This is false. Even though your abs have a slightly different fiber type as discussed above, they still need to rest and recover after they have been worked.
If your abs are not sore for a day or two after you work them out, then you more than likely need to utilize new exercises. Your abs will become immune to a technique quicker than other skeletal muscles -- usually within a couple weeks.
There are three major areas of your abdominal wall. Your have upper, lower, and side oblique’s.
1. Upper- Utilize crunching type movements where your head is curled down to stationary legs
2. Lower - Utilize leg lift and knee-pull type exercises where you pull your knee’s / legs up to a stationary upper body
3. Side Obliques - Use movements where you incorporate a twisting movement. Also a side bridge or plank type exercise.
A sample work out may be to pick one exercise that targets upper abs and do a set to failure. Then do the same for lower abs and side obliques. Instead of doing all three of them together, try to do one at the beginning, middle, and end of your resistance training session. That way you separate each set of abs by about 30 minutes during a 60-70 minute session.
You only need to work your abs 2 or 3 times per week. Use one exercise for a week or two at most, then switch it up with a new one. All you need is 3 or 4 exercises from each area to have a complete library to choose from.
You can go to www.Mercola.com/peakfitness to see our favorite 20 effective ab exercises.
Every last one of you has the ability to have a tight, toned, midsection. Try some of these techniques and get involved in our fat loss fitness community to let us know how it is going for you.
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Call us on 020 7193 7867 Book an appointment
What is a DEXA scan?
A DEXA scan, or DXA scan, is a type of X-ray that is used to measure bone density. DEXA stands for dual energy X-ray absorptiometry, and there are different ways to refer to the scan, including DXA, bone density scan, and bone densitometry scan.
DEXA Scanner at The Shard
Why is a DEXA scan performed?
Usually, a DEXA scan is performed to diagnose or assess the risk of osteoporosis. Osteoporosis weakens the bones, so a DEXA scan can help to identify this and check the density of your bones.
Who should have a DEXA scan for osteoporosis?
A DEXA scan is recommended in those over 50, at risk from developing osteoporosis. You are more likely to be at risk if members in your family have experienced fractures at some point. A bone density scan may also be taken with those under 50 with additional risk factors, such as smoking, excessive drinking, or having fractured a bone already.
A DEXA scan may also be considered if:
• You are a woman experiencing early menopause, or who has had early menopause and not received hormone replacement therapy. After menopause, oestrogen in the body declines, which can result in a bone mineral density decrease.
• You have a condition such as arthritis, or other inflammatory conditions, which can result in low bone density
• You take medication which can contribute to bone weakening over time
• You are a woman with large gaps between periods
How is a DEXA scan performed?
DEXA scans are quick and painless. You may be able to remain dressed, but you have to remove clothes with metal in, such as hooks, or zips. You do not need to prepare anything, fast, or follow any special diet.
When the scan is performed, you lie on your back, but a DEXA scan is not like an MRI, where you must go into a tunnel-like device. The X-ray table is flat, and open, so you are unlikely to feel closed in or claustrophobic.
A large scanning machine is passed over the body, emitting a low-dose X-ray beam to measure bone density in your skeleton. The machine can scan various parts of your body, but the most common areas examined are the hip, spine, and wrist.
Scans take a very short amount of time, perhaps five minutes – depending on the part of the body being scanned. There is no need to wait in hospital and you can go home after the scan.
What do DEXA scan results mean?
Bone density has a healthy-level ‘score’ – a number which varies on age, ethnicity, and gender. The DEXA scan will give you a certain score too, and the difference between the expected healthy score, and your DEXA result is called the T score.
T scores are classified like this:
• Normal: above -1 deviation
• Slightly reduced: between -1 and -2.5 deviation
• Osteoporosis: at or below 2.5
These results will give a fair indication of bone strength, but cannot tell you whether you will get a fracture, or not. Some people even with normal bone density can experience a fracture at some point.
Your doctor will look at your results after the test, and take into account risk factors, before deciding on a course of treatment, or deciding if it is necessary.
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Characteristics of Skin Lesions Associated With Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study Ann Intern Med . Secondary skin lesions appear as a result of irritated primary skin lesions. They are: Primary skin lesions: These lesions are present at the time or birth or acquired during the lifetime. Papule, nodule, plaque and tumor What are the four palpable/fluid-filled primary skin lesions? Bulla: a circumscribed, elevated fluid-filled lesion greater than 1 cm in size (e.g. Primary lesions Primary lesions are those lesions that arise de novo and are therefore the most characteristic of the desease process. Erythema 2. Vesicle, bulla, pustule and wheal <1cm, non-palpable macule Describe a macule. there are several skin lesions that are very common and benign (non-cancerous). Skin lesions are classified into two different types based on the occurrence of lesion. A skin mole that is normal is black, brown or tanned, circular and generally less than a quarter of an inch in diameter. Identification and classification of a patient's skin lesions are important steps in the diagnosis of any skin disorder. What are the four palpable/firm primary skin lesions? A skin lesion is a part of the skin that has an abnormal appearance compared to the skin around it. Ephilides are genetically determined well-defined small brown macules with the following characteristics: Use this combination quiz and worksheet before or after viewing the lesson on primary skin lesions to supplement your studies. This refers to tunnels under the skin, typically due to an infestation of some type of parasite. In this post, we look at the most common skin lesions, their characteristics and typical courses of On the other hand, skin lesions that those moles that have changed in color, shape or size. Please know that skin lesions can be of different types and can also be in the form of an underlying disease of any form. Common benign skin lesions of melanocytic origin include the ephilis, lentigo simplex, and melanocytic naevus (mole). Lesions are often classified by their tissue types or locations. warts, acne, or psoriasis), allergic reactions (e.g. The numerous descriptive terms used in dermatology can be overwhelming and at times confusing as there are some variations in the use and meaning of these words in the literature. Primary skin lesions Macule: A macule is a circumscribed discoloration without elevation or depression that may be hypopigmented or pigmented in a … Papules are small, solid eruptions in the epidermis and are approximately 1 cm in diameter or smaller. Skin Lesions: Definition A skin lesion is a superficial growth or patch of the skin that does not resemble the area surrounding it. Another kind of primary lesion is called a burrow. [1] The major function of this system is as a barrier against the external environment. The clinical and dermoscopic characteristics and risk factors of new-onset proliferative skin lesions (benign verrucous lesions and KAs/cuSCCs) developing after the initiation of treatment with vemurafenib, dabrafenib, and XL281 Types of primary skin lesions: Types Of Skin Lesions Due to the broad range of skin conditions that qualify as skin lesions, the medical community classifies them according to their texture, color and distribution. Primary skin lesions are present from birth or are acquired during a person’s lifetime. HOME > Shimizu's Textbook of Dermatology: Contents TOP > Chapter 4 Skin Lesions Buy the Textbook Purchase order: Click here Chapter 4: Skin Lesions A. Primary skin lesions: the initial recognizable skin lesion or basic skin changes (macule, papule, patch, plaque, vesicle, bulla, nodule, tumor, pustule, wheal, cyst, telangiectasia) Purpura : larger (>5mm) hemorrhagic (red-purple) non-blanchable discolorations (<5mm petechiae) These tunnels appear as straight lesions on the top of the skin. The To facilitate accurate communication of the description of skin lesions between medical personnel, a multitude of descriptive terms have been developed. 1 However, a few simple terms can be used to describe the cutaneous findings in most skin diseases. these conditions include moles, freckles, skin tags, benign lentigines, and seborrheic keratoses. Black eschars are collections of dead skin that can arise from infarction, which may be caused by infection (eg, anthrax , angioinvasive fungi including Rhizopus, meningococcemia ), calciphylaxis , arterial insufficiency, or vasculitis . Primary skin lesions are those which develop as a direct result of the disease process. Primary skin lesions 1. Morphology of skin lesions 1. A skin lesion can appear as a rash, blister, mole, bump, etc. Skin lesions are areas of skin that look different from the surrounding area. These 2 types Primary skin lesions are variations in color or texture that may be present at birth, such as moles or birthmarks, or that may be acquired during a person's lifetime, such as those associated with infectious diseases (e.g. For example, a " skin lesion " or a " brain lesion " are named for the tissue where they are found. Black eschars are collections of dead skin that can arise from infarction, which may be caused by infection (eg, anthrax , angioinvasive fungi including Rhizopus, meningococcemia ), calciphylaxis , … In contrast, secondary skin lesions result from changes over time caused by disease progression, manipulation (scratching, picking, rubbing), or treatment. A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, hair, nails, and related muscle and glands. Skin lesions can be grouped into two categories: primary and secondary. MORPHOLOGY OF SKIN LESIONS Dr. Riaz Uddin Ahmed MBBS, DDV, MCPS, FCPS Associate Professor of Dermatology Bangladesh Medical College 2. Skin lesions are part of the skin that has a different appearance or abnormal growth when compared to the skin around it. 2016 Jan 5;164(1):10-22. doi: 10.7326/M15-0729. Whether a simple rash or a severe disease like melanoma, many types of skin lesions can occur on our body’s largest organ. A. All skin lesions are the result of the combination of one or several primary lesions, i.e., the most elementary lesions that can represent various skin diseases and may be used to describe them. It is most commonly. epidermolysis bullosa, bullous impetigo). They are often bumps or patches, and many issues can cause them. If you're dealing with an issue like skin tags , rashes, or blisters, you probably want to take action to have it reduced or removed. skin cancer) via growths. Skin lesions can be inherited or caused by inflammation, injury, or disease. Primary Skin Lesions Papule Morphology. This can be determined, on many occasions, by an ASDS member dermatologist. They occur if someone were to, for example, scratch a mole until it Most skin lesions are benign though some, such as actinic keratosis and certain moles, can be a pre-cursor to a skin cancer or already a skin cancer. The … Black skin lesions may be melanocytic, including nevi and melanoma. Skin lesions can be a sign of serious health condition (e.g. Primary Skin Lesions: Before discussing Primary Skin Lesions, let’s first make you aware about skin lesions in the general sense. Primary skin lesions are present at the onset of a disease. Secondary lesions are those which evolve from primary lesions or develop as a … Most of the patients (44%) were in the age group of 40-60 years and female (58%). Of the 5,127 patients referred to our dermatology clinic, 48 patients with generalized pruritus without primary skin lesions were evaluated. Purpura 3. Design: Prospective study collecting clinical, patient, and histopathologic details of excisions or biopsies of skin lesions by random samples of primary care physicians. Description Skin lesions can be grouped into two categories: primary and secondary. Black skin lesions may be melanocytic, including nevi and melanoma. If there is an added significance to regions within the tissue—such as in neural injuries where different locations correspond to different neurological deficits—they are further classified by location. 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Desire and dread from the nucleus accumbens: Cortical glutamate and subcortical GABA differentially generate motivation and hedonic impact in the rat
Alexis Faure, Jocelyn M. Richard, Kent C. Berridge
Research output: Contribution to journalArticlepeer-review
78 Scopus citations
Abstract
Background: GABAergic signals to the nucleus accumbens (NAc) shell arise from predominantly subcortical sources whereas glutamatergic signals arise mainly from cortical-related sources. Here we contrasted GABAergic and glutamatergic generation of hedonics versus motivation processes, as a proxy for comparing subcortical and cortical controls of emotion. Local disruptions of either signals in medial shell of NAc generate intense motivated behaviors corresponding to desire and/or dread, along a rostrocaudal gradient. GABA or glutamate disruptions in rostral shell generate appetitive motivation whereas disruptions in caudal shell elicit fearful motivation. However, GABA and glutamate signals in NAc differ in important ways, despite the similarity of their rostrocaudal motivation gradients. Methodology/Principal Findings: Microinjections of a GABAA agonist (muscimol), or of a glutamate AMPA antagonist (DNQX) in medial shell of rats were assessed for generation of hedonic "liking" or "disliking" by measuring orofacial affective reactions to sucrose-quinine taste. Motivation generation was independently assessed measuring effects on eating versus natural defensive behaviors. For GABAergic microinjections, we found that the desire-dread motivation gradient was mirrored by an equivalent hedonic gradient that amplified affective taste "liking" (at rostral sites) versus "disliking" (at caudal sites). However, manipulation of glutamatergic signals completely failed to alter pleasure-displeasure reactions to sensory hedonic impact, despite producing a strong rostrocaudal gradient of motivation. Conclusions/Significance: We conclude that the nucleus accumbens contains two functional affective keyboards for amino-acid signals: a motivation-generating keyboard and a hedonic-generating keyboard. Corticolimbic glutamate signals and subcortical GABA signals equivalently engage the motivation keyboard to generate desire and-or dread. Only subcortical GABA signals additionally engage the hedonic keyboard to amplify affective "liking" and "disliking" reactions. We thus suggest that top-down cortical glutamate signals powerfully regulate motivation components, but are relatively unable to penetrate core hedonic components of emotion. That may carry implications of limits to therapeutic regulation of pathological emotions.
Original languageEnglish (US)
Article numbere11223
JournalPloS one
Volume5
Issue number6
DOIs
StatePublished - 2010
Externally publishedYes
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Open Access Open Badges Original article
Anxiety and depression in COPD patients and correlation with sputum and BAL cytology
Cuneyt Tetikkurt1*, Imran Ozdemir1, Seza Tetikkurt2, Nail Yılmaz1, Turan Ertan3 and Nihal Bayar1
Author Affiliations
1 Pulmonary Diseases Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
2 Pathology Department, Bagcılar Research and Training Hospital, Istanbul, Turkey
3 Psychiatry Department, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey
For all author emails, please log on.
Multidisciplinary Respiratory Medicine 2011, 6:226-231 doi:10.1186/2049-6958-6-4-226
The electronic version of this article is the complete one and can be found online at: http://www.mrmjournal.com/content/6/4/226
Received:17 October 2010
Accepted:18 January 2011
Published:31 August 2011
© 2011 Novamedia srl
Abstract
Background and aims
Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD). The degree of lung function may not explain anxiety and depression. The aim of our study was to assess the psychological aspects of COPD, to test the BODE index (a composite score of body mass, obstruction, dyspnea and exercise capacity), and to evaluate the association between atypical cytologic findings of sputum, bronchoalveolar lavage (BAL) and the pyschological components of the disease.
Methods
COPD was classsified according to the GOLD stages based on forced expiratory volume in 1 second (FEV1) in 60 stable patients. The BODE index was calculated for grading COPD. The Hospital anxiety and depression (HAD) scale was used to appraise the anxiety and depression symptoms. Cytologic examination of sputum and BAL samples were performed in each patient. The cytologic findings were classified as normal, mild, moderate or severe atypia.
Results
The overall prevalance of anxiety and depression symptoms was 41.7% and 46.7% respectively. The prevalance of these symptoms increased with increasing BODE stages and correlated well with the severity of atypical BAL cytology results (p < 0.001). Dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with COPD.
Conclusions
We conclude that the BODE index is superior to GOLD stratification for explaining anxiety and depression symptoms in COPD. BAL cytologic findings, which reflect the distal parenchymal lung structure, correlated significantly with the presence of the anxiety and depression symptoms.
Keywords:
Anxiety; bronchoalveolar lavage; BODE index; COPD; depression; GOLD
Introduction
Chronic obstructive pulmonary disease (COPD) is a progressive disorder with substantial mortality and morbidity. The main goals of treatment in COPD are prevention or slowing of disease progression and improving the quality of life [1]. COPD patients carry a substantial psychological burden related to their disease and frequently suffer from anxiety and depression [2-5]. Anxiety and depression are risk factors for rehospitalisation in these patients [4,6]. Irrespective of the presence of somatic diseases, anxiety and depression themselves constitute a substantitial risk for increased mortality, although the mechanism for this association is unknown [7,8]. The severity of pulmonary function impairment related to anxiety and depression in COPD patients has been the subject of research but in most studies no correlation was found between psychological aspects of the disease and the forced expiratory volume in 1 second (FEV1) value. On the other hand, the presence of respiratory symptoms leads to significant anxiety or depression and dyspnea has been shown to correlate significantly with anxiety and depression in these patients [9,10].
Lung damage due to the inflammation of small airways appears to be the primary mechanism for dyspnea and physical disability leading to psychiatric comorbidities in COPD patients [2,6,8,9]. Sputum and bronchoalveolar lavage (BAL) cytology may be useful for identifying depression and anxiety in these patients by revealing inflammatory and cellular changes of the lung parenchyma. The aim of our study was to assess the psychological aspects of COPD, evaluate the correlation of the BODE index (a composite score of body mass, obstruction, dyspnea and exercise capacity) with anxiety and depression symptoms, and to evaluate the association between sputum and BAL cytology and the psychological disorders associated with COPD.
Patients and methods
This was a prospective cross-sectional study performed at the Respiratory Diseases Department of Cerrahpasa Medical Faculty between January 2008 and June 2010. The study was approved by the Institutional ethics commitee and informed consent was obtained from all patients. Sixty adult patients with stable COPD were included in the study. Inclusion criteria were: COPD diagnosed according to the Global Initiative for Obstructive Lung Disease (GOLD) consensus, stable disease, absence of any other chronic disease, ability to perform a 6-minute walking test, to complete the questionnaires, and no contraindications for bronchoscopy and BAL. Spirometry was performed according to the ATS/ERS recommendations with a body plethysmograph unit (Zan 500, Messgeraete, Oberthulba, Germany). Blood gases were determined from radial artery samples using the Radiometer ABL800 FLEX blood gas analyzer.
The patients were stratified according to the GOLD classification of severity. Sputum samples were obtained from every patient. If the sputum sample contained 10 or more squamous epithelial cells per low-power (×100) magnification field then the specimen was considered unsatisfactory and was discarded. BAL was performed by instilling five 20 ml aliquots of sterile saline into a subsegment of lingula or middle lobe. After removal of mucus fluid the sample was prepared for cytologic examination by cytocentrifugation. BAL findings were evaluated by a pathologist and a cytologist. Cytologic findings were classified as normal, mild, intermediate or severe atypia. BAL cytology was evaluated according to the staining characteristics, cellular cohesion, nucleus, cytoplasmic features and nucleus cytoplasm ratio epithelial cells, Goblet (brush border) cells, Clara cells, neutrophils, and type I and type II alveolar cells. Mild atypia showed pale, abundant cytoplasm, nucleus with a fine chromatin pattern, round or oval nucleus, and cohesive cell sheets with a mild disruption of the nucleus cytoplasm ratio. Severe atypia revealed acidophilic cytoplasm, discohesive cells, hyperchromatic and irregular nucleus, conspicuous nucleolus and a significant increase in the nucleus cytoplasm ratio. Cytologic findings that did not fit into either mild (Figure 2) or severe (Figure 1) type were designated as intermediate atypia. The cytologic results were classified as follows: normal = 0, mild atypia = 1, intermediate atypia = 2, and severe atypia = 3.
thumbnailFigure 1. Bronchoalveolar lavage (bal) cytology revealing severe atypia (papanicolau, 400x).
thumbnailFigure 2. Bronchoalveolar lavage (bal) cytology showing mild atypia (papanicolau, 400x).
The BODE index was calculated for classification of COPD. The index score comprises body mass index (BMI), FEV1, dyspnea grade as measured by the Modified Medical Research Council (MMRC) scale, and the 6-minute walking distance (6MWD) [11,12]. The Hospital anxiety and depression (HAD) scale was used for screening psychiatric disorders. It has been used for screening COPD patients previously. The scale consists of seven questions related to anxiety and depression, rated on a 4-point scale. The test provides maximum subscale scores of 21 for anxiety and depression, with a score of ≥ 8 describing the presence of these symptoms [2,3,6,13,14]. In each patient who scored ≥ 8 the existence of anxiety and depression was investigated by a consultant psychiatrist.
Statistical data were expressed as mean ± standard deviation. Differences between groups were tested with the Student's t-test and non-parametric Mann-Whitney test for continuous data. The chi-square test was used for noncontinuous data. To analyze differences of anxiety and depression scores between different stages of COPD one-way ANOVA was used. COPD or BODE stages were compared by the chi-square test to evaluate how well they explained anxiety and depression symptoms. Linear regression was used for BODE components associated with the HAD scores. Statistical analysis was performed using the SPSS 17.0 statistical package. A p value of less than 0.05 was accepted as statistically significant.
Results
Sixty stable COPD patients (males 35, mean age 66 ± 11 years) participated in the study. The patient characteristics are outlined in Table 1. The number of COPD patients in stages II to IV by GOLD classification and the mean BODE index of the patients are shown in Table 2. The BODE index ranged from stage II to IV. The mean scores for anxiety and depression were 8.2 ± 4.6 and 7.9 ± 4.3 respectively. Twenty-five patients (41.7%) were found to have symptoms suggestive of anxiety and 28 patients (46.7%) had symptoms suggestive of depression.
Table 1. Characteristics of the patients
Table 2. Patient classification according to gold and bode indexes
There was no correlation between the presence of anxiety or depression symptoms and age, gender or smoking level (pack/years) (Table 3). Anxiety and depression scores correlated with the BODE index (Kτ = 0.19, p < 0.001; Kτ = 0.34, p < 0.001). The prevalance of anxiety increased with increasing BODE index (χ2 = 7.46, p < 0.001) but not with increasing GOLD stages (χ2 = 3.72, p < 0.42). The prevalance of depression increased with both increasing BODE index and GOLD stages (χ2 = 28.54, p < 0.001; χ2 = 38.24, p < 0.001). The mean anxiety score for GOLD stages II, III, and IV was 4.1 ± 2.8, 7.4 ± 3.8 and 8.9 ± 5.1, respectively (p < 0.054). The mean depression score for GOLD stages II, III, and IV was 2.1 ± 1.6, 5.8 ± 4.2 and 9.4 ± 5.2, respectively (p < 0.001). The mean anxiety score for BODE stages I, II, III and IV was 5.9 ± 4.1, 8.2 ± 3.9, 9.7 ± 3.6 and 9.2 ± 5.3, respectively (p < 0.001). The mean depression score for BODE stages I, II, III and IV was 5.2 ± 3.1, 6.8 ± 3.4, 9.4 ± 3.2 and 10.2 ± 4.6, respectively (p < 0.001).
Table 3. Comparison of various parameters with anxiety and depression
Sputum and BAL cytology results with regard to anxiety and depression symptoms are shown in Tables 4 and 5. Although the correlation of moderate or severe cytologic atypia of sputum was not statistically significant for anxiety or depression symptoms, the specifity and sensitivity was found to be 67.2% and 68.4%, respectively (p < 0.05). The prevalance of both anxiety and depression increased with the increasing severity of cellular atypical findings of BAL cytology (χ2 = 20.36, p < 0.001; χ2 = 9.46, p < 0.001). Moderate or severe atypical changes of BAL cytology showed a significant correlation with the anxiety and depression symptoms with an 86% sensitivity and 89% specificity for identifying their presence. The MMRC dyspnea index and 6MWD showed a significant correlation with the increasing degree of atypical changes of BAL cytology (β = 0.284, p < 0.002; β = 0.426, p < 0.001). MMRC dyspnea scale was significantly associated both with the anxiety score (β = 0.346, p < 0.023) and the depression score (β = 0.284, p < 0.042) while FEV1% predicted did not correlate with anxiety or depression score.
Table 4. Distribution of anxiety and depression according to sputum cytology classification
Table 5. Distribution of anxiety and depression symptoms according to bal cytology classification
Discussion
COPD is considered not only as a disease of the lungs but as a part of the chronic systemic inflammatory syndrome [1]. The complex pathogenesis of COPD along with the associated frequent comorbidities compel further evaluation and staging because the degree of airflow obstruction is not adequate on its own to fully describe this multicomposite disease. Previous studies have revealed symptoms of anxiety and depression in up to 41% and 44% of COPD patients respectively [6,13]. Our results confirm that anxiety and depression symptoms are common in COPD and may correlate with the severity of the disease. Dyspnea due to the reduced exercise capacity is probably the primary factor leading to the psychiatric morbidities encountered in our patients.
The degree of lung function impairment is not adequate on its own to explain the presence of anxiety and depression symptoms in COPD. Our findings are in concordance with previous studies that FEV1% predicted alone did not predict or correlate with the presence of anxiety and depression symptoms [4,10,13]. Dyspnea and reduced exercise capacity which are indicators of advanced COPD correlated significantly with the presence of the anxiety and depression symptoms. They may be predictive of COPD outcomes. The BODE index was a better predictor of the psychological impact of COPD than the GOLD classification in regard to FEV1% predicted.
COPD duration, number of yearly exacerbations, and long term oxygen therapy (LTOT) did not correlate with anxiety and depression symptoms. There was a weak correlation of depressive symptoms with the noninvasive mechanical ventilation (NIMV) treatment. Our findings verified that dys pnea correlated with the psychological consequences of COPD.
Another important aspect of our study is the association between atypical changes in BAL cytology with the anxiety and depression symptoms. As the atypical changes of BAL cytology increased in severity, the prevalence of these symptoms grew higher. This association may be explained by the fact that BAL cytology reflects the structure of the lung parenchyma. As the lung damage gets worse the functional burden of dyspnea increases. Anxiety and depression symptoms were best delineated by dyspnea score and the 6-minute walking distance. Worsening dyspnea affects physical conditioning and produces functional limitation, as demonstrated by the decreased 6MWD, which is probably the predominant mechanism leading to anxiety and depression symptoms in our patients. Patients whose exercise capacity has been limited because of COPD have the greatest risk of psychiatric comorbidities.
A typical changes in sputum cytology were not significantly associated with the presence of anxiety or depression symptoms of COPD, while the sensitivity and specifity of sputum cytology for predicting these symptoms was intermediate. We believe that cytologic examination of sputum samples may be useful for pointing out the psychiatric symptoms in COPD patients. On the other hand, moderate or severe cytologic findings of BAL were able to identify psychiatric comorbidities of the disease. The high correlation of atypical BAL cytology findings with the presence of anxiety or depression symptoms we attributed to the fact that BAL reflects the structure of lung parenchyma. The significant correlation between the severity of the atypical findings of BAL cytology and the MMRC index and the 6MWD shows that the major risk factor for dyspnea and the consequent functional physical limitation is the severity of lung damage which may be identified by BAL cytology.
Our study included a mixture of males and females at different GOLD stages. The small sample size of our study may be considered as a disadvantage in comparison to the other large prospective studies. The HAD questionnaire used in this study may have limitations in diagnosing anxiety and depression but our patients were also evaluated by a consultant psychiatrist. This questionnaire has been used successfully in previous studies as a screening tool for psychiatric morbidity [6,15]. We did not compare the current psychiatric status of our patients after psychiatric treatment and pulmonary rehabilitation which may be another limitation of our study. Pulmonary rehabilitation may have had an influence on this because the patients would feel better and gain self-confidence vis-à-vis the functional limitation due to the disease. In addition to the high prevalence of respiratory symptoms, many of the patients had anxiety and depression symptoms. Cognitive and behavioral therapy, psychopharmacology and pulmonary rehabilitation may be useful treatment modalities for psychyatric disorders in COPD patients.
We conclude that anxiety and depression symptoms are common in COPD. The psychological status is important in these patients. Although there is a clear association between dyspnea level and anxiety or depression symptoms, their presence is often underdiagnosed and undertreated especially when they coexist with physical illness [2,16]. The results of our study suggest that the major risk factor for anxiety or depression is dyspnea and the consequent functional physical limitation. Cytologic examination of BAL cytology appears to be a useful modality for identifying patients with psychiatric comorbidities because it reflects the lung damage which is the predominant mechanism underlying dyspnea and the limited physical limitation of COPD patients. BAL cytology can be used along with the HAD index for screening COPD patients to determine the presence of anxiety or depression symptoms. Sputum cytology, in view of its borderline significant association with and intermediate sensitivity and specifity for anxiety and depression scores, may be used as a noninvasive diagnostic tool for identifying psychiatric comorbidities of COPD.
Conflict of interest statement
None of the authors has any conflict of interest to declare in relation to the subject matter of this manuscript.
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-4,510,098,403,122,296,300
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Regarding Incomplete Width or even second Level Uses up
Incomplete width Uses up: Should you ever end up confronted by the uses up incident, the most crucial motion you are able to consider, following getting rid of the actual target in the supply of the actual uses up, would be to AWESOME the actual Uses up region along with AWESOME, NOT REALLY CHILLY, drinking water, possibly from the hose pipe, or even drenched bath towels transformed frequently. The actual air conditioning ought to carry on with regard to 20 min’s, because a few uses up may still permeate cells with regard to 20 min’s.
The skin is actually ruined and also the skin is actually broken in order to different levels however the fundamental subcutaneous problems stay un-damaged. This really is exactly where quick AIR CONDITIONING may avoid the Incomplete Width Burn off through increasing to some Complete Width Burn off.
The actual skin is really a liquid wealthy coating underneath the pores and skin. Inside the skin place the neural endings, skin pores, follicles of hair as well as tissue accountable for the actual development as well as regeneration associated with pores and skin. With respect to the level associated with participation, many of these features are in danger. With no pores and skin, your skin isn’t any lengthier guarded through UV gentle, as well as, more to the point, germs. Incomplete as well as complete width uses up are in excellent danger with regard to an infection. (ref. 01)
Therefore using Metallic Sulfadiazine upon these types of much deeper uses up. It had been utilized on me personally thirty unusual 12 months back and it is nevertheless being used these days. Even though there has been a few current research upon using Heparin, to date not yet proven.
With respect to the degree associated with skin harm the individual could also shed a chance to perspiration as well as, consequently, awesome your body. This is actually the just enduring heritage which i possess through my personal uses up. The actual remaining equip can’t perspiration, neither may my personal remaining ribcage, each which are essential towards the system’s air conditioning program. It might be a little just like a vehicle along with fifty percent the actual radiator obstructed upward along with lawn seed products or even grasshoppers, the vehicle might overheat, just like I actually do.
In the event that neural endings tend to be ruined the individual will forfeit sensation in the area, however I actually do think that over time the actual anxiety perform regenerate somewhat. Locks might no more develop inside the broken region and when development tissue tend to be ruined, your skin will forfeit it’s capability to regenerate as well as recover.
Sufferers along with much deeper incomplete width uses up are in threat with regard to dropping a few of the range of motion in your body area impacted.
Incomplete width uses up might be included in the actual ruined skin coating or even open up. In the event that pores and skin handles the actual burn off it will likely be grey, old and wrinkly or even blistered. Open up uses up is going to be red-colored or even whitened and appearance damp.
Much deeper incomplete width uses up may scar tissue, as well as display like a somewhat elevated area, as well as since the Melanin tissue happen to be ruined or even broken, which region may have absolutely no skin tones, and become really vunerable to sunburn.
In the event that these types of much deeper second level uses up possess stress clothes or even bandages installed following recovery, the actual marks is going to be very toned, however since the melanin tissue tend to be pretty near the top of pores and skin, they’d happen to be broken or even ruined, and also the region won’t ever suntan upward.
Regions of pores and skin which have been utilized because Donor Websites with regard to Pores and skin Grafting will also be handled just like Incomplete Width Uses up. My personal 2 upper thighs had been cropped 3 as well as twice respectively in the leg towards the groin, that has remaining me personally along with very toned marks, because of my personal Stress Match, however without any melanin tissue or even skin tones, as well as sun-tanning the region isn’t a choice.
Referrals
01 http: //theemtspot. com/2009/02/10/emt-burn-management-part-1/
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5eff3d1f6f98e57329caed0ceb9053d3
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8,026,491,582,162,493,000
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Upstream / Downstream
pathwayImage
Explore pathways related to this product.
Antibody Guarantee
CST Antibody Performance Guarantee
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To Purchase # 2969S
2969S 100 µl (10 western blots) $299.00
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REACTIVITY SENSITIVITY MW (kDa) Isotype
H M R Endogenous 95 Rabbit IgG
Western Blotting
Western blot analysis of extracts from MCF7 cells untreated (-) or treated with hIGF-I #8917 (+) using Phospho-IGF-I Receptor β (Tyr1135/1136)/Insulin Receptor β (Tyr1150/1151) (19H7) Rabbit mAb (Biotinylated).
Learn more about how we get our images
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Western Blotting Protocol
For western blots, incubate membrane with diluted primary antibody in 5% w/v BSA, 1X TBS, 0.1% Tween® 20 at 4°C with gentle shaking, overnight.
NOTE: Please refer to primary antibody datasheet or product webpage for recommended antibody dilution.
A. Solutions and Reagents
NOTE: Prepare solutions with reverse osmosis deionized (RODI) or equivalent grade water.
1. 20X Phosphate Buffered Saline (PBS): (#9808) To prepare 1 L 1X PBS: add 50 ml 20X PBS to 950 ml dH2O, mix.
2. 10X Tris Buffered Saline (TBS): (#12498) To prepare 1 L 1X TBS: add 100 ml 10X to 900 ml dH2O, mix.
3. 1X SDS Sample Buffer: Blue Loading Pack (#7722) or Red Loading Pack (#7723) Prepare fresh 3X reducing loading buffer by adding 1/10 volume 30X DTT to 1 volume of 3X SDS loading buffer. Dilute to 1X with dH2O.
4. 10X Tris-Glycine SDS Running Buffer: (#4050) To prepare 1 L 1X running buffer: add 100 ml 10X running buffer to 900 ml dH2O, mix.
5. 10X Tris-Glycine Transfer Buffer: (#12539) To prepare 1 L 1X Transfer Buffer: add 100 ml 10X Transfer Buffer to 200 ml methanol + 700 ml dH2O, mix.
6. 10X Tris Buffered Saline with Tween® 20 (TBST): (#9997) To prepare 1 L 1X TBST: add 100 ml 10X TBST to 900 ml dH2O, mix.
7. Nonfat Dry Milk: (#9999).
8. Blocking Buffer: 1X TBST with 5% w/v nonfat dry milk; for 150 ml, add 7.5 g nonfat dry milk to 150 ml 1X TBST and mix well.
9. Wash Buffer: (#9997) 1X TBST.
10. Bovine Serum Albumin (BSA): (#9998).
11. Primary Antibody Dilution Buffer: 1X TBST with 5% BSA; for 20 ml, add 1.0 g BSA to 20 ml 1X TBST and mix well.
12. Biotinylated Protein Ladder Detection Pack: (#7727).
13. Prestained Protein Marker, Broad Range (Premixed Format): (#7720).
14. Blotting Membrane and Paper: (#12369) This protocol has been optimized for nitrocellulose membranes. Pore size 0.2 µm is generally recommended.
15. Streptavidin-HRP: (#3999).
16. Detection Reagent: SignalFire™ ECL Reagent (#6883).
B. Protein Blotting
A general protocol for sample preparation.
1. Treat cells by adding fresh media containing regulator for desired time.
2. Aspirate media from cultures; wash cells with 1X PBS; aspirate.
3. Lyse cells by adding 1X SDS sample buffer (100 µl per well of 6-well plate or 500 µl for a 10 cm diameter plate). Immediately scrape the cells off the plate and transfer the extract to a microcentrifuge tube. Keep on ice.
4. Sonicate for 10–15 sec to complete cell lysis and shear DNA (to reduce sample viscosity).
5. Heat a 20 µl sample to 95–100°C for 5 min; cool on ice.
6. Microcentrifuge for 5 min.
7. Load 20 µl onto SDS-PAGE gel (10 cm x 10 cm).
NOTE: Loading of prestained molecular weight markers (#7720, 10 µl/lane) to verify electrotransfer and biotinylated protein ladder (#7727, 10 µl/lane) to determine molecular weights are recommended.
8. Electrotransfer to nitrocellulose membrane (#12369).
C. Membrane Blocking and Antibody Incubations
NOTE: Volumes are for 10 cm x 10 cm (100 cm2) of membrane; for different sized membranes, adjust volumes accordingly.
I. Membrane Blocking
1. (Optional) After transfer, wash nitrocellulose membrane with 25 ml TBS for 5 min at room temperature.
2. Incubate membrane in 25 ml of blocking buffer for 1 hr at room temperature.
3. Wash three times for 5 min each with 15 ml of TBST.
II. Primary Antibody Incubation
1. Incubate membrane and primary antibody (at the appropriate dilution as recommended in the product datasheet) in 10 ml primary antibody dilution buffer with gentle agitation overnight at 4°C.
2. Wash three times for 5 min each with 15 ml of TBST.
3. Incubate membrane with Streptavidin-HRP (#3999 at the appropriate dilution) in 10 ml of blocking buffer with gentle agitation for 1 hr at room temperature.
4. Wash three times for 5 min each with 15 ml of TBST.
5. Proceed with detection (Section D).
Do not add Anti-biotin, HRP-linked Antibody for detection of biotinylated protein markers. There is no need. The Streptavidin-HRP will also visualize the biotinylated markers.
D. Detection of Proteins
Directions for Use:
1. Wash membrane-bound HRP (antibody conjugate) three times for 5 minutes in TBST.
2. Prepare 1X SignalFire™ ECL Reagent (#6883) by diluting one part 2X Reagent A and one part 2X Reagent B (e.g. for 10 ml, add 5 ml Reagent A and 5 ml Reagent B). Mix well.
3. Incubate substrate with membrane for 1 minute, remove excess solution (membrane remains wet), wrap in plastic and expose to X-ray film.
* Avoid repeated exposure to skin.
posted June 2005
revised November 2013
protocol id: 266
Western Blot Reprobing Protocol
Reprobing of an existing membrane is a convenient means to immunoblot for multiple proteins independently when only a limited amount of sample is available. It should be noted that for the best possible results a fresh blot is always recommended. Reprobing can be a valuable method but with each reprobing of a blot there is potential for increased background signal. Additionally, it is recommended that you verify the removal of the first antibody complex prior to reprobing so that signal attributed to binding of the new antibody is not leftover signal from the first immunoblotting experiment. This can be done by re-exposing the blot to ECL reagents and making sure there is no signal prior to adding the next primary antibody.
A. Solutions and Reagents
NOTE: Prepare solutions with reverse osmosis deionized (RODI) or equivalently purified water.
1. Wash Buffer: Tris Buffered Saline with Tween® 20 (TBST-10X) (#9997)
2. Stripping Buffer: To prepare 100 ml, mix 0.76 g Tris base, 2 g SDS and 700 μl β-mercaptoethanol. Bring to 100 ml with deionized H2O. Adjust pH to 6.8 with HCl.
B. Protocol
1. After film exposure, wash membrane four times for 5 min each in TBST. Best results are obtained if the membrane is not allowed to dry.
2. Incubate membrane for 30 min at 50°C in stripping buffer (with slight agitation).
3. Wash membrane six times for 5 min each in TBST.
4. (Optional) To assure that the original signal is removed, wash membrane twice for 5 min each with 10 ml of TBST. Incubate membrane with LumiGLO® with gentle agitation for 1 min at room temperature. Drain membrane of excess developing solution. Do not let dry. Wrap in plastic wrap and expose to x-ray film.
5. Wash membrane again four times for 5 min each in TBST.
6. The membrane is now ready to reuse. Start detection at the "Membrane Blocking and Antibody Incubations" step in the Western Immunoblotting Protocol.
posted June 2005
Product Usage Information
Application Dilutions
Western Blotting 1:1000
Storage: Supplied in 136 mM NaCl, 2.6 mM KCI, 12 mM sodium phosphate (pH 7.4) dibasic, 2 mg/ml BSA, and 50% glycerol. Store at –20°C. Do not aliquot the antibodies.
Specificity / Sensitivity
Phospho-IGF-I Receptor β (Tyr1135/1136)/Insulin Receptor β (Tyr1150/1151) (19H7) Rabbit mAb (Biotinylated) recognizes endogenous levels of IGF-I receptor and insulin receptor only when phosphorylated at Tyr1135/1136 or Tyr1150/1151, respectively. It does not cross-react with other related tyrosine-phosphorylated tyrosine kinases.
Species Reactivity: Human, Mouse, Rat
Species predicted to react based on 100% sequence homology: Bovine, Dog
Source / Purification
Monoclonal antibody is produced by immunizing animals with a synthetic phosphopeptide corresponding to residues surrounding Tyr1135/1136 of human IGF-I receptor β protein.
Product Description
This Cell Signaling Technology antibody is conjugated to biotin under optimal conditions. The biotinylated antibody is expected to exhibit the same species cross-reactivity as the unconjugated Phospho-IGF-I Receptor β (Tyr1135/1136)/Insulin Receptor β (Tyr1150/1151) (19H7) Rabbit mAb #3024.
Type I insulin-like growth factor receptor (IGF-IR) is a transmembrane receptor tyrosine kinase that is widely expressed in many cell lines and cell types within fetal and postnatal tissues (1-3). Receptor autophosphorylation follows binding of the IGF-I and IGF-II ligands. Three tyrosine residues within the kinase domain (Tyr1131, Tyr1135, and Tyr1136) are the earliest major autophosphorylation sites (4). Phosphorylation of these three tyrosine residues is necessary for kinase activation (5,6). Insulin receptors (IRs) share significant structural and functional similarity with IGF-I receptors, including the presence of an equivalent tyrosine cluster (Tyr1146/1150/1151) within the kinase domain activation loop. Tyrosine autophosphorylation of IRs is one of the earliest cellular responses to insulin stimulation (7). Autophosphorylation begins with phosphorylation at Tyr1146 and either Tyr1150 or Tyr1151, while full kinase activation requires triple tyrosine phosphorylation (8).
1. Adams, T.E. et al. (2000) Cell Mol Life Sci 57, 1050-93.
2. Baserga, R. (2000) Oncogene 19, 5574-81.
3. Scheidegger, K.J. et al. (2000) J Biol Chem 275, 38921-8.
4. Hernández-Sánchez, C. et al. (1995) J Biol Chem 270, 29176-81.
5. Lopaczynski, W. et al. (2000) Biochem Biophys Res Commun 279, 955-60.
6. Baserga, R. (1999) Exp Cell Res 253, 1-6.
7. White, M.F. et al. (1985) J Biol Chem 260, 9470-8.
8. White, M.F. et al. (1988) J Biol Chem 263, 2969-80.
Entrez-Gene Id 3480 , 3643
Swiss-Prot Acc. P08069 , P06213
For Research Use Only. Not For Use In Diagnostic Procedures.
Cell Signaling Technology is a trademark of Cell Signaling Technology, Inc.
U.S. Patent No. 5,675,063.
2969
Phospho-IGF-I Receptor β (Tyr1135/1136)/Insulin Receptor β (Tyr1150/1151) (19H7) Rabbit mAb (Biotinylated)
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Harvard Catalyst Profiles
Contact, publication, and social network information about Harvard faculty and fellows.
Canned soup consumption and urinary bisphenol A: a randomized crossover trial.
Canned soup consumption and urinary bisphenol A: a randomized crossover trial. JAMA. 2011 Nov 23; 306(20):2218-20.
View in: PubMed
Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.
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Tender-Date Site looking for love
Marriage counseling near me can be a helpful and necessary resource for couples experiencing difficulties in their relationship. Whether there are communication issues, trust problems, or simply the desire to strengthen the bond between two partners, seeking professional help can provide valuable guidance and support. With increasing therapy providers nearby, finding the right marriage counselor is crucial for success.
When considering local marriage counseling options, it's essential to understand the variety of therapeutic approaches and the role of a licensed marriage and family therapist. In addition, couples should be aware of the growing availability of virtual counseling in today's digital age, providing convenience and flexibility in accessing help.
Key Takeaways
• Marriage counseling near me offers guidance and support for couples facing relationship challenges.
• Understanding various therapeutic approaches enhances the chances of success.
• Virtual counseling provides an accessible option for couples in the digital age.
Understanding Therapy and Therapists
Therapy, also known as psychotherapy, is a process that involves a professional helping individuals, couples, or families work through various emotional, behavioral, or relational issues. The professionals who engage in this process are called therapists. They have extensive training in counseling techniques and are skilled at working with individuals and couples facing multiple problems.
Therapists often have different specialties and backgrounds, but they share a common goal: to help people improve their mental well-being and relationships. Finding a well-suited therapist to meet your needs and concerns is essential. Some therapists primarily work with individuals, whereas others specialize in couples or family therapy.
There are various types of therapy, such as cognitive-behavioral therapy (CBT), psychodynamic therapy, and dialectical behavior therapy (DBT). Each type of therapy has its own set of techniques and approaches to addressing emotional and behavioral problems. The therapists are trained in their respective approaches and tailor their treatment plans to suit the unique needs of their clients.
When searching for marriage counseling, considering the therapist's experience and background in working with couples is essential. Couples therapy requires a unique set of skills and training to navigate the complex dynamics within a partnership. A qualified marriage counselor will have appropriate training in couples therapy and a proven track record of helping couples improve their relationships.
In conclusion, understanding the therapist's role and the various types of therapy available is crucial in finding the right professional for your needs. As you search for "marriage counseling near me," keep these factors in mind to ensure you find a therapist who can effectively help you and your partner overcome challenges and strengthen your relationship together.
The Importance of Mental Health
Maintaining good mental health is crucial for everyone, especially couples seeking to strengthen their bond. Marriage counseling can be immensely beneficial when dealing with stress, depression, anxiety, trauma, or grief. In this section, we will delve into the importance of mental health for married couples and explore how therapy can help.
Addressing mental health issues is vital in any relationship. When left unresolved, stress can negatively impact communication and connection between partners. Mental illness can create additional stress in a marriage, making couples need to work together to manage their mental health challenges.
Depression and anxiety are among the most common mental health problems couples face. These issues can make it difficult for individuals to engage in discussions or express their emotions effectively and thoroughly. In marriage counseling, couples learn to recognize and work together to overcome these barriers.
Trauma and grief are significant factors that can affect a couple's mental health. Events like losing a loved one or experiencing a traumatic incident can cause lasting emotional pain. Marriage counseling can assist in the healing process by helping couples navigate these complex emotions and find ways to support each other.
Mental health problems can also manifest as physical health issues. Chronic stress or anxiety can lead to poor sleep, weight gain, and high blood pressure. By addressing these concerns in counseling, couples can improve their overall well-being.
In conclusion, paying attention to mental health is essential for couples to build a strong foundation for their marriage. By addressing and overcoming mental health issues together, couples can enhance their emotional connection and pave the way for a healthier and happier life.
Approaching Marriage and Relationship Issues
Marriage counseling is a valuable resource for couples experiencing various relationship issues. It involves seeking help from a qualified marriage and family therapist who can facilitate discussions, improve communication, and help foster a stronger bond between partners.
One common issue addressed in marriage counseling is communication. Many couples struggle with expressing their thoughts and feelings effectively, leading to misunderstandings, anger, and frustration. A marriage counselor can teach couples techniques to improve their communication skills, which can result in more productive and satisfying interactions within the relationship.
Another challenge many couples face is trust. Trust is a fundamental aspect of any healthy relationship; when broken, it can be challenging to rebuild. Marriage counselors can guide partners through reestablishing trust and addressing the root causes while providing a safe and supportive environment for healing.
Emotionally Focused Therapy (EFT) is a practical approach often used in marriage counseling. This method helps couples understand and recognize the emotion and attachment patterns underlying their conflicts. By focusing on the emotional needs of each partner, EFT can result in a deeper connection, more empathy, and, ultimately, a stronger bond.
Relationship issues such as anger, jealousy, or infidelity can lead a couple to separation or divorce. Marriage counseling can provide guidance and support during these difficult times, helping partners explore their options and make informed decisions about their future.
In summary, marriage counseling is a valuable tool for addressing and resolving relationship issues, whether they are rooted in communication, trust, or more complex emotional dynamics. Working with a skilled marriage counselor allows couples to find the support and guidance to build a stronger, healthier, and more fulfilling relationship.
Career and Life Transitions
Marriage counseling can benefit relationship issues and couples facing career and life transitions. As individuals go through different stages of life, they might need guidance on navigating these changes together harmoniously.
One example of a life transition is when one partner decides to switch careers or pursue a new job opportunity. This change can bring about stress and require adjustment within the relationship. Career counseling can help couples understand each other's needs and support their partner's growth.
Another type of transition that couples may experience is the arrival of a new family member. This life-changing event certainly brings joy but may also cause anxiety and strain on the relationship. Marriage counselors can guide how to balance the responsibilities and nurture their bond.
Couples might struggle with decisions about relocating for work or personal reasons. As they weigh the pros and cons, marriage counselors can promote effective communication and conflict resolution skills to ensure a smooth transition. This guidance can build a stronger relationship built on mutual understanding and support.
In conclusion, addressing career and life transitions in marriage counseling cannot be overlooked. Counselors can provide valuable insights and support to help couples embrace change and maintain a robust and healthy partnership throughout life's many stages.
Dealing with Behavioral Issues
Marriage counseling is valuable for couples facing various challenges, including behavioral issues. When one partner has difficulty managing their behavior, it can lead to conflicts and strained relationships. This section will discuss marriage counselors' techniques to address behavioral issues, such as ADHD, and resolve conflict.
One approach to behavioral issues is implementing Cognitive Behavioral Therapy (CBT). This technique helps individuals recognize the thoughts and feelings behind their behavior, allowing for healthier responses to situations. Couples where one partner has ADHD may find CBT particularly beneficial, as it can teach them how to manage symptoms effectively.
Another critical aspect of addressing behavioral issues is fostering effective communication. Couples are encouraged to actively listen to one another and express their thoughts and feelings openly. This not only helps resolve conflict but also supports the understanding of each other’s needs and preferences. In cases where behavioral issues stem from ADHD, open communication enables both partners to discuss adjustments needed to support each other.
Marriage counselors may also provide strategies for couples to handle conflicts constructively. This includes setting boundaries, learning to compromise, and recognizing each other’s triggers. As a result, teams can learn to resolve conflict in a manner that respects each other’s emotions and needs.
Finally, couples must learn, accept, and appreciate each other's behavioral differences. Through counseling, they can uncover the root causes of certain behaviors and find ways to foster a healthier connection. As they understand and embrace each other’s unique qualities, couples can transform behavioral issues into opportunities for growth and lasting harmony. With the help of marriage counseling, couples dealing with behavioral problems can find the support and guidance they need to nurture a more robust and healthier relationship.
Coping Mechanisms for Stress and Anxiety
In today's fast-paced world, stress and anxiety have become an inevitable part of our lives, often leading to relationship challenges. Marriage counseling professionals often help couples by teaching them essential coping skills for dealing with these issues. In this article, we will discuss some common coping mechanisms for stress and anxiety.
Stress and anxiety can occasionally be related to specific situations or events, such as the COVID-19 pandemic. Understanding and accepting the things you cannot control is a crucial coping skill in such uncertainty. It is essential to focus on what you can control – your actions and responses to situations.
For some, obsessive-compulsive disorder (OCD) can significantly contribute to stress and anxiety. By seeking professional help and employing coping techniques such as exposure and response prevention therapy, individuals with OCD can learn to manage their thoughts and behaviors more effectively.
Regular exercise is another effective coping mechanism significantly reducing stress and anxiety. Exercise helps release endorphins, natural mood elevators that can help combat negative emotions. Incorporating physical activities like walking, yoga, or jogging into your daily routine can positively affect your mental and emotional well-being.
Implementing various relaxation techniques can also help in managing stress and anxiety. Some examples include:
• Deep breathing exercises
• Progressive muscle relaxation
• Mindfulness meditation
These techniques can help to calm racing thoughts, alleviate tension in the body, and provide a greater sense of relaxation during stressful periods.
Lastly, communication with your partner is vital in addressing stress and anxiety within a relationship. Open and honest discussions about feelings and emotions can help couples better understand each other's needs, resolve conflicts, and strengthen their bond.
In conclusion, coping mechanisms for stress and anxiety are essential tools in maintaining a healthy and loving relationship. By utilizing these strategies and seeking professional help, couples can work together to navigate life's challenges and build a stronger foundation for their partnership.
Family Matters
Regarding marriage counseling, it's important to remember that family matters. As couples navigate the sometimes turbulent waters of their relationships, the impact on their children and the overall family unit needs to be considered.
In many cases, family therapy can be an essential component of successful marriage counseling. This therapy focuses on creating a healthier family dynamic where every family member is heard and supported. Family therapy involves working through conflicts and examining communication patterns to foster healthier relationships.
Parenting plays a pivotal role in shaping the family environment. Couples experiencing marital difficulties may encounter challenges regarding their parenting styles. Marriage counseling can help parents come together and develop a united front in raising their children, promoting consistency and stability for the entire family.
Divorce is a complex reality for many families. However, it does not always mean the end of a family unit. With marriage counseling, couples can explore whether it is possible to reconcile and move forward together. In cases where divorce is the best option, counselors can aid in transitioning through this change, ensuring minimal negative impact on the children involved.
The incorporation of family systems theory into marriage counseling sessions can be invaluable. This approach acknowledges that their relationships within the family unit influence an individual's behavior and emotional well-being. Understanding these interconnecting relationships helps couples and therapists to identify underlying issues and work towards healthier family dynamics.
In conclusion, addressing the family context in marriage counseling is essential to achieve lasting results. By considering the roles of children, family therapy, parenting, divorce, and family systems, therapists can help couples build a stronger foundation, ensuring a healthier and happier family life.
Navigating Major Life Situations by Using Marriage Counseling Near Me
Marriage counseling can provide support and guidance in navigating significant life situations. Various challenges can arise in a relationship, such as substance abuse, eating disorders, autism, and other life situations. Couples can develop the tools and strategies necessary to face these challenges and maintain a healthy partnership through counseling.
Substance abuse can profoundly affect a relationship. When one partner suffers from addiction, it can cause emotional and financial strain on the couple. Marriage counseling offers a safe space to discuss the impact of substance abuse on the relationship and create a plan for recovery or support.
Eating disorders, such as anorexia, bulimia, and binge eating, can also burden a relationship. Like substance abuse, these disorders often involve secrecy and increased emotional distance between partners. Marriage counselors can work with the couple to build a support system that helps the affected partner while ensuring the other partner's needs are met.
In relationships where one or both partners are on the autism spectrum, communication can be a significant challenge. Couples in these situations may struggle to understand each other's perspective and express their emotions effectively. Marriage counselors trained in autism spectrum disorders can provide guidance and tailor their approach to the couple's unique needs.
Life situations such as job loss, relocation, or becoming parents can strain a relationship. These changes may result in emotional and practical adjustments that can be difficult for a couple to navigate. Marriage counseling helps couples to develop practical communication skills and create a solid foundation in facing these challenges together.
Marriage counseling can be a valuable resource for couples navigating significant life situations, providing a supportive environment to work towards a healthier and stronger relationship.
Different Types of Counseling and Therapies
Couples therapy is a type of counseling meant to help partners in romantic relationships communicate better, resolve conflicts, and build a healthier, stronger bond. It can apply to married and unmarried couples, addressing partners' challenges and issues.
Marriage counseling is similar to couples therapy but focuses specifically on married couples. This form of counseling assists spouses in addressing and overcoming marital problems, strengthening their bond, and enhancing their understanding of each other. Marriage counseling can prevent potential relationship breakdowns or help those experiencing a crisis.
As a therapeutic method, hypnotherapy utilizes the power of the subconscious mind to shift behaviors, patterns, and emotional responses impacting relationships. This approach can be implemented in couples therapy to help partners overcome communication barriers, rebuild trust, or manage stress and anxiety.
The Gottman Method is a research-based approach to relationship therapy that emphasizes strengthening the couple's friendship, enhancing their conflict management skills, and creating shared goals. This method often includes assessments, interventions, and exercises tailored to the couple's needs and circumstances.
Marital therapy generally encompasses various counseling approaches and techniques to improve relationships, address specific issues, and enhance couples' happiness and satisfaction. These techniques may involve communication strategies, problem-solving skills, and understanding individual and relational patterns.
Couples can find the most suitable approach to nurture and strengthen their relationships by considering the different types of counseling and therapies mentioned above.
The Role of a Licensed Marriage and Family Therapist
A Licensed Marriage and Family Therapist (LMFT) plays a significant role in helping couples and families navigate through various challenges they might be facing. Trained and licensed professionals, LMFTs possess the skills and expertise to foster open communication, facilitate understanding, and promote healing in relationships.
Marriage and family therapists, licensed professional counselors, and mental health counselors often work with couples experiencing conflict, dissatisfaction, or other relationship issues. They utilize various therapeutic approaches to help clients identify behavior patterns, improve communication, and implement positive change.
In addition to working with couples, a licensed marriage and family therapist may support families coping with significant life changes or stressors. These services may be particularly beneficial for families dealing with issues such as divorce, grief, and loss or the challenges of blended families. The LMFT's role here is to aid in improving family dynamics and strengthen bonds between family members.
Moreover, LMFTs often work alongside clinical psychologists to address mental health concerns within relationships and family dynamics. This collaboration allows for an integrated approach to ensure comprehensive care for clients with relationship and mental health struggles.
In summary, the role of a licensed marriage and family therapist is diverse, extending beyond marital counseling to encompass family-focused care. By addressing various relationship issues, LMFTs help clients build healthier and more fulfilling connections with their loved ones.
Building Better Relationship Skills
Developing strong relationship skills is crucial for couples seeking to improve their connection, communication, and happiness. By focusing on enhancing these skills, partners can deepen their empathy and intimacy levels, leading to a healthier, more fulfilling bond. This section will discuss various ways to build better relationship skills.
One essential element of relationship skills is effective communication. Open, honest, and respectful dialogues between partners can pave the way for a deeper understanding of one another's needs and feelings. Communication involves expressing oneself more clearly and actively listening to one's partner instead of focusing on one's response. This fosters mutual trust and respect, which is vital for a thriving partnership.
Cultivating empathy is another crucial aspect of relationship skills. Understanding and sharing your partner's feelings is key to building emotional intimacy. To develop empathy, put yourself in their shoes and genuinely try to feel their perspective. Recognize the differences in your partner's emotions, validate them, and show support through empathetic actions, such as offering a comforting hug or reassuring.
Intimacy in a relationship refers to closeness and connection with one's partner. To improve intimacy, couples must actively nurture their relationship's emotional and physical aspects. Building emotional intimacy involves developing trust and supporting each other, while physical intimacy solidifies a couple's bond through touch and affection. Engaging in shared activities and prioritizing time together can also enhance closeness.
Self-awareness plays a significant role in building better relationship skills. Understanding one's emotions, needs, and communication patterns improves interactions and connections with your partner. Self-awareness helps identify areas for personal growth, which can positively impact your relationship. Practicing mindfulness and self-reflection can lead to a heightened sense of self-awareness and a better understanding of how to interact with your partner effectively.
In conclusion, focusing on essential aspects such as communication, empathy, intimacy, and self-awareness can significantly impact a couple's relationship skills. Partners can achieve a more harmonious, fulfilling, and loving connection by dedicating time and effort to building better relationship skills.
Virtual Counseling in the Digital Age
The onset of the COVID-19 pandemic has propelled the adoption of virtual counseling services by therapists and clients. This digital shift has made marriage counseling more accessible and convenient for couples seeking help. Virtual platforms now offer various options for couples who prefer privacy or live in areas where in-person sessions might be difficult to arrange.
Virtual counseling services have fine-tuned their programs to cater to the unique needs of married couples. Therapists can address the partners ' challenges and offer tailored solutions through video calls, chat support, and other digital communication methods. This has made the experience more personalized and effective, even though the couples and therapists are physically apart.
The digital age also allows couples to be more comfortable in their environment and open up more quickly during virtual counseling sessions. This relaxed atmosphere often leads to more genuine conversations, increasing the chances of successful outcomes.
Another advantage of virtual counseling during the COVID-19 pandemic is the elimination of potential health risks associated with in-person sessions. Couples can attend therapy without worrying about the virus's transmission, providing a safe and healthy therapeutic journey.
In conclusion, virtual counseling in the digital age has made marriage counseling more flexible and accessible for needy couples. Despite the challenges imposed by COVID-19, technology has played a significant role in ensuring continued support for marital relationships through innovative and effective online platforms.
Frequently Asked Questions
What types of therapies do marriage counselors use?
Marriage counselors use various types of therapies to help couples resolve their issues. Some common approaches include:
• Cognitive Behavioral Therapy (CBT) focuses on identifying and changing unhealthy thought patterns that may be causing strain in the relationship.
• Emotionally Focused Therapy (EFT) emphasizes the importance of attachment and emotions in maintaining a healthy relationship.
• Family Systems Therapy examines the patterns and dynamics within the couple's family of origin.
How do you choose the right marriage counselor?
Choosing the right marriage counselor is crucial for the success of therapy. Consider the following factors when searching for one:
• Credentials and experience: Ensure the counselor is licensed and has expertise in couples therapy.
• Compatibility: Look for a counselor with whom both partners feel comfortable sharing their thoughts and feelings.
• Approach and specialization: Some counselors specialize in specific types of therapies, so selecting one who matches your needs is essential.
Do marriage counselors accept insurance?
Many marriage counselors accept insurance, but you must check with your insurance provider and the counselor before beginning therapy. Some insurance plans may require a referral from a primary care physician or cover only a certain number of sessions.
Can we get free marriage counseling sessions?
Free marriage counseling may be available through community organizations, religious institutions, or non-profit groups. However, these services might have limited availability, and couples should research and inquire about the qualifications of the counselor providing the sessions.
Is online marriage counseling near me effective?
Online marriage counseling has grown in popularity, and many couples have found it a practical option. It offers advantages such as increased accessibility, convenience, and the ability to choose from a broader range of therapists. However, some couples may prefer in-person sessions for various reasons, such as comfort level or personal preference.
What is the Gottman method in couples therapy?
The Gottman method, developed by Drs. John and Julie Gottman is a widely recognized approach in couples therapy. It focuses on strengthening the couple's friendship, improving communication, and helping them manage conflict effectively. The method is evidence-based and has successfully improved relationship satisfaction and stability.
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Thursday, 02 May 2019
Hypertension: The Oft-Ignored Cause of a Heart Attack
Hypertension: The Oft-Ignored Cause of a Heart Attack
Some people suffering from hypertension do not feel any disturbing symptoms. That is why this dangerous disease is called “the silent killer,” since the process of hypertension itself can affect or harm all body organs.
Commonly, the sufferers don’t even realize that they have hypertension for they never take a checkup on their blood pressure. The normal value of blood pressure for people with normal body weight, height, and physical activity is 120/80 mmHg. In daily activities, the blood pressure is relatively stable and remains within the normal range. Yet, generally the number of blood pressure reading decreases when sleeping, and increases while doing activities or exercises.
Both primary and secondary hypertension are equally dangerous
High blood pressure disease or hypertension is classified into two, namely primary hypertension and secondary hypertension.
Primary hypertension is a condition in which the high blood pressure is caused by an unhealthy lifestyle and several environmental factors. An uncontrolled dietary pattern leading to overweight or even obesity is the initial trigger of high blood pressure disease. Similarly, people living in a very stressful environment or condition are highly exposed to high blood pressure disease, including those with a sedentary lifestyle.
Secondary hypertension is a condition in which the high blood pressure is caused by other diseases, such as heart failure, kidney failure, or damage in the endocrine system of the body. Meanwhile, pregnant mothers generally have their blood pressure increased when the pregnancy reaches 20 weeks. This particularly occurs in overweighted or obese women.
Primary hypertension is the most common type of hypertension. Nevertheless, both primary and secondary hypertension cause nearly similar harm: organ damage and accelerated atherosclerosis (clog in the blood vessels).
The increased blood pressure can be caused by the frequent or continuous use of drugs, such as corticosteroid drugs (cortisone), hormone, or anti-inflammatory drugs. In addition, smoking might also increase the blood pressure due to the nicotine contained within the tobacco. Alcoholic beverages are also considered as a cause of high blood pressure.
Everyone should beware
Something more dangerous than hypertension is its complication. Hypertension accelerates atherosclerosis, causing clot more quickly in the blood vessels. When taking place in the brain, it causes stroke; in the kidney, it causes kidney failure; whereas in the heart it will cause a heart attack or coronary heart disease.
To prevent hypertension from developing into the complications of kidney failure, stroke, heart attack, or erectile dysfunction, it is suggested that the sufferers do regular exercise and change their lifestyle. The sufferers of hypertension must also realize that it is important to return the blood pressure into normal, or as low as possible.
Celebrating Ramadan and World Hypertension Day, Prodia offers 20% discount for Prohealthy Ramadan Package and Hypertension Panel during May 2019. For further information, click here.
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Have questions? Visit https://www.reddit.com/r/SNPedia
rs41261344
From SNPedia
Orientationplus
Stabilizedplus
Geno Mag Summary
(C;C) 0 common in clinvar
(C;T) 1 Probably benign; previously, thought to confer possible susceptibility to long QT syndrome
(T;T) 1 Probably benign; previously thought to confer possible susceptibility to long QT syndrome
ReferenceGRCh38 38.1/141
Chromosome3
Position38575385
GeneSCN5A
is asnp
is mentioned by
dbSNPrs41261344
dbSNP (classic)rs41261344
ClinGenrs41261344
ebirs41261344
HLIrs41261344
Exacrs41261344
Gnomadrs41261344
Varsomers41261344
LitVarrs41261344
Maprs41261344
PheGenIrs41261344
Biobankrs41261344
1000 genomesrs41261344
hgdprs41261344
ensemblrs41261344
geneviewrs41261344
scholarrs41261344
googlers41261344
pharmgkbrs41261344
gwascentralrs41261344
openSNPrs41261344
23andMers41261344
23andMe allrs41261344
SNPshotrs41261344
SNPdbers41261344
MSV3drs41261344
GWAS Ctlgrs41261344
GMAF0.01194
Max Magnitude1
rs41261344, also known as c.3575G>A, Arg1193Gln or R1193Q, is a SNP in cardiac sodium channel SCN5A gene.
It is unclear how penetrant (causative) the rare allele of this SNP is for cardiac issues such as long QT syndrome. It was thought to be causative, based on observations in Caucasians, but then a report came out stating that 14% of Han Chinese carry this variant, most without any apparent problem. See OMIM and the GetEvidence summary below on right for more discussion.
Although now considered benign by ClinVar consensus, this variant meets the criteria published in 2013 by the ACMG regarding incidental findings in exome or genome sequencing, as a variant that they do recommend informing a patient about.[PMID 23788249OA-icon.png]
A 2019 publication based on a Chinese patient reports that the R1193Q variant may predispose individuals to develop drug-induced Brugada syndrome when treated with propafenone.[PMID 30984031OA-icon.png]
OMIM600163
Desc
Variant0023
Relatedalso
ClinVar
Risk Rs41261344(T;T)
Alt Rs41261344(T;T)
Reference Rs41261344(C;C)
Significance Other
Disease Brugada syndrome 1 Long qt syndrome 3 not provided not specified Primary familial hypertrophic cardiomyopathy Brugada syndrome Cardiovascular phenotype
Variation info
Gene SCN5A
CLNDBN Brugada syndrome 1 Long qt syndrome 3, acquired, susceptibility to not provided not specified Primary familial hypertrophic cardiomyopathy Brugada syndrome Cardiovascular phenotype
Reversed 0
HGVS NC_000003.11:g.38616876C>T
CLNSRC OMIM Allelic Variant
CLNACC RCV000009990.5, RCV000009991.4, RCV000058578.6, RCV000154828.2, RCV000157488.1, RCV000171819.5, RCV000252422.1,
[PMID 16155] Cryptorchidism and abdominal pain.
[PMID 11823453] Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.
[PMID 12639704] Nucleotide changes in the translated region of SCN5A from Japanese patients with Brugada syndrome and control subjects.
[PMID 15121794OA-icon.png] The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel.
[PMID 15689442OA-icon.png] R1193Q of SCN5A, a Brugada and long QT mutation, is a common polymorphism in Han Chinese.
[PMID 15851227] Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.
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Sex Differences in Heat Shock Protein 72 Expression in Peripheral Blood Mononuclear Cells to Acute Exercise in the Heat
AUTHORS
Trevor Gillum 1 , * , Matthew Kuennen 2 , Cheryl Gourley 3 , Karol Dokladny 4 , Suzanne Schneider 3 , Pope Moseley 4
1 Department of Kinesiology, California Baptist University, Riverside, USA
2 Department of Sports and Exercise Science, West Texas A&M University, Canyon, USA
3 Department of Health, Exercise and Sport Sciences, The University of New Mexico, Albuquerque, USA
4 Department of Internal Medicine, The University of New Mexico, Albuquerque, USA
How to Cite: Gillum T, Kuennen M, Gourley C, Dokladny K, Schneider S, et al. Sex Differences in Heat Shock Protein 72 Expression in Peripheral Blood Mononuclear Cells to Acute Exercise in the Heat, Int J Endocrinol Metab. 2013 ; 11(4):e8739. doi: 10.5812/ijem.8739.
ARTICLE INFORMATION
International Journal of Endocrinology and Metabolism: 11 (4); e8739
Published Online: October 1, 2013
Article Type: Research Article
Received: October 26, 2012
Revised: March 17, 2013
Accepted: April 27, 2013
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Abstract
Background: Heat shock protein 72 (Hsp72) is responsible for maintaining critical cellular function during heat stress. Hsp72 confers thermotolerance and may play a role in heat acclimation. Animal research suggests a difference between sexes in Hsp72 expression in response to exercise, however, human data is lacking.
Objectives: To determine sex differences in intracellular heat shock protein 72 (Hsp72) following exercise in the heat.
Patients and Methods: Nine non-heat acclimated women with normal menstrual cycles (VO2pk 58 ± 5 mL.kgFFM-1∙min-1) and nine non-heat acclimated men (VO2pk 60 ± 7 ml.kgFFM-1.min-1) completed 2 treadmill bouts at 60% VO2pk for 60 min in a 42°C, 20% RH environment. Women were tested in follicular (fol) and luteal (lut) phases. The duplicate trials were separated by 12 days for men and women. Blood samples were drawn pre, immediately post, 1, and 4 hrs post-exercise.
Results: Men and women differed in their Hsp72 response after exercise (time X sex X trial interaction; P < 0.05). Men increased Hsp72 after exercise more than women. Both men and women produced less Hsp72 during trial 2 compared to trial 1. Estrogen (r = 0.24; P > 0.05) and progesterone (r = 0.27, P > 0.05) concentrations were not correlated with Hsp72.
Conclusion: Our findings suggest that men and women differ in their cellular stress response. Men up-regulated Hsp72 after a single bout of exercise in the heat, which persists for 12 days, suggesting an accumulation of Hsp72 which may lead to acquired cellular thermotolerance.
Keywords
Menstrual Phase Thermoregulation Endogenous antioxidants Thermotolerance
Copyright © 2013, Research Institute For Endocrine Sciences and Iran Endocrine Society. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background
The cellular stress response is characterized by the accumulation of intracellular heat shock proteins, including the highly heat inducible 72-kDa heat shock protein 72 (Hsp72). Hsp72 expression is linked to thermotolerance (1) in that increased Hsp72 protects cells against normally lethal increases in core temperature (2, 3). Hsp72 may protect cells by acting as an intracellular chaperone enhancing protein folding (4), inhibiting intracellular pro-inflammatory cytokine synthesis (5-8), and/or limiting cellular apoptosis (7). Males have shown an increased expression of Hsp72 in peripheral blood mononuclear cells (PBMC) (6, 7, 9, 10), skeletal muscle (11), brain (12) and liver (13) within 4 hrs after exercise or heat stress.
Given that Hsp72 is accumulated in response to stress, it is interesting that animal studies have shown a difference in the expression of Hsp72 between sexes. Under resting conditions, basal levels of Hsp72 in cardiac and renal tissue are higher in female compared to male rats (14, 15). However, in response to running (16, 17) and hyperthermia (18), male animals are able to express higher Hsp72 than females in the gastrocnemius and cardiac tissue. In the above studies, sham treated ovariectomized females had similar post stress Hsp72 levels as males, while estrogen treated ovariectomized females showed unaltered Hsp72 levels after stress, similar to intact females. Animal studies suggest an increased basal expression of Hsp72 may reduce the cellular response to an exercise stress and thus limit the need for additional Hsp72 production after the stress (19). The mechanism behind the relationship between estrogen and the blunted intracellular Hsp72 response to stress currently is not known. It was suggested that estrogen mediates this effect through a nongenomic hormonal pathway (17). Currently, there are no human studies that have tested for possible sex differences in the cellular stress response to exercise in the heat.
2. Objectives
Therefore, the objective of this study was to compare the expression of Hsp72 in PBMC at rest and after exercise in the heat in men and women. We hypothesized that women would have an increased baseline expression of Hsp72, but an attenuated post exercise response compared to men.
Furthermore, we examined if women in follicular (fol) and luteal (lut) phases of the menstrual cycle differed in their amount of Hsp72 expressed in response to exercise in the heat. We hypothesized that during lut, when estrogen levels are elevated, there would be a decrease in Hsp72 at rest and after exercise compared to fol.
3. Materials and Methods
3.1. Subjects
Eighteen (9 men and 9 women) subjects completed two treadmill sessions in a hot, dry environment (42.3 ± 1°C, 22.5 ± 12% relative humidity). Men were matched with women for aerobic fitness (ml ∙ kg lean body mass -1 min -1 ) and age (Table 1). None of the women were taking hormonal contraceptives and all had menstrual cycles of 28-32 days for three months prior to testing. Women were tested during the fol (day 7 ± 2) and lut (days 20 ± 1) phases of their menstrual cycle. Progesterone concentration was used to validate the presence of the luteal phase, as previously done ( 20 , 21 ). The same length of time elapsed between the two exercise trials for men and women (M: 12 ± 4 days, W: 12 ± 2 days). Each exercise trial for a given subject was conducted at the same time of day. Between exercise trials, subjects were asked to continue their normal physical activity patterns. The University of New Mexico’s Institutional Review Board approved this protocol and the subjects provided written, informed consent prior to participation.
3.2. Preliminary Testing
Body composition and cardiorespiratory fitness were assessed for all subjects. Three site skinfold (Lange, Beta Technology, Santa Cruz, CA) measurements (M: chest, abdomen, thigh; W: triceps, suprailiac, thigh) were used to determine percent body fat. Each site was measured in triplicate and the mean value was used to calculate percent body fat (22). A continuous graded treadmill test in a temperate room (22-24°C, 30% RH) was used to determine VO2peak. VO2peak was assessed through open circuit spirometry (ParvoMedics, Sandy, UT) and defined as the highest 30 second value when 2 of the following criteria were met: 1) a plateau in VO2 (change in VO2 < 150 mL min-1) with increased workload, 2) a maximal respiratory exchange ratio greater than 1.1 and 3) heart rate greater than 95% of the age predicted maximum (220-age). VO2 peak was expressed per mL of fat free mass (FFM) so that the aerobic fitness of sexes could be compared.
3.3. Experimental Design
Each subject performed two exercise trials (treadmill running at 60% VO2peak for 60 min) in an environmental chamber maintained at 42°C, 20% RH. The trials for women were counterbalanced so that 4 subjects performed the first exercise bout in the lut phase while 5 subjects performed the first exercise bout in the fol phase. Plasma estrogen and progesterone values were obtained to corroborate the appropriate menstrual cycle phase.
3.4. Exercise Trial
Data collection took place during the Fall and Winter months (October – February) to limit the effects of heat acclimation. Subjects were instructed to avoid exercise and alcohol for 24 hrs and to avoid caffeine for 12 hrs prior to each exercise trial. Subjects were given a list of high carbohydrate foods to consume for dinner on the night before and for breakfast on the morning before each trial. Subjects were asked to consume the same foods before the two trials.
On the day of the trial, nude body weight was recorded to the nearest 0.1 kg (Seca Scale, Birmingham, UK) and urine osmolality was used to assess the subjects’ hydration status (Advanced Osmometer, Model 303, Advanced Instruments Inc, Norwood, MA).
Core temperature (Tr) was measured by inserting a thermistor (YSI precision 4400 Series, Yellow Springs Inc, Yellow Springs, OH) 10 cm past the anal sphincter. An intravenous catheter was inserted in an antecubital vein and kept patent by infusing 3 ml of isotonic saline every 15 min during and after the exercise trial. Samples were drawn pre, immediately post, 1 hr post and 4 hrs post exercise.
The exercise intensity was set to elicit 60% of VO2peak. The intensity of exercise was selected such that active individuals who were not endurance trained would be able to complete the protocol. VO2 was measured every 15 min during exercise. The speed and grade were adjusted during the first 15 min of trial 1 to obtain a VO2 of 60% of VO2peak. This exercise level was maintained for the remainder of the exercise trial. When subjects repeated the exercise trial, the treadmill speed and grade were identical to the first exercise trial. During the first exercise trial, the subjects were allowed to drink water ad libitum. Each subject then ingested the same volume of water during their second trial. After exercise, each subject dried themselves with a towel and obtained their nude body weight. Sweat loss was calculated as the difference in pre to post weight, corrected for fluid intake. One male and one female subject were unable to complete their first 60 min exercise trial due to nausea and light headedness. When the trial was repeated, these subjects then exercised for this same duration. Hsp72 for these subjects was not anomalously higher after the first trial compared with the second. Therefore, data from these subjects are included in the analysis.
3.5. Blood Collection and Preparation
Three ml of blood were drawn at each time point and transferred to EDTA treated tubes. Half of the blood was aliquotted to measure hematocrit, plasma estrogen, and progesterone. The other half was used to measure Hsp72. Hematocrit was analyzed within 15 min of the blood draw and used to correct plasma protein concentrations for plasma volume changes during exercise as described elsewhere (23). After measuring hematocrit (microcentrifuge technique), the blood was centrifuged and the plasma separated and stored at -80ºC until later analysis.
PBMC’s were separated from 1 mL of blood using density gradient centrifugation (15 min, 2100 RPM, 0 ACC) with 1.077 g/mL Histopaque (Sigma-Aldrich, St. Louis, MO). PBMC were washed with phosphate buffered saline (PBS) and then treated with Reagent A (Fix and Perm kit, Invitrogen, Carlsbad, CA) and incubated at room temperature for 15 min. Cells were then washed and treated with Reagent B (Fix and Perm kit, Invitrogen, Carlsbad, CA) combined with a monoclonal Hsp72 FITC antibody (Assay Designs, Ann Arbor, MI) at 100 μg/mL. Cells were incubated for 20 minutes in the dark at room temperature. Cells were washed a final time, and then diluted in 300 mL sheath fluid and analyzed using a FACSCAN cytometer (BD Scientific, San Jose, CA). Ten thousand events were collected. Data was analyzed using Cellquest software (BD Scientific, San Jose, CA). The amount of protein produced per cell population was quantified as mean fluorescent intensity (MFI). To determine MFI, cells were gated and corrected for auto-fluorescence based upon unstained control. The gating strategy is shown in Figure 1.
Plasma was analyzed for estrogen and progesterone using ELISA kits (Genway Bioscience, San Diego, CA) according to manufacturer’s instruction. The minimum detectable concentration was 5 ± 2 pg/mL for estradiol and 0.08 ± 0.03 ng/mL for progesterone. Inter-assay variability was 6% for estradiol and 8.8% for progesterone. Intra-assay variability was 4.6% for estradiol and 9.7% for progesterone.
Figure 1. Representative Flow Cytometry Data From PBMCs.
Representative Flow Cytometry Data From PBMCs.
A) Gating strategy: SSC vs FSC for PBMC. B) Expression of Hsp72 in 1) unstained cells, 2) pre exercise, and 3) after 42°C incubation.
3.6. Statistical Analysis
Hsp72 was expressed as MFI, and, to more accurately assess sex differences due to exercise, pre exercise values were normalized to 1. Thus, the post exercise expression of Hsp72 was expressed as the change from the pre exercise value as previously reported (24, 25). A three factor (time x trial x sex) ANOVA was used to determine changes due to exercise. Sampling times included pre-exercise, immediately post exercise, 1 hr post exercise, and 4 hrs post-exercise.
Menstrual cycle comparisons were done only for those women in whom their phase of the cycle was confirmed by hormonal analysis (see results). A two-factor (time x phase) repeated measures ANOVA was used to test for differences due to the menstrual cycle phase. Here we compared fol vs. lut data, n = 7. To determine the potential effect of ovarian hormones on Hsp72, a correlation analysis between estrogen and Hsp72 in addition to progesterone and Hsp72 was conducted for all women.
All descriptive data were analyzed using a t-test (weight, aerobic capacity, % body fat, and hormonal analysis of estrogen and progesterone). Independent t-tests were used to compare men’s and women’s values for Tr, HR, urine osmolality, and relative exercise intensity.
The necessary n size was estimated to be 8 subjects, given a power of 0.80 and an alpha level of 0.05, using Statistica. Because sex differences in Hsp72 have not been assessed, we estimated n size according to the change from baseline in monocyte’s of males after treadmill exercise in the heat (6, 9) .
Statistical significance was set at α ≤ 0.05 and analysis was performed using Statistica 10 (StatSoft Inc, Tulsa, OK). Data were assessed for normality and homogeneity of variance prior to statistical analysis. Hsp72 data were not normally distributed and thus log transformed prior to analysis. Tukey’s post hoc test was used if necessary. Data is presented as mean ± SD in text and tables. For simplicity, data in figures is presented as mean ± SEM .
4. Results
4.1. Subject Characteristics
Men and women differed significantly for height (P = 0.01), weight (P = 0.01), % body fat (P = 0.01), and aerobic capacity expressed as ml kg -1 min -1 (P = 0.03). However, when aerobic capacity was expressed relative to fat free mass, there was no difference between sexes (Table 1). For men, trial 2 was repeated 12 ± 4 days after trial 1. For women, trial 2 was repeated 12 ± 2 days after trial 1.
Table 1. Subject Characteristics.
Age, y Height, cm Weight, kg VO2pk, ml-1kg-1min-1 VO2pk, ml-1kgFFM-1min-1 Body Fat, %
Men 26 ± 5 182 ± 7a 81.0 ± 15a 52.6 ± 8a 60.0 ± 7.7 12.0 ± 5.5a
Women 24 ± 3 170 ± 3 63.1 ± 12 44.9 ± 5 58.8 ± 5.2 21.4 ± 2.5
aDifference (P < 0.05) between sexes.
4.2. Exercise Response
Men and women did not differ in starting or ending T r , HR, pre or post urine osmolality, or relative exercise intensity. Men had significantly greater sweat rates than women (P = 0.01). One woman experienced heat illness symptoms at 45 min during trial 1, and one male subject stopped exercising for similar reasons at 30 min on trial 1. The second bout for both subjects was identical in duration and intensity to the first bout. Hsp72 levels for these subjects were not anomalously higher after the first trial compared with the second. Therefore, data from these subjects are included in the analysis. All other subjects completed 60 min of exercise. There was no significant effect of menstrual phase on baseline or exercise T r , urine osmolality, ending HR, or exercise intensity (Table 2).
Table 2. Thermal and Cardiovascular Responseato Exercise (n = 9 Men and 9 Women) (Mean ± SD).
Pre Tc (C)End Tc (C)Pre Urine Osm, mOsm/kgPost Urine Osm, mOsm/kgEnd HRMean % VO2pk, mL/kg/minSweat Rate, mL/min
Women Trial 137.21 ± 0.0839.05 ± 0.15499 ± 143453 ± 105162 ± 460 ± 1.316 ± 2
Women Trial 237.17 ± 0.0638.95 ± 0.17424 82362 ± 62160 ± 458 ± 1.617 ± 2
Men Trial 137.04 ± 0.0739.19 ± 0.09559 ± 72520 ± 83166 ± 257 ± 1.529 ± 2b
Men Trial 236.98 ± 0.1139.07 ± 0.14442 ± 91547 ± 95163 ± 258 ± 0.7526 ± 4b
aResponse to 60 min of treadmill running at 60% VO2 pk in a 42°C environment.
bP < 0.05 from Women's trials.
4.3. Menstrual Phase Hormones
Data from two subjects were removed from the menstrual cycle comparison after examining their progesterone values. In these subjects, progesterone values were not higher in the lut compared to fol phase. Therefore, all menstrual phase analyses are shown with n = 7 . Of the seven subjects analyzed for menstrual phase differences, five completed their first exercise trial in the fol phase, and two subjects exercised in the lut phase first. Estrogen and progesterone levels were significantly higher (P = .01) in the lut compared to fol phase (Table 3).
Table 3. Sex Hormones and Menstrual Cycle Phase (n = 7) (mean ± SD).
Estrogen, pmol/LProgesterone, nmol/LEnding HR% VO2pkPre Tc (C)End Tc (C)
Follicular344 ± 95a3.35 ± 1.2a160 ± 7.156 ± 0.0237.19 ± 0.1639.01 ± 0.53
Luteal436 ± 8930.1 ± 13.9 163 ± 7.058 ± 0.0137.35 ± 0.2839.06 ± 0.44
aP < 0.05 from Lut
4.4. Hsp72 Exercise Response
There was no difference in pre exercise values of Hsp72 MFI between sexes on trial 1 (men: 111±30, women: 121 ± 34) or 2 (men: 145 ± 38, women: 151 ± 43). The normalized, overall Hsp72 response after exercise was greater in men than women (time x trial x sex interaction P = 0.01) (Figure 2). Men expressed higher Hsp72 at +1 and +4 hrs post exercise compared to women pre and post during trial 1. However, this sex difference did not occur during trial 2. While the normalized increase in Hsp72 from pre exercise values was not significant in women during either trial, men increased Hsp72 at +1 and +4 hrs from pre exercise values in trial 1 (time x sex interaction P = 0.05). Both men and women expressed less Hsp72 in trial 2 compared to trial 1 (time x trial interaction P =<0.001).
Figure 2. Normalized Hsp72, Exercise Responses
Normalized Hsp72, Exercise Responses
Hsp72 response to 60 min of treadmill running at 60% VO2pk in a 42°C environment, as a percentage of baseline values. Dark bars represent men, open bars represent women. The dashed line separates trial 1 from trial 2. There was a time x trial x sex interaction: * P < 0.05 from pre exercise values for men trial 1. and P < 0.05 from trial 1 at the same time points for men. + P < 0.05 from women pre and post exercise during trial 1. Data represent mean ±± SEM.
4.5. Hsp72 Exercise Response – Menstrual Phase
In the 7 women included in the menstrual phase analysis, there was no difference in pre exercise values of Hsp72 MFI expression in fol (117 ± 14) versus lut (123 ± 24) phases. The normalized, overall Hsp72 response increased after exercise (main effect of time, P = 0.01), but was not different between fol and lut phases (Figure 3). For all female subjects, estrogen (r = 0.24, 0.12, 0.17, -0.7) and progesterone (r = 0.27, 0.13, 0.14, -0.1) concentrations were not correlated to Hsp72 MFI values at pre, post, +1, and +4 hrs post exercise, respectively (Figures 4 and 5).
Figure 3. Menstrual Phase
Menstrual Phase
Hsp72 response to 60 min of treadmill running at 60% VO2pk in a 42°C environment, as a percentage of baseline values. Closed bars represent follicular phase, open bars represent luteal phase (n = 7). There was a main effect of time: * P < 0.05 from pre values. Data represents mean ± SEM.
Figure 4. Correlation between Estrogen and Hsp72.
Correlation between Estrogen and Hsp72.
Pre exercise estrogen concentration was not correlated with Hsp72 at any time point. Data represents n = 9.
Figure 5. Correlation Between Progesterone and Hsp72.
Correlation Between Progesterone and Hsp72.
Pre exercise progesterone concentration was not correlated with Hsp72 at any time point. Data represents n = 9.
5. Discussion
Our major finding is that men and women have different Hsp72 stress responses to exercise in the heat. Men expressed greater Hsp72 after exercise in trial 1 than women, and subsequently up-regulated their baseline Hsp72 expression by ~30% before trial 2. This increase in baseline Hsp72 led to reduced Hsp72 expression when the same exercise stress was repeated 12 days later. Women produced less Hsp72 than men on trial 1 and did not up regulate baseline Hsp72 expression during trial 2. Thus, in response to an initial exercise challenge, women had a blunted cellular stress response compared to men. This sex difference may highlight the redundant mechanisms of estrogen and Hsp72 in mediating the stress response to exercise in the heat. Estrogen may help to stabilize cell membranes, thus reducing the need to up regulate Hsp72 after an acute stress. Thus, we reject our hypothesis that women would have an increased pre exercise expression of Hsp72, but retain our hypothesis that the post exercise response in women would be attenuated compared to men. In addition, there was no effect of menstrual phase either at rest or after exercise on Hsp72 expression. Therefore, we reject our hypothesis that during lut, when estrogen levels are elevated, there would be a decrease in Hsp72 at rest and after exercise compared to fol.
Hsp72 expression has a significant role in maintaining cellular homeostasis during and after stress (4, 26). While numerous animal studies have found sex differences in Hsp72 expression with acute hyperthermia or exercise, to our knowledge this is the first study to examine this effect in humans. Results from animal studies imply that estrogen is responsible for increased baseline Hsp72 expression (14, 15, 23) and this up-regulation exerts protective effects that reduce the need for Hsp72 production during exercise (16, 19), ischemia (17), or hyperthermic (18) stresses. In our study in humans, the baseline Hsp72 did not differ between sexes. However, men expressed greater Hsp72 compared to women in response to stress. Thus, while it is understood that male animals increase Hsp72 to a greater extent in response to stress than females, we report for the first time that this sex effect is also evident in humans.
Acquired cellular thermotolerance occurs when a single exposure to a severe, but sub-lethal heat stress leads to protection against future, more severe heat exposure. This process involves the increased expression of basal Hsp72 (2, 3) and leads to decreased Hsp72 induction in response to a second exposure (24). In this fashion, Hsp72 can act as a marker for thermal history (10). In men, we found a greater percent increase in baseline PBMC Hsp72 content 12 days after trial 1 compared to women. Although this was not statistically significant, it is likely that the increased baseline expression seen in men in trial 2 abrogated the need for further Hsp72 production during trial 2. As such, neither men nor women showed a significant accumulation of Hsp72 in PBMCs during the second trial. Thus, it appears that Hsp72 may be regulated differently after an acute bout of exercise in the heat in non- heat acclimated men and women. It has not been previously appreciated that baseline Hsp72 could be up-regulated 12 days after a single acute bout of exercise in the heat. This data raises interesting questions regarding the role of thermotolerance in women. Estrogen may relegate the process of acquired cellular thermotolerance redundant, diminishing the need for Hsp72 accumulation.
This paper also is the first to examine possible effects of the menstrual cycle on Hsp72 expression. If estrogen is responsible for the decreased Hsp72 induction during exercise, then the variation of estrogen across the menstrual cycle could alter baseline or stress induced Hsp72 expression. The mechanism behind the relationship between estrogen and the blunted intracellular Hsp72 response to stress currently is not known. It was suggested that estrogen mediates this effect through a nongenomic hormonal pathway. Treating animals with tamoxifen, a known estrogen receptor agonist, caused the same blunted post exercise Hsp70 expression as in ovariectomized animals treated with 17β and 17α estradiol (17). Since tamoxifen, 17β, and 17α estradiol all suppress the post exercise expression of Hsp70, researchers suggest that these estrogen related compounds stabilize cell membranes and attenuate oxidative stress (25). Such an effect could protect thermal sensitive cells against exercise-induced damage, and thereby result in a blunted Hsp72 expression. However, we found no difference in baseline or exercise Hsp72 response when women exercised in the fol compared to the lut phase. While our statistical power was limited with only 7 subjects included, there was no correlation between ovarian hormone concentrations and Hsp72 expression with n = 9. Our findings are supported by animal data that suggest no effect of the estrous cycle on Hsp72 production in the pituitary or adrenal gland, spleen, lymph nodes, liver or heart in response to stress (27). Thus, the physiologic variations in estrogen and progesterone during the menstrual cycle may not be sufficient to alter Hsp72 expression.
Our main finding is that non-acclimated men increased Hsp72 more than women in PBMCs in response to exercise in the heat. After this single bout of exercise, men’s Hsp72 was up-regulated for up to 12 days, suggesting that men had acquired cellular thermal tolerance. We suggest that estrogen may provide cellular protection and thus decrease the need to up-regulate Hsp72 in non-acclimated women. These data raise intriguing questions about the role of acquired cellular thermal tolerance between sexes.
Acknowledgements
Footnotes
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5eff3d1f6f98e57329caed0ceb9053d3
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144,352,915,537,492,320
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Vecuronium (Norcuron)
1. Class:
Non-depolarizing neuromuscular-blocking agent
2. Description:
Derivative of pancuronium, provide muscle relaxation for ET intubation
3. Mechanism of Action:
Competes with acetylcholine for cholinergic receptor sites on the post-junctional membrane. This completion results in paralysis of muscle fibers served by the occupied neuromuscular junction. Does not cause initial depolarization wave, as does succinylcholine
4. Onset of Action:
• Onset: <1 min
• Peak: 3-5 min
• Duration: 25-40 min
• Half Life: 30-80 min
5. Indications:
Facilitate paralysis for endotracheal intubation
6. Contraindications:
Known hypersensitivity to drug
7. Precautions:
Persons skilled in ET intubation present, Emergency resuscitative drugs available, Paralysis occurs in 1 minute and lasts 30 minutes
8. Side effects:
Apnea, aspiration, bradycardia, bronchospasm, cardiac arrest, dysrhythmias, hypotension, HTN, increased intraocular pressure, intracranial pressure, prolonged paralysis, respiratory depression, wheezing
9. Adult dose:
.08-.1 mg/kg
10. Pedi dose:
.1 mg/kg
11. Max dose:
No answer yet....one dose I would assume?
12. Routes of administration:
IV/IO
13. How supplied:
No answer yet
Author
fyrems
ID
77180
Card Set
Vecuronium (Norcuron)
Description
Paramedic Drugs
Updated
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-5,628,911,525,322,441,000
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Main
MATERIA MEDICA
(Reversed Kent's Repertory)
Presented by Sylvain Cazalet
Artemisia Vulgaris
MIND
Mind, delirium, look fixed on one point staring (p. 19)
Mind, excitement, excitable (p. 40)
Mind, excitement, epilepsy, before (p. 40)
Mind, fright, complaints from (p. 49)
Mind, imbecility (p. 53)
Mind, irritability (See Anger) (p. 57)
Mind, irritability, convulsion, before (p. 59)
Mind, kleptomania (p. 61)
Mind, morose (p. 68)
Mind, restlessness, nervousness (p. 72)
Mind, shrieking, convulsions, before (p. 80)
Mind, somnambulism (p. 81)
VERTIGO
Vertigo, colored glass, light shining thro, from (p. 98)
Vertigo, epileptic (p. 98)
EYE
Eye, lachrymation (See Tears) (p. 245)
Eye, open, half open (p. 247)
Eye, staring (p. 265)
Eye, turned, upward (p. 268)
VISION
Vision, diplopia (p. 277)
Vision, run together, letters (p. 283)
FACE
Face, lockjaw (p. 379)
MOUTH
Mouth, biting, tongue, morning (p. 397)
Mouth, biting, tongue, spasms in (p. 397)
Mouth, dryness, tongue (p. 404)
Mouth, froth, foam, from (p. 405)
Mouth, froth, convulsions, during (p. 405)
Mouth, lacerated tongue (p. 407)
Mouth, speech, difficult, chorea, from (p. 419)
Mouth, speech, difficult, words, can utter single, with great exertion (p. 419)
Mouth, speech, unintelligible (p. 420)
TEETH
Teeth, grinding (p. 432)
STOMACH
Stomach, epileptic aura (p. 489)
BLADDER
Bladder, retention, children, in (p. 650)
Bladder, urination, involuntary, convulsions, during (p. 659)
GENITALIA MALE
Genitalia male, seminal emissions, spasms, with (p. 710)
GENITALIA FEMALE
Genitalia female, menses, irregular (p. 726)
Genitalia female, menses, scanty (p. 728)
Genitalia female, placenta retained (p. 743)
RESPIRATION
Respiration, rattling (p. 774)
CHEST
Chest, palpitation heart (p. 873)
EXTREMITIES
Extremities, clenching, thumbs (p. 956)
Extremities, convulsion (p. 968)
Extremities, convulsion, right, left side, paralyzed (p. 968)
Extremities, convulsion, one side other side paralyzed (p. 968)
Extremities, drawn, inwards, thumbs (p. 984)
Extremities, jerking, left side paralyzed, right side convulsed (p. 1029)
Extremities, jerking, one side, other side paralyzed (p. 1029)
Extremities, paralysis (p. 1176)
Extremities, paralysis, hemiplegia, twitching of one side, the other is paralyzed (p. 1176)
Extremities, twitching, one side, paralysis of the other (p. 1215)
SLEEP
Sleep, dreams, snow (p. 1243)
PERSPIRATION
Perspiration, odor, cadaverous (p. 1298)
Perspiration, odor, offensive (p. 1298)
Perspiration, odor, rank (p. 1298)
GENERALITIES
Generalities, catalepsy (p. 1347)
Generalities, chorea (p. 1347)
Generalities, chorea, daytime (p. 1347)
Generalities, convulsions (p. 1351)
Generalities, convulsions, right, left paralyzed (p. 1351)
Generalities, convulsions, morning (p. 1351)
Generalities, convulsions, night (p. 1351)
Generalities, convulsions, children (p. 1352)
Generalities, convulsions, clonic (p. 1352)
Generalities, convulsions, dentition, during (p. 1352)
Generalities, convulsions, emission of semen during (p. 1353)
Generalities, convulsions, epileptic (p. 1353)
Generalities, convulsions, epileptic, aura, solar plexus, from (p. 1353)
Generalities, convulsions, fright, from (p. 1354)
Generalities, convulsions, grief, after (p. 1354)
Generalities, convulsions, injuries, from (p. 1354)
Generalities, convulsions, one-sided (p. 1354)
Generalities, convulsions, one-sided, paralysis of the other (p. 1354)
Generalities, convulsions, puerperal (p. 1355)
Generalities, shocks, electric-like (p. 1399)
Copyright Sylvain Cazalet 2004
Main
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Welcome to Wave Dental
Contact : (281) 888-1150
Periodontics
A healthy smile starts with proper hygiene, which begins below the surface to include the gums and bone that hold the teeth in place. Many adults do not realize that periodontal, or gum disease can progress beneath the teeth, weakening the roots and ultimately causing infections and tooth loss.
Brushing and flossing daily will keep bacterial plaque from forming a sticky film on your teeth. But over time, plaque can become calcified and harden, adhering to your tooth tenaciously and providing a scaffolding for more bacteria to disrupt the connection between your teeth and your gums. This is called periodontal disease and leads to bone loss, tooth mobility, infections, and tooth loss, not to mention foul breath. For patients with periodontal disease, a deep cleaning, otherwise called a scaling and root planing, is required to remove the calculus and restore your gums to proper health.
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Bedside clues to the diagnosis of heart disease
Embed Size (px)
Text of Bedside clues to the diagnosis of heart disease
• Bedside Clues to the Diagnosis of
Heart Disease*
JOHN F. GOODWIN, M.D .
London, England
A
PARTof bedside diagnosis, the modern
cardiologist is entitled to an electrocardio-
gram and good chest x-ray film in order to make
a clinical assessment of cardiovascular disease .
In this lecture I shall hope to show how, on
the basis of the personal experience of myself and
of my colleagues at the Postgraduate Medical
School of London, bedside clues have helped to
arrive at a final diagnosis in certain forms of
congenital and acquired disease . Naturally,
such a lecture can touch only superficially on a
few disorders, but it is hoped that what I have to
say will be of some value in indicating the impor-
tant principles of diagnosis at the bedside . In
particular, I should like to stress that clinical
bedside diagnosis is essential in planning the
type of investigation needed to arrive at a final
and comprehensive picture of the patient's illness .
JUGULAR VENOUS PULSE
I shall begin by considering the jugular venous
pressure, to the study of which the late Paul
Wood brought so much fruitful endeavor .' It
should be realized that this pulse has much to
tell the physician before the external jugular
veins become distended . Jugular venous dis-
tension is often merely a sign of mediastinal
obstruction or gross elevation of jugular venous
pressure . The aim should be to recognize the
normal jugular venous pulse, and its abnormal
characteristics in various forms of disease at a
stage when pulsation of the deep veins only can
he seen and there may be no filling of the ex-
ternal jugular veins .
The normal venous pressure should just he visible
to a height of I to 3 cm. above the sternal angle
with the patient lying at 45 .
A normal venous pulse consists of three main
waves, the a wave due to atrial contraction,
which is followed by a negative or x wave due to
atrial relaxation .' This is followed by a second
positive deflection, the v wave due to atrial filling
and obstruction to blood flow during ventricular
systole, which in turn is succeeded by a negative
deflection, the y wave, which is due to emptying
of the atrium as the tricuspid valve opens and
the blood enters the ventricle . There is some-
times a small positive deflection on the down-
stroke of the x wave, the c wave, which may be
due to ventricular contraction and tricuspid
valve closure, but often, at least on external
jugular phlebographic records, is due to carotid
artefact .
Figure 1 shows a very crude and purely
diagrammatic representation of the jugular
venous pulses and the auscultatory phenomena
in four heart diseases which affect the jugular
venous pulse in a distinctive way . This diagram
is not to scale.2
Pulmonary Hypertension : The upper of the
four diagrams represents the jugular venous
pulse in pulmonary hypertension . As a result
of the right ventricular hypertension, right atrial
hypertrophy occurs, and this produces an aug-
mented a wave in the jugular venous pulse,
which can be seen as a flicking pulsation above
the sternal angle lateral to the carotid pulse and
preceeding it . In cases of extreme right atrial
hypertrophy, the a wave may be palpable .
The auscultatory phenomena in severe pul-
monary hypertension consist of a short ejection
systolic murmur, which is often soft, preceded
by a pulmonary ejection click . The pulmonary
component of the second heart sound is always
accentuated and narrowly separated from aortic
closure . There may be a fourth heart sound
due to atrial hypertrophy and corresponding to
the a wave, and occasionally a soft high pitched
* From the Postgraduate Medical School and Hammersmith Hospital, London, England .
Guest Lecture read at the 13th Annual Meeting of the American College of Cardiology, New Orleans, February 16,
1964.
VOLUME 15, JANUARY 1965 81
• 82
FVLMOEMRY
MYDERTENION
(SEVERE
LONE
MILMONAtY
~TENOOP
sEVERE
TRICVSEID
STENOS/5
CARDIAC
CONSTRICTION
JVOVLAR
VENCELt NLSE
cAfMAC SOVNSS
AND MMRMDRS
(LEFTSYERNALEoRSit
FIG . 1 . Schematic representation of the jugular uenour pulse and
auscultatory signs in pulmonary hypertension, lone pulmo-
nary stenosis, tricuspid stenosis and cardiac constric-
tion . (The drawings are not to scale .) (A = atrial
sound . I = first heart sound . C = systolic c lick . SM =
systolic murmur. A, = aortic valve closure . P, =
pulmonary valve closure . PDM = pulmonary dia-
stolic murmur . TSM = tricuspid systolic murmur .
TMDM = tricuspid mid-diastolic murmur) . See text
for description of jugular venous pulse waves . (Repro-
duced from Clinical Disorders ofthe Pulmonary Circula-
don by permission of the publishers . J. & A . Churchill
Ltd.%).
early diastolic murmur is heard at the left sternal
edge, due to pulmonary valvar incompetence .
Pulmonary Stenosis :Although the jugular
venous pulse in pulmonary stenosis with closed
ventricular septum differs in no way from that of
pulmonary hypertension, because the cause is
the same, the auscultatory phenomena are en-
tirely different . The systolic murmur is of a
diamond shape, maximal in mid- and late
systole, extremely loud and accompanied by a
thrill . The murmur extends over the sound
made by aortic closure up to the soft and de-
layed pulmonary closure . In both conditions
the right ventricle is large and may be felt as a
tapping substernal impulse or sometimes may
lift the sternum when dilatation is added to
hypertrophy. When tricuspid incompetence
occurs as a complication, the x descent of the
Goodwin
jugular venous pulse is obliterated and replaced
by a large systolic wave due to regurgitation of
blood from the ventricle into the atrium during
ventricular systole .
Tricuspid Stenosis : In this condition, de-
picted in the third diagram, the a wave is also
augmented, but the y descent due to atrial
emptying, instead of being sharp, is slow and
leisurely, reflecting the obstruction to inflow to
the ventricle . There is commonly an atrial
sound, and since tricuspid incompetence may
accompany tricuspid stenosis, there may be a
systolic murmur in the tricuspid area . Usually,
there is a low-pitched rumbling diastolic mur-
mur heard in the same area, increasing on in-
spiration .
Cardiac Constriction : Finally, when the heart
is constricted by constrictive pericarditis, peri-
cardial effusion or by endomyocardial disease,
the a and v waves are augmented, and x and y
descents sharp, the y descent being particularly
obvious . The a and v waves reflect the high
ventricular end-diastolic pressure which causes
an increased right atrial pressure ; the sharp x
descent indicates the absence of tricuspid in-
competence while the y descent reflects rapid
filling of the ventricle due to absence of tricuspid
valve obstruction . The murmurs in cardiac
constriction are often trivial, as shown in the
diagram, the second sound being commonly
widely split, and there is nearly always a third
sound which coincides in time with the end-
diastolic pressure in the right ventricle and with
the y descent . The third sound is due to the
sudden arrest of ventricular filling by the thick
pericardium . The cardiac impulse reveals a
diastolic thrust coinciding with the early dia-
stolic sound . 8
Thus, by attention to the jugular venous pulse
and auscultation, considerable information of
great value may be obtained at the bedside in
elucidating these four groups of disorder .
There are, of course, many other abnormalities
of thejugular venous pulse . These have merely
been selected to illustrate the value of appreciat-
ing the form of the venous pulse .
PULMONARY HYPERTENSION
Returning to pulmonary hypertension, it must
be noted that there are many causes and degrees
of severity. The physical signs which have
been mentioned represent extreme pulmonary
hypertension such as is met with in conditions in
which the pulmonary vascular bed at arteriolar
level is obliterated by extreme vasoconstriction
THE AMERICAN JOURNAL OF CARDIOLOGY
• or obliterative disease such as thromboembolism .
The facies in such pulmonary hypertension may
be characteristic, consisting of bright red cheeks,
with marked circumoral pallor . The color of
the cheeks differs slightly from the characteristic
mitral facies in that the color tends to be red or
scarlet rather than purple, but the difference on
occasions may only be slight . These facies are
not usually seen in patients with milder forms of
pulmonary hypertension such as that due to
excessive pulmonary blood flow or moderate
vasoconstriction .
The cause of pulmonary hypertension may often be
substantially elucidated at the bedside . One of
the commonest causes is a left-sided cardiac
lesion which produces pulmonary venous hyper-
tension, which in turn excites pulmonary ar-
teriolar vasoconstricti
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Journal Logo
InFocus
The Medical Effects of TASERs
Roberts, James R. MD
Author Information
doi: 10.1097/01.EEM.0000312007.12938.04
Figure
Figure
Learning Objectives: After reading this article, the physician should be able to:
1. Discuss the function of the TASER.
2. Describe the known cardiac effects from use of this device.
3. Summarize the pros and cons of the use of a TASER.
Release Date: February 2008
Emergency physicians understand the need for rapid control of acutely delirious and agitated patients in the ED, and in past columns I have suggested various rationales and proposed interventions. It is intuitively obvious that patients must be able to cooperate, or at minimum, no longer flail around like a hooked barracuda in the bottom of a Florida flats boat for even a modicum of medical evaluation and treatment to begin. Prolonged agitation and struggling, especially against restraints, leads to a pathologic downward spiral, replete with metabolic acidosis, hyperthermia, rhabdomyolysis, coagulopathy, ARDS, and multisystem failure. Fatalities from uncontrolled or prolonged agitation are rare but well documented, often occurring precipitously, unexpectedly, and without warning. The physiology is usually one of PEA/bradycardia/asystole rather than ventricular fibrillation; however, once cardiac arrest occurs, it may be very difficult for resuscitation to be successful, even if medical personnel are on the scene.
Physical restraints and/or a bevy of burly security guards are often necessary to initially incapacitate a raving lunatic bent on hurting himself and everyone around him. Nonetheless, it appears prudent to expeditiously institute pharmacological restraint with doses potent enough to get the job done. I had suggested that a combination of benzodiazepines and haloperidol is the time-honored first approach to the medically undifferentiated individual, and generally this combination is the safest and most effective regimen for agitated delirium. If there is predominantly underlying psychiatric disease, there is increasing support for using rapidly acting atypical parenteral antipsychotics, such as IM olanzapine (Zyprexa) or ziprasidone (Geodon). The exact pharmacologic cocktail that is prospectively best suited for each individual circumstance has not been identified, and there is likely little difference between regimens. The key is to provide rapid and effective tranquilization so that an organized medical evaluation can commence.
Figure
Figure
Figure. Ba
Figure. Ba:
rbed TASER darts with wires attached often have to be removed. Local lidocaine and a small puncture at the entrance site with a #11 blade usually do the trick. Photo courtesy of Joseph D'Orazio, MD
Law enforcement authorities face similar challenges in the field. They are often first on the scene, and must make important decisions with regard to their safety and the safety of everyone involved. The etiology of the delirium, the individual's underlying medical problems or metabolic milieu, or the severe co-morbidity accompanying cocaine/amphetamines, not to mention the individual's personal arsenal of dangerous weapons, simply cannot be determined before incarceration, cooperation, or submission are mandated. Many chronic stimulant users, for example, have clandestine cardiac disease, waiting to emerge as a lethal dysrhythmia when the milieu is right.
Chokeholds, hastily delivered gunshots, hogtying, and clubbing have been largely abandoned, and generally are believed to constitute unnecessary and unusual force. First responders who must quickly incapacitate a dangerous criminal have turned to the conducted electrical weapon, often called a stun gun but most commonly called a TASER, which, besides being its brand name, is the device studied in virtually all medical research because of its widespread use by law enforcement. (The TASER was designed in 1969 by Jack Cover, and was named after a fictional teenage adventurer and inventor, Thomas Swift [Thomas A. Swift's Electric Rifle].)
Unfortunately, an altercation with police can occasionally lead to the death of an alleged perpetrator. Now a police action becomes a highly charged social, racial, and emotional conundrum, an event that can draft all involved, even the EP, onto the 6 o'clock news or precipitate a neighborhood riot. The particularly unlucky ones garner instant, albeit unwanted and usually unwarranted, worldwide stardom on YouTube.com.
This month's column will attempt to put the use of the TASER into medical perspective. The TASER is loved and embraced by police, hated and disdained by human rights groups and those who have been on the receiving end of its voltage, and likely misunderstood by most. I will attempt to cull out important medical issues, and eschew the omnipresent social and legal been implicated as a direct cause of death by some, this bad rap has not been medically proven to my analysis. Medical complications can occur, but well documented serious sequelae are actually few and far between. It is certainly difficult to differentiate direct TASER complications from many other complex confounding issues. In reality, there is surprisingly little medical information identifying exactly what true medical havoc a TASER discharge actually inflicts on a human recipient of the shock.
Cardiac Electrophysiological Consequences of Neuromuscular Incapacitating Device Discharges: Cardiovascular Consequences of Stun Gun, Manthakumar K, et al J Am College Cardiol 2006;48:798
This article from the Canadian Institute of Health Research and the University of Toronto evaluated the cardiac consequences of neuromuscular incapacitation with a TASER discharge in an experimental animal model. The aim was to determine if large voltage electrical discharges dispensed from a TASER pose risks for triggering lethal cardiac arrhythmias. Given the impossibility of performing this in humans, a pig model was used.
Anesthetized pigs were monitored with intracardiac catheters and blood pressure transducers prior to the application of TASER discharges. Two commercially available models were used, and discharges were of 5 and 15 seconds duration. The devices delivered pulses of 50,000 V, 11 us to 50 us in duration, at a rate of 16 to 20 pulses per second. Per the author's introduction, this short duration of stimulation has been expected to have only a small chance of stimulating the myocardium, but will capture and stimulate nerves and skeletal muscle. The discharging wires were placed to provide two different vectors of electrical discharge, one being thoracic and parallel to the long access of the heart, and the other non-thoracic, being away from the heart (over the abdomen). In addition, an intravenous infusion of epinephrine was instituted to simulate the adrenergic storm produced by a struggling, delirious, or uncontrolled individual.
A total of 150 discharges were delivered. None of the nonthoracic discharges stimulated the heart, but about 80 percent of the over-the-heart discharges did produce electrical capture of the myocardium. When the electrical device was discharging, mechanical capture produced heart rates in the 300 beats per minute range. Only one of the discharges produced VT and one produced VF, both occurring during the epinephrine infusions. The VT spontaneously converted. It is unclear whether the epinephrine infusion or the electricity produced the ventricular arrhythmias. The authors theorized that structural heart disease could predispose to catastrophic ventricular arrhythmias when a rapid ventricular stimulation is produced by the device. They concluded that electrical TASER discharge across the chest of their experimental animal can capture the myocardium and could produce ventricular fibrillation. The intracardiac catheters may have found abnormalities not reported in other studies where surface EKGs were disrupted by the electrical discharges.
The authors were careful to avoid postulating that VF could be precipitated in humans. They caution that their model only describes the worst-case scenario in which the discharge is vectored across the heart, and they believe that their model rules out arrhythmias as a cause of death when the vectors are not across the heart or when death occurs after the discharges. Importantly, this study demonstrated that the discharges across the chest caused electrical and mechanical capture of the myocardium in this model.
In their conclusion, the authors state that their experimental model suggests that electrical discharges across the chest can produce cardiac stimulation at high rates, possibly suggesting cardiac risk in humans. Importantly, they do not conclude that the device can cause ventricular fibrillation in humans.
Comment: TASERs are being increasingly used by law enforcement officers worldwide. They have often replaced the 9 mm police handgun as the intervention of choice when other measures have failed. The device is said to deliver 50,000 volts of electricity, arching between two propelled metal barbed darts that are imbedded in the skin when the device is discharged. In reality, significantly less voltage is actually delivered to the recipient, but the myth is perpetuated by many.
The electricity is delivered through the attached wires, and is intended to produce incapacitation by severe stimulation/contraction of skeletal muscle. There has never been definitive proof that the TASER can precipitate sudden death in humans, although sudden death temporally associated with these devices has been reported. Of course, sudden death after a police struggle was around long before the TASER was invented.
When EKG monitoring has been performed in human volunteers who have received a TASER application, significant adverse cardiac electrical physiological consequences have not been found. These authors believe that their intracardiac catheters were a unique addition to the study of this device. This model actually proves that the myocardium is directly stimulated and captured.
This study has been criticized as being an artificial circumstance, and creating an electrical event not possible in humans. (J Am Coll Cardiol 2007;49[6]:732.) It has been noted that swine may be more sensitive to electrical induction of arrhythmias. Although this article may show that there is myocardial capture, there was no conclusion, even from the authors, that these data can be extrapolated to humans.
Importantly, deaths related to TASER use often occur after the discharge has finished, rendering VF an unlikely culprit. Finally, those few deaths following acute delirium that have been electrically studied demonstrate bradyarrhythmias and asystole, rather than ventricular fibrillation. Although it seems evident that the TASER can stimulate the myocardium of the pig when the electrodes are directly over the heart (but not elsewhere), it's a far stretch to state that this device can cause VF in a human when used in the manner prescribed by the manufacturer.
Effective Cocaine Intoxication on Threshold for Stun Gun Induction of Ventricular Fibrillation, Lakkireddy D, et al J Am Coll Cardiol 2006;48(4):805
This manufacturer-sponsored study sought to evaluate the effect of cocaine on TASER-induced VF threshold in a pig model. Because violent subjects who are restrained or controlled by police are often intoxicated with cocaine or other drugs, the interaction of cocaine with a TASER, particularly with the production of VF, would be an important parameter to study. Again, the adult pig model was used.
A custom device (not an actual TASER) was attached to five locations on the animal's body, and standard discharges associated with the commercially available TASER were applied. No ventricular fibrillation was seen in any of the locations before or after cocaine infusion. The electrical discharges were then escalated above the level possible with the TASER until VF was induced. The VF threshold increased as the distance of the electrodes from the heart increased.
Interestingly, cocaine increased the required strength of the electrical discharge that was required to produce ventricular capture. The study demonstrated that cocaine actually increased the safety margin by one-and-a-half to two times from baseline. The authors conclude that the use of cocaine increases the safety margin (raises the VF threshold) by 50 percent to 100 percent above baseline with regard to potential vulnerability of the pig heart to VF from the TASER discharges.
Comment: Like the previous study, the TASER was demonstrated to produce ventricular capture as the device is discharging. The studies also found that once the shock stopped, myocardial capture was lost. Therefore, if an individual maintains vital signs but collapses minutes after the event, it seems intuitively reasonable to acquit the TASER as the prime suspect. This study showed, however, that VF cannot be induced using a standard TASER discharge when it was applied to the authors' definition of the most sensitive area of the body.
The conclusion that cocaine decreases the potential for TASER-induced VF in cocaine use is an interesting one. In this study, cocaine increased the safety margin of arrythmia up to two times baseline. There was less myocardial capture after cocaine infusion. As with other studies, these authors were unable to demonstrate any cardiac enzyme leak or injury to the heart by histopathological analysis.
The Safety of the TASER
It is difficult to separate unsubstantiated newspaper articles, emotionally charged TV reports, or current YouTube videos from scientific data with regard to the safety of the TASER. Likewise, so-called scientific studies, either on volunteers or animals, are not the same as the real issue at hand. Autopsy reports often assume that the TASER is “related” to the death just because it was used premortem and because no specific cause of death can be found (not uncommon in many deaths). In the past, medical examiners have related deaths to the TASER. Most quote reports from the 1990s before any true electrical data were available. (J Forensic Sci 1991;36:434; J Forensic Sci 1992;37:956.)
It should be noted that although studies on this device are very incomplete, there is no credible proof that the TASER induces cardiac arrest when used by law enforcement officials in a prescribed manner. In fact, the voltage required to induce VF has been calculated to be 15 to 42 times the charge possible to be delivered from the TASER. (Pacing Clin Electrophys 2005;28(Suppl 1):S284.) It has been stated that there have been no documented cases of VF directly caused by the device in more than 600,000 police uses. (J Am Coll Cardiol 2007;49[6]:732.)
Contrast this with lay press headlines that the TASER kills many people. (“167 Cases of Death Following Stun-Gun Use,” Arizona Republic, February 5, 2006.) If one reads the UpToDate database, the 2007 version states that the TASER is “capable of inducing fatal arrhythmias and other injuries.” My analysis: We simply don't know for sure, but many self-proclaimed authorities come down on both sides of the debate, many have a personal, financial, or social bias, and many simply don't read the literature.
Other injuries claimed to be associated with the TASER include burns, lacerations, testicular torsion, and miscarriage. Although the concepts may be believable, these are often anecdotal and poorly characterized reports. A miscarriage two weeks after a TASER application is hardly a scientific cause-effect. Thoracic spine compression fractures from the TASER in a volunteer who did not fall but experienced severe muscle contraction has recently been reported. (Ann Emerg Med 2007;50[5]:584.) Fracture and dislocation from electrical shock are well documented.
All articles that claim the TASER can cause VF reference a short letter to the editor by Kim and Franklin (New Engl J Med 2005;353:958) titled “Ventricular Fibrillation after Stun Gun Discharge.” If one actually reads this sketchy report, it is hardly proof of the article's title. This is clearly only a worrisome observation and certainly not quotable science based on my read. Specifically, a violently agitated subject was subdued with a TASER. Later he had VF but was resuscitated to normal with ACLS interventions. No drug screen or medical history was reported.
Kroll claims that this particular case was “misreported with serious omissions.” His version (personal communication: “Obtained from police records”) was that following submission of a violently agitated man with a TASER, paramedics found a normal pulse and respirations. Twenty some minutes after this episode, the subject experienced a cardiorespiratory collapse. It is my understanding that no ventricular fibrillation was documented until many minutes after TASER use, and after interventions including multiple medic-delivered cardiac shocks, atropine and epinephrine were administered. As stated, most agitated patients die via bradycardia. I am leery of this supposed documentation of VF after TASER discharge, yet it is universally quoted. So far, I have received no response from the author to my email query.
A theoretical discussion by Ideker (Am J Forensic Med Patho 2007;28[3]:195) states that fundamental laws of electrical stimulation predicted the TASER pulse will not stimulate an ectopic beat in a large majority of normal adults. It is unlikely, at least from a theoretical stance, that a TASER can initiate ventricular fibrillation. It's a nice theoretical discussion but hardly firm clinical evidence.
Ho et al recently reported on respiratory effects of prolonged electrical weapon application to human volunteers. (Acad Emerg Med 2007;14:197.) Human volunteers received a 15-second application of electrical current while wearing respiratory measurement devices. These were certainly brave volunteers. Respiratory parameters were collected during and after exposure. The aim of the article was to see if the TASER contributed to death by impairing respirations. In this study, respiratory measurements were taken pre-exposure, during electrical weapon exposure, and during the first and second minute after exposure. No respiratory impairment was demonstrated either during prolonged continuous or prolonged intermittent TASER discharge. There was no decrease in tidal volume nor was there hypercapnia, hypoxia, or apnea associated in this volunteer model.
Other work has failed to demonstrate any significant changes in cardiac serum markers, hyperkalemia, or acidosis following TASER application. Transient mild increases in CPK and lactate were observed, likely due to muscle contraction. (Acad Emerg Med 2006;13:589.) Shocking does not cause hyperthermia (Forensic Sci Int November 2007, abstract only), and minimal testing has shown no disruption of pacemakers, ICDs, or their leads when exposed to TASERs. (Europace 2007;9[7]:551.)
Conclusions
It may be difficult to convince family members that the death of their loved one following a TASER episode by police was not related to the use of this device. After all, lightning and the electric chair kill, and he was shocked and then died, and so likely was “electrocuted.” However, it is difficult to find any credible medical evidence that such is the case or even possible. These scenarios are always multifactorial, and frequently clouded by underlying unknown heart disease, drug overdose, massive stimulant use, alcohol withdrawal, or other unknown variables. Specifically, to my analysis, ventricular fibrillation has not been demonstrated as a direct result of TASER use in humans.
Certainly the TASER dart can cause physical damage, and I have had to dig out a few during my ED shifts; a dart in the eye would be potentially blinding. (Am J Ophthalmol 2005;139:713.) Injuries from falls during muscle incapacitation can be expected, so the emergency physician needs to be aware of occult injuries, particularly cervical spine injuries. Fractures and dislocations may occur secondary to intense muscular contractions.
Many police departments have protocols mandating that all subjects who have had TASER applied be brought to the ED for medical clearance. It has not been my experience that the police politely escort the suspect into the ED wearing a cervical collar, so C-spine precautions should be high on the list of priorities for the clinician.
When I took an informal poll of my colleagues and our residents, it was the common belief, almost unanimous, that the TASER can cause death and rather frequently. Referenced sources: YouTube, newspapers, and the 6 o'clock news. The American Civil Liberties Union and Amnesty International are passionate opponents of the TASER, viewing it as an anathema at its zenith. The National Institute of Justice is a firm supporter, citing the device's safety profile.
For those interested in the social debate, I suggest you Google the web sites of these organizations and surf YouTube. Some believe that the TASER violates civil rights, and is a prime example of unnecessary force and police brutality. Any police officer will tell you that the TASER is a rather remarkable device, and many of them have to experience the TASER firsthand prior to being issued the device. Newspapers report that police injuries and the number of shot suspects have plummeted following TASER introduction.
In my experience, these devices can certainly be overused by zealous police officers, but the general consensus by the law enforcement community is that fewer policemen are injured and fewer perpetrators are shot with conventional weapons. I certainly would not like to be the recipient of a TASER application, nor would I ever like to be a police officer called to the scene of a raving lunatic with lethal weapons who is capable of gargantuan physical acts.
A civilian TASER is now available (about $400 and requiring a background check performed by the company). These devices are illegal in Philadelphia, but my wife wants one.
Finally, Boseman (Ann Emerg Med 2005;46[3]:300) has likened the TASER to the now federally mandated automobile airbags: They may harm a small subset of individuals but save the lives of countless others. Is this a reasonable tradeoff? Importantly, research into the full adverse effects of the TASER is nascent, to say the least, so the bottom line is never say never until more data are available.
Bad Press for TASERs?
Jeffrey Ho, MD, Christian Sloane, MD, and Gary Vilke, MD, all of whom have extensively researched the medical effects of TASERs, wade through the hype looking for the truth, and distill the evidence into opinions you can count on. See p. 4.
Reader Feedback: Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to [email protected]. Dr. Roberts requests feedback on this month's column, especially personal experiences with successes, failures, and technique.
TASER Trivia
• ▪ The TASER was designed in 1969 by Jack Cover, and the TASER was named after a fictional teenage adventurer and inventor, Thomas Swift (Thomas A. Swift's Electric Rifle).
• ▪ The devices are used worldwide by about 12,000 law enforcement agencies, and an estimated 600,000 people have been shocked.
• ▪ The only readily available TASER is produced by TASER International, Inc., in Scottsdale, AZ.
• ▪ Models are M26 (military) and X26 (police). A civilian model is now available (C2).
• ▪ Barbed dart-like electrodes are propelled by nitrogen, and wires attached to the darts deliver electricity to the subject. Although 50,000 V is often quoted, significantly less is actually delivered to the subject.
• ▪ Some models have cameras to record events, and some have laser sights.
• ▪ Electric source is 8 AA batteries in the device, which deliver a pulse of electricity for five seconds, but the duration of discharge can be prolonged by the operator to 15 seconds.
• ▪ Electricity arcs between electrodes, so direct skin penetration is not always needed to incapacitate subject. Older models required darts to penetrate skin to be effective, and clothing could interfere with effect.
• ▪ Systemic effects of shock usually last a few minutes after discharge has ended.
• ▪ Maximum range is about 20 to 30 feet.
• ▪ Some models have electrodes in the tip of the device so it can be held directly against the skin and discharged without need to fire darts, hence the name “stun gun.”
• ▪ Unwanted effects include eye injury and skeletal trauma from muscle contraction and falling.
TASER Clarifies Voltage in Weapon
Dr. Roberts: The peak open circuit voltage of the TASER X26 Electronic Control Device (ECD) is approximately 50,000 volts. This voltage represents the peak voltage potential across the probes when the circuit is in the open state, that is, when no current is flowing. The 50 KV is an important factor for calculating how much clothing and air gap the arc can penetrate (the higher the peak open circuit voltage, the greater the gap that the current can arc across).
While the 50 KV potential is important for calculating how far the arc can bridge across an air gap, however, it is not relevant to the bio-effect of the current on the target person. The human subject never experiences the 50 KV because the voltage drops as soon as the arc forms and current starts to flow. It's like a blocked water hose: While the hose is blocked, the pressure builds up inside. When the blockage breaks loose and the water begins to flow, the pressure drops immediately, and the pressure measured at the output of the hose never hits the peak pressures experienced within the hose prior to the blockage breaking free. The peak voltage during current flow through the body is about 1,200 volts, and the average voltage during the 100-microsecond duration of the pulse is about 400 volts. I hope this clarifies the operation of our technology. — Rick Smith, Chief Executive Officer, TASER International, Inc., Scottsdale, AZ
CME Participation Instructions
To earn CME credit, you must read the article in Emergency Medicine News, and complete the quiz, answering at least 80 percent of the questions correctly. Mail the completed quiz with your check for $10 payable to Lippincott Continuing Medical Education Institute, Inc., 770 Township Line Road, Suite 300, Yardley, PA 19067. Only the first entry will be considered for credit and must be received by Lippincott Continuing Medical Education Institute, Inc. February 28, 2009. Acknowledgment will be sent to you within six to eight weeks of participation.
Lippincott Continuing Medical Education Institute, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc. designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Figure
Figure
© 2008 Lippincott Williams & Wilkins, Inc.
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Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease
A1 Journal article (refereed)
Internal Authors/Editors
Publication Details
List of Authors: Graham F. Brady, Raymond Kwan, Peter J. Ulintz, Phirum Nguyen, Shirin Bassirian, Venkatesha Basrur, Alexey I. Nesvizhskii, Rohit Loomba, M. Bishr Omary
Publisher: WILEY
Publication year: 2018
Journal: Hepatology
Journal acronym: HEPATOLOGY
Volume number: 67
Issue number: 5
Start page: 1710
End page: 1725
Number of pages: 16
ISSN: 0270-9139
eISSN: 1527-3350
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina-associated proteins predispose to NAFLD and used a candidate gene-sequencing approach to test for variants in 10 nuclear lamina-related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina-related genes (ZMPSTE24, TMPO, SREBF1, SREBF2). The majority of NAFLD patients (>90%) had at least one variant compared to <40% of controls (P < 0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P < 0.0001). Presence of a lamina variant segregated with NAFLD independently of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina-associated polypeptide-2 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin-LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin-binding protein p62/SQSTM1. Conclusion: Several variants in nuclear lamina-related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (Hepatology 2018;67:1710-1725).
Last updated on 2020-26-01 at 04:50
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A brief review of relationship between occupational benzene exposure and hematopoietic cancer
Abstract
We reviewed articles to clarify the current evidence status for 1) types of cancer which related to benzene exposure, and 2) certain benzene exposure level which might cause the hematopoietic cancers. Hematopoietic function of the bone marrow is involved in the production of all blood cells types. The benzene metabolites including benzoquinone and mucoaldehyde affect hematopoietic stem cells as well as differentiation steps of progenitor cells for each blood cell. Hence, we concluded that benzene was associated with all lymphohematic carcinogenesis. First, it is supported by biological plausibility. Second, it is supported by meta-analysis although sing study did not show relationship due to lack of sample size or statistical power. More recent studies show lesser exposed level related to risk of cancer, compare to past studies did. Actually, early studies show the risk of malignancies in workers who exposed more than 200 ppm-years. However, only 0.5 to 1 ppm-year benzene exposed show significant linking to risk of malignancies in recent study. As reviewed research articles, we concluded that the relatively lower exposure level, such as 0.5–1 ppm-year, will be considering at risk of hematopoietic cancer. However, more research needs to be done on dose-response analysis.
Background
The International Agency for Research on Cancer (IARC) concluded that benzene exposure has sufficient carcinogenic evidence in both humans and animals study in 1987 [1]. That report shows strong evidences that benzene exposure causes acute myeloid leukemia (AML) and acute non-lymphocytic leukemia (ANLL). There are also positive association between benzene exposure and acute/chronic lymphocytic leukemia, non-Hodgkin lymphoma, and myeloma [2].
National Institute for Occupational Safety and Health (NIOSH) in USA conducted cohort study of 459 benzene exposure workers from 1940 through 1975 [3]. That study was undertaken using workers in Pliofilm manufacture, and that results supported Occupational Safety and Health Administration (OSHA) to reduce permissible exposure limit from 10 ppm to 1 ppm [4]. Exposure standard in Korea was also established at level of 10 ppm in 1986, but it was change to 1 ppm in 2003 to prevent leukemia patients from benzene exposure.
According to the Enforcement Decree of Industrial Accident Compensation Insurance Acts of specific criteria in 2003, “1 ppm or more benzene exposure during 10 years or more” are regarded as sufficient exposure level to cause occupational diseases of leukemia and multiple myeloma. Cumulative exposure exceeds 10 ppm-year is also regarded as sufficient exposure level even though the total exposure duration is below 10 years. Furthermore, if there were no record for benzene exposure in past job exposure history, the 10 years’ cumulative exposure amount is more than 1 ppm based on current job exposure concentrations is also regarded as a sufficient exposure level for occupational disease.
Recently, a Cohort study reported that even 1 ppm-year or below benzene exposed workers also suffered from leukemia [5, 6]. One ppm-year exposures are ten times lower levels of Korea stand exposure level for occupational relatedness. Hence, current Korea Act of standards for occupational diseases relatedness should be reviewed using recent studies. We reviewed articles to clarify the current evidence status for 1) types of cancer which related to benzene exposure, and 2) certain benzene exposure level which might cause the hematopoietic cancers.
Main text
General characteristic of benzene
Benzene is a pale yellowish liquid with molecular formula C6H6, molecular weight of 78.11 and a flammable substance with aromatic odor. It is almost insoluble in water and soluble in organic solvents and oils. Benzene reacts violently with oxidizing agent, easy to vaporize. Benzene is absorbed into the body through inhalation, skin exposure, and ingestion. In animal experiments, about 50% of aspirated benzene is absorbed into the body [7]. In the case of skin exposure, the absorption rate is low because a significant amount is vaporized before absorption, and a high uptake rate when ingested orally. Benzene is rapidly metabolized mainly in the liver and becomes water-soluble and is released into the urine within 48 h. Some of the metabolites of benzene migrate to the bone marrow. Benzene itself appears to be non-toxic, and the metabolites from the liver, especially benzoquinone and mucoaldehyde, have bone marrow toxicity [8]. These metabolites can damage DNA and produce DNA adducts. Benzene is metabolized in different concentrations. At low concentrations, much of benzene is metabolized to hydroquinone and other toxic substances than to high concentrations.
Benzene has been used as an ingredient in inks in the printing industry, in organic solvent solvents, as a starting material and intermediate for the production of rubber, lubricants, dyes, cleaners and pesticides in the chemical and pharmaceutical industries, as an additive to unleaded gasoline. A recent major use is the manufacture of organic chemicals [2]. It is mainly used for the production of styrene, phenol, cyclohexane, aniline, maleic anhydride, alkyl benzene and chlorobenzene in Europe and also for anthraquinone, hydroquinone, benzene hexachloride, benzenesulfonic acid and drugs, dyes, pesticides and plastics. It is also an intermediate of other products. In Korea, it is usually used for the production of styrene, phenol and cyclohexane. Benzene is naturally occurring in petroleum products (crude oil, gasoline, etc.) and is added to unleaded gasoline to increase the octane number of unleaded gasoline and to suppress engine knocking. Benzene content varies from country to country, but about 1–2%. Petroleum benzene content standard of Korea are currently less than 0.7% [9].
Biological mechanism of benzene on hematopoietic cancer
Leukemia refers to the overgrowth of abnormal immature leukocytes caused by cancer derived from blood itself or bone marrow cell. Word Health Organization classified leukemia according to precursor cells of lymphocytic and myeloid [10]. Both precursor cells of lymphocyte and myeloid cells are derived from same hematopoietic stem cells by the cell differentiation process [11]. There are also scientific reports that certain cells have both characteristics of lymphoid and myeloid cell even after differentiation process [12]. Hence, we used the word of “hematopoietic cancer” for all types of blood cell malignancies.
Hematopoietic function of the bone marrow is involved in the production of all blood cells types, and hematopoietic stem cells are differentiated into the ancestral cells of each blood cell type. Thereafter, various blood cells are produced by self-renewal and differentiation of each ancestral cells. The benzene metabolites including benzoquinone and mucoaldehyde affect hematopoietic stem cells as well as differentiation steps of progenitor cells for each blood cell. Consequently, benzene metabolites may affect all leukemic stem cells of all blood cell type in every step [13, 14]. Thus, there are biological plausibility the benzene exposure and its metabolites can cause all types of hematopoietic tumors derived from hematopoietic stem cell [15].
Despite the biological causality that benzene can cause all hematopoietic cancer, IARC has reported that other blood cancers have limited relevance to benzene, except in the case of ANLL, AML [2]. The reason for this can be explained by the low incidence of diseases except ANLL.
In adults, the incidences of other malignant hematopoietic diseases except AML are too low to elucidate association from epidemiological studies. From 2006 to 2010, the incidence of AML increased rapidly after age 40, which is much higher than that of the incidence of acute lymphoblastic leukemia (ALL) [16]. Similarly, Korean’s data show high incident rate of AML compare to that of ALL [17]. Those low incidence level of ALL may explain current status of lack of epidemiological evidence between benzene exposure and ALL incidence. If the relatively low incidence is cause of lack of evidence, the large prospective cohort study will give more realistic scientific evidence. Alternatively, meta-analysis of gathering multiple studies can solve the such low incidence related problem. Hence, we estimate Meta-Standardized mortality ratio (SMR) using by studies which published IARC reports [2].
We conducted a meta-analysis of five cohort studies in which ALL was found in more than 5 cases of exposure among 10 cohort studies in which IARC report [2]. Finally, 5 studies were selected: Yin et all 1996, Saint et all 1996, Rushton et all 1993, Divin et all 1999. Among 5 studies, only one study of Saint et all show statistical significant evidence between benzene exposure and ALL (relative risk (RR) =2.59, 95% confidence interval (CI) = 1.12 to 5.11). In contrary to Saint’s study, others did not show statistical significance. However, the pooling of those RR got statistical significance in Meta-analysis. The Meta-SMR is 1.96 and it’s 95% CI is 1.25 to 2.95 (Fig. 1). Current result of meta-analysis suggest that relatively large cohort or relatively high incidence disease can get statistical significant even those relationships did not statistical significant when using relatively small sample size or low incidence diseases.
Fig. 1
figure 1
Meta-Analysis for ALL SMR using 5 studies of IARC report (ALL: acute lymphoblastic leukemia, SMR: Standardized mortality ratio)
In the same contexts, incidence of multiple myeloma is lower than that of ALL. Infante et all undertook meta-analysis using seven studies [18]. The incidences of individual studies due to benzene exposure were very low and there was no statistically significant result except for one study. However, meta-analysis showed a statistically significant and positive correlation between benzene exposure and multiple myeloma [18]. The SMR (95% CI) of each studies are 4.35 (0.1–24.2), 4.09 (1.1–10.5), 3.57 (0.4–12.9), 2.88 (0.6–8.4), 0.40 (0.1–10.7), 1.90 (0.8–3.8), 0.72 (0.2–2.1). However, the pooled estimation show significant relationship between multiple myeloma and benzene exposure (RR = 2.13, 95% CI = 1.31–3.46) [18].
In summary, the metabolism of benzene influences the whole process of hematopoietic differentiation that starts from hematopoietic stem cells. Hence, benzene exposure can cause all type of hematopoietic malignancies. Large-scale studies are required to obtain sufficient numbers of cases for other types of hematopoietic cancer, except for AML, in which epidemiological evidence is not yet sufficient. Alternatively, the results of meta-analysis result supported that biological plausibility by epidemiological concepts.
Benzene exposure level and risk of hematopoietic malignancies
The analysis of cumulative benzene exposure and hematopoietic cancer development is as follows.
(1) Research by Wong et al. [19]
Wong et al. quantified the exposure and calculated the standardized mortality ratio (SMR) from the cohort data of workers in the factory in the US using Pliofilm (a transparent sheet made from hydrochloric rubber). Risk of AML did not be increased in 200 ppm-year exposure group, but SMRs (95% CI) for AML were sharply increased in 200 ppm-year exposure or more group. The SMRs (95% CI) for AML were 27.2 (3.3–98.0) and 98.3 (20.3–287.6) in 200–400 ppm-year and more than 400 ppm-year exposed group, respectively.
(2) Research by Hayes et al. [20]
Hayes et al. found a relative risk (RR) according to the exposure level of Acute non-lymphocytic leukemia (ANLL) in follow-up data of benzene exposed / unexposed workers at 672 plants in 12 Chinese cities. RR (95% CI) of ANLL was 1.9 (95% CI: 0.5–7.0) in less than 20 ppm-year exposed group. However, RRs (95% CI) of ANLL were 4.3 (1.1–16.0) and 3.6 (1.1–11.6) in 40–99 ppm-years and 100 ppm-year or more exposed group, respectively. The risk of ANLL was also estimated according to average level of benzene exposure. The RRs (95% CI) of ANLL were 2.0 (0.6–7.0), 5.8 (1.8–18.9) and 2.6 (0.7–9.9) in exposed group of less than 10 ppm, 10–24 ppm and more than 24 ppm, respectively. In summary, significant increment of risk for ANLL was observed in 40 ppm-year of cumulative exposure and 10 ppm of average exposure group.
(3) Study of Schnatter et al. [21]
Schnatter et al. reported a significant increase in the incidence of myelodysplastic syndrome (MDS) at low concentrations of benzene exposure after updating the cohort of Australian, Canadian, and British oil workers. The cumulative exposures of 2.93 ppm-years group show high risk of MDS compare to less than 0.35 ppm-year exposed group. The RR (95% CI) of MDS was 4.33 (1.31–14.3) in 2.93 ppm-years or more exposed group. The RR (95% CI) of MDS was 6.32 (1.32–30.2) when highest exposure level exceeded over 3 ppm.
(3) Research by Glass et al. [22, 23]
In the “Health Watch” study of Glass et al., which followed up 16,000 Australian workers from 1980 to 1998, 79 hematologic malignancies cases occurred (Glass et al., 2001). In a nested case-control study using 395 control groups, the cumulative exposure was calculated as ppm-year and divided into 5 levels to identify the risk of malignancies. The concentrations of the lowest exposed group were 0.005 ppm-year to 0.33 ppm-year, followed exposed group was 1.42 ppm-year, 3.53 ppm-year, and 7.82 ppm-year. 18 cases of malignancies were observed in the third level cumulative exposure group, and RR (95% CI) of hematologic malignancies was 2.54 (1.05–6.18). In the fourth exposed group, the RR (95% CI) did not show significant relationship, 2.20 (0.89–5.43). In contrary to that, 22 cases were observed in the fifth exposed group and RR (95% CI) was 3.32 (1.40–7.91). Glass et al. did not undertook the trend analysis. We undertook Cochran-Armitage Trend Test using reported number of cases and controls in published article of Glass et al. The p value of trend analysis was 0.011 (below 0.05). Hence, we concluded that cumulative exposure of 1.46 ppm-year or more significantly related to risk of hematopoietic malignancy.
Glass et al. (2005) reanalyzed this cohort and found that OR (95% CI) of workers with cumulative exposures in excess of 8 ppm-year benzene exposure was 7.2 (1.3–40.4) compare to worker who exposed less than 4 ppm-year [23]. For all types of leukemia, the risk was significantly increased in more than 2 ppm – years exposed group. In the group exposed to less than 10 years, benzene exposed group was divided by cut level of 0.5 ppm-year, 1 ppm-year, 2 ppm-year, 4 ppm-year and 8 ppm-year or more. The RR (95% CI) was 2.27 (1.14–4.54) in 0.5-1 ppm-year exposed group when comparing the risk in less than 0.5 ppm-year exposed group. Thus, workers who exposed benzene only 0.5 ppm-year or more during 10 years are at risk of ANLL. In other words, exposed to 0.05 ppm for 10 years or more can be considered to be associated with a higher risk of hematopoietic cancers in that study.
In summary, more recent studies show lesser exposed level related to risk of cancer, compare to past studies did. Actually, early studies show the risk of malignancies in workers who exposed more than 200 ppm-years. However, only 0.5 to 1 ppm-year benzene exposed show significant linking to risk of malignancies in recent study. This phenomenon may be observed in other occupational diseases such as heavy metal induced diseases. In the high exposure period, it is not easy to find non-exposure group. Hence, the non-healthy reference group might be control group in relatively high exposed period or society. Non-healthy reference or exposed reference group may make underestimate of risk. Hence, the cut level of statistical significant easy upward in that period. In the contrary to that, the lower exposed period can find heathy reference and non-exposed reference in same factory or same research design. It supported by research of Glass et al. Hence, the recently result that 0.5–1 ppm-year benzene exposure significantly related to hematopoietic cancer can give us important message. Hence, recent studies suggest that 0.5 to 1 ppm-year benzene exposure significantly related to risk of lymphohematic malignancies.
Conclusions
Finally, it was concluded that benzene was associated with all lymphohematic carcinogenesis. First, it is supported by biological plausibility. Second, it is supported by meta-analysis although sing study did not show relationship due to lack of sample size or power. In relation between the cumulative exposure of benzene and hematopoietic cancer, the relatively lower exposure level, such as 0.5–1 ppm-year, will be considering at risk level. However, more research needs to be done on dose-response analysis.
Abbreviations
ALL:
acute lymphoblastic leukemia
AML:
acute myeloid leukemia
ANLL:
acute non-lymphocytic leukemia
CI:
confidence interval
IARC:
International Agency for Research on Cancer
NIOSH:
National Institute for Occupational Safety and Health
OSHA:
Occupational Safety and Health Administration
RR:
Relative risk
SMR:
Standardized mortality ratio
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JH Yoon and YS Ahn reviewed articles and wrote manuscript. JH Yoon undertook statistical analysis. All authors read and approved the final manuscript.
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Yoon, JH., Kwak, W.S. & Ahn, YS. A brief review of relationship between occupational benzene exposure and hematopoietic cancer. Ann of Occup and Environ Med 30, 33 (2018). https://doi.org/10.1186/s40557-018-0245-9
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Keywords
• Benzene
• Hematopoietic cancer
• Leukemia
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Project Details
Description
Obesity is accompanied by elevated plasma free fatty acid (FFA), which, in turn, induces insulin resistance and diabetes. More than half of diabetic patients develop myocardial dysfunction, known as diabetic cardiomyopathy, characterized by left ventricular hypertrophy, fibrosis and diastolic dysfunction. Some patients develop heart failure with preserved ejection fraction (HFpEF). Thus, elucidating the underlying molecular mechanism of diabetic cardiomyopathy is critically important. The hearts of patients with obesity, insulin resistance, type II diabetes, and HFpEF often develop a low grade of inflammation. Pro-inflammatory cytokines and chemokines, including TNF-?, IL-1?, IL-6, and MCP-1, produced in adipose tissues, infiltrating inflammatory cells, and local cell types, including endothelial cells and cardiomyocytes (CMs), play an essential role in mediating fibrosis, hypertrophy, diastolic dysfunction and insulin resistance, thereby contributing to the development of diabetic cardiomyopathy. However, which cell types produce cytokines during the initial phase of diabetic cardiomyopathy and what the underlying mechanism is are poorly understood. Furthermore, the significance of the local mechanisms compared to systemic inflammation remains to be clarified. Our preliminary results suggest that FFA activates IL-6 production in CMs through a PPAR?-NF-?B-dependent mechanism, which, in turn, promotes the development of diabetic cardiomyopathy. In this study, we will clarify the role of PPAR? and IL-6 in CMs in mediating cardiac dysfunction in response to high fat diet (HFD) consumption and the molecular mechanisms through which elevated FFA stimulates IL-6 in CMs. Our overall hypotheses are: PPAR? in CMs is a sensor of increased FFA that triggers diabetic cardiomyopathy through production of IL-6. Increases in plasma FFA directly stimulates IL-6 transcription in CMs through increased binding of PPAR?-NF-?B heterodimer to the NF-?B element located in the IL-6 promoter. IL-6 produced in CMs acts as an autocrine/paracrine factor to induce diabetic cardiomyopathy. Aim 1: Elucidate the role of cardiac endogenous PPAR? and IL-6 in mediating the initial development of diabetic cardiomyopathy. Aim 2: Elucidate the molecular mechanism by which PPAR??stimulates transcription of IL-6 in CMs. Aim 3: Evaluate whether suppression of PPAR?-NF-?B heterodimer formation inhibits CM production of IL-6 and the development of diabetic cardiomyopathy in response to HFD consumption. We will address these issues using newly generated CM-specific loss-of-function mouse models. In addition, we will obtain a proof-of-concept that PPAR?-NF-?B heterodimer is a novel therapeutic target for diabetic cardiomyopathy. We expect that our study should demonstrate a novel mechanism stimulating local innate production of IL-6 in CMs and its role in mediating the initial development of diabetic cardiomyopathy which is highly relevant to many patients with obesity and borderline metabolic syndrome.
StatusFinished
Effective start/end date12/1/2011/30/21
ASJC
• Cardiology and Cardiovascular Medicine
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TEENAGERS AND SLEEP
Sleep research suggests that a teenager needs between nine and 10 hours of sleep every night. Yet most adolescents only get about seven or eight hours. Some get less.
Regularly not getting enough sleep leads to chronic sleep deprivation. This can have dramatic effects on a teenager's life, including reduced academic performance at school.
Causes of sleep deprivation
• Hormonal time shift - puberty hormones shift the teenager's body clock forward by about one or two hours, making them sleepier one to two hours later. Yet, while the teenager falls asleep later, early school starts don't allow them to sleep in. This nightly 'sleep debt' leads to chronic
• Hectic after-school schedule -homework, sport, part-time work and social commitments can cut into a teenager's sleeping time.
• Leisure activities -the lure of stimulating entertainment such as television, the internet and computer gaming can keep a teenager out of bed.
• Light exposure - light cues the brain to stay awake. In the evening, lights from television, mobile phones and computers can prevent adequate production of melatonin, the brain chemical (neurotransmitter) responsible for sleep.
• Vicious circle - insufficient sleep causes a teenager's brain to become more active. An over-aroused brain is less able to fall asleep.
• Social attitude - in Western culture, keeping active is valued more than sleep.
• Sleep disorders - sleep disorders, such as restless legs syndrome or sleep apnoea, can affect how much sleep a teenager gets.
• Some effects of sleep deprivation: concentration difficulties, mentally 'drifting off ' in class, shortened attention span, lack of enthusiasm, moodiness and aggression, depression, slower physical reflexes, reduced sporting performance, reduced academic performance, increased number of 'sick days' from school because of tiredness.
Preventing sleep deprivation
Some suggestions include:
• choose a relaxing bedtime routine; for example, have a bath and a hot milky drink before bed.
• Avoid using mobile phone, computer, loud music, homework, or any other activity that gets your mind racing for about an hour before bedtime.
• Keep your room dark at night. The brain's sleep-wake cycle is largely set by light received through the eyes. In the morning, expose your eyes to lots of light to help wake up your brain.
• Avoid having any food or drink that contains caffeine after dinnertime. This includes coffee, tea, cola drinks and chocolate.
• Avoid recreational drugs (including alcohol, tobacco and cannabis) as they can cause you to have broken and poor quality sleep.
• Do the same bedtime routine every night for at least four weeks to make your brain associate this routine with going to sleep.
• Avoid staying up late on the weekends. Late nights will undo your hard work.
• Remember that even 30 minutes of extra sleep each night on a regular basis makes a big difference.
• See your doctor if self-help techniques don't increase your nightly sleep quota.
For further information go to: www.sleephealthfoundation.org.au
www.sleepoz.org.au
Thankyou
Jenny Hill
College nurse
Reference: Better Health Channel
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Connect public, paid and private patent data with Google Patents Public Datasets
US7438208B2 - Septal stapler apparatus - Google Patents
Septal stapler apparatus Download PDF
Info
Publication number
US7438208B2
US7438208B2 US11338131 US33813106A US7438208B2 US 7438208 B2 US7438208 B2 US 7438208B2 US 11338131 US11338131 US 11338131 US 33813106 A US33813106 A US 33813106A US 7438208 B2 US7438208 B2 US 7438208B2
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US
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Grant
Patent type
Prior art keywords
staple
arm
trigger
apparatus
stapling
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US11338131
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US20060163313A1 (en )
Inventor
Michael C. Larson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ARTHROCARE Corp (A DELAWARE CORPORATION)
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Entrigue Surgical Inc
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• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/24Surgical instruments, devices or methods, e.g. tourniquets for use in the oral cavity, larynx, bronchial passages or nose; Tongue scrapers
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/064Surgical staples, i.e. penetrating the tissue
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/068Surgical staplers, e.g. containing multiple staples or clamps
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/0057Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/10Surgical instruments, devices or methods, e.g. tourniquets for applying or removing wound clamps, e.g. containing only one clamp or staple; Wound clamp magazines
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/00234Surgical instruments, devices or methods, e.g. tourniquets for minimally invasive surgery
• A61B2017/00238Type of minimally invasive operation
• A61B2017/00243Type of minimally invasive operation cardiac
• AHUMAN NECESSITIES
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• A61B2017/00535Surgical instruments, devices or methods, e.g. tourniquets pneumatically or hydraulically operated
• AHUMAN NECESSITIES
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• A61B2017/00575Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
• AHUMAN NECESSITIES
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• A61B2017/00575Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
• A61B2017/00588Rigid or stiff implements, e.g. made of several rigid parts linked by hinges
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/0057Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
• A61B2017/00575Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
• A61B2017/00606Implements H-shaped in cross-section, i.e. with occluders on both sides of the opening
• AHUMAN NECESSITIES
• A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
• A61BDIAGNOSIS; SURGERY; IDENTIFICATION
• A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
• A61B17/064Surgical staples, i.e. penetrating the tissue
• A61B2017/0647Surgical staples, i.e. penetrating the tissue having one single leg, e.g. tacks
Abstract
A septal stapling apparatus includes an instrument body having proximal and distal end portions. A handle at the distal end portion enables a user to hold and manipulate the instrument body. A pair of spaced apart arms are extending from the handle and include a staple arm and a tensioning arm. The body provides a trigger that moves between resting and firing positions. An actuator link moves between first and second positions, the actuator link being moved by the trigger, wherein the actuator link includes a staple moving member that is attached to the staple arm. The staple arm has a staple bank that includes multiple staples. The trigger, actuator link, staple bank, and staple moving member are configured to move a staple to a stapling position when the trigger is pulled. The staple arm and tensioning arm move together when the trigger is pulled.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
U.S. Provisional Patent Application No. 60/646,734, filed 25 Jan. 2005, and U.S. Provisional Patent Application No. 60/733,714, filed 4 Nov. 2005, are incorporated herein by reference. Priority of those applications is hereby claimed.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable
REFERENCE TO A “MICROFICHE APPENDIX”
Not applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to septal surgery. More particularly, the present invention relates to an improved septal stapler apparatus that places surgical staples in a patient's septal tissue responsive to a trigger pull that moves two elongated spaced apart appendages together, one pushing a staple toward the other and through the selected tissue.
2. General Background of the Invention
The following U.S. Patent, which contain background information, are incorporated herein by reference:
TABLE I
U.S. PAT. NO. TITLE ISSUE DATE
5,540,240 Intranasal Septal Fastener Driving 30 Jul. 1996
Method
5,361,782 Intranasal Septal Stapling Method 8 Nov. 1994
5,370,294 Intranasal Septal Stapling Device 6 Dec. 1994
and Method
6,283,121 Manual Pump and Ambu Bag 4 Sep. 2001
6,131,790 Surgical Stapler and Cartridge 17 Oct. 2000
5,351,871 Intranasal Septal Stapling Device 4 Oct. 1994
5,915,615 Tissue Fastening Device 29 Jun. 1999
BRIEF SUMMARY OF THE INVENTION
The present invention provides an improved septal stapling apparatus that provides an instrument body having proximal and distal end portions. A handle at the proximal end portion enables a user to hold and manipulate the instrument body. A pair of spaced apart arms extend distally from the handle. The arms include a staple arm and a tensioning arm. There is a gap between the arms that enables placement of the arms on opposing sides of the tissue to be stapled.
The body provides a trigger that moves between resting and firing positions. The trigger moves an actuator link between first and second positions. The actuator link includes a staple moving member that is attached to the staple arm.
The staple arm has a staple bank that includes multiple staples. The trigger, actuator link, staple bank, and staple moving member are configured to move a staple to a stapling position when the trigger is pulled. The staple arm and tensioning arm move together when the trigger is pulled in order to place the staple in the selected tissue.
The present invention includes a septal stapling apparatus, having an instrument body with proximal and distal end portions. A handle at the distal end portion enables a user to hold and manipulate the instrument body.
A pair of spaced apart arms extends from the handle. The arms include a staple arm and a tensioning arm. The body has a trigger that moves between resting and firing positions. An actuator link moves between first and second positions, the actuator link being moved by the trigger. The actuator link includes a staple moving member that is attached to the staple arm.
The staple arm carries a staple bank that includes multiple staples. The trigger, actuator link, staple bank and staple moving member are configured to move a staple to stapling position when the trigger is pulled. The staple arm and tensioning arm move together when the trigger is pulled. Preferably, the tensioning arm has a receptacle that receives at least a part of a staple during stapling. Preferably, the tensioning arm pivots relative to the body during stapling.
The staple arm is preferably fixed relative to the body. The actuator preferably slides relative to the body. The actuator and staple moving member can be pivotally attached. The staple arm can house the staple magazine with a bank of staples therein. The actuator slides relative to the body and simultaneously causes the staple moving member to pivot, engaging and dispensing a staple from the staple magazine. Preferably, the staple arm and tensioning arm each have head portions that come together to dispense a staple when the trigger is pulled.
The handle fits comfortably in an operator's palm, and can permit equal access to the trigger from either side, i.e. either right hand or left hand operation. Emanating from the handle are the staple arm and the tensioning arm. These are of suitable dimensions to be inserted into a typical patient's nose, one arm into each nostril. At the end of the staple arm is the staple head which houses a bank of staples which are dispensed one-at-a-time.
The end of the tensioning arm can provide a recess for accommodating the heads of the staples as they are pushed from the staple head.
The tensioning arm moves so that the device can pass the relatively wide columella at the base of the nose between the nostrils but still gently come together on opposite sides of the relatively thin mucosal layers inside the nose which are to be stapled.
A handle cover and handle base can be fastened together (as with recessed Philips-head screws) to form the handle. The trigger slides within the handle, against the force of a trigger spring. The motion of the trigger causes the movement of the tensioning arm which pivots at the back of the handle cover.
Movement of the trigger also causes the translation of the actuator link by pivoting the trigger link about a fulcrum which protrudes from the inner surface of the handle base. The motion of the actuator link is transferred to the head link, causing one of the staples in the bank of staples to be dispensed from the staple head. The bank of staples are positioned by the staple advance rod which is moved by the advance rod spring being compressed between the body of the staple advance rod and the advance rod base.
The contoured shape of the tensioning arm mates with a projection or peg of the trigger. During the first part of the trigger's travel, the projection or peg pushes against the force of the tensioning arm spring to bring the tensioning arm into the proper position for stapling. The final portion of the trigger's travel acts to maintain the same position of the tensioning arm.
The trigger link moves and pivots, e.g. on a fulcrum on the inner wall of the handle base. When the bottom of the link is pressed by the trigger, the top moves the actuator link. The actuator link is retracted by the actuator spring.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
For a further understanding of the nature, objects, and advantages of the present invention, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements and wherein:
FIG. 1 is a perspective view of the preferred embodiment of the apparatus of the present invention in an open position;
FIG. 2 is a front, fragmentary view of the preferred embodiment of the apparatus of the present invention showing a staple;
FIG. 3 is a side, fragmentary view of the preferred embodiment of the apparatus of the present invention showing a staple;
FIG. 4 is a partial perspective view of the preferred embodiment of the apparatus of the present invention showing a staple bank;
FIG. 5 is a partial side view of the preferred embodiment of the apparatus of the present invention in an open position showing a staple bank;
FIG. 6 is an exploded perspective view of the preferred embodiment of the apparatus of the present invention;
FIG. 7 is a sectional view taken along lines 7-7 of FIG. 1;
FIG. 8 is a partial perspective view of the preferred embodiment of the apparatus of the present invention;
FIG. 9 is a partial, cut-away view of the preferred embodiment of the apparatus of the present invention;
FIG. 10 is a partial sectional, side view of the preferred embodiment of the apparatus of the present invention;
FIG. 11 is a perspective view of the preferred embodiment of the apparatus of the present invention;
FIG. 12 is a partial, perspective cut-away view of the preferred embodiment of the apparatus of the present invention;
FIG. 13 is a partial, sectional, elevation view of the preferred embodiment of the apparatus of the present invention;
FIG. 14 is a partial, sectional, elevation view of the preferred embodiment of the apparatus of the present invention;
FIG. 15 is a perspective view of the preferred embodiment of the apparatus of the present invention shown in stapling position;
FIG. 16 is a partial perspective view of the preferred embodiment of the apparatus of the present invention shown in stapling position;
FIG. 17 is a partial sectional view of the preferred embodiment of the apparatus of the present invention shown in stapling position;
FIG. 18 is a partial sectional view of the preferred embodiment of the apparatus of the present invention shown in stapling position;
FIG. 19 is a fragmentary perspective view of the preferred embodiment of the apparatus of the present invention;
FIG. 20 is a partial perspective view of the preferred embodiment of the apparatus of the present invention;
FIG. 21 is a sectional, elevation view of an alternate embodiment of the apparatus of the present invention;
FIG. 22 is a sectional, elevation view of an alternate embodiment of the apparatus of the present invention;
FIG. 23 is a perspective view of a third embodiment of the apparatus of the present invention;
FIG. 24 is another perspective view of the third embodiment of the apparatus of the present invention;
FIG. 25 is a partial, sectional, elevation view of a fourth embodiment of the apparatus of the present invention; and
FIG. 26 is a partial, sectional, elevation view of a fourth embodiment of the apparatus of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
FIGS. 1 and 6-20 show the preferred embodiment of the apparatus of the present invention designated generally by the numeral 10. Septal stapler apparatus 10 provides a tool body 11 having a proximal end portion 12 and a distal end portion 13. A trigger 14 is movably mounted to the tool body 11. The trigger 14 is used to activate the device when it is held by a user 48. A user 48 grips the tool body 11, depresses the trigger 14 in the direction of arrow 49 in FIG. 11, which then dispenses a staple 50 from staple bank 51 to the selected septal tissue layers 59, 60. FIGS. 2 and 3 show one embodiment of a single shaft staple 50 with one end pointed to facilitate membrane penetration. FIGS. 4 and 5 show a bank of staples 51 which is housed in the staple head 55. The bank of staples can be formed of any material. Polymeric staples, even absorbable ones, may be molded as a bank of staples by any number of processes, including injection molding, fused deposition, etc. Metal, ceramic or polymeric staples may be formed, cast, molded or machined individually and then adhesively attached together to form a bank of staples or loaded into the stapler body individually and held in a bank by friction at the surfaces.
A pair of arms are attached to the tool body 11. These include a moving arm 15 and a fixed arm 16. The moving arm 15 has a proximal end portion 17 and a distal end portion 18. The distal end portion 18 provides a receptacle 19 having a socket 20 that is receptive of an end portion (pointed section 42) of a staple 50 when the trigger 14 is depressed in the direction of arrow 49 in FIG. 11 and the moving arm 15 pivots in the direction of arrow 66 in FIG. 11 to meet the fixed arm 16 (see FIG. 14).
The moving arm 15 provides a contoured section 21 having a concavity 22 (see FIG. 12). This concavity 22 engages a camming surface 24 on projection or peg 23 of trigger 14 in the open position before the trigger 14 is depressed. When a user 48 depresses the trigger 14, the camming surface 24 of the projection 23 moves proximally (see arrow 56, FIG. 12), disengaging from the concavity 22 and thus rotating the moving arm 15 toward the fixed arm 16.
The trigger 14 is biased to return to a relaxed beginning position by compressive trigger spring 25. This trigger spring 25 can be mounted at its end portions on respective cylinders 26, 27. One of the cylinders 26 is mounted on the trigger 14. The other cylinder 27 is mounted on the tool body 11 (see FIGS. 6, 8, 9, and 13).
When the trigger 14 is depressed, lever 28 (FIGS. 6, 13) is rotated to push staple actuator link 34 in a distal direction. The lever 28 has a lower end portion 29 that is engaged by rod 57 on the rear surface of the trigger 14 when the trigger is depressed. The lever 28 rotates about fulcrum 30 so that its upper end portion 33 pushes the staple actuator link 34 distally. The central portion 31 of the link 28 engages the fulcrum 30. Upper end portion 33 of the lever 28 provides a transverse pin 32 that is mounted in slotted portion 40 provided at the proximal end 35 of staple actuator link 34.
Spring 37 connects at its end portions to hooks 38, 39. The hook 38 is attached to and travels with staple actuator link 34. The hook 39 is attached to the tool body 11. When the trigger 14 is depressed, lever 28 rotates so that the transverse pin 32 pushes the staple actuator link 34 in a distal direction.
Distal end portion 36 (FIG. 6) of actuator link 34 has a rectangularly shaped head 41 that engages a staple 50 to be placed in the selected tissue. The staple 50 is one of a plurality of staples that form a staple bank 51 (see FIGS. 2-5). The rectangularly shaped head 41 can be pivotally attached to the distal end 36 of the staple actuator link 34. The head 41 provides a transverse bar 43 (FIG. 6) that contacts the transverse beam 58 (FIG. 2) of staple 50 when the trigger 14 is depressed. The bar 43 of rectangular head 41 initially travels in a longitudinal slot 44 (FIG. 10), then curved slot 47, then in transverse slot 46. The longitudinal slot 44 and transverse slot 46 are connected with the curved transition slot section 47.
When the trigger 14 is depressed, the staple actuator link 34 (FIG. 14) moves distally, forcing the transverse bar 43 of rectangular head 41 to engage a staple 50 of staple bank 51. The transverse bar 43 engages the nearest staple 50 and pushes its pointed section 42 into the selected tissue 59, 60 (FIG. 18). The staple bank 51 is advanced using a staple advance rod 53 (FIGS. 6, 17). Rod 53 is urged in a distal direction with rod-advance spring 54. The advance rod 53 can provide an enlarged head 55 (FIGS. 6, 14) that is sized and shaped to contact and push staple bank 51.
FIGS. 8-18 show the interplay of the trigger 14 and the trigger link 28. FIG. 9 corresponds to the first part of the motion of trigger 14 (which moves the moving or tensioning arm 15, as in FIG. 6). FIGS. 9 and 13 show the point in the travel when the trigger 14 first contacts the trigger link 28. FIGS. 11, 17 and 18 show the full extent of the travel of the trigger 14, having pushed the bottom of the link 28 back, causing its upper end 33 to move forward, thus pushing the actuator link 34 forward.
FIG. 18 depicts the staple head at the distal end 13 portion of the arm 16 and partially broken away to show the locations of the bank 51 of staples 50, the head 41 and the actuator link 34.
FIGS. 10, 14, and 18 show views of the ends of the staple arm 16 and moving arm 15 during the process of dispensing a staple 50 from the bank 51 of staples and when joining two mucosal membrane layers 59, 60 or tissue flaps together with a staple 50. FIGS. 10 and 14 represent the pre-stapled state, after the cartilage and bone are removed during the septoplasty operation. FIG. 14 represents the state after the first stage of trigger 14 actuation when the arm 15 moves to bring the two membranes 59, 60 into contact. FIG. 18 represents the state after complete trigger 14 actuation when the lead staple 50 penetrates the two membranes 59, 60. After the trigger 14 is released, leaving the staple 50 holding the two membranes 59, 60 together, the arms 15, 16 return to the starting position of FIGS. 7-10.
The present invention encompasses other mechanisms for imparting the necessary driving force to a staple within the geometrical constraints of a typical nasal passageway, in addition to a compression linkage. A description of three of these alternate embodiments or mechanisms follows with reference to FIGS. 21-26. Each may be housed within a chassis similar to that envisioned for the compression linkage, namely an arm carrying a bank of staples opposite an arm with a staple receptacle.
The first embodiment variant 61 (FIG. 21) is based on magnetic or electromagnetic principles, whereby the force to move staples 50 is provided by a magnetic field at magnet 62. The magnet 62 can be either permanent, e.g., a rare earth magnet, or induced by an electric current, e.g., a solenoid. FIGS. 21 and 22 show staples 50 being sequentially acted upon by an actuating member, such as plunger 65, or a bar, link, or the like, which moves in relation to arm 16 which holds the staples 50 in the ready position as with the preferred embodiment. A moving arm 15 moves into proximity of the staple 50 and carries a magnetic field e.g. magnet 62. Arm 15 can be made either completely or partially from magnetic material and/or contain an electromagnet coil. The magnetic attraction pulls the actuating arm member 15 to arm 16, causing the staple 50 to fire into the membranes 59, 60 to be stapled. After firing, the magnetic force on the actuating member is diminished through moving the arm 15 away from arm 16 and/or turning off the electromagnet 62. FIGS. 21 and 22 show external representations of the arms 15, 16 and how the actuating member (e.g. plunger 65) may be held in, and returned to, the ready position by an actuator return spring 64 (leaf, tension, or compression). FIG. 21 shows a leaf spring 64 supporting the actuating member 65 in the ready position. FIG. 22 shows the actuating member 65 in the actuated position, i.e., at the end of a staple stroke, wherein the magnetic force of the swing arm overcomes the lesser restraining force of the leaf spring 64 to pull the plunger 65 and dispense staple 50. Once the magnetic force is diminished, the actuating member or plunger 65 returns to the position shown in FIG. 21 under the action of the leaf spring 64.
An additional variant, depicted in FIGS. 23 and 24, is based on the rotation of shaft 67 and cam 68 which presses on the head of the staple 50 to be fired. The rotation of the cam 68 can be caused by the torsional twist of attached shaft 67. FIG. 23 shows the cam 68 in the un-actuated position in contact with the staple 50 to be fired from the bank 51 of staples. FIG. 24 shows the same staple 50 being displaced by the movement of the cam 68 due to the twist of the torsion shaft 67. The twist of the shaft 67 can be induced from the linear or angular motion of a trigger 114 using gears, linkages, bearings, and/or the like. FIG. 24 shows a bearing surface fixed to a trigger 114 pushing a helix-shaped bearing surface 72 on the surface of a torsional cylinder 69. FIGS. 23 and 24 show details of the bearing interaction between peg 70 on the translating trigger 114 and the rotating cylinder 69. A torsional spring 71 provides the constraint to return the cam 68 and shaft 67 to the un-actuated position against the motion of the trigger 114.
Another variant shown in FIGS. 25 and 26 and designated by the numeral 73 is configured to fire staples utilizing the resultant force from pressurizing a cavity. This can be accomplished with either a gas (e.g., air for a pneumatic device) or a liquid (e.g., water for a hydraulic device). The cavity 74 can be the space adjacent the staple 50, sealed with a translating surface (e.g., a piston), an expanding bladder (e.g., a balloon or diaphragm), or combination of the two. The liquid or gas system can either be closed or open. An open system would vent the pressurized medium when the staple exits, e.g., through an orifice normally sealed by a staple. A closed system, such as the embodiment depicted in FIGS. 25 and 26, would use the motion of a trigger to push water down a pressurization tube 75 and expand an elastic balloon 76 into a volume which displaces the staple to be fired from the staple bank 51. FIG. 25 shows the balloon 76 in the ready, contracted state. FIG. 26 shows the balloon 76 in the inflated, stapling state.
It should be understood that the staple 50 can be any shape that will be passed through the mucosal bilayer of the nasal septum and may include cartilage between the mucosal layer. This staple 50 will pull the mucosal layers in proximity preventing the formation of a hematoma. The staple 50 will preferably be made of an absorbable material such as polyglycolic acid (PGA) or polylactic acid (PLA) or may be made as a combination of copolymers.
The stapler and staples may be produced and packaged in a sterile environment or sterilized before use. A range of options is available and the choice will depend in part on the particular component materials employed. Irradiation, as with gamma rays or electron beams, can be used assuming all components are compatible, particularly component rubbers and plastics. Exposure to sterilizing gasses, such as ethylene oxide, may be used, as long as component plastics do not retain amounts which exceed accepted levels. Likewise, liquids may also be used, such as those containing glutaraldehyde, in accordance with accepted standards.
The present invention can also include a nasal spray which facilitates the absorption of the staple polymer. The spray is preferably made of ingredients that will maintain moisture in the nasal cavity such as saline, but will also be formulated to increase degradation of the staple 50 which may include either a base or acid, an enzyme such as pepsin, or the formulation may be hypertonic to pull moisture into the nasal cavity. The nasal spray is preferably used around 6-8 times per day for 4-6 weeks (or until the staples 50 are completely absorbed).
PARTS LIST
The following is a list of parts and materials suitable for use in the present invention:
Part
Number Description
10 septal stapler apparatus
11 tool body (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal
such as aluminum, stainless steel, or titanium -
e.g. 7-15 cm long, 2-6 cm high, and 2-5 cm wide)
12 proximal end portion
13 distal end portion
14 trigger (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal such
as aluminum, stainless steel, or titanium - e.g. 1-5 cm
long, 1-4 cm high, and 1-4 cm wide)
15 moving or tensioning arm (unfilled or filled plastic such
as ABS, PVC, polypropylene, polyester or polycarbonate,
or metal such as aluminum, stainless steel, or titanium -
e.g. 5-16 cm long, 2-8 mm high, and 1-5 mm wide)
16 fixed arm (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal such
as aluminum, stainless steel, or titanium - e.g. 5-16 cm
long, 2-8 mm high, and 1-5 mm wide)
17 proximal end portion
18 distal end portion
19 receptacle
20 socket
21 contoured section
22 concavity
23 projection
24 camming surface
25 trigger spring (such as model no. C0240-020-2000-S
produced by Associated Spring Raymond, a subsidiary
of Barnes Group, Inc. of 1705 Indian Wood Circle,
Maumee, OH 43537, US)
26 cylinder
27 cylinder
28 lever (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal such
as aluminum, stainless steel, or titanium - e.g. 1-2 cm
long, 1-4 mm high, and 1-4 mm wide)
29 lower end portion
30 fulcrum
31 central portion
32 transverse pin
33 upper end portion
34 staple actuator link (unfilled or filled plastic such as
ABS, PVC, polypropylene, polyester or polycarbonate, or
metal such as aluminum, stainless steel, or titanium -
e.g. 5-16 cm long, 2-8 mm high, and 1-5 mm wide)
35 proximal end
36 distal end
37 spring (such as model no. E0063-007-0250-S
produced by Associated Spring Raymond, a subsidiary of
Barnes Group, Inc. of 1705 Indian Wood Circle, Maumee,
OH 43537, US)
38 hook
39 hook
40 slotted portion
41 rectangular head (unfilled or filled plastic such as
ABS, PVC, polypropylene, polyester or polycarbonate,
or metal such as aluminum, stainless steel, or titanium -
e.g. 3-8 mm long, 3-8 mm wide, and 0.5-1.5 mm thick)
42 pivotal connection
43 transverse bar
44 longitudinal slot
46 transverse slot
47 curved slot section
48 user
49 arrow
50 staple (bio-absorbable polymers or copolymers such as
polyglycolic acid (PGA), polylactic acid (PLA),
polydioxanone, polycaprolactone, polyhydroxybutyrate,
polyester, or other polymer such as PVC, polypropylene,
or polycarbonate, or metal such as aluminum, stainless
steel, or titanium - e.g. 2-6 mm long and 0.5-2.5 mm
thick)
51 staple bank
52 pointed section
53 staple advance rod (unfilled or filled plastic such as
ABS, PVC, polypropylene, polyester or polycarbonate,
or metal such as aluminum, stainless steel, or titanium -
e.g. 4-10 cm long, 0.5-5 mm high, and 0.5-5 mm wide)
54 advance rod spring (such as model no. C0057-006-0310-S
produced by Associated Spring Raymond, a subsidiary of
Barnes Group, Inc. of 1705 Indian Wood Circle, Maumee,
OH 43537, US)
55 enlarged head
56 arrow
57 rod
58 transverse beam
59 mucosal membrane layer
60 mucosal membrane layer
61 septal stapler apparatus
62 magnet
64 leaf spring (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal such
as aluminum, stainless steel, or titanium - e.g. 1-10 mm
long, 0.1-2 mm high, and 0.1-2 mm wide)
65 plunger (a magnetic material containing such substances
as iron, nickel, cobalt, wairauite, magnetite, oxides,
or sulfides in whole or in part)
66 variant with cam
67 shaft (unfilled or filled plastic such as ABS,
PVC, polypropylene, polyester or polycarbonate,
or metal such as aluminum, stainless steel, or
titanium - e.g. 5-16 cm long, 2-4 mm
diameter,)
68 cam (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal
such as aluminum, stainless steel, or titanium -
e.g. 3-8 mm long, 0.5-2 mm thick, and 0.5-2 mm
wide)
69 cylinder (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal
such as aluminum, stainless steel, or titanium -
e.g. 1-3 cm long, 1-2 cm diameter)
70 peg
71 torsional spring
72 bearing surface
73 variant with pressure
74 cavity
75 pressurization tube
76 balloon (an elastic material such as rubber, latex or
silicone)
77 cavity
114 trigger (unfilled or filled plastic such as ABS, PVC,
polypropylene, polyester or polycarbonate, or metal such
as aluminum, stainless steel, or titanium - e.g. 1-5 cm
long, 1-4 cm high, and 1-4 cm wide)
All measurements disclosed herein are at standard temperature and pressure, at sea level on Earth, unless indicated otherwise. All materials used or intended to be used in a human being are biocompatible, unless indicated otherwise.
The foregoing embodiments are presented by way of example only; the scope of the present invention is to be limited only by the following claims.
Claims (31)
1. A nasal septal stapling apparatus, comprising:
a) an instrument body having proximal and distal end portions;
b) a handle at the distal end portion that enables a user to hold and manipulate the instrument body;
c) a pair of spaced apart arms extending from the handle including a staple arm and a tensioning arm;
d) the body having a trigger that moves between resting and firing positions;
e) an actuator link that moves between first and second positions, the actuator link being moved by the trigger, wherein the actuator link includes a staple moving member that is attached to the staple arm;
f) the staple arm having a staple bank that includes multiple staples;
g) wherein a gap exists between the staple arm and the tensioning arm when the trigger is in the resting position and when the trigger is in the firing position;
h) wherein the trigger, actuator link, staple bank and staple moving member are configured to move a staple to stapling position when the trigger is pulled from the resting position to the firing position;
i) wherein the tensioning arm is configured to move toward the staple arm when the trigger is pulled from the resting position to the firing position; and
j) wherein the trigger is configured to move in a line parallel to the staple arm when the trigger is pulled from the resting position to the firing position.
2. The nasal septal stapling apparatus of claim 1 wherein the tensioning arm has a receptacle that receives at least a part of a staple during a stapling operation and wherein the tensioning arm comprises a concavity configured to engage a camming surface of the trigger.
3. The nasal septal stapling apparatus of claim 2 wherein the trigger is configured to engage a lever that rotates when the trigger is depressed and wherein the lever is configured to push on the actuator link when the lever rotates.
4. The nasal septal stapling apparatus of claim 1 wherein the gap exists between the staple arm and the tensioning arm proximal to where the tensioning arm and staple arm extend from the body.
5. The nasal septal stapling apparatus of claim 1 wherein the staple arm is fixed relative to the body.
6. The nasal septal stapling apparatus of claim 1 wherein the actuator link slides relative to the body.
7. The nasal septal stapling apparatus of claim 6 wherein the actuator link slides and simultaneously causes the staple moving member to pivot, engaging and dispensing a staple from the staple magazine.
8. The nasal septal stapling apparatus of claim 1 wherein the actuator link and staple moving member are pivotally attached.
9. The nasal septal stapling apparatus of claim 1 wherein the staple arm and tensioning arm each have head portions that dispense a staple when the trigger is pulled.
10. A nasal septal stapling apparatus, comprising:
a) an instrument body having proximal and distal end portions;
b) a handle on the instrument body that enables a user to hold and manipulate the instrument body;
c) a pair of spaced apart arms extending from the handle including a staple arm and a tensioning arm, each arm having a distal end portion with a stapling portion thereon;
d) the body having a trigger that moves between resting and firing positions;
e) an actuator link that moves between resting and firing positions, the actuator link being moved by the trigger, wherein the actuator link includes a staple moving member that is attached to the staple arm at the distal end portion thereof, said staple moving member comprising part of the stapling portion of the staple arm;
f) the staple arm having a staple bank that includes multiple staples;
g) wherein the trigger, actuator link, staple bank and staple moving member are configured to move a staple to a stapling position when the trigger is pulled;
h) wherein the tensioning arm is configured to move toward the staple arm when the trigger is pulled from the resting position to the firing position;
i) wherein the staple arm and the tensioning arm are spaced to accommodate a patient's columella when the trigger is in the resting position and when the trigger is in the firing position; and
j) wherein the trigger is configured to move in a line parallel to the staple arm when the trigger is pulled from the resting position to the firing position.
11. The nasal septal stapling apparatus of claim 10 wherein the tensioning arm has a receptacle that receives at least a part of a staple during a stapling operation.
12. The nasal septal stapling apparatus of claim 10 wherein the tensioning arm pivots relative to the body.
13. The nasal septal stapling apparatus of claim 10 wherein the staple arm is fixed relative to the body.
14. The nasal septal stapling apparatus of claim 10 wherein the trigger is configured to engage a lever that rotates when the trigger is depressed and wherein the lever is configured to push on the actuator link when the lever rotates.
15. The nasal septal stapling apparatus of claim 10 wherein the actuator link and staple moving member are pivotally affached.
16. The nasal septal stapling apparatus of claim 15 wherein the actuator slides and simultaneously causes the staple moving member to pivot, engaging and dispensing a staple from the staple magazine.
17. The nasal septal stapling apparatus of claim 10 wherein the staple arm houses a staple magazine.
18. The nasal septal stapling apparatus of claim 10 wherein the staple arm and tensioning arm each have head portions that dispense a staple when the trigger is pulled.
19. The nasal septal stapling apparatus of claim 10 wherein the staple moving member is pivotally attached to the actuator link and the staple arm has a guide that controls movement of at least a part of the staple moving member.
20. The nasal septal stapling apparatus of claim 19 wherein the guide is a curved track on the staple arm.
21. The nasal septal stapling apparatus of claim 10 wherein magnet force moves a staple to a stapling position when the trigger is pulled.
22. The nasal septal stapling apparatus of claim 10 wherein electromagnet force moves a staple to a stapling position when the trigger is pulled.
23. The nasal septal stapling apparatus of claim 10 wherein a cam moves a staple to a stapling position when the trigger is pulled.
24. The nasal septal stapling apparatus of claim 10 wherein hydraulic force moves a staple to a stapling position when the trigger is pulled.
25. The nasal septal stapling apparatus of claim 10 wherein pneumatic force moves a staple to a stapling position when the trigger is pulled.
26. The nasal septal stapling apparatus of claim 10 wherein a piston moves a staple to a stapling position when the trigger is pulled.
27. The nasal septal stapling apparatus of claim 10 wherein mechanical force moves a staple to a stapling position when the trigger is pulled.
28. The nasal septal stapling apparatus of claim 1 or 10, wherein when the trigger is pulled, a majority of the length of the staple arm is spaced apart from the tensioning arm to accommodate the nasal septum, including the columella, during stapling.
29. The nasal septal stapling apparatus of claim 1 or 10, wherein the staple arm has a longitudinal axis and the staple bank protrudes away from the staple arm longitudinal axis, and wherein the tensioning arm has a longitudinal axis and the tensioning arm has an anvil that protrudes away from the longitudinal axis of the tensioning arm.
30. The nasal septal stapling apparatus of claim 1 or 10, wherein the tensioning arm has an anvil that protrudes toward the staple bank and wherein the gap is in between the staple bank and the anvil of the tensioning arm when the trigger is pulled.
31. The nasal septal stapling apparatus of claim 1 or 10, wherein the gap is in between the staple bank and the tensioning arm when the trigger is pulled.
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EP1853174B1 (en) 2017-10-18 grant
CA2595838C (en) 2014-03-11 grant
US20090084825A1 (en) 2009-04-02 application
EP1853174A2 (en) 2007-11-14 application
CA2595838A1 (en) 2006-08-03 application
EP1853174A4 (en) 2009-12-23 application
US20060163313A1 (en) 2006-07-27 application
WO2006081235A2 (en) 2006-08-03 application
US9241726B2 (en) 2016-01-26 grant
US20140046365A1 (en) 2014-02-13 application
US8579179B2 (en) 2013-11-12 grant
WO2006081235A3 (en) 2007-07-12 application
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Advertisement
Cued Overeating
• Anita Jansen
• Remco C. Havermans
• Chantal Nederkoorn
Chapter
Abstract
The cued overeating model that is presented in this chapter states that cues that reliably signal highly palatable food intake – such as the sight, smell, and taste of highly palatable foods – and also the context in which (over)eating takes place – like place and time and feelings and thoughts – may start to act as conditioned stimuli. This means that soon after, the cues alone can trigger food cue reactivity and food cravings. The learned cue reactivity increases the probability of (over)eating and might sabotage dieting. It is argued that for successful dieting it is necessary to extinguish learned cue reactivity. To reach that goal, the way of dieting is relevant: dieters who avoid highly palatable food cues and dieters who intermittently keep eating high-calorie high-fat palatable foods will remain cue reactive. Only dieters who expose themselves to highly palatable food cues without eating them are expected to show the desired extinction of cue reactivity. Extinction of cue reactivity can be accelerated by prolonged cue exposure with response prevention. During the exposure the overeater is exposed to the cues (e.g., smell and sight of tasty foods) that elicit appetite or craving. The exposure is long lasting and without eating. Whether cue exposure with response prevention is an effective intervention that promotes successful dieting remains to be studied.
Keywords
Conditioned Stimulus Anorexia Nervosa Unconditioned Stimulus Binge Eating Bulimia Nervosa
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Abbreviations
WHO
World Health Organisation
CS
Conditioned stimulus (= cues)
US
Unconditioned stimulus
UR
Unconditioned response
CR
Conditioned response
CBT
Cognitive behaviour therapy
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Copyright information
© Springer Science+Business Media, LLC 2011
Authors and Affiliations
• Anita Jansen
• 1
• Remco C. Havermans
• Chantal Nederkoorn
1. 1.Department of Clinical Psychological ScienceMaastricht UniversityMaastrichtThe Netherlands
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Top Cbda Cannabidiolic Acid Questions Answered By Cbd Science
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However, the amount of research in favor of CBD has yet to spill over into the domain of CBDa. If you’re interested in trying CBD or CBG to support your wellness routine, both are legal and widely available throughout Europe do cbd gummies make you happy and the US. However, there can be issues with the THC content of inferior quality oils, so always ensure you buy products from a reputable seller. We’ll cover more on how to pick a high-quality CBD or CBG oil shortly.
American Shaman recommends that customers only use a drop or two of their CBD cream at a time because a little goes a long way. They also recommend that you pat the cream in rather than slather it on and rub it in. The CB1 and CB2 receptors are the body’s two main endocannabinoid receptors. While the CB1 receptors are mostly found in the central nervous system, CB2 receptors are located in the peripheral nervous system. Once the endocannabinoids have carried out their mission, enzymes like fatty acid amide hydrolase and monoacylglycerol acid lipase go to work to break the endocannabinoids down.
Delta 10 Thc In Distillates
RSHO® Liquids are created by mixing our popular CBD oil with MCT oil, providing high concentrations of CBD along with essential vitamins, minerals, and fatty acids. There are lots of different ways to absorb THC.THC Tincturescan be used to absorb it sublingually . Creams can be used to absorb it directly into the skin, and edibles are also often used. So now you know enough to make your own decision about the CBD-versus-THC question.
NSAIDS have been linked to increasing risk of stomach ulcers, kidney damage, high blood pressure, headaches, and the ability to bleed easier. Most research focuses on the effects of CBD, not the acid form of the molecule. Still, some scientists are looking into the therapeutic potential of this cannabinoid. Cannabis leaves can be used in salads, as a garnish, or in smoothies and juices like just about any other nutrient-rich leafy green. Fortunately, most major seed breeders and many cannabis access points now offer at least one or two CBD varieties.
What Is CBDa? Everything You Need To Know About This Curious Cannabinoid Acid
Below you can find the answers to CBDA frequently asked questions, as well as explore the differences between CBDA vs CBD. This product is not intended to diagnose, treat, cure or prevent any disease. As of this writing, the majority of CBDA studies have been performed on animals, not on humans. As a result, human trials will be needed to verify many of their findings. As companies continue to research CBDA treatments, we can expect more and better news in the years to come. As we already mentioned, CBDA has only been studied for a little over a decade.
Just like other plant-derived products, there’s a difference between organic and non-organic essential oils. Unlike THC, CBN does not have psychoactive effects unless it is taken in very large doses. Many people like to take CBN for sleep and believe that it is the most sedative cannabinoid. CBN may help people fall asleep faster and stay asleep longer, especially when combined with other cannabinoids or terpenes that promote relaxation and sleep.
Cbd For Skin Care
The most preferred flavors are chocolate, orange, strawberry, and mint. Whether you need full-spectrum high dosage CBD oil, a pack of best CBD oil with multiple flavors, or a starter pack of CBD oil, Charlotte’s Web has your back. The health and wellness company strongly believes that its consumers have a right to total transparency. This is why each and every product is lab tested, and one can scan the QR code on each of their CBD products to access the third-party lab results. Cbdistillery is one of the few brands that has set a high standard for quality in the CBD industry. All its products can be traced right from what they have been sourced and how they have been manufactures.
Being able to see all the ingredients before buying puts you in control of what goes in your body and knowing what it may interact with. In an exciting turn of events for CBDa, researchers recently discovered that the cannabinoid acid could potentially be stabilized by converting it into another derivative. The derivative, cannabidolic acid methyl ester, has recently been opened up for partnerships among scientists and medical communities. CBDA contains more powerful benefits when it comes to CBD applications based on the treatment of nausea, pain, anxiety, and seizures. CBD and CBDa, both compounds, have anti-inflammatory properties but may overlap with different mechanisms for enhancing an individual’s health.
A reputable company will always provide a COA from an independent third-party accredited laboratory for each batch of every product they make. CBD oil can be taken in a variety of ways, including sublingually, , orally and even topically, , through vaping, capsules, edibles and so on. CBD is not a “miracle cure-all.” But it can be an effective supplement and another “tool in the toolbox” to achieve wellness.
Full Spectrum Cbd
This is a partial agonist at both CB1 and CB2 receptors and is most commonly used as an antiemetic in clinical settings. Dr. Josh Jones noted that harsh chemicals can be used to produce delta-10 THC. Although, he is currently patenting a food-grade operating procedure that can effectively isomerize cannabinoids into D10. 10xPURE™-GOLD Super 1500 contains 450 mgs of CBDa, up to 1000 times more effective than most CBD products on the market. CBDa has been found to support reduced discomfort while providing relief.
Nausea and vomiting, the cannabinoid appears more potent before decarboxylation, aka before it is converted to CBD with heat. Unfortunately, the majority of cannabis research has focused on psychoactive THC or activated CBD, not CBDa. This means that the little information that is available is subject to change and is considered preliminary evidence at best. Here, “raw cannabis” refers to fresh leaves and flowers that have not been dried, cured, or heated. Here at Hemplucid, we are huge advocates for health, and helping people reach their optimal wellness. Because of this, we teamed up with Save a Brain for our Giving Tuesday campaign.
CBDa transforms into CBD through a process called decarboxylation. Baking, lighting, or heating cannabis removes the acid group from CBDa and transforms it into CBD. CBDa is one of anestimated113 compounds known as cannabinoids in the cannabis plant.
Please view our full Terms Of Use Agreement for more information and the terms and conditions governing your use of this site. When it comes to the future of CBDA, there are still a lot of unknowns. Scientists have been examining CBDA for a relatively brief amount of time.
You can also use CBDA flowers to experience the health benefits of the cannabinoid. You’ll need to put in some work to be able to use this particular form of CBDA. An herbalizer or empty cigarette must be loaded with the flower, sans the stems and seeds, and there will be a strong hemp taste. Even though CBD is more commonly available, CBDA exists in several forms.
I hope the side bar links don’t deter anyone from actually supporting companies that have put themselves out there for the betterment of the CBD Movement. And toxins are something customers absolutely don’t have to worry about, as these products don’t contain any. The brand creates a wide array of unique products including a CBD balm, CBG oils, CBD tinctures, and CBD soft gels. Lastly, Lazarus Naturals also owns a facility that’s current cGMP certified and also holds USDA Organic certifications. Green delta 8 thc concentrate Roads provides customers with a solid range of full-spectrum and broad-spectrum products. The brand’s oils come in concentrations of 25mg daily dose, 300mg, 750mg, and 1500mg, and in flavors of original, Mint Breeze, and Apple Kiwi.
Unfortunately, studies into the compound remain at the earliest stages, as CBDA’s acidic nature makes it notoriously difficult to isolate in large quantities. Still, here’s what they’ve uncovered so far about its mechanism of action. It’s important to speak to your healthcare provider, and also consider these factors before deciding on whether or not to try CBD hemp oil yourself. One of the most important positive impacts you can have on your body is consistently eating an adequate amount of healthy food. Some individuals who suffer from various types of nausea or loss of appetite have claimed that CBD oil has helped reduce their symptoms. They have anti-inflammatory properties that minimize any inflammation.
New research that is creating quite the buzz found that two compounds commonly found in hemp have the potential to combat the SARS-CoV-2 coronavirus. The compounds, cannabidiolic acid, or CBDA, and cannabigerolic acid, or CBGA, block a critical step in the process the virus uses to infect people. Cannabinoids go through major transformations over time, such as when they are harvested, aged, or exposed to heat. In fresh hemp, cannabinoids are found in the form of acids and they are considered inactive. This is the case with tetrahydrocannabinolic acid , cannabigerolic acid , cannabichromenic acid , and of course, CBDa.
Hawaii Cbda: Enjoying The Islands Benefits
Now that you understand the difference between CBD and CBDA, it is clear that CBDA will offer different benefits than CBD. However, CBDA benefits are only just beginning to be fully understood. Researchers are still investigating the benefits of CBDA, including how the compound may be able to promote health and wellness. CBD is present in only very small amounts in growing cannabis plants. Instead, most CBD initially exists as CBDA, and it isn’t until the plant is cut, dried, and heated that CBDA transforms into CBD. As we mentioned, CBDA’s affinity for the 5-HT receptor is a great benefit for serotonin production.
Cannabidiolic acid is a little-known cannabinoid with major therapeutic potential. In preliminary animal studies, CBDA has shown to be promising against inflammation, anxiety, seizures, and even certain types of cancer. CBDA is now seen as the next frontier in cannabinoid-based therapy.
However, like Delta-8-THC, which is also derived from CBD and hemp, it is likely to be banned in many states soon. He carbon-dioxide extraction process is a safe, natural way to extract CBD and other cannabinoids from hemp. In this process, pressurized carbon dioxide is used to pull the desired cannabinoids from the plant material.
Bacteria may infect the topmost layers of skin, the follicles, or the deeper layers of skin. If not treated correctly, these infections may spread throughout the body. These tests are conducted by reputable laboratories, most of which are ISO compliant. Unscrupulous companies use their in-house labs for testing, and they don’t disclose their certificates of analysis. Sol CBD oil and bound using organic MCT oil to make them easier to absorb. The tinctures come in a spray bottle, which makes dosing and administration easy.
Raw Cbda Oil Now Available
CBDA interacts with your endocannabinoid system to help create balance in the body, which is why it is important to find the products and amounts that work best for you individually. Hemp serums can be great to help with more serious conditions, such as psoriasis on the scalp, eczema on the face, or sebborheic dematitis on the cbd fruchtgummis erfahrungsberichte face. The serum is specially effective as the oil quickly soaks into your skin and scalp, allowing you to experience complete absorption relieving itchy and flaky scalp. The nature of hemp oil also prevents the oil from getting your skin or hair greasy. No doubt you have shared valuable information regarding vegan diet.
The oil is safe for use by most people and, unlike many other skin products, works well on different types of skin. In addition to skin combinations, there are people who have sensitive skin. This means their skin, though normal in its natural oil levels, reacts to some ingredients that are present in skin products. Unlike CBD oil, which contains very low levels of tetrahydrocannabinol , high-value hemp oil has no traces of THC. Whether you ingest it directly or you apply it on the skin, hemp oil offers various benefits thanks to its nourishing vitamins and moisturizing qualities. Many of these nutrients provide the body necessary minerals and also contribute to overall health.
As the compound that CBD is derived from, researchers consider this as the precursor compound to CBD. During the process of harvesting, hemp plants are abundant in CBDa. After heat is applied through the process of decarboxylation, the CBDa transitions into CBD by removing the carboxyl group.
Buyers shared that they were looking for something to help them handle rather intense pain such as chronic pain and injury. They were glad to see that this CBD product brought them the relief they needed and they didn’t directly note any downsides. This is what makes all the difference when you are choosing which type of pet CBD Oil to give your Dog. Unfortunately, many companies lie about how much CBD Oil is actually in their product. This is awarded to companies that have had their CBD Oil for Dogs independently tested for quality, accuracy, and safety.
Since he is conveniently CLN’s resident scientist, I decided to call him. We will explore other potential toxins and degradation products in a future installment. For now, stay tuned to learn how Vitamin E Acetate found its way into THC vapes and before the first case of lung damage. Unfortunately, we still don’t know how THC itself reacts in a red hot vape cartridge. This is what I was told by CLN’s resident scientist Dr. Markus Roggen.
The brand offers both full-spectrum and broad-spectrum oil varieties. Today, more people are learning about the healing power of CBD as they research natural alternative methods to help calm and eventually end their pain. In a 2020 study, scientists analyzed cell and human studies conducted on CBD from 2000 to 2019. They studied more than 800 patients with different formulations, dosages, and benefits. They also found out that CBD has mild side effects but is well tolerated.
You Know Cbd, So Maybe Its Time To Meet The Parent: Cbda
Psychedelic research labs sometimes rely on reference standards synthesized from modified psilocybin. An example is the acetylated, 4-ACO-DMT, which can be used to synthesize standards of a rare relative of psilocybin known as 4-HO-TMT. Rather than consume peculiar molecules, though, synthetic copies are better intended for clinical research or discovering substances in nature for the first time. He essentially broke down their approach into three stages and precise quantification of the main ingredients is the first. To take the initial step, Delic Labs had to first improve chromatography and extraction to be able to analyze those ingredients. Numinus has its own research exemption for psilocybin as well as other psychedelics.
The endocannabinoid system is an intricate network of internal communication. Put simply, cannabinoids control how cells communicate with one another, particularly within the brain and central nervous system. Cannabinoids are molecules that either carry or direct signals, or messages, between the body’s cells.
But the marvelous hemp plant offers many more wonderful cannabinoids that can support a healthier life. Some such compounds include cannabigerol and cannabinol , both of which are now being used because of their own unique natural benefits. Just as you should when shopping for CBD products, it’s important to find a manufacturer or raw hemp oil that you can trust.
In the U.S., the 2018 Farm Bill legalized industrial hemp production. Under the law, CBD products must contain less than 0.3% THC by dry weight. GW Pharma, the pharmaceutical company responsible for Epidiolex, has performed studies comparing the effects of CBDA vs CBD. In some studies, the team found that CBDA can have better bioavailability and a faster-acting effect than its parent compound. Simply explained, COX-2 is an enzyme that plays a role in the development of pro-inflammatory compounds called prostaglandins. This enzyme is a target of non-steroidal anti-inflammatory drugs , like aspirin and ibuprofen.
CBD products that have high THC content come from marijuana plants, while the majority of CBD products you see on the market are those that have a THC content of 0.3% or less. While CB1 primarily binds to the brain and nervous system, the CB2 receptor mainly interacts with our immune system. Our body naturally produces its own endocannabinoids, but when they are out of balance, we feel things like anxiety, stress, other mood disorders and may even have trouble sleeping. These cannabinoids are what causes the effects of marijuana , CBD, CBDA, and other cannabinoid products users have come to enjoy.
We don’t have an answer for that, however, the more cannabichromene’s effects are explored the more benefits are discovered. CBC appears to be swiftly catching up to its more famous siblings. With growing understanding of the healing, preventative, and wellness enhancing properties of cannabinoids, cannabis is gaining acceptance as a powerful natural modern medicine. As science analyzes the beneficial effects of THC and CBD on our endocannabinoid system, the better we understand how cannabinoids help our health.
Remember that cannabinoids control the body’s communication system. Cannabinoids intercept pain signals before they can reach the brain, and pain signals that don’t reach the brain aren’t felt. Cannabinoids are so effective at pain relief that many pain patients are replacing opioids with cannabis.
Are you looking for a way to boost the health effects of medical cannabis? Raw cannabis might provide some extra relief from pain, inflammation, and nausea. Whether you’re a first time CBDA user or just want to know more, it’s important to note that everyone is different. Like any other CBD products or CBD oil, it’s important to “start low and go slow” when trying out a new cannabinoid or cannabinoid acid.
So, in no way will the CBD skin-care products we are talking about get you high. When consumed, the cannabinoids interact with these receptors, which then send messages to the body’s various systems to get working. If you overheat, vape juices have a chance of converting the therapeutic and safe compounds into hazardous benzenes. While edibles with THC how long does cbd oil work have a reputation of being almost too potent for first timers, the digestive system doesn’t break down CBD the same way. “That’s not a whole lot of CBD to get any effects when you’re consuming it orally,” Capano said. Still, she points out that both alcohol and cannabinoids are processed through the liver, so it’s like drinking and taking a Tylenol.
When it comes to CBDA vs CBD research, our understanding of CBDA is only just beginning to develop. However, there are some other significant benefits that are worth mentioning. For those of you who are just dipping your toes into the CBD/health supplement waters, CBDA may indeed where can i buy delta 10 thc near me offer another good option to add to your health and wellness routine. CBDA is thought to be risk-free and comes without any high or potential risks related to THC . Additionally, CBDA appears to share most of the benefits CBD users seek, such as anti-anxiety properties and more.
Statements within these testimonials have not been clinically reviewed or evaluated by the FDA. Please consult your veterinarian about potential interactions or other what is full spectrum cbd oil uk possible complications before using any product. The information on our website is intended to inform the public in the most honest and transparent way possible.
Now there are a lot of people who are heading towards adding vegan products in their diet. Its a good way to get a healthy lifestyle and protect environment also. Dr. Caldwell Esselstyn has been able to reverse even very bad cases of cardiovascular disease by feeding his patients a low-fat vegan dietand saved countless lives. It’s widely acknowledged, even by major health organizations, that animal products rich in saturated fat and cholesterol are a major contributor to both heart disease and diabetes. The Receptra naturals Hemp Balm is an all-natural option to deal with pain.
In addition, then you have control over the carrier oil you want to use, as well as the potency. Unfortunately, though, there is very little regulatory oversight of CBD oil in general—even though vaping is one of the most popular ways of using the oil. In fact, the FDA has not yet determined how to regulate CBD vaping products just yet. But before you buy any CBD capsule or CBD pill, be sure to do your homework. First, check to see if a company is reputable through their reviews.
Strains can also be re-created to some extent by mixing and matching cannabinoids and terpenes. For example, a cannabis staiva strain such as Durban Poison contains a high amount of rare cannabinoid THCV. Durban Poison offers an energizing feel with less hunger than many cannabis strains. By combining THC with THCV oil one can have the intoxicating feel of the THC with the uplifting, stimulating, appetite suppressing properties of THCV. Hemp is a variety of cannabis that contains little or no THC , the psychoactive compound found in cannabis.
We’ve known that people eating plant-based tend to have healthier mood states—less tension, anxiety, depression, anger, hostility, and fatigue. This is due to the higher level of antioxidants in plant-based foods, particularly fruits and vegetables. Humans all over the world have to suffer because of the huge demand for animal products. I don’t want to up my dog’s prescription pain medication since there could be side effects, so by combining the CBD with his prescription, his pain is relieved.
As far as the debate between CBDa and CBD is concerned, evidence suggests that each cannabinoid has its own properties. This doesn’t answer the question of which one is better but instead suggests that each cannabinoid has its own specific attributes and effects on users. The process of decarboxylation occurs when applied heat removes a carboxyl group from a cannabinoid. By removing the carboxyl weedy huile de cbd group, the cannabinoid breaks down and transitions into another cannabinoid. With over a decade of experience writing about CBD and cannabinoids, Luke is an established journalist working as the lead writer for Cibdol and other cannabinoid publications. Committed to presenting factual, evidence-based content, his fascination with CBD also extends to fitness, nutrition, and disease prevention.
It minimizes large pores that produce too much oil and cause greasy skin. It has astringent properties, which help to tighten and firm skin. In addition, its high levels of anti-inflammatory CBD E-liquid and antioxidant properties can help to calm any existing acne that may be present. Hemp seed oil is harvested by cold-pressing the seeds of the cannabis plant. While it’s true that many people use these terms interchangeably, CBD oil and cannabis oil are actually two different things. Of course, this is just a few of the reasons that people are using CBD oil.
11-hydroxyl-THC, top left, is a more well-known version of THC that is created in the liver after digestion. This is not its own isomer of THC, but rather a hydroxylated version of D9-THC with a hydroxyl group at the eleventh position. So, we have covered all of the isomers of THC – inside the cyclohexene ring. There is still one more position the double-bond can move and that is up and outside of the molecule. In this configuration, there is a double-bond at the methyl group on the eleventh position situated above the conjunction between the eighth and ninth positions.
Texas Governor Abbott signed legislation clarifying which hemp products are legal and which are not. A hemp flower is the most basic form of CBD and serves as the foundation for all other CBD products … If you’re just starting to learn about CBD and its potential benefits, you likely have many questions. CBD oil products are everywhere now, but ambiguity surrounding the use of CBD oil still abounds, especially in the world … Anyone investigating the therapeutic potential of CBD has likely encountered more than a few sources claiming CBD products are legal … This level of transparency will enable you to know what cannabinoids are present in your product and at what concentration.
In a large study in over 13,000 people, increased arginine intake corresponded with decreased levels of C-reactive protein , an inflammation marker. The difference it makes to your body is incredible and he benefits just keep coming. Water-rich fruits and vegetables can give your skin an additional boost in health due to their high amounts of vitamins and minerals.
But some people prefer the all-natural form, even though it can be challenging to obtain. CBDA is more water-soluble than CBD, allowing your body to absorb and utilize it more efficiently. They are taken for their stimulating properties and may aid weight loss by suppressing CBD Tincture appetite . Rare Cannabinoid Company has the strongest THCV gummies on the market. This is a document that shows the results of lab testing for contaminants and cannabinoid potency. Reviewing the COA is important as it can help consumers avoid fake or contaminated products.
However, CBD tinctures, which are sold in those pretty glass bottles sealed with a dropper, are more ambiguous. CBDa is actually deemed as one of the most prevalent constituents in hemp plants. In scientific terms, CBDa is a cannabinoid acid, not technically a cannabinoid—yet. CBDa happens due to a synthase process during the growth process of the plant, and is later converted into CBD.
The study also discovered that the terpene pinene counteracted THC’s ability to compromise memory. Interestingly, that same study found that CBD and terpene limonene could potentially work together to help calm anxiety. In short, these fantastic gummies can help you feel rested and rejuvenated so that you can power through your busy day.
Once these precursor acids are exposed to heat or other actions, the acids decarboxylate, losing their acid molecules. Therefore, CBDa translates into CBD; likewise, THCa would translate into THC. Terpenes are molecules that are found in hemp, cannabis, and other plants. These molecules interact with the human endocannabinoid system and are responsible for many of the different scents and flavors of the plants. Some terpenes such as linalool and myrcene are known to have relaxing and sedative effects. Others such as limonene and pinene are known to be stimulating and energizing.
The parent of CBD may just have something valuable to offer all of us. It is said to be three times as strong as THC and has been called “the psychedelic cannabinoid” for its borderline hallucinatory effects. Because it is derived from hemp, and not from cannabis, it is skirting the law in many states.
You can rest assured that their oils are high quality because they are USDA Organic certified. Their oil is sourced from plants grown in Colorado and are free of harmful substances, including parabens, sulfates, phthalates, formaldehyde, and other toxins. CBDPure sources their oils from plants grown in Washington and Colorado. You don’t have to worry about being exposed to harmful chemicals because their plants are organically grown. It is unlikely you will be able to determine how fresh the buds are by how they look. When purchasing other hemp-derived products, your CBD has a clear expiration or “best by” date.
But there’s now research showing high doses can increase blood glucose. GLA (gamma-linolenic acid) is an omega-6 fatty acid that has anti-inflammatory benefits. It helps with hormone balance how to use cbd oil for ibs and supports your dog’s coat and skin. The herb possesses natural cooling properties that soothe the skin, relieving it of skin inflammations and rashes during scorching heat. We believe that they are one of the few people who really care about the well-being of customers. They have never concealed the legalization of marijuana to inform the public about its real benefits.
Exposure to heat initiates a process called decarboxylation that converts the carboxylic acid into carbon dioxide and hydrogen, the chemical composition of CBD. Inflammation is a natural and important response to stress, injury, and illness. However, chronic inflammation is painful and can be detrimental to health. Laboratory research performed in cell cultures has found that CBDa has potential anti-inflammatory properties.
Recent preprint studies performed by OHU have found that CBDa can impact the spread of Covid in the body by aiding the bodies innate immune response. Different types of CBD products have unique things to offer, and no single product will suit every individual. We hope the information below helps explain about the different types as you begin your CBD journey. Is comprised of a multidisciplinary team of doctor and researchers who are all united by wanting to help others through the therapeutic benefits of cannabis. However, CBDA and other acidic forms of cannabinoids don’t affect the body’s endocannabinoid system in the same way that their decarboxylated forms, like CBD and THC, do. When investigating cannabis products, it’s easy to become overwhelmed by all the varieties available.
You can find CBDistillery’s products online on their website, as well as over 1,500 retailers across the United States. They have been featured in stories by CNN, USA Today, and PopSugar. They have a pretty impressive history, and the future looks just as bright for this CBD company. Use has been widely documented across cultures as an anti-inflammatory, pain reliever, anti-seizure, and recreational enjoyment. 4,700 years document the medicinal use of cannabis, including indigineous populations in China, India, and Tibet.
Sweet almond oil is a highly effective, easily absorbed skin softener and conditioner. It contains a number of important fatty acids, vitamins, and minerals to soothe dry, irritated dog snouts. Many people use vitamin E supplements in the hopes that the vitamin’s antioxidant properties will prevent or treat disease. But studies of vitamin E for preventingcancer, heart disease, diabetes, cataracts, and many other conditions have been disappointing. Gummies are a popular way to take CBD since they are small, discreet, and come in a variety of flavors. Although you can use CBD gummies to help with painful joints and muscles, or to help bring in a sense of calm to your day, did you know that you can also use them to help with sleep?
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DCS cs Title of Assignment: Diabetes Case Study Purpose of Assignment: Complications from endocrine disorders can result in wide systemic effects.
cs
Title of Assignment:
Diabetes Case Study
Purpose of Assignment:
Complications from endocrine disorders can result in wide systemic effects. Analyzing disorders related to the endocrine system can be complex. Consideration of an endocrine case study will help the student learn the complexities of understanding the pathophysiology of an endocrine disorder.
Using the case study below, prepare a 3 page paper.
Diabetes Case Study
A 21-year old female (A.M.) presents to the urgent care clinic with symptoms of nausea, vomiting, diarrhea, and a fever for 3 days. She states that she has Type I diabetes and has not been managing her blood sugars since she’s been ill and unable to keep any food down. She’s only tolerated sips of water and juices. Since she’s also been unable to eat, she hasn’t taken any insulin as directed. While helping A.M. from the lobby to the examining room you note that she’s unsteady, her skin is warm and flushed, and that she’s drowsy. You also note that she’s breathing rapidly and smell a slight sweet/fruity odor. A.M. has a challenge answering questions but keeps asking for water to drink.
You get more information from A.M. and learn the following:
· She had some readings on her glucometer which were reading ‘high’
· She vomits almost every time she takes in fluid
· She hasn’t voided for a day but voided a great deal the day before
· She’s been sleeping long hours and finally woke up this morning and decided to seek care
Current labs and vital signs:
1. What is the disorder and its pathophysiology that you expect the health care provider to diagnose and treat?
2. Describe the etiology of the disorder A.M. is experiencing.
3. Identify and describe the clinical manifestations of the disorder A.M. is experiencing.
4. Identify and describe the expected treatment options for A.M. based on the disorder and clinical manifestations.
Instructions:
Summarize the questions above and formulate what may be happening with A.M. and the expected treatments to improve her condition.
Use at least one scholarly source to support your findings. Examples of scholarly sources include academic journals, textbooks, reference texts, and CINAHL nursing guides. Be sure to cite your sources in-text and on a References page using APA format.
Chart information
Vital signs
Blood pressure: 88/46 mmHg
Additional data
Lab results
Glucose: 657 mg/dl
Heart rate: 132 bpm
Respiratory rate: 36/min, deep
Temperature: 101.30 F (tympanic)
Potassium: 6.2 mEq/L
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Understanding ADHD in Adults: Navigating Life with Attention Deficit/ Hyperactivity Disorder
adhd
Although ADHD is most easily recognized in children, many adults, even much older in life, suffer similar consequences. In the last decade, adult ADHD has gradually been receiving more acknowledgment, and only then have the unique difficulties been identified of those who grapple with this neurodevelopmental condition throughout their lives.
What Is Adult ADHD?
ADHD is one of the behavioural conditions, which means a person has restlessness, difficulty in concentrating, and impulsive behaviour. ADHD is usually diagnosed among children, but childhood is not the only period of its prevalence. Many adults continue dealing with symptoms of ADHD, which can significantly affect one’s behaviour and quality of life as an adult. Characteristics of adult ADHD should be realized so that measures could be undertaken to manage it well, thereby improving one’s quality of life.
Causes of ADHD in Adults
The exact cause of ADHD is not known, but several possible factors are currently being researched:
• Genetic Factors: ADHD is said to run in the family, which may help shed light on its genetic component. Parents and siblings of one with ADHD are more likely to have this condition.
Brain Differences: Brain scans reveal that in the majority of ADHD subjects, structural differences have been evidenced in their brains. Some parts of their brains could be either underdeveloped or overdeveloped, while others may have an imbalance in the neurotransmitter levels.
Early Life Factors: Pre-maturity at birth, low birth weight, brain damage, epilepsy all can raise the threshold of susceptibility to ADHD.
• Unidentified Causes: Sometimes ADHD was not diagnosed at all in childhood and is revealed in adult life. The symptoms lighten with age, but many adults still continue to have problems.
Types of Adult ADHD
There are three main types of ADHD that an adult can have:
1. Inattentive ADHD: Difficulty to pay attention, disorganization, often losing things, and difficulties to follow instructions. This type was earlier called ADD.
2. Hyperactive/Impulsive ADHD: Impulsive behaviour, too much activity or restlessness, and having a hard time remaining seated; speaking excessively and interrupting.
3. ADHD Combined: Combined is the most common type of ADHD in which symptoms of both inattentive and hyperactive/.
The Signs and Symptoms of ADHD in Adults
Adults with ADHD encounter several challenges that could affect several life aspects:
• Poor Concentration and Focus: The difficulty in maintaining attention can lead to disturbances that interfere with academic and professional performance.
Over-Concentration: High attention to stimulating tasks helps but may result in other duties being ignored.
• Poor Time Management: Timekeeping challenges, underestimation of task duration, and distractions lead to procrastination.
Organizational Challenges: Time management problems turn organizing responsibilities into a gruelling task.
Difficulty Starting Tasks: Procrastination is common, especially when it comes to tasks needing a lot of attention.
Restlessness: Restless, adults with ADHD will find it hard to relax and will usually take up active jobs.
Emotional Control: Impulsivity and a rapidly changing anger challenge emotional regulation.
Relationship Struggles: Poor listening and unmet commitments.
Diagnosis of ADHD in Adults
Diagnosing ADHD in adults involves a comprehensive assessment by a healthcare professional. This may include:
• Physical Examination: To exclude any other medical cause for the symptoms.
Psychological Testing: For mental health and behavioural assessment.
Review of health history: Discussion on past and current symptoms, and the impact on quality of life.
Treatments for Adults with ADHD
In most cases, multimodal treatment is needed to manage ADHD in adults:
• Medication: Stimulant medications, typically used in prescription, include methylphenidate and amphetamines. Also taken are non-stimulant options.
Therapy: Therapies of behavioural nature, such as cognitive-behavioural therapy, can help in designing coping strategies and time management.
Lifestyle Changes: Regular exercise, adequate sleep, and a well-balanced diet help to improve symptoms.
Support Groups: Interacting with fellow ADHD individuals will offer insight, encouragement, and support in a community.
Conclusion
ADHD among adults is a serious but manageable condition. Appropriate diagnosis, support, and creation of personalized treatment approaches will help an ADHD adult to identify strengths, minimize negative impacts of their problem areas, and be able to function in society effectively. If you think you or someone you know might have ADHD, seek professional help in order to get a full assessment and proper intervention.
Share it with someone you care.
Reference: Manage My Health – Discover Health
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E-Cigarettes – Most Common And Safest Smoking Threats
E-Cigarettes – Most Common And Safest Smoking Threats
Vaporizing: HEALTH THREATS, Popularity and Socio-economic Impact Vaping or e cigarettes have become extremely popular over recent years. It comes in many different shapes and sizes, incorporating trendy flavors and customizable add-ons. Considered a slick tobacco alternative, they are appealing to both adults and old alike. But recent reports reveal a steadily increasing lung disease associated with vaporizing. This is a short list of the most frequent vaporizing health threats.
vaping health risks
Many teens and students are unaware of the adverse affects that utilizing the cigarettes can have on their lungs. With little or no risk to your health, vaporizing cigarette butts can drastically decrease the Vape Pen volume of toxins inhaled by way of a smoker. A study published in May 2021 reports that among high school students, there exists a significant link between the amount of cigarette butts smoked and the increased threat of cardiovascular disease. As smoking becomes popular amongst teenagers and young adults alike, the chance of vaporizing cigarette butts will continue steadily to increase in tandem.
Among the newest issues to face the planet due to our reliance on electronic cigarettes is heart disease. IN-MAY of 2021, researchers published a study which found strong evidence that longterm side effects of tapering cigarettes are dangerous to your health. The report directly cites two main findings which directly contradict each other. According to the research, longterm use of the cigarettes escalates the risk of heart disease. However, the second finding demonstrates although long term side effects of e cigarette smoking may result in a higher risk of heart disease, it is unlikely to cause death.
Lots of people may be surprised to get that vaporizing your own cigarettes can result in serious lung damage. Because some vapers usually do not yet recognize that the temperature they use to heat up their device can severely damage the cells and tissues within the outer layers of the lungs. Damage caused by prolonged smoking can also lead to weakening of the esophageal sphincter, that is responsible for maintaining the strength of the walls of your lungs.
Long term use of any vaporizing device may also negatively affect the mind. Children who smoke while using the cigarettes have been proven to have slower reflexes and so are more prone to experience short attention spans. Longterm exposure can even bring about the loss of mental faculties. This is one of the primary e-cigarette smoking dangers and one of why it has become so difficult for parents to avoid teens from getting involved with this harmful activity.
The ultimate vaporizing health risks we will discuss are the ramifications of long term use of the unit. Nicotine in the liquid used in most vaporizers can stay in your system for up to six hours after you finish smoking. Therefore you could be exposing your body to cigarette toxins for much longer than you realize. E cigarettes, due to their porous and thin nature, can absorb a substantial amount of tar and toxic gases in to the body. Tar deposits can build-up on the lungs and in severe cases cause cancer. Nicotine is highly addictive and may be a remarkably hard habit to break.
Just about the most common complications of long-term nicotine use is lung injury. The liquid may enter the lungs through the mouth and nose and get into the airways, where it continues to irritate the lining of the lungs. The more frequent and longer the smoker uses the device, the more chance that he or she will develop chronic lung injuries. Chronic nicotine use is one of the biggest of using tobacco dangers and the sort of lung injury that may develop is very severe.
Chronic bronchitis is an extremely serious condition that may develop if a smoker will not quit. Chronic bronchitis is caused by the constant irritation of the liner of the lungs. If it goes untreated, then it can turn into pneumonia, that can be deadly. Nicotine in addition has been linked to cases of skin rash and oral cancer. E using tobacco is one of the biggest verified deaths due to the hazards of the product and the risk that it poses to your health.
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Which snake is more poisonous king cobra or black mamba?
Which snake is more poisonous king cobra or black mamba?
In general, Black Mamba has more dangerous venom when compared to the King Cobra because it contains dangerous components including Calciseptine, Cardiotoxins, and Neurotoxins. To conclude, the king cobra is the most dangerous snake in the world, and it will easily win during the head to head fight.
Can a human outrun a Black Mamba?
The fastest snake happens to be the black mamba. The black mamba can travel up to 12 mph in short bursts, which is faster than humans. Though speeds of this snake have sometimes been exaggerated in myths and legends, the average person could not outrun this snake once it has locked you in its sight.
Which is the deadliest snake in the world?
What is the black mamba? Black mambas are fast, nervous, lethally venomous, and when threatened, highly aggressive. They have been blamed for numerous human deaths, and African myths exaggerate their capabilities to legendary proportions. For these reasons, the black mamba is widely considered the world’s deadliest snake.
What kind of venom does a black mamba snake have?
The venom of the black mamba is a protein of low molecular weight and as a result is able to spread rapidly within the bitten tissue. The venom of this species is the most rapid-acting venom of any snake species and consists mainly of highly potent neurotoxins; it also contains cardiotoxins, fasciculins, and calciseptine.
How long does it take a black mamba to kill a human?
This kind of snake uses highly toxic venom to kill its prey. If a man accidentally get a bite from black mamba, and there is no rapid antivenom treatment available, he can expect his death within 20 to 60 minutes. This time duration may vary depends on the nature of bite. The minimum recorded time of death is calculated as 20 minutes.
Is the black mamba snake faster than a horse?
The black mamba’s bite is called the “kiss of death,” and it’s said to balance on the end of its tail, towering over victims before striking. The snake is also believed to slither faster than a man or horse can run. However, despite this fearsome reputation, many of the legends are false.
What is the black mamba? Black mambas are fast, nervous, lethally venomous, and when threatened, highly aggressive. They have been blamed for numerous human deaths, and African myths exaggerate their capabilities to legendary proportions. For these reasons, the black mamba is widely considered the world’s deadliest snake.
The Black Mamba is one of the most-deadliest snakes in the world. Its venom is composed primarily of neurotoxins, and can induce symptoms within ten minutes after biting. Black Mamba bites are often fatal if antivenom is not administered rapidly, as the venom quickly attacks both the central nervous system and heart of its victims.
What kind of animal is the Black Mamba?
Black mambas are fast, nervous, lethally venomous, and when threatened, highly aggressive. They have been blamed for numerous human deaths, and African myths exaggerate their capabilities to legendary proportions.
Why are black mamba bites so deadly to humans?
This aspect, alone, is one of the main reasons that Black Mamba bites are so potent and deadly, as “dry bites” (bites that fail to produce envenomation) rarely occur with this particular species.
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RARA fusion genes in acute promyelocytic leukemia: a review.
Abstract
The t(15;17)(q24;q21), generating a PML-RARA fusion gene, is the hallmark of acute promyelocytic leukemia (APL). At present, eight other genes fusing with RARA have been identified. The resulting fusion proteins retain domains of the RARA protein allowing binding to retinoic acid response elements (RARE) and dimerization with the retinoid X receptor protein… (More)
DOI: 10.1586/17474086.2014.903794
Topics
Cite this paper
@article{Braekeleer2014RARAFG, title={RARA fusion genes in acute promyelocytic leukemia: a review.}, author={Etienne de Braekeleer and Nathalie Douet-Guilbert and Marc de Braekeleer}, journal={Expert review of hematology}, year={2014}, volume={7 3}, pages={347-57} }
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Effects of Sequential Bouts of Resistance Exercise on Androgen Receptor Expression
WILLOUGHBY, DARRYN S.; TAYLOR, LEMUEL
Medicine & Science in Sports & Exercise: September 2004 - Volume 36 - Issue 9 - p 1499-1506
doi: 10.1249/01.MSS.0000139795.83030.D1
BASIC SCIENCES: Original Investigations
Free
WILLOUGHBY, D. S., and L. TAYLOR. Effects of Sequential Bouts of Resistance Exercise on Androgen Receptor Expression. Med. Sci. Sports Exerc., Vol. 36, No. 9, pp. 1499–1506, 2004.
Purpose: Increased serum testosterone (TST) occurs in response to resistance exercise and is associated with increased muscle mass. However, the effects of elevated TST and sequential resistance exercise bouts on androgen receptor (AR) expression in humans are not well known. This study examined three sequential bouts of heavy-resistance exercise on serum total TST, sex hormone-binding globulin (SHBG) and free androgen index (FAI), skeletal muscle AR mRNA and protein expression, and myofibrillar protein content.
Methods: Eighteen untrained males were randomly assigned to either a resistance-training [RST (N = 9)] or control group [CON (N = 9)]. RST performed three lower-body resistance exercise bouts, each separated by 48 h. At each exercise bout, RST performed three sets of 8–10 repetitions at 75–80% one-repetition maximum using the squat, leg press, and leg extension exercises, respectively, whereas CON performed no resistance exercise. Muscle biopsies were obtained immediately before the first exercise bout and 48 h after each of the three bouts, whereas blood samples were obtained immediately before, immediately after, and 30 min after each bout. Data were analyzed with two-way ANOVA and bivariate correlations.
Results: Serum TST and FAI were significantly increased after each exercise bout (P < 0.05); however, there were no significant changes for SHBG. AR mRNA and protein were significantly increased (P < 0.05) after the second and third exercise bouts, respectively, and were significantly correlated to TST and FAI (P < 0.05). Myofibrillar protein increased after the third bout (P < 0.05).
Conclusions: Three sequential bouts of heavy resistance exercise increases serum TST and are effective at up-regulating AR mRNA and protein expression that appears to correspond to subsequent increases in myofibrillar protein.
Exercise and Biochemical Nutrition Laboratory, Department of HHPR, Baylor University, Waco, TX
Address for correspondence: Darryn S. Willoughby, Ph.D., FACSM, Department of Health, Human Performance, and Recreation, Baylor University, P.O. Box 97313, Waco, TX 76798; E-mail: [email protected].
Submitted for publication January 2004.
Accepted for publication May 2004.
Testosterone (TST) is a steroid hormone that is not freely soluble in blood. Consequently, the majority (~98%) of this hormone is bound to either sex hormone-binding globulin [~40% (SHBG)] or albumin (11); therefore, only the unbound or free TST is considered to be biologically active where it can readily diffuse across the sarcolemma, allowing it to interact with intracellular androgen receptors (AR) and activate downstream androgen-signaling mechanisms. Previous studies have shown that elevated serum TST increases AR expression in proliferating myoblasts (23) and may be associated with elevated myofibrillar protein synthesis.
Resistance exercise is known to induce acute increases in serum TST levels that can vary depending on exercise-related variables such as intensity (27), volume (13), an acute bout (1), sequential bouts (22,28), and type of muscular contractions (4,11). Only one of these studies investigated AR mRNA expression after a single bout of resistance exercise (4); however, apparently no studies have examined the effects on AR mRNA and protein expression after sequential bouts of resistance exercise. The increased TST observed following resistance exercise is typically not associated with significant changes in SHBG levels (13). This is noteworthy because both the unbound/active fraction of TST and the total TST level is increased with resistance exercise. Consistent elevations in serum TST resulting from resistance exercise may enhance androgen-AR interactions within skeletal muscle and, along with increased number of AR, may up-regulate the expression of various muscle-specific genes (15). This is due to the fact that the binding of TST to its ligand-binding domain transforms the AR to an active transcription factor that regulates gene expression by interacting in a ligand-specific manner with a specific regulatory DNA sequence known as the androgen response element (ARE) located within the promoter of muscle-specific genes (19). Therefore, the central element of androgen signaling in skeletal muscle is the androgen-AR complex, and this signaling pathway likely plays a key role in regulating the hypertrophic response to resistance training (18).
In regard to AR signaling, muscle hypertrophy induced by electrical stimulation in rodents administered an AR antagonist (16) seems to suggest that the androgen-AR signaling pathway has a significant effect in exercise-induced muscle hypertrophy and emphasizes the importance of the AR in exercised muscle. A single bout of lower-body resistance exercise has been shown to significantly increase AR mRNA expression in humans (4); however, the responsiveness of the AR gene to sequential resistance exercise bouts characteristic of a typical training program along with the specific role that an up-regulation in AR expression may have on myofibrillar protein content is not well known. Therefore, rather than employ a single bout of resistance exercise, we attempted to determine the effects of three sequential bouts of heavy lower-body resistance training within a 7-d period (characteristic of a typical training regimen) on serum TST and SHBG levels, AR mRNA and protein expression, and myofibrillar protein. We hypothesized that heavy resistance exercise would increase serum TST and correspond to an increase in AR expression and myofibrillar protein content.
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METHODS
Approach to the problem.
As previously mentioned, many studies have shown elevated TST responses to heavy resistance exercise that vary in terms of the intensity, duration, volume, and types of muscular contractions. However, in lieu of the increased TST levels in these aforementioned studies, the critical element for AR signaling, the expression of the AR, has chiefly gone undetermined in human skeletal muscle in response to heavy resistance exercise. Because any TST-induced effects on skeletal muscle hypertrophy resulting from resistance exercise will likely occur by way of its AR interaction and subsequent transcription activation of muscle-specific genes, of primary purpose in relation to the AR was an attempt to determine the relative effects on AR mRNA and protein expression in response to sequential bouts of heavy-resistance exercise.
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Participants.
The present study included 18 apparently healthy, untrained (had not participated in any consistent resistance training involving the lower body or ingested any nutritional supplements for at least 6 months before the study) males comprising either a resistance exercise [RST (N = 9)] or a control [CON (N = 9)] group. Participants within the RST group had and average (±SD) age of 19.36 ± 2.17 yr, height of 181.60 ± 9.88 cm, and total body mass of 87.65 ± 20.24 kg, whereas the CON group was 20.66 ± 1.82 yr, 181.45 ± 2.16 cm, and 91.83 ± 13.91 kg. Before being considered eligible for the study, all participants were to be nonsmokers who agreed to abstain from using any caffeine and alcohol for at least 48 h before testing or the exercise trials, to limit their participation to any resistance training to only that involved in the study, and to abstain from ingesting any nutritional supplements for the duration of the study. Participants with contraindications to exercise as outlined by the American College of Sports Medicine (2) were not allowed to participate. All eligible participants signed university-approved informed consent documents, and approval was granted by the Institutional Review Board for Human Subjects. Additionally, all experimental procedures involved in the study conformed to the ethical consideration of the Helsinki Code. The subjects were explained the purpose of the training program, the protocol to be followed, and the experimental procedures to be used.
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Strength testing.
Approximately 12 d before the first resistance exercise session, all participants were subjected to a testing session in which each subject’s lower-body maximum strength [one-repetition maximum (1-RM)] was determined using the free-weight barbell squat, bilateral leg press, and leg-extension exercises (Cybex-Eagle, Owatonna, MN). For the three exercises, subjects were required to lower the resistance to approximately 90° of knee flexion. A rest interval of 3 min was required between attempts. However, due to the possibility of fatigue as a result of excessive trials (i.e., > five trials) during 1-RM testing, based on our previous work, a goal of no more than five trials was set for all 1-RM testing sessions throughout the study (30). All participants were able to obtain their 1-RM within five, and the average (±SD) trials for all subjects over the four 1-RM testing sessions was 4.17 (0.82). Upon arrival to the laboratory for testing, all participants were instructed perform a slow jog for 5 min as a warm-up. All participants were then lead through a stretching protocol to stretch the leg and lower-back areas. The stretching protocol involved static stretching of three sets for a 10-s count for each stretch. The stretches that were used were the standing quad stretch, toe touches, the adductor stretch, sit-and-reach stretch, and the knee to chest stretch. After stretching, participants were instructed to do two warm-up sets of 10 repetitions at 55% and 65% of their perceived 1-RM separated by 3 min. The 12-d time lapse between the 1-RM testing session and the first exercise session was chosen to allow for any up-regulation in mRNA and/or for AR protein expression to return to baseline levels. Also, this period of time would not likely result in significant strength decrements to occur from strength testing before the first session was conducted (21).
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Resistance exercise protocol.
Only the RST group participated in the three resistance exercise sessions. However, the CON group was required to be in attendance at each exercise session and also underwent muscle biopsies and blood sampling at the same time intervals as the RST group. The exercise sessions utilized the same warm-up and stretching protocol that was used before 1-RM testing (walk/jog, stretch, submax sets). The exercise sessions also occurred at the same approximate time of day as the 1-RM testing for each participant. The training sessions were separated by 48 h for rest and recovery. Using the order principle and performing multi-joint before uni-joint exercises (3), the protocol involved three sets of 8–10 repetitions at 75–80% of the subjects 1-RM on each of the three exercises (squat, leg press, and leg extension). For every repetition of each exercise, subjects were required to lower the resistance to approximately 90° of knee flexion. Resistances were adjusted accordingly during the exercise bouts if a participant could not complete the exercise so that each set of each exercise was performed within the desired range of 8–10 repetitions. Rest intervals of 3 min were required between each set and exercise. The duration of each bout was approximately 50 min from warm-up to completion. At the conclusion of the study, it was shown that for all three exercise bouts the RST group completed all three exercises contained within each bout for an average (±SD) of 8.98 (0.08) repetitions and a relative intensity of 75.4% (5.66).
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Muscle biopsies and venous blood sampling.
Consistent with previous work, we elected to biopsy the vastus lateralis muscle 48 h after the exercise bouts (4) so that the sample time coincided with data suggesting increased mixed muscle protein synthesis after an acute bout of heavy resistance exercise (24). Percutaneous muscle biopsies were obtained immediately before each exercise session (48 h after session 1 and 2) and 48 h after the third session. Upon receiving a local anesthetic (2% Xylocaine with epinephrine), muscle samples were obtained using the fine needle aspiration procedure and a 16-gauge biopsy needle (Medical Device Technologies, Gainesville, FL). An average (±SD) of 6.32 (2.94) mg of muscle was obtained from the middle portion of the right vastus lateralis muscle at the midpoint between the patella and the greater trochanter of the femur at a depth between 1 and 2 cm. For biopsies 2–4, attempts were made to extract tissue from approximately the same location by using the previous biopsy puncture scar, depth markings on the needle, and a successive puncture that was made approximately 0.5 cm to the former from medial to lateral (30). After removal, muscle specimens were immediately frozen in liquid nitrogen and then stored at −80°C for later analysis.
There was a total of nine blood draws over a 7-d period. The blood draws took place immediately before, immediately after, and 30 min after each exercise session. Venous blood samples were obtained from the antecubital vein into a 10-mL collection tube using a standard Vacutainer apparatus standardized to the same time of day for each sample. Blood samples were allowed to stand at room temperature for 10 min and then aliquots were used to assess plasma volume (10) while the remaining blood was centrifuged at 800 × g for 10 min. The serum was removed and frozen at −80°C for later analysis.
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Total RNA isolation.
Total cellular RNA was extracted from the homogenate of biopsy samples with a monophasic solution of phenol and guanidine isothiocyanate (7) contained within the TRI-reagent (Sigma Chemical Co., St. Louis, MO). The RNA concentration was determined by optical density (OD) at 260 nm (by using an OD260 equivalent to 40 μg·μL−1) (8), and the final concentration was adjusted to 1 μg·μL−1. Aliquots (5 μL) of total RNA samples were then separated with 1% agarose gel electrophoresis, ethidium bromide stained, and monitored under an ultraviolet light (Chemi-Doc, Bio-Rad, Hercules, CA) to verify RNA integrity and absence of RNA degradation. This procedure yielded undegraded RNA, free of DNA and proteins as indicated by prominent 28s and 18s ribosomal RNAbands (Fig. 1), as well as an OD260/OD280 ratio of approximately 2.0 (8). The RNA samples were stored at 380°C until later analysis.
FIGURE 1
FIGURE 1
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Reverse transcription and cDNA synthesis.
Two micrograms of total skeletal muscle RNA were reverse transcribed to synthesize cDNA. A reverse transcription (RT) reaction mixture [2 μg of cellular RNA, 10× reverse transcription buffer (20 mM Tris-HCL, pH 8.3; 50 mM KCl; 2.5 mM MgCL2; 100 μg of bovine serum albumin per milliliter), a dNTP mixture containing 0.2 mM each of dATP, dCTP, dGTP, and dTTP, 0.8 μM MgCl2, 1.0 u·μL−1 of rRNasin (ribonuclease inhibitor), 0.5 μg·μL−1 of oligo(dT)15 primer, and 25 u·μg−1of AMV reverse transcriptase enzyme (Promega, Madison, WI)] was incubated at 42°C for 60 min, heated to 95°C for 10 min, and then quick-chilled on ice. Starting template concentration was standardized by adjusting the RT reactions for all samples to 200 ng before PCR amplification (30).
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Oligonucleotide primers for PCR.
The following 5′ sense and 3′ antisense oligonucleotide primers were constructed using Primer 3 online software (http://www.broad-.mit.edu/cgi-bin/primer/primer3_www.cgi) and used to isolate the mRNA expression of the skeletal muscle AR (5′ primer: bases 2804–2824, GC% = 60, Tm = 59.99°C; 3′ primer: bases 3272–3252, GC% = 50, Tm = 59.89°C, GenEMBL M34233). These primers were shown to amplify a PCR fragment of 469 bp. Due to its consideration as a constitutively expressed “housekeeping gene,” glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an external reference standard for detecting the relative change in the quantity of AR mRNA using PCR. For GAPDH mRNA (5′ primer: bases 616–636, GC% = 55, Tm = 60.12°C; 3′ primer: bases 1189–1169, GC% = 55, Tm = 59.96°C, GenEMBL AC NM 002046), we have previously shown these primers to amplify a PCR fragment of 574 bp (30).
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PCR amplification.
A total of 200 ng of cDNA were added to each of the 25-μL PCR reactions for GAPDH and AR. Specifically, each PCR reaction contained the following mixtures: [10× PCR buffer, 0.2 μM dNTP mixture, 1.0 μM of a cocktail containing both the sense and antisense RNA oligonucleotide primers (Ransom Hill Biosciences, Ramona, CA), 2 mM MgCL2, 1.0 u·μL−1 of Taq DNA polymerase (Sigma, St. Louis, MO), and nuclease-free dH2O]. Each PCR reaction was amplified with a thermal cycler (Bio Rad). The amplification profile involved a denaturation step at 95°C for 30 s, primer annealing at 55°C for 30 s, and extension at 72°C for 60 s (30). To help control for differences in amplification efficiency during thermocycling, all PCR reactions were prepared from the same stock solution. Also, the number of cycles was optimized at 25 so that the amplified signal was still on the linear portion of a plot with the yield expressed as a function of the absorbance at OD260 and the number of cycles for the two target amplifications (Fig. 2A). The specificity of the PCR was demonstrated with an absolute negative control using a separate PCR reaction containing no cDNA. To assess reliability between amplifications, two separate PCR amplifications were performed for each sample to control for systemic differences between samples that could affect amplification efficiencies. Intra-assay coefficients of variation in mRNA concentrations for the two PCR runs for all participants were performed and resulted coefficients of variation of 3.85% and 4.12%, respectively, for GAPDH and AR mRNA. Additionally, the external control standard GAPDH displayed only a small amount of variation in expression from one sampling point to the next. Considering sampling point 1 as the baseline, the variation between sampling points 1–2, 1–3, and 1–4 were 5.12%, 7.34%, and 6.88%, respectively, for CON; and 5.48%, 6.34%, and 6.26% for RST, respectively (Fig. 2B).
FIGURE 2
FIGURE 2
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mRNA quantitation.
The DNA within each amplified PCR reaction was purified of contaminants such as primer dimers and amplification primers using the Wizard PCR Preps DNA Purification System (Promega, Madison, WI). Aliquots (20 μL) of the purified PCR reaction mixtures were electrophoresed in 1.5% agarose gels in 1X Tris-Acetate-EDTA (TAE) buffer to verify positive amplification of AR mRNA and the gel stained with ethidium bromide (present in the TAE buffer at 1 μg·mL−1) and illuminated with UV transillumination (Chemi-Doc, Bio-Rad). Aliquots of each remaining purified PCR reaction were used to quantify mRNA spectrophotometrically at a wavelength of OD260, at which point the mRNA concentration of AR was calculated and normalized relative to GAPDH (25). It should be noted, however, that this method of PCR quantitation determines relative mRNA concentration only and should not be interpreted as absolute concentration values.
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Serum testosterone and SHBG quantification.
The concentrations of serum total TST and SHBG were determined in duplicate and the average concentrations reported using an enzyme-linked immunoabsorbent assay (ELISA) (30) incorporating human-specific monoclonal antibodies against total TST and SHBG (Research Diagnostics Inc., Flanders, NJ). The secondary antibody immunoglobulin-G (IgG) was conjugated to the enzyme horseradish per-oxidase (ICN Biomedical, Aurora, OH). Standard curves were generated for TST (r2 = 0.95, P = 0.004) and SHBG (r2 = 0.91, P = 0.01) using specific control antigens for TST and SHBG (Research Diagnostics Inc., Flanders, NJ). The concentrations of TST and SHBG were determined at an optical density of 450 nm with a microplate reader (Bio Rad) and expressed relative to plasma volume. Intra-assay coefficients of variation were determined for each duplicate for all subjects and resulted in coefficients of 3.87% and 4.06% for TST and SHBG.
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Free androgen index.
Based on previous work (22), the free androgen index (FAI) was determined as an indirect measurement of biologically active TST. The FAI (total TST/SHBG) is an indicator of the ratio of total TST concentration to the concentration (or binding capacity) of SHBG. In males, the central range encompassing the 95th percentile is 15% to 95%, with a corresponding median value of 35% (29).
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Skeletal muscle androgen receptor quantification.
Muscle protein was isolated from the organic phase of the total RNA isolation using ethanol, isopropanol, and a 95% ethanol solution containing 0.3 M guanidine hydrochloride (30). The binding affinity of the anti-AR and selected purified protein samples was qualitatively verified with dot blotting (Fig. 4A) using a standard immuno-blotting protocol (Immuno-Blot Colorimetric Assay Kit, Bio-Rad). Briefly, equal amounts of myofibrillar protein extract (20 μg) were blotted onto a nitrocellulose membrane, blocked with 2% gelatin in TBS buffer, incubated with the a polyclonal anti-AR antibody (5 μg·mL−1) (Santa Cruz Biotech, Santa Cruz, CA), incubated with a secondary IgG antibody conjugated to alkaline phosphatase, and the color developed with BCIP/NBT. The blot was then illuminated with white light transillumination (Chemi-Doc, Bio-Rad).
FIGURE 4
FIGURE 4
Based on our previous procedures (30), the AR concentrations were then quantified in duplicate and the average concentrations reported using an ELISA (Fig. 4B). This incorporated the same human-specific poly-clonal anti-AR antibody (5 μg·mL−1) we used for immuno-blotting. The secondary antibody immunoglobulin-G (IgG) was conjugated to the enzyme horseradish peroxidase (ICN Biomedical, Aurora, OH). A standard curve was generated for AR (r2 = 0.92, P = 0.003) using a specific control antigen for AR (Research Diagnostics Inc., Flanders, NJ). Skeletal muscle AR concentrations were determined at an optical density of 450 nm with a microplate reader (Bio-Rad) and expressed relative to myofibrillar protein content. An intra-assay coefficient of variation was determined for each duplicate for all subjects and resulted in a coefficient of 4.67% for AR.
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Myofibrillar protein quantitation.
Total protein remaining from the total RNA isolation procedure was isolated with isopropanol, ethanol, and 0.3 M guanidine hydrochloride. Myofibrillar protein was further isolated with repeated incubations in 1% SDS at 50°C. Based on our previous work (30), myofibrillar protein content was determined spectrophotometrically based on the Bradford method (6) at a wavelength of 595 nm. A standard curve was generated (r2 = 0.96, P = 0.001) using bovine serum albumin (Bio-Rad) and myofibrillar protein was quantified relative to muscle wet-weight. All assays were performed in duplicate with a coefficient of variation of 3.15%.
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Statistical analysis.
Using SPSS (version 11.1, SPSS Inc., Chicago, IL), for AR mRNA and protein expression statistical analyses were performed using separate 2 × 4 [Group (CON, RST)] × Test (4 muscle samples) factorial ANOVA with repeated measures. Serum TST and SHBG were analyzed with separate 2 × 9 [Group × Test (9 blood samples)] ANOVA with repeated measures. In the event of a significant F-ratio, between-group differences were determined involving the Newman-Keuls post hoc test. However, to protect against Type II error, the conservative Hunyh-Feldt epsilon correction factor was used to evaluate observed within-group F-ratios. Bivariate correlations between AR mRNA and protein and serum hormone levels were determined using the Pearson product moment correlation procedure. Statistical power and the effect size were determined using the partial eta2 statistic. Statistical power was also determined. For the standard curves generated from the spectrophotometric procedures (ELISA and Bradford), linear regression analysis was used. A probability level of ≤0.05 was adopted throughout to determine statistical significance, and statistical power was estimated a priori at 0.48 for a large effect size of 0.80.
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RESULTS
Serum testosterone, SHBG, and free androgen index.
A significant Group × Test interaction was observed for serum TST (P = 0.001). However, no significant differences were located for SHBG (P > 0.05). For TST, post hoc analysis for the Test factor indicated that RST experienced significantly greater increases compared with CON at each of the three blood sampling points occurring immediately postexercise (samples 2, 5, and 8) when compared with each of the corresponding preexercise values (Fig. 3A). Significant main effects for Group (P = 0.029) were located for FAI indicating greater increases in estimated free TST for RST when compared with CON. In addition, significant main effects for Test (P = 0.043) were located for FAI. Post hoc analysis for the Test factor indicated that RST also experienced significantly greater increases in FAI at each of the three blood sampling points occurring immediately postexercise (samples 2, 5, and 8) when compared with each of the corresponding preexercise values (Fig. 3C). Plasma volume shifts between exercise bouts were not significantly different (P > 0.05).
FIGURE 3
FIGURE 3
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Skeletal muscle androgen receptor mRNA and protein expression.
Significant Group × Test interactions were observed for skeletal muscle AR mRNA (P = 0.003) and protein (P = 0.039), indicating RST to be significantly different from CON. Post hoc analyses for the Test factor indicated that RST experienced significantly greater increases in skeletal muscle AR mRNA occurring 48 h after all three exercise bouts (muscle sampling points 2, 3, and 4) compared with the initial preexercise value for bout 1 (sample 1) (Fig. 4). The AR mRNA expression occurring 48 h after bout 1 (sampling point 2) was significantly correlated to the serum TST occurring immediately after bout 1 [sampling point 2 (r = 0.890, P = 0.023)], immediately after bout 2 [sampling point 5 (r = 0.846, P = 0.028)], and immediately after bout 3 [sampling point 8 (r = 0.790, P = 0.035)]. The AR mRNA expression occurring 48 h after bout 2 (sampling point 3) was significantly correlated to the FAI occurring immediately after bout 1 [sampling point 2 (r = 0.911, P = 0.004)] and immediately after bout 2 [sampling point 5 (r = 0.853, P = 0.015)], serum TST occurring immediately after [sampling point 5 (r = 0.757, P = 0.047)] and 30 min after [sampling point 6 (r = 0.938, P = 0.002)] after bout 2, and serum SHBG occurring immediately after bout 1 [sampling point 2 (r = −0.814, P = 0.026)], 30 min after bout 1 [sampling point 3 (r = −0.768, P = 0.044)], and 30 min after bout 3 [sampling point 9 (r =− 0.767, P = 0.044)]. The AR mRNA expression occurring 48 h after bout 3 (sampling point 4) was significantly correlated to the FAI occurring immediately after bout 1 [sampling point 2 (r = 0.799, P = 0.030)] and immediately after bout 2 [sampling point 5 (r = −0.832, P = 0.020)], and the serum TST occurring immediately after bout 3 [sampling point 8 (r = 0.776, P = 0.040)].
For AR protein expression, significantly greater increases occurred 48 h after the second and third exercise bouts (muscle sampling points 3 and 4) compared with the initial preexercise value for bout 1 (sample 1) (Fig. 5). The AR protein expression occurring 48 h after bout 1 (sampling point 2) was significantly correlated to the serum TST occurring immediately after bout 1 [sampling point 2 (r = 0.821, P = 0.024)]. The AR mRNA expression occurring 48 h after bout 3 (sampling point 4) was significantly correlated to the serum TST occurring immediately after bout 1 [sampling point 2 (r = −0.833, P = 0.020)] and immediately after bout 2 [sampling point 5 (r = 0.901, P = 0.014)].
FIGURE 5
FIGURE 5
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Myofibrillar protein.
A significant Group × Test interaction was observed for myofibrillar protein (P = 0.002) indicating RST to be significantly different from CON. Post hoc analysis of the Test factor indicated that RST experienced significantly greater increases in myofibrillar protein content 48 h after the third exercise bout (muscle sampling point 4) compared with sampling points 1, 2, and 3 (Fig. 6).
FIGURE 6
FIGURE 6
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DISCUSSION
The results of the present study demonstrate that the mRNA and protein expression of the AR receptor to be significantly correlated to serum TST levels and also up-regulated after only three sequential bouts of heavy lower-body resistance exercise (P < 0.05). This increase in skeletal muscle AR expression likely occurs pretranslationally and is governed by androgen-AR signaling mechanisms (i.e., myogenic regulatory factors and steroid receptor co-activators). The AR mRNA results presented herein coincide with other data in humans, demonstrating AR mRNA concentration to be elevated 63% and 102%, respectively, 48 h after a single bout of either eccentric or concentric resistance exercise (4). Herein, we also show 35% and 43% increases, respectively, in AR mRNA levels 48 h after the first and third resistance exercise bouts; however, a peak of 68% (P < 0.05) was observed 48 h after the second bout compared with 2% for the control.
Up-regulation of the androgen-AR signaling pathway increases lean muscle mass, muscle strength, and muscle protein synthesis in rodents (5,26) and emphasizes the importance of the increase in the number of androgen receptors in exercised muscle (16). The AR content has been shown to preferentially increase in Type II (extensor digitorum longus) muscle after resistance training in rodents (9). Also in rodents, hypertrophy of the gastrocnemius (a mixed fiber muscle composed of red, white, and mixed portions contains approximately 88% Type II fibers) by electrical stimulation was shown to be associated with an increase in muscle AR content (17). Our present results illustrate that heavy resistance exercise in humans resulted in increases in AR protein expression of 40% and 100% 48 h after the first and second exercise bouts, respectively. However, a peak increase in AR protein expression of 202% (P < 0.05) occurred 48 h after the third exercise bout compared with 6% for the control. This, in turn, also corresponded to a peak increase in myofibrillar protein content of 79% (P < 0.05) occurring at the same sampling point. However, the human vastus lateralis only contains approximately 57% Type II muscle fibers (14). Therefore, irrespective of a predominance of Type II fibers, our results highlight preferential increases in skeletal muscle AR protein expression that occur as a result of three sequential bouts of lower-body heavy resistance exercise.
Much work has been done to determine the TST responsiveness to a single bout (1,4) or several bouts of resistance exercise (21); however, little has been done to determine any corresponding responsiveness of the AR to elevated serum TST that accompanies sequential bouts of resistance exercise. This issue is of importance because load-mediated modulation of AR receptor expression via resistance exercise may explain the increases in myofibrillar protein content that apparently occurs with elevated serum TST. By way of the FAI, we observed a resistance exercise-induced peak increase of 42% (P < 0.05) in the percent of unbound TST occurring immediately after the first exercise bout (sampling point 2) that was significantly correlated to both AR mRNA and protein expression (P < 0.05). We observed modest exercise-induced increases in SHBG following each bout, with a peak increase of 15% (P > 0.05) also occurring immediately after the first bout. Although, any increases that occur for SHBG typically mimic changes in serum total TST (13) in an attempt to maintain the level of free TST. Assuming the level of SHBG remains constant, and increase in total TST should lead to an increase in free TST (11). Therefore, our results for SHBG were not unexpected since the androgen binding affinity of SHBG does not appear to significantly change after acute exercise (12).
The TST response to resistance exercise is highly variable (20); however, it is the unbound (biologically active) fraction of TST that is able to serve as the ligand for AR binding. Furthermore, consistent with animal studies, it has also been suggested that consistent elevations in serum TST enhance AR expression, thereby likely mediating increased muscle protein synthesis (5) and hypertrophy (15), resulting from enhanced trans-activation and subsequent interaction of the androgen-AR DNA binding complex (ligand-activated AR) within the regulatory androgen response element present in the promoter of muscle-specific genes (16). However, because other hormones and growth factors such as T3 and IGF-1 are also involved in stimulating myofibrillar protein synthesis in response to resistance exercise, their possible involvement here cannot be discounted. In the present study, however, it is conceivable that the consistent elevations in serum TST after each exercise bout mediated the up-regulation in AR expression, which subsequently led to an enhanced ligand-binding capacity and a concomitant increase in myofibrillar protein.
Herein, we have presented evidence suggesting heavy resistance training to possibly increase myofibrillar protein content by way of the androgen-AR signaling pathway. Specifically, we demonstrated that both total and free TST (by order of the FAI) levels are subject to increases in response to individual sequential bouts of heavy lower-body resistance exercise. In addition, the mRNA and protein expression of the AR were significantly up-regulated after the second and third exercise bouts, respectively, correlated to serum TST, and corresponded to significant increases in myofibrillar protein by the third exercise bout. Therefore, we conclude that three sequential bouts of lower-body heavy resistance exercise to be effective in up-regulating AR expression, likely by way of a pretranslational mechanism that may be contingent on increases in free TST. Furthermore, the increased AR expression may have increased myofibrillar protein content by way of the androgen-AR signaling pathway.
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REFERENCES
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Keywords:
TESTOSTERONE; SEX HORMONE BINDING GLOBULIN; FREE ANDROGEN INDEX; MYOFIBRILLAR PROTEIN
©2004The American College of Sports Medicine
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Therapy options
This application helps to propose an appropriate fertility therapy method and to find the most suitable clinic worldwide based on the price, duration and legislative options of the treatment in various countries.
Search Results
Nothing found. Please try searching for a different keyword.
Self therapy does not exist.
Conventional medicine does not exist.
Assisted reproduction therapy does not exist.
How can Early onset of pubarche affect fertility
Thelarche (onset of breast development) and pubarche represent observable markers of underlying hormones that are dependent on the maturation of unique endocrine axes, i.e., the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axis, respectively. Premature pubarche has been associated with a relative adrenal hyperandrogenism and hyperinsulinemia (high blood level of insulin). Those girls are at higher risk of developing ovarian hyperandrogenism (excess of male sex hormones – androgens), polycystic ovary syndrome and oligomenorrhea (infrequent menstruation) causing ovulatory dysfunction, which can lead to infertility because no eggs are released to be fertilized.
See full description
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BistroMD Health Library
Get excited about reading again with fun and interesting tips from our experts, including The M.D., our dietitians, and our fitness expert. In our health library, you will find all of the information you need to achieve your goals of making a healthy lifestyle change. So, start reading and start losing!
Nutrition
Get excited about nutrition, and learn as you go with these information-packed articles on a wide variety of nutrition-centric topics! Discover the importance of the macronutrients protein, fat, and carbohydrates, as well as how to make them work most efficiently for you.
What Are Antioxidants?
What Are Antioxidants?
We’ve all heard about the importance of antioxidants in our diet. We know they’re good for us but do we always know where to find them? Our expert dietitian dishes on what antioxidants are, why they’re helpful, and how you can easily find them at your local grocery store.
Antioxidants are nutrients that help protect our bodies from the many harmful toxins that we are exposed to every day. These harmful toxins are mostly made up of oxidants, hence the name antioxidants.
Oxidants are released when something is burned, whether it be a cigarette, fuel or even the food our bodies burn for energy.
Oxidants are responsible for damaging the cells that your body is built on— this ultimately causes aging and disease. Antioxidants are nutrients in our food that slow and can even prevent the damage caused by oxidants.
The most effective antioxidants come in the form of Vitamins A, C, and E and can be found in all kinds of food at the supermarket.
Vitamin A is found in foods like carrots, broccoli, tomatoes, and sweet potatoes. Vitamin C is found in foods like citrus fruits, green peppers, broccoli, and tomatoes. Vitamin E is found in foods like nuts, seeds, whole grains, and green leafy vegetables. Anthocyanins are good as well and can be found in berries and red and purple vegetables.
The lesson learned? Do what your mother always said and eat your carrots, broccoli, fruits, and tomatoes. They’ll save you from disease and protect your body against aging. It seems as though mothers really do know best.
If you’re ready to start making healthy choices, maybe it’s time to try a diet meal delivery program from BistroMD? It's a simple, delicious, and effective way to lose weight and keep it off for good.
Start Your Diet Today!
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Skip to main content
Vaccine Hub offers general information only. Please see a healthcare professional for medical advice.
Disease
Cholera
Cholera is not regularly found in Australia. There have been a very small number of cases reported in Australia over the past few years, however they were mostly contracted overseas.
Page last updated 16 November 2023
Cholera is a vaccine-preventable disease, which typically spreads through contaminated water or food. Modern sewage and water treatment have helped to eliminate cholera in most countries. However, it’s still a problem in countries affected by war, poverty, and natural disasters and where conditions may force people to live in crowded areas without proper sanitation.
In most cases (up to 75% of reported cases), people infected with cholera show no signs of symptoms of the disease, but the person does remain potentially infectious to others. Common symptoms include watery diarrhoea and vomiting. Although cholera is easily treated, if symptoms are ignored and left untreated then it can be fatal in a matter of hours, even in people who were otherwise healthy.
Reported cases of cholera are usually linked to a recent history of travel to a cholera-endemic area. Vaccination is recommended for some people, in particular travellers at increased risk of acquiring diarrhoeal disease.
For further information on cholera and its prevention, speak with your healthcare professional.
Commonly asked questions
What is cholera?
Cholera is an acute (sudden onset) disease with symptoms of severely, watery diarrhoea (“rice-water stools”) and vomiting. This causes rapid fluid loss, leading to dehydration – which can be fatal. However, some people experience only mild symptoms and some none at all.
Cholera is caused by the bacterium Vibrio cholerae, which is found in water and soil contaminated with faeces (poo). Therefore, cholera is acquired by eating food or drinking fluid that is contaminated with faeces.
The best way to prevent getting cholera is to practice good personal hygiene, and ensure food and water is not contaminated with faeces. While cholera is generally not found in Australia (only a small number of cases have been reported, and almost always in relation to overseas travel), if you are planning on travelling to a country that is at risk of a cholera outbreak, precautions are important to consider.
How is cholera spread?
Spreading cholera between person-to-person is unlikely, however, cholera is a disease often found in areas with poor sanitation, poor water treatment, and low levels of personal hygiene (mostly in developing countries).
Cholera is spread by:
• drinking contaminated water
• eating food contaminated by dirty water, soiled hands or flies
• eating fish or shellfish from contaminated waters.
What are the symptoms of cholera?
In most cases), people infected with cholera show no signs or symptoms of the disease, but the infected person can still remain infectious to others. Symptoms may appear quickly, in as little as 12 hours after initial exposure to the bacterium, or may appear up to five days later.
Symptoms of severe cholera include:
• sudden onset of painless, but severe, watery diarrhoea
• nausea and vomiting (early in the illness)
• severe dehydration (as a result of rapid fluid loss)
In severe untreated cases, death may occur within hours, but with simple treatment, full recovery can be expected.
How do you treat cholera?
In severe cases, where a large amount of fluid is lost through vomiting and diarrhoea, rapid fluid replacement is immediately required.
Patients can drink an oral rehydration solution (ORS), which is pre-packaged sugar and salts mixed with water, or if required, intravenous fluids (i.e. drips) and electrolytes (salts) may be administered through a needle in a vein.
Antibiotics may also be used to shorten the duration of symptoms.
Before administering treatment see your healthcare professional who will assess your situation.
Which countries are affected by cholera?
Cholera is not usually found in Australia, but the bacteria have been found in some rivers along the eastern coast as well as, on rare occasions, in river mouths.
Cholera is commonly found in developing countries with poor sanitation, poor water treatment and lower levels of personal hygiene. Regions where cholera is most commonly found include parts of Africa, Asia, and Latin America. Intermittently it has also been reported in the Middle East and the Pacific Islands.
Sources & Citations
1. Australian Government Department of Health. The Australian Immunisation Handbook. Cholera. Available at: immunisationhandbook.health.gov.au/vaccine-preventable-diseases/cholera (accessed 24 November 2021).
2. World Health Organization. Cholera. Available at: www.who.int/en/news-room/fact-sheets/detail/cholera (accessed 24 November 2021).
3. Queensland Health. Cholera Queensland Health Guidelines for Public Health Units. Available at: www.health.qld.gov.au/cdcg/index/cholera (accessed 24 November 2021).
4. NSW Health. Cholera Factsheet. Available at: https://www.health.nsw.gov.au/Infectious/factsheets/Factsheets/cholera.pdf (accessed 24 November 2021).
5. Healthy WA. Cholera. Available at: healthywa.wa.gov.au/Articles/A_E/Cholera (accessed 24 November 2021).
6. World Health Organization. Cholera Frequently asked questions and information for travellers. Available at: https://www.who.int/cholera/technical/FaqTravelersNov2010.pdf?ua=1 (accessed 24 November 2021).
MAT-AU-2102456 Date of preparation December 2021
Related
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JP5378751B2 - Pharmacotherapy confirmation system and method - Google Patents
Pharmacotherapy confirmation system and method Download PDF
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Publication number
JP5378751B2
JP5378751B2 JP2008270389A JP2008270389A JP5378751B2 JP 5378751 B2 JP5378751 B2 JP 5378751B2 JP 2008270389 A JP2008270389 A JP 2008270389A JP 2008270389 A JP2008270389 A JP 2008270389A JP 5378751 B2 JP5378751 B2 JP 5378751B2
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patient
system
drug
clinician
information terminal
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JP2009054183A5 (en
JP2009054183A (en
Inventor
ビュイ チュアン
アチャーヤ ミータリ
ウィルクス ゴードン
マルトゥッチ ジェイムス
ポール エリック
ミハイ ダン
Original Assignee
バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ
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Priority to US10/135,180 priority patent/US20030140928A1/en
Application filed by バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ filed Critical バクスター・インターナショナル・インコーポレイテッドＢａｘｔｅｒ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃｏｒｐ０Ｒａｔｅｄ
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Publication of JP2009054183A5 publication Critical patent/JP2009054183A5/ja
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• GPHYSICS
• G06COMPUTING; CALCULATING; COUNTING
• G06FELECTRIC DIGITAL DATA PROCESSING
• G06F19/00Digital computing or data processing equipment or methods, specially adapted for specific applications
• G06F19/30Medical informatics, i.e. computer-based analysis or dissemination of patient or disease data
• G06F19/34Computer-assisted medical diagnosis or treatment, e.g. computerised prescription or delivery of medication or diets, computerised local control of medical devices, medical expert systems or telemedicine
• G06F19/3456Computer-assisted prescription or delivery of medication, e.g. prescription filling or compliance checking
• G06F19/3462Computer-assisted distribution of medication from dispensers, i.e. making sure that medication is correctly delivered to patients
• GPHYSICS
• G06COMPUTING; CALCULATING; COUNTING
• G06QDATA PROCESSING SYSTEMS OR METHODS, SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL, SUPERVISORY OR FORECASTING PURPOSES; SYSTEMS OR METHODS SPECIALLY ADAPTED FOR ADMINISTRATIVE, COMMERCIAL, FINANCIAL, MANAGERIAL, SUPERVISORY OR FORECASTING PURPOSES, NOT OTHERWISE PROVIDED FOR
• G06Q50/00Systems or methods specially adapted for specific business sectors, e.g. utilities or tourism
• G06Q50/10Services
• G06Q50/22Social work
• G06Q50/24Patient record management
• GPHYSICS
• G16INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
• G16HHEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
• G16H40/00ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
• G16H40/40ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the management of medical equipment or devices, e.g. scheduling maintenance or upgrades
• HELECTRICITY
• H04ELECTRIC COMMUNICATION TECHNIQUE
• H04LTRANSMISSION OF DIGITAL INFORMATION, e.g. TELEGRAPHIC COMMUNICATION
• H04L63/00Network architectures or network communication protocols for network security
• H04L63/12Applying verification of the received information
• H04L63/126Applying verification of the received information the source of the received data
• GPHYSICS
• G06COMPUTING; CALCULATING; COUNTING
• G06FELECTRIC DIGITAL DATA PROCESSING
• G06F19/00Digital computing or data processing equipment or methods, specially adapted for specific applications
• G06F19/30Medical informatics, i.e. computer-based analysis or dissemination of patient or disease data
• G06F19/34Computer-assisted medical diagnosis or treatment, e.g. computerised prescription or delivery of medication or diets, computerised local control of medical devices, medical expert systems or telemedicine
• G06F19/3418Telemedicine, e.g. remote diagnosis, remote control of instruments or remote monitoring of patient carried devices
• GPHYSICS
• G06COMPUTING; CALCULATING; COUNTING
• G06FELECTRIC DIGITAL DATA PROCESSING
• G06F19/00Digital computing or data processing equipment or methods, specially adapted for specific applications
• G06F19/30Medical informatics, i.e. computer-based analysis or dissemination of patient or disease data
• G06F19/34Computer-assisted medical diagnosis or treatment, e.g. computerised prescription or delivery of medication or diets, computerised local control of medical devices, medical expert systems or telemedicine
• G06F19/3456Computer-assisted prescription or delivery of medication, e.g. prescription filling or compliance checking
• G06F19/3468Computer-assisted delivery of medication via infusion or injection
• GPHYSICS
• G16INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
• G16HHEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
• G16H10/00ICT specially adapted for the handling or processing of patient-related medical or healthcare data
• G16H10/60ICT specially adapted for the handling or processing of patient-related medical or healthcare data for patient-specific data, e.g. for electronic patient records
Abstract
A system and method for providing medical treatment, such as medication, to a patient. The administration of the medication may include the use of an infusion pump. The system may be implemented in a variety of ways including as a computer program. The computer program accessing information related to the identity of a clinician, the identity of a patient, the identity of a medical treatment, and the identity of a medical device. The computer program determines whether the medical treatment has been previously associated with the patient and whether a plurality of operating parameters for the medical device are consistent with the medical treatment. The computer program also includes logic for providing a first error signal if the medical treatment has not been previously identified with the patient; and a second error signal if the operating parameters for the medical device are not consistent with the medical treatment.
Description
This application relates generally to systems and methods for operating medical devices and communicating between devices. More specifically, the present invention relates to a system and method for verifying that the correct drug is being provided to the correct patient, at the correct dose, at the correct time and by the correct route.
A typical patient care system includes a computer network, medical devices for treating a patient, and controls for the medical devices. While patient care systems have improved through the use of computerized automated systems and methods, patient care systems continue to rely heavily on manual data management processes for medical devices and medical device control. For example, in modern hospitals, a nurse station is typically connected to a computer network, but typically the computer network is not extended to the patient's room. Computer networks provide opportunities for automated data management processes, including medical device operation and monitoring, and control of medical devices in a nursing setting. Despite advances in this area, automatic data management techniques are sufficient for nursing care applications due to the lack of more efficient systems and methods for operating medical devices such as infusion pumps. It is not utilized in.
(Summary of the Invention)
The present invention provides systems and methods for operating medical devices. The system and method can be used to program an infusion pump. The system can be implemented in various ways, including a computer program. When implemented as a computer program, the program includes the following logic. Logic to access information related to the identity of the patient and logic to access information related to the identity of the medication treatment, the medication treatment having a treatment type; Logic to determine whether it is associated; logic to provide a first error signal if the medication is not previously associated with the patient; and logic to access information related to the identity of the medical device And wherein the medical device is configured to administer the drug treatment type and logic to determine whether a plurality of operating parameters of the medical device match the drug treatment, the operation Parameters are provided from a central computer and the operating parameters pass through a remote computer Rather, logic provided to the medical device, logic providing a second error signal if the operating parameter of the medical device does not match the drug treatment, and providing the drug treatment to the patient Logic to enable the medical device and logic to confirm that the medical device is providing the medication to the patient.
Other systems, methods, features and advantages of the present invention will be apparent to those skilled in the art with reference to the accompanying drawings and detailed description. All such additional systems, methods, features and advantages included in this description are within the scope of the invention and are protected by the following claims. Accordingly, the present invention also provides the following.
(1) A method of administering drug treatment comprising the use of a first computer and a second computer comprising:
Accessing information related to patient identity from the second computer at a remote location;
Accessing information related to the identity of a medication from the second computer, wherein the medication has a treatment type;
Determining whether the medication has been previously associated with the patient;
Providing a first error signal if the medication is not previously associated with the patient;
Accessing information related to the identity of the medical device from the second computer, wherein the medical device is configured to administer the drug treatment type;
Determining whether a plurality of operating parameters of the medical device are consistent with the medication, the operating parameters being provided from the first computer at a central computer, the operating parameters being the second Provided to the medical device without passing through a computer of:
Providing a second error signal if the operating parameter of the medical device does not match the drug treatment;
Enabling the medical device to provide the medication to the patient;
Confirming that the medical device is providing the medication to the patient;
Including the method.
(2) The method of item 1, wherein the medication is previously associated with the patient by providing a patient identifier and a medication identifier to the first computer, the medication identifier including the patient identifier.
(3) Accessing information related to the identity of the medication treatment includes inputting a second medication identifier into the second computer, wherein the second medication identifier comprises a patient identifier. The method described in 1.
(4) The method according to item 3, wherein the step of providing an operating parameter of the medical device is performed only when the first and second drug identifiers include the same patient identifier.
(5) The method according to item 1, wherein the medical device is an infusion pump.
(6) The method of item 1, wherein providing a drug identifier to the first computer comprises converting a signal generated by the input device into a computer readable medium format.
(7) The patient identifier is one of a group of identifiers, and the group of identifiers includes a patient name, a patient social security number, a patient blood type, a patient address, a patient allergy, a hospital patient Item 2. The method according to item 1, comprising the ID number, the position of the bed in the hospital, and the name of the patient's relative.
(8) The operation parameter is one of a group of operation parameters, and the operation parameter group includes a drug flow per unit time, a drug amount, a dose unit, a dose duration, a dose volume, The method of item 1, consisting of a name, a dosage unit, and monitoring restrictions.
(9) A method according to item 1, wherein the step of inputting from the first source to the second computer includes the step of converting the signal generated by the input device into a computer readable medium.
(10) accessing information related to the clinician's identity includes reading the clinician's badge using a barcode scanner, the operating parameters being provided to the medical device using a wireless communication path; The method according to item 1, wherein:
The invention can be better understood with reference to the following drawings. The parts in the drawings do not necessarily have to be drawn to scale, but are emphasized to clearly illustrate the principles of the invention. In the drawings, like reference numerals refer to corresponding parts throughout the several views.
FIG. 1 is a diagram of a patient care system 100. Patient care system 100 includes a pharmacy computer 104, a central system 108, and a treatment venue 106 linked by a network 102. The pharmacy computer 104 includes a processing device 104a, a keyboard 104b, a video display 104c, a printer 104d, a barcode reader 104e, and a mouse 104f. Although not shown in FIG. 1, patient care system 100 also includes a hospital office subsystem, nurse station, clinical information subsystem, hospital information subsystem, hospitalization, discharge and transfer (ADT) subsystem, billing subsystem The system, and / or other subsystems normally included in patient care systems may be included.
Central system 108 may include central service device 108a, database 108b, video display 108c, input / output components, and many other components known to those skilled in the art. Network 102 may include a portion of cable communication system 110 and a portion of a wireless communication system. The cable communication system 110 may be, but is not limited to, an Ethernet (registered trademark) cable system and a thin net system.
The treatment venue 106 may include a treatment bed 106a, an infusion pump 120, and a medication therapy cart 132. In FIG. 1, a clinician 116 and a patient 112 are shown in a treatment field 106. The drug 124 can be of a type that can be administered using the infusion pump 120. The drug 124 may also be of a type that is administered without the use of an infusion pump. The medication may be stored in a medication storage area 132a of the medication therapy cart 132. The clinician 116 uses the information terminal 118 to administer the drug 124 to the patient 112.
In treating the patient 112, the clinician 116 may use the information terminal 118 to communicate with the cable communication system 110 of the network 102 via the first wireless communication path 126. The infusion pump 120 may also have the ability to communicate with the cable communication system 110 via the second wireless communication path 128. The drug cart 124 may also have the ability to communicate via a wireless communication path (not shown in FIG. 1). The wireless transceiver 114 interfaces with the cable communication system 110. The wireless communication system portion of the network includes: IEEE 802.11b “Wireless Ethernet (registered trademark)”, local area network, wireless local area network, network with tree type, network with ring type, wireless Internet point of presence system, Ethernet Technologies known to those skilled in the art such as, but not limited to, (registered trademark), the Internet, wireless communication, infrared, optical fiber, and telephone can be employed. Although shown as a wireless communication system in FIG. 1, the communication path may be a hard wire communication path.
In patient care system 100, a physician (not shown) may order medication 124 for patient 112. The order may also originate from the clinician 116 at the treatment site 106. The physician and / or clinician 116 may order a medication 124 for the patient 112 using a computerized physician order entry system (CPOE) and / or a medication cart 132. Basic CPOE is well known to those skilled in the art. Despite its name, CPOE may be used by clinicians 116. If the drug 124 is efficient to administer using the infusion pump 120, the order may include information for generating operating parameters for the infusion pump 120. The operating parameter is the information and / or instruction set required to program the medical device 332 (FIG. 3) to operate according to the order.
The order may be entered into the pharmacy computer 104 via input / output devices such as a keyboard 104b, mouse 104f, touch panel display, CPOE system and / or medication therapy cart 132. These input / output devices and the like are well known to those skilled in the art. The processor 104a can convert manually entered orders into computer readable data. A device, such as a computerized prescription order entry system, may convert the order into computer readable data prior to introduction into the processor 104a. The operating parameters can then be printed in barcode format on the medication label 124a by the printer 104d. The drug label 124a can then be affixed to the drug 124 container. Thereafter, the container of drug 124 is transported to the treatment site 106. Drug 124 can then be administered to patient 112 in a variety of ways known in the art, including oral or infusion pump 120. If drug 124 is administered orally, clinician 116 may communicate via information terminal and / or drug cart 132. The drug cart 132 is computerized and generally has other input / output devices such as a keyboard (not shown), a display 132b, and other bar code scanners (not shown).
In the treatment setting, the drug 124 can be attached to the infusion pump 120 and an intravenous (IV) line 130 can be extended from the infusion pump 120 to the patient 112. Infusion pump 120 may include a pumping device 120a, a keypad 120b, a display 120c, and an infusion pump ID 120d, and an antenna 120e. Prior art infusion pumps may be provided with a wireless adapter (not shown) in order to fully implement the medical care confirmation system 210 (FIG. 2) of the present invention. The wireless adapter may have its own battery if it is necessary to avoid reducing the battery life of prior art infusion pumps. The wireless adapter may also use intelligent data management, such as storage and transfer data management, and data compression to minimize power consumption, but intelligent data management is not limited thereto. The wireless adapter may also include the ability to communicate with the information terminal 118 even when the network 102 is not functioning.
The patient care system 100 may include various identifiers such as staff identifiers, device identifiers, drug identifiers, but the identifiers are not limited to these. In FIG. 1, clinician 116 may have a clinician badge 116a identifier, patient 112 may have a wristband 112a identifier, infusion pump 120 may have an infusion pump ID 120d identifier, and drug 124 may have a drug label 124a. It can have an identifier. Clinician badge 116a, wristband 112a, infusion pump ID 120d, and drug label 124a include information for identifying the associated employee, device, or drug. The identifier may also include additional information. For example, the drug label 124a may include information about the intended recipient of the drug 124, operating parameters of the infusion pump 120, and information about the lot number and expiration date of the drug 124. Information contained in the identifier can be printed, but devices such as optical readable device formats such as barcodes, radio frequency (RF) device readable formats such as RFID, iButton, smart cards, and laser readable formats A readable format is preferred. The device readable format is not limited to the above. The information terminal 118 may include a display 118a and may have the ability to read an identifier that includes biometric information such as a fingerprint.
The wristband 112a is typically attached to the patient 112 when the patient 112 enters a medical care facility. The wristband 112a includes a patient identifier. The patient identifier may include printed information for identifying the patient and additional information such as the name (s) of the treating physician. The patient identifier for patient 112 may include information such as, but not limited to, patient name, age, social security number, patient blood type, address, allergy, hospital ID number, patient relative name, etc. .
FIG. 2 is a block diagram of the computer 200. The computer 200 may be a computer included in any number of other subsystems that communicate via the pharmacy computer 104, central system 108, CPOE, information terminal 118, and / or network 102 of FIG. Computer 200 includes a medication therapy confirmation system 210. In some embodiments, the medication therapy verification system 210 verifies that the correct medication is provided to the correct patient at the correct dose and at the correct time via the correct route. In other embodiments, the drug therapy confirmation system 210 provides a subset of these desired confirmation functions. In some embodiments, infusion pump 120 programming may be based on operating parameters received from pharmacy computer 104 and / or other remote computers. In other embodiments, infusion pump 120 programming may be based on pharmacy computer 104, other remote computers, and / or operating parameters ascertained by clinician 116. Operating parameters and / or confirmations may be transferred via the cable communication system 110 and the first and second wireless communication paths 126 and 128.
A major concern in the art is whether the correct drug is being administered to the correct patient. Accordingly, the medication therapy verification system 210 includes functionality that ensures that the correct drug is administered to the correct patient in an efficient manner. The drug therapy verification system 210 of the present invention may be implemented in software, hardware, or a combination thereof. In certain modes, the medication therapy verification system 210 is implemented in software as an executable program, such as a personal computer (PC; IBM compatible, Apple compatible, or others), personal digital assistant, workstation, minicomputer, or Performed by one or more of a dedicated or general purpose digital computer (s), such as a mainframe computer. An example of a general purpose computer that may implement the drug therapy verification system 210 of the present invention is shown in FIG. The medication therapy verification system 210 may reside on or have a resident portion of any computer such as, but not limited to, the pharmacy computer 104, the central system 108, and / or the information terminal 118. Accordingly, the computer 200 of FIG. 2 may be representative of any computer on which the medication therapy verification system 210 resides or partially resides.
In general, from a hardware architecture perspective, as shown in FIG. 2, a computer 200 includes a processor 202, a memory 204, one or more inputs and / or communicatively connected via a local interface 208. Or output (I / O) device 2
06 (or peripheral device). The local interface 208 can be, for example, but not limited to, one or more buses, or other wires or wireless connections, as is known in the art. The local interface 208 may have additional elements such as a controller, a buffer (cache), a driver, a repeater, and a receiver to allow communication, but is omitted for simplicity. In addition, the local interface may include address, control, and / or data connections to allow proper communication between other computer components.
The processor 202 is a hardware device that executes software, in particular software stored in the memory 204. The processor 202 can be any custom-made or commercially available processor, a central processing unit (CPU), an auxiliary processor among several processors associated with the computer 200, a semiconductor-based micro (in the form of a microchip or chipset). It can be a processor, a macro processor, or generally any device that executes software instructions. Examples of suitable commercially available microprocessors are: PA-RISC series manufactured by Hewlett-Packard Company, Pentium (registered trademark) series microprocessor manufactured by Intel Corporation, Power PC microprocessor manufactured by IBM, Sun Microsystems, Inc. It is a SPARC microprocessor manufactured by or a 68xxx series microprocessor manufactured by Motorola Corporation. The processor 202 may also represent a distributed processing architecture such as SQL, Smalltalk, APL, KLisp, Snobol, Developer 200, MUMPS / Magic, but the distributed processing architecture is not limited thereto.
The memory 204 may be any one of a volatile memory element (for example, random access memory (RAM such as DRAM, SRAM, SDRAM, etc.)) and a non-volatile memory element (for example, ROM, hard drive, tape, CDROM, etc.). One or a combination thereof. Further, the memory 204 may incorporate electronic, magnetic, optical, and / or other types of storage media. Memory 204 has a distributed architecture in which various components are located remote from one another, but are accessed by processor 202.
The software in memory 204 may include one or more separate programs. A separate program contains an ordered list of executable instructions that implement a logical function. In the example of FIG. 2, the software in memory 204 includes a medication therapy verification system 210 and a suitable operating system (O / S) 212 according to the present invention. The following is a list of examples of suitable commercial operating systems 212, but this is not exhaustive. (A) Windows (registered trademark) operating system (registered trademark) manufactured by Microsoft Corporation; (b) Novell, Inc .; Network operating system made by (c) Apple
Computer, Inc. Macintosh operating system from (d) a number of suppliers such as Hewlett-Packard Company, Sun Microsystems, Inc. And the UNIX® operating system, available from AT & T Corporation, (e) LINUX operating system, a freeware readily available on the Internet, (f) Wind River Systems, Inc. Run time Vxworks operating system manufactured by or manufactured by a product-based operating system such as a handheld device or a personal digital assistant (PDA) (for example, PalmOS manufactured by Palm Computing, Inc., and Microsoft Corporation) Windows® CE). The operating system 212 substantially controls the execution of other computer programs, such as the medication therapy verification system 210, and provides scheduling, input-output control, file and data management, memory management, and communication control and related services. To do.
The medication therapy verification system 210 can be a source program, executable program (object code), or any other entity that includes a set of instructions to be performed. In the case of a source program, the program is converted through a compiler, an assembler, an interpreter, or the like that may or may not be included in the memory 204 so as to operate properly with the O / S 212. It is necessary to In addition, the medication therapy verification system 210 may be written as (a) an object-oriented programming language having classes of data and methods, or (b) a procedural programming language having routines, subroutines, and / or functions. Examples include, but are not limited to, C, C ++, Pascal, Basic, Fortran, Cobol, Perl, Java (registered trademark), and Ada. In certain embodiments, the medication therapy verification system 210 is written in C ++. In other embodiments, the medication therapy confirmation system 210 is created using Power Builder. The I / O device 206 may include an input device. Examples of the input device include, but are not limited to, a keyboard, a mouse, a scanner, a microphone, a touch panel, various medical device interfaces, a bar code reader, a stylus, a laser reader, and a radio frequency device reader. Further, I / O device 206 may also include an output device. The output device is, for example, a printer, a barcode printer, a display, or the like, but is not limited thereto. Finally, I / O device 206 may further include a device that communicates both input and output. Examples include, but are not limited to, modems (modems for accessing other devices, systems or networks), radio frequency (RF) or other transceivers, telephone interfaces, bridges, routers, and the like.
If the computer 200 is a PC, workstation, PDA, etc., the software in the memory 204 may further include a basic input output system (BIOS) (not shown in FIG. 2). The BIOS is a set of critical software routines that initialize, test, start up the O / S 212, and support the transfer of data between hardware devices at startup. The BIOS is stored in ROM so that the BIOS can be executed when the computer 200 is started.
While computer 200 is operating, processor 202 executes software stored in memory 204, communicates data to and from memory 204, and generally controls the operation of computer 200 in accordance with the software. Set to Drug therapy verification system 210 and O / S 212 may be read in whole or in part (but often the latter) by processor 202, possibly buffered in processor 202 and then executed. .
As shown in FIG. 2, if the medication therapy confirmation system 210 is implemented in software, the program of the medication therapy confirmation system 210 can be read by any computer-related system or method, or any computer read for use with them. Note that it can be stored on a possible medium. In the context of this specification, a computer-readable medium is an electronic, magnetic, optical, or other medium that may contain or store a computer program for use by or in conjunction with any computer-related system or method. It is a physical device or means. The medication therapy verification system 210 may be an instruction execution system, apparatus, or other system such as a computer-based system, a system that includes a processor, or other system that may fetch instructions from an instruction execution system, apparatus, or device and execute the instructions. It can be implemented by any device-readable medium for use with or with the device. In the context of this specification, a “computer-readable medium” is any means that can store, communicate, propagate, or transfer a program for use by or in conjunction with an instruction execution system, apparatus or device. obtain. A more specific example of a computer readable medium (a list not exhaustive) is as follows. Electrical connection (electronic) with one or more wires, portable computer diskette (magnetic), random access memory (RAM) (electronic), read only memory (ROM), erasable programmable read only memory (EPROM, EEPROM, or Flash memory) (electronic), and optical fiber (optical), portable compact disc read-only memory (CDROM) (optical). Note that the computer readable medium may be paper or other suitable medium on which the program is printed. Because such programs are captured electronically, eg, by optically scanning paper or other media, and compiled, interpreted, or otherwise processed as appropriate, as appropriate. And
This is because it can be stored in a computer memory.
In other embodiments where the drug therapy verification system 210 is implemented in hardware, the drug therapy verification system 210 may be implemented using any of the following techniques well known in the art, or combinations thereof: . Discrete logic circuit (s) with logic gates that implement logic functions in the data signal, application specific integrated circuit (ASIC) with appropriate combinational logic gates, programmable gate array (PGA) (s), field Such as a programmable gate array (FPGA).
It should be understood that any process description or block in diagrams such as FIGS. 3 and 4 represents a module, segment, or portion of code that includes one or more executable instructions. As will be appreciated by those skilled in the art, other implementations in which functions may be performed substantially simultaneously or in the opposite order, depending on the functionality involved, rather than the order described. Are included within the scope of embodiments of the present invention.
FIG. 3 is a block diagram 300 illustrating functional members of the patient care system 100 of FIG. FIG. 3 also includes functional blocks that generate an infusion order that includes operating parameters that are confirmed in the medication therapy confirmation system 210. The medication therapy confirmation system 210 may be implemented as a modular system in which the modules represent various functions of the patient care system including the medication therapy confirmation system 210. FIG. 3 shows a drug therapy confirmation system 210 as a drug confirmation system. However, using a drug therapy confirmation system is broader than just drug confirmation. The flexibility of the system can be enhanced when the system is implemented as a modular system. The modules of the system can be included in various parts of the patient care system 100. The patient care system 100 includes a drug management module 302, a prescription creation module 304, a prescription execution module 306, and a prescription approval module 308.
The drug management module 302 may coordinate the functions of other modules in the patient care system 100 that are involved in administering drug therapy. The drug management module 302 generally cooperates with other parts within the patient care system 100. The drug management module 302 operates with and / or interfaces with the CPOE, operates with the treatment site module, and / or communicates with the treatment site module, operates with the drug therapy comparison module, and / or Or it may include a sub-module in communication with the medication therapy comparison module. In FIG. 3, an admission, discharge and transfer (ADT) interface 310, a billing interface 312, a laboratory interface 314, and a pharmacy interface 316 are shown. The ADT interface 310 can be used to capture information such as patient size, weight, and allergies. The pharmacy interface 3164 imports orders from the pharmacy. The pharmacy interface 316 may be an HL7 type interface that interfaces with other systems for entering orders, eg, CPOE. This capability reduces the need to enter data into the patient care system 100 more than once. The pharmacy interface 316 may be configured to communicate with commercial systems such as Cerner, HBOC, Meditech, SMS, and Pharmous. Commercial systems are not limited to these. Various other interfaces are also known to those skilled in the art, but are not shown in FIG.
Drug management module 302 includes the ability to check side effects due to drug incompatibility, duplicate drug administration, drug allergies, drug dose limits, drug frequency limits, drug duration limits, and drug disease contraindications, etc. It may have additional functions. Food and alcohol interactions may also be noted. Drug restrictions include, but are not limited to, for example, adults, children, infants, newborns, premature babies, the elderly, age groups, weight groups, height groups, and body surface areas. In general, the drug management module 302 also prevents entry of the same prescription for the same patient from two different sources within the patient care system 100.
The drug management module 302 may also include the ability to generate reports. Reports include, but are not limited to, end of shift, titration information, patient event list, infusion history, pump performance history, pump position history, and pump maintenance history. The end-of-shift report is pumped, start time, end time, main infusion, piggyback infusion, drug, dose, speed, pump status, infused volume, remaining volume, remaining time, and empty May include the last time. The infusion history report includes the drug and the amount infused.
The drug management module 302 may also include a medical device status database. The medical device status database includes data indicating the location of the medical device 332 within the patient care system 100. The medical device status database may also include data indicating past performance of the medical device 332. The medical device status database may also include data indicating a medical device 332 maintenance schedule and / or history.
The prescription creation module 304 creates hard prescriptions and electronic (E-copy) prescriptions. Hard prescriptions are generally made in triplicate in medical facilities. The first hard copy 318 is generally sent to the pharmacy, the second hard copy 320 is generally kept for patient records, and the third hard copy 322 is sent to the treatment site 106. The electronic prescription is sent to the drug management module 302.
A computerized physician order entry (CPOE) system may be used to perform some or all of the functions of the prescription creation module 304. Clinician 116 may enter data in a variety of ways, including, but not limited to, using a tablet wireless computer, treatment cart 132, and workstation.
Formulation can include calculating doses, drug amounts, dilution volumes, concentrations, rates based on the patient's weight and / or height (from the ADT interface 310). Prescription creation 304 may include checking operational parameters. This operational parameter may be based on information from the prescription entry module 324. Prescription creation may occur anywhere in the patient care system 100, including but not limited to a pharmacy, a treatment location 10, and a nursing center.
Infusion formulations may include, but are not limited to, single dose infusion, intermittent infusion, continuous infusion, sequencing, titration, and other types. Infusion formulations may also include total parenteral nutritional mix (TPN), chemotherapy continuous infusion, piggyback, bulk parenteral, and other infusion formulations. The patient care system 100 can function without an order end date. The patient care system 100 may use a persistent schedule generator that pre-reads for a predetermined period of time and generates a schedule for filling the mixture during that period. The predetermined time period may be defined at the level of the patient care system 100 or may be defined at the subsystem level, for example, the clinical field level and the tissue level. The predetermined period may be adjustable by the clinician 116 who enters the order. The schedule may be automatically extendable as long as the order is active in the patient care system 100.
The drug management module 302 may interface with more than one prescription creation module 304. The drug management module may receive orders from any location within the patient care system 100.
The pharmacy computer 104 can access an electronic copy from the drug management module 302. The prescription execution module 306 is a computer-aided system that coordinates prescription filing and labeling. The filing of the prescription and the creation or location of the drug 124 from the stock is handled by the prescription execution module 306.
While performing a prescription, the prescription execution module 306, if not specified in the prescription, displays the flow rate, the number of solutions / bags required for a specified period, the period during which each solution / bag is administered, and each solution / bag. Can be calculated based on the concentration of the components in the solution. The flow rate, injected volume, and / or duration can be adjusted in the system 100, and the system 100 automatically calculates the dependency amount based on the calculation. If the highest dose of an ingredient at a concentration exceeds the dose listed in the ingredient's drug file, the patient care system 100 may alert the physician and / or clinician 116 and request a reason code for adjustment.
The patient care system 100 may omit the prescription execution module 306. This can happen if the clinician, e.g. the patient's doctor, has the right to execute the order immediately. If the order is executed immediately, the drug management module 302 may proceed directly to the prescription labeling module.
At block 326, the patient care system 100 prints the medication label 124. The prescription can be printed remotely and is often printed by the pharmacy printer 104d. After block 326, the patient care system proceeds to block 328. At block 328, a drug label 124a is attached to the drug 124. Generally, the pharmacist makes a visual confirmation 334 that the drug label 124a is compatible with the first hard copy 318 of the prescription. FIG. 3 shows that the visual confirmation 334 is also associated with the prescription approval module 308. The drug 124 can then be transported from the pharmacy to the treatment site 106. A portable medication therapy cart 132 may be used for the portion of the route from the pharmacy to the treatment site 106.
The drug label 124a may include information for mixing. If not generated within the patient care system 100, the drug label 124a may be provided by a bulk drug supplier. When provided by a bulk drug supplier, the patient care system 100 has the ability to gather information from the drug label 124a. In addition, the patient care system 100 has the ability to add information, eg, a patient identifier, to the medication label 124a.
Drug labeling module 328 attaches drug label 124 a to drug 124. This can be done manually. This may also be done using an automatic prescription filling and packaging system (not shown). If an automatic filling and packaging system is used, the drug labeling module 328 provides data that coordinates the labeling of the drug 124 with the filling and packaging system.
At the treatment site 106, the clinician 116 uses a wireless device 330, such as the information terminal 118 and / or drug therapy cart 132, to identify and administer the medication 124 to the patient 112. The wireless device 330 communicates with the drug management module 302 via a communication path, eg, the first communication path 126.
The clinician 116 generally verifies his identity by scanning the badge 116a, confirming the patient 112 by scanning the wristband 112a, confirming the drug 124 by scanning the drug label 124a, The medical device 332 such as the infusion pump 120 is identified by scanning the label 120d. The clinician 116 may also prove his identity by providing a fingerprint and / or password. The medical device 332 can be a medical device capable of two-way communication with the drug management module 302. Alternatively, the medical device 332 sends information to the drug management module 30
2 may only be provided. Drug therapy confirmation system 210 assists clinician 112 in administering and confirming drug therapy. The medication therapy confirmation system 210 can generally lead to downloading operating parameters of the medical device 332. Clinician 116 may generally provide a visual confirmation that third copy 322 and / or MAR is compatible with labeled drug 124. A scanner 338 may be used to input machine readable information from the third copy 322 to the wireless device 330 and the medical device 332.
Patient care system 100 includes the ability to adjust and change infusion orders. Among other modules that may include the ability to make infusion adjustments are the prescription entry 324, prescription execution 306, prescription approval 308, and prescription change module 336. Clinician 116 may access prescription change module 336 to make order adjustments. Clinician 116 may access prescription change module 336 throughout patient care system 100. However, one of the most useful locations for the clinician 116 to access the prescription change module 336 is at the treatment site 106.
In the prescription approval module 308, the patient care system 100 determines whether the clinician 116 has the authority to independently change the infusion order. Clinician 116 may be recognized by patient care system 100 as having the authority to independently change certain portions of the order. If the clinician 116 does not have the authority to change the order independently, a pharmacist or doctor may be requested to approve the changes entered by the clinician 116.
FIG. 4 is a flowchart illustrating a first exemplary embodiment 400 of the medication therapy verification system 210 of FIG. The medication therapy confirmation system 400 is invoked at block 402. At block 404, the system 400 accesses information regarding the identity of the clinician 116. A first source 406, eg, information terminal 118, may provide information regarding the identity of clinician 116. The information terminal 118 may obtain information by reading the clinician's badge 116a using a bar code reader. The first source 406 may also be another computer located at a remote location. The first source 406 is a source of other information, for example, a barcode such as a barcode contained in the clinician's badge 116a, a tag, laser readable data, radio frequency readable data, keyboard, iButton reader, fingerprint Although a scanner and a barcode reader not associated with the information terminal 118 may be used, the source of information is not limited to these. Block 404 may include converting the signal generated by the first source 406 to a computer readable media format. Block 404 also includes using the information provided by the first source 406 to match the information with the identity of the clinician 116 through the use of a lookup table stored in the memory 204. After block 404, the system 400 proceeds to block 408.
At block 408, the system 400 identifies the patient 112. The first source 406 may provide information related to the identity of the patient 112. The information terminal 118 can obtain information by reading the patient's wristband 112a using a barcode reader. Block 408 may include converting the signal generated by the first source 406 to a computer readable media format. Block 408 also includes using the information provided by first source 406 to verify the information with the identity of patient 112 through the use of a lookup table stored in memory 204 or any other verification process. . After block 408, the system 400 proceeds to block 410.
At block 410, the system 400 identifies the treatment. The treatment may be administration of drug 124. The first source 406 may provide information related to the treatment identity. The identity of treatment can be the identity of drug 124. The identity of the drug can be correlated with the drug identifier. The drug identifier may include information such as drug identification number, mixture identification number, patient 112 contact number, drug name, dose, manufacturer, batch, expiration date, and / or dosing instructions prescriber, etc. It is not limited. At block 410, any edubytes, messages, danger alerts, and / or dosing instruction information terminal 118 may be displayed. Dosing instructions can include special sets, filter requirements, warnings, and cautions. At block 410, if the drug therapy is a drug, the system 400 may check the expiration date, such as the expiration date of the mixture and lot recall.
The information terminal 118 can acquire information by reading the drug label 124a with a barcode reader. Block 410 may include converting the signal generated by the first source 406 to a computer readable media format. Block 408 also includes using the information provided by the first source 406 to match the information with the identity of the medication therapy through the use of a lookup table stored in memory 204 or any other matching process. . After block 410, the system 400 proceeds to block 412.
At block 412, the system 400 determines whether drug therapy has been previously associated with the patient 112. The determination is often made by a device that gathers information related to the patient and medication identity. For example, the clinician 116 may read the barcode from the patient wristband 112a using the information terminal 118 as the first source 406. Thereafter, the clinician 116 reads the drug label 124 a using the information terminal 118. Thereafter, the information terminal 118 determines whether the patient identifier from the patient wristband 112a is equivalent to the patient identifier from the drug label 124a.
One way to pre-associate medication with a patient is to associate the patient with medication in the central system 108 and / or pharmacy system 104. The physician can make the association through a computerized prescription ordering system. The pharmacist may make the association by entering the patient identifier and the drug identifier into the pharmacy system 104 where the drug identifier includes the patient identifier. The patient identifier can be obtained from an input source such as an admission record, an order, an electronic physician order entry system, and / or a prescription, but the input source is not limited thereto.
If the system 400 determines that no medication has been previously associated with the patient 112, the system 400 proceeds to block 416 where a warning / error status is provided by the system 400. Block 416 may include displaying a warning / error status on information terminal 118. If the system 400 determines that the medication has been previously associated with the patient 112, the system 400 proceeds to block 414.
At block 414, the system 400 identifies a medical device. The medical device is configured to deliver drug therapy to the patient. For example, if the drug therapy is drug 124, the medical device can be infusion pump 120. The first source 406 may provide information regarding the identity of the medical device. The information terminal 118 can acquire information by reading the label 120d using a barcode reader. Block 414 may include converting the signal generated by the first source 406 to a computer readable media format. Block 414 also includes using the information provided by the first source 406 to match the information with the identity of the medical device through the use of a lookup table stored in memory 204 or any other matching process. .
Block 414 may include identifying a subsystem of the medical device. For example, if the medical device is an infusion pump, the infusion pump can have multiple conduits. The conduit may have a barcode. The conduit may be associated with the main drug and the “piggyback” drug. Block 414 may include identifying those subsystems that include piggybacks. After block 414, the system 400 proceeds to block 418.
At block 416, the drug confirmation system 400 provides a warning / error status signal. The warning / error status signal may be an operating parameter in various environments, for example, the system 400 does not recognize the patient, the system 400 does not recognize the treatment, the system 400 cannot match the treatment and the order, the system 400 cannot recognize the medical device, Can be triggered by, for example, unequal and treatment parameters are outside treatment tolerances, but the environment is not limited to these. The treatment tolerance may be defined at the patient care system 100 level or a subset of the patient care system 100.
At block 418, the medication therapy verification system 400 determines whether the operating parameters are correct. The operating parameters are correct if they are consistent with the confirmed medication. System 400 may include downloading operating parameters to the medical device. Operating parameters can be downloaded from various sources, such as pharmacy computer 104, drug label 124a, information terminal 118, etc., and clinician 116 can manually enter the operating parameters. The various sources are not limited to those described above. One check that can be performed is to verify that the dose is higher than a predetermined tolerance. The operating parameters can be, but are not limited to, parameters such as flow rate per unit time, amount of drug, dose unit, dose duration, dose volume, drug name, dose unit, monitoring limits. The dosing information may be provided directly or may be based on the attributes of the patient 112, such as the patient's weight.
If the operating parameters are not correct, the medication therapy confirmation system 201 proceeds to block 416 and returns an error message. If the operating parameters are correct, the medication therapy confirmation system 400 may display flow rate and dose information. The display may appear on display 120c and / or information terminal 118.
At block 420, the medication therapy verification system 400 determines whether the treatment is correct. If the treatment is correct, the treatment includes the correct drug 124, the treatment includes the correct amount of drug, and the treatment is administered at the correct time. The clinician can also be queried to confirm the correct route by viewing the medical device and associated equipment visually. The clinician 116 may change some parameters, such as the timing of drug therapy. When changing, a record of the change is generally maintained in the patient care system 100. If the medication therapy confirmation system 400 determines that the treatment is not correct, the system 400 returns to block 416 and provides an error message. If the medication therapy confirmation system 400 determines that the treatment is correct, the system 400 proceeds to block 422.
Among the factors that can be considered in determining whether a treatment is correct, the system 400 may note a general rule, a “similar” check, and a “similar name” check. General rules can include the highest flow rate that applies to all drugs throughout the treatment facility, the highest flow rate of that drug, and general rules based on patient characteristics, and combinations of these rules, It is not limited to these.
At block 422, the medication therapy verification system 400 enables the medical device. This may include the clinician 116 providing a start signal to begin the infusion. If the medical device is in delayed start mode, block 420 may include the step of providing a signal that the operating parameters are downloaded and that the medical device needs to provide therapy as soon as the delay period is over.
At block 424, the medication therapy confirmation system 400 monitors the delivery of medication. Any changes to the operating parameters of the pump can be reflected throughout the patient care system 100 within 10 seconds while the system 400 monitors medication delivery. The change can be represented on the information terminal 118. During infusion, the clinician 116 can adjust infusion parameters. Adjustment can be made to the infusion flow rate. The clinician 116 generally has the authority to adjust the flow rate within a predetermined range. This allows the clinician 116 to “catch up” if the infusion tube is prevented or other interruption occurs.
At block 426, the medication therapy verification system 400 records the results of the medication therapy administration. The result can be a successful administration of drug therapy according to the operating parameters. However, other results are possible. For example, a patient refuses to receive medication, changes in medication, equipment failure, and invasive injection errors. In the case of drug therapy changes, a modified order may be generated. The modified order can be linked to the original order in the drug management module 302.
Various blocks of the medication therapy verification system, eg, blocks 418-424, may include displaying treatment information on information terminal 118. This may include displaying information reflecting information on the display 120c of the infusion pump 120. Information on display 120c of infusion pump 120 may be supplemented by information about the patient, patient location, and infusion order. This information may include information about multiple conduits of infusion pump 120. The displayed information may include, but is not limited to, information such as personalities, prompt lines, status lines, operational icons, and pump head displays. The action icons include falling drops, stop sign, flow check piggyback, Guardian, and delayed start. The pump head display includes information such as drug label and infusion rate. Those skilled in the art are familiar with the information and action icons displayed above.
In other embodiments, the medication therapy verification system 210 may determine that information regarding the medication therapy that the clinician 116 wishes to administer to the patient 112 is not stored in the patient care system. If the patient care system 100 recognizes that the clinician 116 has the authority to initiate the desired medication, the system may allow administration of medication without the block 416.
Throughout this specification and claims, “central location” and “remote location” are terms that relate to each other. A “remote location” is any place where a patient is treated via a controlled medical device, eg, a patient treatment field 106 where a patient 112 is treated via an infusion pump 120. A “central location” is any location other than a remote location where parameters for operating the medical device are accessible, such as, but not limited to, the location of the pharmacy computer 104 and the central system 108. In a typical arrangement, several remote locations, such as treatment location 106, are in communication with a central location.
The downloading of the operating parameter determines whether the patient identifier associated with the medication and / or the patient identifier retrieved from the wristband 112a is the same as the patient identifier associated with the medication at the central location. Can be included. The determination is often made by a first computer, for example, the pharmacy computer 104a. If the system 400 determines that the various patient identifiers are not the same, the system will block 416.
You can go on. If the system 300 determines that the various patient identifiers are the same, the transfusion system 400 may download the operating parameters directly to the medical device 332. System 400 may send operating parameters to a medical device, such as infusion pump 120.
One advantage of the medication therapy verification system 210 is that the operating parameters for the medical device can be stored in the information terminal 118 or any other remote location before the operating parameters are available to the medical device program. It is not necessary to pass. By avoiding a remotely located computer, the source of possible errors in administering the drug 124 to the patient 112 is eliminated. The operating parameters for the medical device can be sent “directly” to the medical device, assuming that various checks have been made. In this context, “directly” means that the operating parameters can be sent without passing through the information terminal or computer at any other remote location.
In other embodiments, the system 400 may include additional blocks (not shown) that allow the central computer to accept the second drug identifier. The second drug identifier may be entered by the clinician 116 at the remote location. The second drug identifier may be a review of the first drug identifier. For example, the second drug identifier may be part of a prescription or electronic physician order entry that is the source of the first patient's ID and operating parameters. Thereafter, the system 300 may confirm that the first and second drug IDs are equal before sending the operating parameters to the medical device. The second drug ID may be replaced by the reviewed first drug ID between when the prescription is entered and when the drug 124 arrives at the treatment venue 106. Thereafter, the system 400 sounds a warning if the second drug identifier is not equal to the first drug identifier included in the drug label 124a.
In further embodiments, the system 400 may include additional blocks (not shown) in which operating parameters are used to program the medical device 332.
In one implementation of system 400, the order is entered into pharmacy computer 104. The order includes a first patient identifier and operating parameters. The pharmacy computer 104 generates a drug label 124 a attached to the drug 124. The drug 124 is sent to the treatment site 106. At treatment site 106, clinician 116 uses information terminal 118 to read clinician badge 116a, patient wristband 112a, and drug label 124a. The information terminal 118 determines whether the medication label 124a and the wristband 112a prove the identity of the same patient 112. Thereafter, the system 400 sends the drug identifier to the pharmacy computer 104. The pharmacy computer 104 verifies that the medication label 124a verifies the identity of the same patient as the order and sends operating parameters to the infusion pump. The operating parameters can be sent directly to the infusion pump 120. The operating parameters are then used to program the infusion pump to deliver the drug 124 to the patient 112.
FIG. 5 is a flowchart illustrating a first exemplary embodiment 500 of the medication therapy verification system 210 of FIG. The medication therapy confirmation system 500 is invoked at block 502. The system 500 then proceeds to a function similar to blocks 404-412 described with reference to the embodiment 400. From block 412, the medication therapy verification system 500 proceeds to block 512.
At block 512, the medication therapy verification system 500 determines whether the treatment is acceptable. System 500 may include various tolerances, such as injection flow tolerances, but the tolerances are not limited thereto. If the system 500 determines that the treatment is out of tolerance, the system proceeds to block 416 and provides an error signal. System 500 may also provide the ability to change treatments and / or tolerances. If the system 500 determines that the treatment is acceptable, the system proceeds to block 414 and continues as described with reference to FIG.
FIG. 6 is a flowchart illustrating a third exemplary embodiment 600 of the medication therapy verification system 210 of FIG. The third exemplary embodiment 600 may be used with medications that do not include an infusion order, eg, oral medications. Drug therapy that does not include infusion orders is not limited to this. The medication therapy confirmation system 600 is invoked at block 602. The system 600 then proceeds to a function similar to blocks 404-408 described with respect to the embodiment 400. From block 408, the medication therapy verification system 600 proceeds to block 610.
At block 610, the system 600 identifies a treatment. The treatment can be the administration of an oral drug. The first source 406 may provide information related to the treatment identity. The identity of treatment can be the identity of an oral drug. The identity may be encoded on the drug and / or drug package. The identity of an oral drug can be correlated with a drug identifier. At block 610, if the drug therapy is a drug, the system 600 may check for an expiration date and recall.
The information terminal 118 can obtain information by reading the oral drug label with a barcode reader. Block 610 may include converting the signal generated by the first source 406 to a computer readable media format. After block 610, the system 600 proceeds to block 612.
At block 612, the system 600 determines whether drug therapy has been previously associated with the patient 112. The determination is often made by a device that gathers information related to the patient and medication identity. For example, the clinician 116 may read the barcode from the patient wristband 112a using the information terminal 118 as the first source 406. Thereafter, the clinician 116 reads the oral drug label using the information terminal 118. Thereafter, the information terminal 118 determines whether the patient identifier from the patient wristband 112a is equivalent to the patient identifier from the drug label.
If the system 600 determines that no medication has been previously associated with the patient 112, the system 600 proceeds to block 416 where a warning / error status is provided by the system 400. Block 416 may include displaying a warning / error status on information terminal 118. If the system 600 determines that the medication has been previously associated with the patient 112, the system 600 proceeds to block 626.
At block 626, the system 600 determines whether the treatment is the correct dose. The dose is correct if it is consistent with the confirmed medication. System 400 may include downloading instructions to information terminal 118 and / or drug therapy cart 132 to deliver the drug therapy. The instructions can be downloaded from various sources, for example, pharmacy computer 104, oral drug label, information terminal 118 (to cart 132), drug therapy cart 132 (to information terminal 118), and clinician 116 manually operates parameters. Can be entered. The various sources are not limited to those described above. One check that can be performed is to verify that the dose is higher than a predetermined tolerance. The instructions include, but are not limited to, the amount of drug, the name of the drug, and the dosage unit. The dosing information may be provided directly or may be based on the attributes of the patient 112, such as the patient's weight.
If the dose is not correct, the medication therapy confirmation system 600 proceeds to block 416 and returns an error message. If the dose is correct, the medication therapy confirmation system 600 may display the dose information. The display may appear on display 120c and / or information terminal 118.
At block 628, the system 600 determines whether treatment is being administered at the correct time. If the treatment is not administered at the correct time, the medication therapy confirmation system 600 proceeds to block 416 and returns an error message. If the treatment is being administered at the correct time, the system 600 proceeds to block 630.
At block 630, the system 600 determines whether treatment is being administered by the correct route. If the treatment is not being administered with the correct route, the system 600 proceeds to block 416 and returns an error message. If the treatment is being administered by the correct route, the system 600 proceeds to block 632.
At block 632, the medication therapy verification system 600 records the results of the medication therapy administration. The result can be a successful administration of drug therapy according to the instructions. However, other results are possible. For example, a patient refuses to receive medication, changes in medication, and equipment failure. In the case of drug therapy changes, a modified order may be generated. The modified order can be linked to the original order in the drug management module 302.
FIG. 7 is a flowchart illustrating a fourth exemplary embodiment 700 of the medication therapy verification system 210 of FIG. The medication therapy confirmation system 700 is invoked at block 702. The system 700 then proceeds to a function similar to blocks 404-408 described with respect to the embodiment 400. The system 700 then proceeds to a function similar to blocks 612-626 described with respect to the embodiment 600. From block 626, medical treatment verification system 700 proceeds to block 7 04.
At block 704 , the medication therapy confirmation system 700 determines whether the treatment is acceptable. System 700 may include various tolerance values, such as dose tolerances, but the tolerance values are not limited thereto. If the system 700 determines that treatment is out of tolerance, the system proceeds to block 416 and provides an error signal. System 700 may also provide the ability to change treatments and / or tolerances. If the system 700 determines that the treatment is acceptable, the system proceeds to block 628 and continues as described with reference to FIG.
FIG. 8 illustrates an exemplary computer screen 800 that is useful in implementing various functions of the medication therapy verification system 210. In addition to other functions, the computer screen 800 can be used to enter a new drug order, change the current drug order, or cancel a drug order. The computer screen 800 includes a processing area 802, a search area 804, a drug information area 806, a titration / graduation reference area 808, an instruction and memorandum area 810, and a scheduled solution component area 812. Infusion drug order types include single dose, intermittent, sustained, sequencing, and alteration. Computer screen 800 may be used with information terminal 118, pharmacy computer 104, infusion pump 120, CPOE system, and medication therapy cart 132. The computer screen 800 is generally designed to have a computer screen look and feel accessible to the clinician 116 through the patient care system 100. The functions of computer screen 800 are achieved in part using database linkage techniques that are well known to those skilled in the art, such as hyperlinks, definition boxes, and drop-down menus. It is not limited.
Processing area 802 may include the ability to trigger infusion order creation, infusion order storage, and infusion order cancellation. The clinician 116 may customize the computer screen 800 to provide the clinician 116's preferred order entry procedure. Processing area 802 includes a status indicator for the order. Processing area 802 includes an area that indicates whether a PRN order (an “on demand” order) can be issued by clinician 116. The treatment area 802 also includes medical device 332 operating parameters, infusion order route, infusion line, infusion administration position, infusion order start time, infusion drug order type, infusion flow tolerance, infusion flow rate, infusion duration, and preparation areas. Includes the ability to display and adjust (eg, pharmacy or remote location). The processing area 802 may also include an area that links drug orders with other drug orders, for example, a doctor's infusion order with other drug orders that may be entered by other clinicians 116. The processing area 802 may include triggers that display data for other areas of the computer screen 800, eg, scheduled solution area 812. Other areas are not limited to this.
Search area 804 allows searching for drugs, solutions and / or additives for infusion orders. A default diluent may be provided for ordering. If a default dose of drug is defined in the patient care system 100, the default dose automatically appears with search results that include the drug. Searches from the search area 804 generally include drug name, route of administration, cost, package size, dosage form, generic name, whether the drug is drowsy, whether the drug is controlled, formulary And whether the drug is manufactured.
The drug information area 806 can be used to define infusion order additives and solutions. The drug information area 806 may include separate additive and solution areas. The solution area may include the label “solution / diluent”. Patient care system 100 may use a drug 124 database, a solution database, and an additive database to populate drug information area 806 with drug 124, solutions, and additives. Substances identified in one database can also be identified in other databases. The database may be linked to provide default values for drug 124 and solution combinations.
The titration / decreasing reference area 808 generally applies to continuous infusion orders. Titration defines certain parameters of the order, such as dose and / or flow rate. The dose and flow rate can be entered as absolute values. Mathematical symbols such as greater than “>”, less than “<”, and equal sign “=” may be used alone or in combination to enter information into the titration / decrease reference region 808. The mathematical symbols are not limited to these. A calendar can also be used to enter information into the titration / decreasing reference area 808. The dose and flow rate may be entered as an acceptable range. If a non-persistent infusion order is entered and / or changed, the titration / decreasing reference area 808 may be hidden.
The instructions and memorandum area 810 includes the ability to store information such as a doctor's memorandum about the patient 112 and / or infusion order. The instruction and memorandum area 810 may include a display and reference area that identifies the clinician 116 responsible for the patient 112, eg, the patient's physician.
The scheduled solution area 812 displays the solution schedule and related components based on the current state of the order being processed for the patient 112. The scheduled period may be the default for patient care system 100. The time period may also be adjustable by the clinician 116. The scheduled solution area 812 may include an adjustable display that indicates a scheduled period of time by the patient care system 100. Data displayed in the planned solution area is generally stored when order storage is triggered in the processing area 802. The scheduled solution area 812 may include the ability to look back over a period of time while changing a previously entered order. This allows the clinician 116 to see solutions that can already be prepared according to an unmodified infusion order.
Patient care system 100 includes the ability to adjust and change infusion orders. These adjustment and change functions are included in the prescription change module (336 (FIG. 3). However, adjustments and changes can be made to other parts of the patient care system 100, such as prescription entry 324, prescription execution 306, prescription approval 308. It is also possible to access from, but such other parts are not limited to these.
Patient care system 100 may include a predetermined flow rate adjustment tolerance that is adjustable. The flow adjustment tolerance is arbitrarily defined for all tissue levels of the patient care system 100. The tolerance 542b may relate to the entire patient care system 100 or a subsystem of the patient care system 100. For example, different flow control tolerances may be applied to subsystems such as for newborns, children, psychiatrics, specific nursing devices, and specific patients, but the subsystems are not limited thereto. The flow regulation tolerance may be specified for the original ordered flow rate or for the previous flow rate. The clinician 116 may also specify a flow tolerance that is specific to a particular order. The system 100 may include a pre-determined indication as to whether or not the nurse is allowed to ignore the flow adjustment tolerance without requiring a new order. This instruction may apply to the entire patient care system 100, a subsystem, or an individual clinician 116.
The drug may have a flow tolerance. The system 100 may include a flow ignore reason code. The ignore flow reason code is an annotation that the clinician 116 can select from and / or supply if the clinician 116 needs to change the flow beyond the boundaries defined by the flow tolerance. The system 100 may include a defined setting that indicates whether a message should be sent to the patient's physician if the clinician 116 ignores the flow tolerance defined by the order. The system 100 also indicates if a clinician 116 should send a message and who should be sent if it ignores a tolerance specified at a level other than the order, eg, flow tolerance 542b. A defined message trigger 546k may be included.
The system 100 may include conversion functions such as, for example, a flow rate conversion table, a changing component conversion table, and a changing flow rate conversion table. The conversion function is not limited to these. The flow rate conversion includes the step of converting the infusion order into a flow rate defined by volume / time. Here, the order is originally in any way, such as dose / time at a specific concentration, volume per unit of weight / time, dose per unit of body surface area / time, and total dose and duration. Although specified, it is not limited to these.
Changing component conversion involves converting the order in which the components change to the flow rate of the currently administered solution. The order in which the components change includes, for example, an order such as a sequencing order, but is not limited thereto. In a sequencing order, different bags can have different components and have different flow rates.
The changing flow rate conversion involves the conversion of an infusion order with a changing flow rate to the flow rate of the currently injected solution. Orders in which the flow rate changes include, but are not limited to, a declining dose order and a modified dose order.
System 100 may include a predetermined infusion flow rate. The predetermined infusion flow rate may have a description that allows selection from a drop-down list as a shortcut from entering the flow rate. System 100 may also include an automatic conversion between duration and infused volume.
The system 100 can also include, but is not limited to, a flow rate display, a volume display, a dosing period display, including a settable accuracy display. The flow rate display accuracy can be set to display the flow rate at a predetermined place after the decimal point. Various portions of the patient care system 100 may independently determine the accuracy for the displayed flow rate. For example, the system 100 may display up to the first decimal place at locations treating adults and the third decimal place at locations treating newborns. Similarly, the volume display can be set to display the injected volume to a predetermined place after the decimal point. The configurable dosing period display can be used to calculate the dosing duration based on the flow rate when the infusion is a single dose infusion or an intermittent infusion.
The system 100 may also include defined settings, such as a longest infusion duration setting, an order entry longest infusion duration ignore availability setting, an administration longest infusion duration ignore availability setting, etc. Settings are not limited to these. The maximum infusion duration setting may be separately definable for various parts of the patient care system 100. The longest infusion duration setting may also be specific to a particular drug 124. A longest infusion duration ignore availability setting may be provided at the time of order entry to set whether or not it is allowed to ignore the longest infusion duration setting. The longest infusion duration ignore availability setting determines whether the longest infusion duration setting is allowed to be ignored at the time of dosing and which groups of users are allowed to do so. Can be provided to set. If allowed to be ignored during order entry and / or administration, the system 100 may define a subset of clinicians 116 that have the authority to ignore the longest infusion duration setting.
The system 100 calculates the undelivered volume of the infusion order for the remaining time until the order is completed. When the clinician 116 administers an infusion order using the system 100, when changing the flow rate, when checking the status of the infusion, the system 100 calculates the time and volume not yet administered, and the partial bag Indicates whether the calculation indicates that is used. For example, for the last bag of an order that is stopped before the whole is administered, and / or for a bag in an order that needs to be changed before the whole is administered, the clinician 116 may use the information terminal 118 and / or Alternatively, a warning is received at the cart 132. The warning may include, for example, a message “Please only administer 150 ml”.
For a titration PRN order, the clinician 116 is automatically notified of the required flow rate change if the titration status within the order indicates that the flow rate needs to be changed. The system 100 includes a defined value that calculates the conversion from flow rate to infusion rate. The defined value of the system 100 may be adjustable. System 100 may include automatic conversion of flow rate to infusion rate to assist clinician 116 during administration of treatment.
System 100 includes the ability to document changes in IV infusion rate. The system can be configured to help the clinician 116 capture all changes in flow rate as changes occur. The clinician 116 may change the flow rate as required in the order, for example, to reduce the morphine infusion flow rate from 4 ml to 2 ml. Although the system 100 may recognize the change as a new order, the system 100 can be configured to avoid duplication and the changed order does not lead to the creation of a new bag.
The clinician 116 may also change the infusion rate without order to facilitate fluid balance when the patient 112 complains of discomfort or when, for example, the patient 112 is vomiting.
System 100 includes the ability to document changes such as infusions that are temporarily suspended, not continued, and / or resumed. The change is not limited to this, the clinician 116 may, for example, have noticed that the infusion site has failed, the infusion has been removed, and / or the heparin / saline to facilitate movement of the patient 112. The infusion can be stopped for various reasons such as being locked in water. The infusion can be resumed when the new location / infusion is restored. However, the amount of time this takes is variable and is generally recorded by the system 100.
System 100 includes the ability to document multiple infusions for multiple infusion sites in detail. In many situations, the patient 112 may have multiple drugs 124 and “y-ed” infusions, whereby some infusions flow to one location and other infusions flow to the other location. For example, morphine infusion, antibiotics, and normal saline water are infused into the right arm (place 1) and TPN and 2/3 & 1/3 flow into the double-tube CVL (place 2). System 100 allows clinician 116 to document where various fluids are infused and flowing. An intensive care unit, more than two infusions can flow in one line or one tube. The clinician 116 can indicate in which tube of the CVL the infusion or drug is flowing.
The system 100 includes the ability to document location locations for infusions and any location location changes. The injection location is often changed due to occlusion or policy. Therefore, the clinician 116 needs to document the change in location if the infusion is removed and subsequently resumed.
The method for administering the drug will be described below. This method includes the ability to change the infusion order. Changes include flow rate, changes to the infusion location, suspension of infusion, resumption of infusion, and hanging a new drug 124 into the container. The method scans the barcode associated with the patient, scans the barcode associated with the drug, confirms the expiration date if the infusion is a mixture, and the reason for the change. Selecting and recording the remaining volume of the infusion bag or accepting a value calculated from the previous volume and flow rate. Confirmation of the expiration date of the admixture may include the use of an admixture table and / or barcode.
The reason for the change can be from a specified table. The reason for the change may also include a hard-coded value for the change ordered by the physician. If a hard-coded value is selected, the clinician 116 is prompted to select a physician from a list of physicians. The attending physician may be the default in the list of physicians.
There may be an emergency selection function to discontinue administration of the drug 124. If an emergency selection is not chosen, the following steps may be included. Recording the flow rate and / or accepting a previous value for the flow rate (the previous value is generally displayed on the information terminal display 118a, the infusion pump display 120c, and / or the medical cart 132) and the previous flow rate Are compared with the ordered flow rate (this comparison is accomplished using system 100 or subsystem principles and tolerances), displaying an appropriate message, and converting between flow rate and infusion rate. (Conversion can be calculated based on system 100 prescribed drip rate conversion table 548f). The system 100 typically uses a description based on the tubing used to facilitate the clinician to select the correct infusion rate conversion. Changing the flow rate triggers the system to automatically verify the expiration date of this solution based on the scheduled flow rate. If the solution expires before or during dosing, send a message to the clinician 116 such as "This solution will expire during the scheduled dosing period. Please contact the pharmacy" . If it is a pre-mixed infusion bag and / or a customized infusion bag, the expiration date is ascertained by analyzing the scan code if possible. Accept the previous injection location or select the location of the new injection location from the list or anatomical representation. The schedule is then recalculated to replenish the pharmacy inventory.
The system 100 may also include a defined table definition ignore code to administer the infusion order at a time different from the time specified in the original infusion order. If the clinician 116 administers a drug outside the ordered administration time tolerance, the clinician 116 may be required to select a reason code for the change.
The system 100 may also include a process that requests that a PRN infusion be prepared and delivered. This option may include prompting the clinician 116 to select a PRN infusion from a list of PRN orders presented for the patient and defaulting the requested infusion bag to 1. However, the clinician 116 may have the authority to change the requested amount.
As described above for block 404 (FIG. 4), the system accesses information related to the identity of the clinician 116. The system 100 may identify the clinician 116 by using a device such as a barcode reader that reads the clinician badge 116a. The system also identifies the clinician 116, verifies that the clinician is a legitimate user of the system, and determines whether the clinician 1176 has authority to access portions of the system 100. Metrics can be used. System 100 may require a combination of clinician badge 116a, or other key, and a verified biometric match to grant access to clinician system 100. The system also terminates access to the system 100 when the clinician badge 116a is removed from the proximity of the device used to read the clinician badge 116a or other key.
Biometrics is a technique and science that statistically analyzes measured biological data. One field of biometrics is to determine unique physical features such as fingerprints. Biometrics allows an individual's identity to be revealed to a digital system, such as system 100. A digital persona is created that makes transactions and interactions easier and more secure. Biometric features for identification include, but are not limited to features such as fingerprints, faces, iris and retinal scans, voice recognition, and the like. The biometric device includes a scanning or reading device, software that converts the scanned information into a digital format, and a memory that stores biometric information that is compared to stored records. The software identifies unique fit points in the data processed by the algorithm and compares the data. Unlike passwords, PIN codes and smart cards, System 100 biometrics are never lost, forgotten or stolen.
The biometric scanner may be associated with a device for reading the clinician's badge 116a. For example, the biometric scanner can be a thumb print reader on the handle of a bar code reader. In other embodiments, the biometric scanner and electrical key reader may be located in a portable drug cart and / or medical device. If the clinician 116 places an electronic key within a specific distance from the medical device, the processor knows the specific personal electronic biometric identification file to be predicted. System 100 preferably prompts clinician 116 to scan for biometric information. Biometric information is input into the system 100 using some type of biometric reading or scanning device. A one-to-one comparison is made between the scanned biometric information and the previously stored unique personal electronic biometric identification file. This one-to-one identification comparison is much more efficient than a one-to-many identification file comparison because there is no need to search the entire clinician database for a match. Instead, only one specific comparison is made. If so, the clinician 116 is granted access to the medical device 332. If not, the clinician 116 is denied access.
In other embodiments, after the system 100 grants the clinician access, the system 100 may terminate the access if the electronic key is removed from the biometric scanner or the proximity of the biometric scanner. The neighborhood where the electronic key needs to be kept may be predetermined and / or may be a variable and programmable system 100 parameter.
In an embodiment, block 404 may include an encrypted digital fingerprint template, clinician name, login name and password. One of the technologies for realizing the clinician's identifier includes a technology called “IBUTTON 400” of Dallas Semiconductor technology. System 100 can be activated when a clinician places a finger on a fingerprint scanner. If the system 100 finds a match, the system 100 may request that the clinician 116 log into the system 100. If the system 100 cannot find a biometric fit, the system will not allow the clinician 116 to access the system 100.
In other embodiments, a database storing biometric information may be maintained in the central system 108, pharmacy computer 104, and / or treatment venue 106. In the treatment setting 106, the database is maintained in a portable cart, information terminal 118, and / or medical device 332. This distributed database allows access to remote devices even when the network 102 cannot communicate between various locations. When network 102 communication is restored, the remote and central databases can be synchronized with any information that is changed at other locations, and both system 100 databases are updated appropriately.
System 100 provides a closed loop infusion therapy management system. The closed loop begins with the clinician's 116 order. Among other methods, clinician 116 may enter an order via information terminal 118 and / or medication therapy cart 132. After the order is entered, the order becomes available in real time for pharmacy approval and drug testing. The order is available in real time as an electronic medical management record (MAR). The MAR is available to the clinician 116 for infusion administration. System 100 automatically documents changes such as drug administration and flow rate changes. Through the infusion process, the system 100 simultaneously adjusts the system 100 and / or subsystem inventory. System 100 also provides data for billing. All stages of an order can be processed in real time in one system 100. The system 100 also provides event management and decision support data. System 100 is device dependent, meaning that it can run on workstations, wireless tablets, and handheld information terminals 100.
The closed loop infusion therapy management system includes infusion order entry, order preparation, and availability of infusion status. Infusion order entry may be made by multiple means such as, but not limited to, a prescription entry module 324, a prescription change module 336, and a pharmacy interface 316. The status of the infusion provides patient 112 specific use of the infusion and alerts the pharmacy of the need for additional infusion bags.
Infusion order types can be entered according to multiple features, single dose, load dose, intermittent dose and continuous infusion. Continuous injection includes continuous injection, change injection, sequencing injection, tapering injection, and titration injection.
The volume of the infusion order can be determined according to body weight or body surface area. The procedure may be entered according to speed. If no rate is entered, the system 100 calculates according to the dose and specified period. The ordering clinician can specify the diluent and its amount. The pharmacy may provide defaults for such parameters. A check of the system 100 can be performed to ensure that the net concentration of the mixture and the injection rate are appropriate. System 100 may include a stop order 516 defined throughout system 100. Changes in the patient's condition may generate a defined system 100 message for appropriate behavior. The system 100 cooperates with the ADT interface 310 so that the order is automatically stopped upon discharge or death.
When a mixture order is entered into the system 100, a preparation command is directed to the adjustment position. The control position depends on the admixture program of the system 100 and the admixture type. System 100 may include an adjustable default that specifies where the admixture is filled. The admixture may be filled at the pharmacy or at a remote location, for example, at the floor or treatment site 106. The clinician 116 may be guided using event management information that may be displayed on the information terminal 118 throughout the preparation process. Admixture drug label 124a lists the ingredients and their respective capacities. The drug label 124a can be printed at any location. Upon administration of the mixed drug infusion, the drug label 124 is scanned. Any adjustments made to the flow rate are tracked by using barcode scanning. The pharmacy is alerted in real time to adjust the timing of the next necessary mixture infusion. Mixture preparation and administration monitoring allows for just-in-time delivery of drug 124. This reduces waste due to continual or altered preparation. This also ensures the safety of the patient 112.
The system 100 calculates the infusion flow rate based on the patient's weight, body surface area, and / or the specified frequency and duration of treatment. The ordered infusion rate is confirmed against the maximum push rate tolerance. The concentration of the solution can also be confirmed. During administration and flow, the clinician 116 is alerted at the information terminal about the infusion rate and associated parameters. The change in flow rate is communicated to the pharmacy in real time. The system 100 includes automatic scheduling of solution delivery based on the system 100 specified time tolerance.
Completion of drug administration may trigger patient billing via billing interface 312. The charging interface may include an HL7 interface. If the patient is to be charged based on completion of the infusion order preparation, the system 100 includes a credit process. Credit processing can be triggered when the infusion is returned to the pharmacy for disposal or re-registration with the pharmacy inventory management system.
The system 100 includes automatic message notification to the appropriate clinician 116. For example, when a doctor enters a new order, a message appears at the pharmacy and alerts the pharmacist that an infusion order needs to be approved. Similarly, if the infusion order is properly approved, the clinician 116 will alert the clinician 116 to the information terminal 118 that the infusion order needs to be applied within the time period specified for the order. Receive.
The above-described embodiments of the present invention, and in particular any “preferred” embodiments, are possible examples of implementations and have been set forth merely for a clear understanding of the principles of the invention. Many variations and modifications may be made to the above embodiment (s) of the invention without substantially departing from the spirit and principles of the invention. All such modifications are intended to be included within the scope of this disclosure and the present invention is protected by the following claims.
FIG. 1 is a diagram of a patient care system. The patient care system includes a pharmacy computer, a central system, and an information terminal in a treatment setting. FIG. 2 is a block diagram of a computer system representation of the pharmacy computer, central system, and / or information terminal of FIG. The computer system includes a drug therapy confirmation system or part of a drug therapy confirmation system. FIG. 3 is a block diagram illustrating functional components of the patient care system of FIG. FIG. 4 is a flowchart illustrating a first exemplary embodiment of the drug therapy confirmation system of FIG. FIG. 5 is a flow chart illustrating a second exemplary embodiment 500 of the medication therapy verification system 210 of FIG. FIG. 6 is a flowchart illustrating a third exemplary embodiment 600 of the medication therapy verification system 210 of FIG. FIG. 7 is a flowchart illustrating a fourth exemplary embodiment 700 of the medication therapy verification system 210 of FIG. FIG. 8 is an illustration of an exemplary computer screen useful for implementing various functions of the patient care system of FIG.
Claims (5)
1. Using pharmacy computer and information terminal, a method for verifying whether medication is correct to be applied to the patient, the pharmacy computer comprises a first processor, the information terminal and the second A processor, the method comprising:
Processor said 1, to the pharmacy computer at a central location, the patient identifier from a first source, and by providing the first drug identifier from the information terminal, the medication comprising the steps of associating with the patient , it viewed including the first drug identifier a patient identifier, and the information terminal and the drug station computers are linked by a network comprising a cable communication system, the information terminal, and said cable communication system of the network, first Communicating via a wireless communication path; and
The second processor executing software stored in memory, thereby accessing information associated with the patient's identity from the information terminal at a remote location;
Inputting a second drug identifier into the information terminal , wherein the second drug identifier includes the patient identifier, and the second processor of the information terminal is configured to identify the patient's identity, drug treatment, and medical device Accessing information related to said drug treatment having a treatment type; and
The second processor of the information terminal reads a medication treatment verification system stored in the memory to determine whether the medication treatment has been previously associated with the patient, the medication terminal The treatment confirmation system confirms whether the correct drug is provided to the correct patient at the correct dose and at the correct time through the correct route, and
The information terminal providing a first error signal if the medication is not previously associated with the patient;
The second processor executing software stored in the memory, thereby accessing information related to the identity of the medical device from the information terminal ;
A step first processor to provide a flow operating parameters to the medical device, that whether the first and second drug identifiers contain the same patient identifier is determined by the information terminal,
First processor, the flow rate operating parameters of the medical device is a step of determining whether or not consistent with drug treatment, said operating parameter, said first processor of the pharmacy computer at a central location And the operating parameters are provided to the medical device without passing through the information terminal ;
If said operating parameter of the medical device does not match the drug therapy, the steps of the pharmacy computer provides a second error signal,
Allowing a clinician to regulate a flow rate within a specified flow regulation tolerance associated with a drug provided by the medical device, wherein the information terminal allows the clinician to adjust the flow rate. Stores a pre-determined indication as to whether or not the regulation tolerance is allowed to be ignored and allows the clinician to rewrite the flow regulation tolerance if the clinician is authorized , Steps and
Allowing the pharmacy computer to ignore the flow regulation allowance if the clinician is allowed to ignore the flow regulation tolerance;
Including
Second error signal Unlike the first error signal,
Source bar code of the first, tag, laser readable data, radio frequency readable data, a keyboard, iButton reader, Ru is selected from the group consisting of a fingerprint scanner and a bar code reader,
Method.
2. The method of claim 1, wherein the medical device is an infusion pump.
3. The step of providing a drug identifier to the pharmacy computer comprises a step of converting a signal which the first processor is generated by the input device to a computer readable medium format The method of claim 1.
4. The patient identifier is one of a group of identifiers, which includes a patient name, a patient social security number, a patient blood type, a patient address, a patient allergy, a hospital patient ID number, The method of claim 1, comprising the location of the bed in the hospital and the name of the patient's relative.
5. The method of claim 1, wherein the step of inputting to the information terminal comprises the second processor converting a signal generated by the input device to a computer readable medium format.
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Also Published As
Publication number Publication date
MXPA04010805A (en) 2005-03-07
AT538824T (en) 2012-01-15
US20030140928A1 (en) 2003-07-31
CA2484547C (en) 2012-07-10
ES2380011T3 (en) 2012-05-07
AU2003228727A1 (en) 2003-11-17
JP2009151806A (en) 2009-07-09
EP1499372A1 (en) 2005-01-26
JP2009054183A (en) 2009-03-12
AU2003228727B2 (en) 2008-07-10
EP1499372B1 (en) 2011-12-28
WO2003092769A2 (en) 2003-11-13
CA2484547A1 (en) 2003-11-13
JP2006507560A (en) 2006-03-02
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5eff3d1f6f98e57329caed0ceb9053d3
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Skip to main content
BUY PREGNANCY TESTS & OVULATION TESTS
What Are Evaporation Lines?
What Are Evaporation Lines?
Written by TRACI HOUSTON, WHOLE BODY FERTILITY COACH
Use the discount code LOVE for 15% off your order!
We ship daily to the USA, NZ and Canada with a flat shipping cost
Cheap Pregnancy test Australia
Yes, it is true that a line is a line on a pregnancy test. No matter how dark, light, thick, thin. A second line means that you are, in fact, 100% pregnant! Wrong! While some of us are veterans at trying to conceive and know the ins and outs, some people may not be as familiar with this type of stuff. So why isn’t a line and line on a pregnancy test?
The answer to this question is evaporation lines. What is an evaporation line you ask…
An evaporation line on a pregnancy test is a line caused by the evaporation of urine on the test area causing a false positive result. An evaporation line may be caused by waiting too long and reading the result after the time limit. Although the time limit is usually the culprit for creating an evaporation line it is not always the cause and an evaporation line may develop even within the time limit.
So, a line is a line, is a line, and I am pregnant? Or is a line an evaporation line and I am not pregnant? Hmm, kind of confused here.
An evaporation line does not indicate that a woman is pregnant. When an evaporation line appears, it is best to take another test for an accurate result.
So how do you tell if it’s an evaporation line or a real line? First of all, you can use pink dye pregnancy tests rather than blue dye pregnancy tests. The blue dye tests have been known to be more likely to give you an evaporation line than the pink dye tests.
You can also only read the result within the time limit! Each brand on pregnancy test should indicate on the box when the test results should be read. It is usually somewhere under 10 minutes with the Fertility2Family tests you need to leave the test for 3 minutes, and after this period the results will be ready to read. Do not interpret test results after 5 minutes. Reading the result after this time frame allows the urine time to evaporate on the test resulting in, yes you guessed it, an evaporation line!
Study the line closely. Does it have colour to it? Or is it more of a grey, a white or an indent. A positive pregnancy test result should be pink (or blue) just like the control line. It should also run from the top of the test window to the bottom of the test window. And have the same thickness as the control line. So basically the test time needs to look like the control line but it does not need to be as dark as the control line.
Another tip to avoid the dreaded evaporation line is to dispose of any damaged or expired tests. They cannot be trusted!
A mark on a pregnancy test may be an evaporation line if:
• More than 10 minutes have passed since taking the test.
• The mark is faint and colourless, and it resembles a water spot.
• The mark has no visible dye in it.
If the control line on the test does not change colour, this means that the test has failed.
A line on a pregnancy test may show a positive result if:
• There is visible dye in the line, even if the colour is faint.
• The line appears within the period specified on the instructions, which is usually 3–5 minutes.
• A woman has taken an early-result test at least 11 days after ovulation.
• A woman has taken a regular test at least 14 days after ovulation.
• A woman has missed her period.
So how do you decrease the chances of seeing an evap line?
1. Don’t test too early. The earlier you test, the lowest your hormone (hCG) levels will be. If you have a real squinter, test again in a day or two. As hCG rises, a true positive test will darken.
2. Take a more sensitive test. Different test types and brands have different hCG thresholds in order to display a positive result. Because of this, cheap tests that you order online (such as Fertility2Family tests) are more reliable when you test early than digital tests. Keep in mind that the downside of testing early is that you are more likely to find out if you have a chemical pregnancy. These very early miscarriages are quite common, they usually do not signify any kind of underlying fertility problem, and before the advent of highly sensitive pregnancy tests, women might have had chemical pregnancies without even realising it.
3. Don’t over-hydrate. If you have been drinking a lot of water and/or urinating frequently, your urine may be too dilute for an accurate reading. It’s best to hold your urine for two or three hours to ensure it is not too diluted. First morning urine is usually more concentrated than urine from random hours during the day.
4. Try urinating in a cup before taking the test, then dipping the test in the urine for the duration specified on the packet. This technique prevents too much urine from splashing onto the test.
5. Do not use a pregnancy test that is past its expiration date.
6. Avoid storing pregnancy tests in very hot or cold locations.
Waiting for the results of a pregnancy test can be agonising. A simple way to help ensure accuracy is to take two tests. If both show a line, even a faint one, the result is likely positive.
Anyone who is unsure of the results should give hCG levels time to rise and take another test in a few days. This can reduce the risk of false negatives.
A doctor can provide the most accurate results by testing the blood or the urine.
Read our customer reviews on our Pregnancy Strip tests, Midstream Pregnancy test, Ovulation Strip tests, Midstream Ovulation testBasal Body Thermometer (BBT)
Ovulation tests
Our cheap Ovulation Tests work by allowing you to detect your monthly LH Surge – the sudden and dramatic increase in Luteinizing Hormone (LH) present in your urine just before you ovulate. LH is the hormone that facilitates ovulation (the release of the egg). When you detect your LH surge with an ovulation test, you know you are at your most fertile.
cheap reliable pregnancy tests
Fertility2Family Pregnancy Strip Tests are cheap, easy-to-use, individually packaged and quality assured. This means you can begin testing early and as often as you like without the financial stress.
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Definition of Flexor. Meaning of Flexor. Synonyms of Flexor
Here you will find one or more explanations in English for the word Flexor. Also in the bottom left of the page several parts of wikipedia pages related to the word Flexor and, of course, Flexor synonyms and on the right images related to the word Flexor.
Definition of Flexor
Flexor
Flexor Flex"or, n. [NL.] (Anat.) A muscle which bends or flexes any part; as, the flexors of the arm or the hand; -- opposed to extensor.
Meaning of Flexor from wikipedia
- describing motion in general include: Flexion and extension, which refer to a movement that decreases (flexion) or increases (extension) the angle between...
- from the flexor digitorum to the flexor hallucis. Peroneocalcaneus internus, rare,[clarification needed] arises below or outside the flexor hallucis from...
- muscle belly is located in the forearm. Together the flexor pollicis longus, pronator quadratus, and flexor digitorum profundus form the deep layer of ventral...
- (via the pisometacarpal ligament). The flexor carpi ulnaris flexes and adducts at the wrist joint. The flexor carpi ulnaris is innervated by the ulnar...
- increases in size as it descends. It serves to flex the second, third, fourth, and fifth toes. The flexor digitorum longus muscle arises from the posterior...
- ulnar nerves, p**** on top of the flexor retinaculum. On the radial side of the retinaculum is the tendon of the flexor carpi radialis, which lies in the...
- hand. The Latin carpus means wrist; hence flexor carpi is a flexor of the wrist. The flexor carpi radialis is one of four muscles in the superficial layer...
- Flexor digitorum superficialis (flexor digitorum sublimis) is an extrinsic flexor muscle of the fingers at the proximal interphalangeal joints. It is...
- wrist flexor carpi radialis flexor carpi ulnaris palmaris longus of the hand flexor pollicis longus muscle flexor pollicis brevis muscle flexor digitorum...
- The flexor pollicis longus (/ˈflɛksər ˈpɒlɪsɪs ˈlɒŋɡəs/; FPL, Latin flexor, bender; pollicis, of the thumb; longus, long) is a muscle in the forearm and...
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Take a Stand
You may have heard sitting is bad for your health, but does that mean we should stand all day instead?
If you’re an average office worker, then you’re probably spending over six hours a day sitting at work. Studies tell us that prolonged sitting may increase the risk of cardiovascular disease, type 2 diabetes, high blood pressure and stroke, even if you’re a keen exerciser. Sitting without breaks can also lead to a sore and stiff neck, shoulders and back.
But standing all day can be hard on your body too, and a combination of sitting and standing seems to bring the most benefits. In 2015, the British Journal of Sports Medicine published a review of the scientific evidence on how to best address sedentary behaviour in the office. They recommended ‘accumulating at least two hours per day of standing and light activity (such as light walking) during working hours.’
The sit-stand desk
One popular solution to the increasing sedentary nature of our jobs is the sit-stand desk, which allows you to move between sitting and standing while at work. But how do you use these to ensure you get the recommended two hours of standing or light activity?
The answer, according to Alan Hedge, Cornell University ergonomist, is the Sit-Stand-Stretch or 20-8-2 regimen. The involves, for every 30 minutes of your workday:
• 20 minutes of sitting (in good posture)
• 8 minutes of standing, and
• 2 minutes standing and moving.
For an average workday of seven and half hours, standing for two hours and moving for 30 minutes.
Tomato time
Even if you don’t have access to a standing desk you can still take regular breaks from sitting. One way to do this is to work in 25-minute bursts, after which you stand up and take a five-minute break. This is also known as the Pomodoro Technique, so named because the bursts of time can be measured using little tomato-shaped kitchen timers – Pomodoro is Italian for tomato.
Use your five-minute break to move your body – perhaps walking to the kitchen to refill your water glass or grab a tea or coffee, or doing some simple neck, shoulder and back stretches.
If you don’t have a tomato timer, there are plenty of apps online that can keep track of your sessions.
How to Spot a Heart Attack
Heart disease is responsible for the most deaths worldwide for both men and women of all races. Heart attacks and strokes make up the majority of this group. The symptoms of a heart attack are not always obvious and can differ between men and women.
Women don’t expect to have a heart attack. Even though men are twice as likely to have a heart attack, heart disease remains the second leading cause of death for women.
A heart attack occurs when blood supply to the heart becomes blocked, reducing the amount of oxygen getting to the heart muscle. This can lead to permanent heart damage.
Warning signs of a heart attack
We’re familiar with the classic Hollywood heart attack of a man clutching at his chest and falling to the floor. The reality can be quite different. Heart attack symptoms are not always sudden or severe, can start slowly with only mild pain or discomfort, and may be different for men and women.
The most common symptoms, for both men and women, are sudden central chest pain or discomfort in the chest that doesn’t go away. It can feel like pressure, tightness or squeezing.
You can also experience symptoms you may not expect, such as:
· pain radiating down the left or both arms
· dizziness and/or nausea
· pain in the jaw, back, neck or shoulders
· stomach pain or reflux (burning feeling in the throat)
· fatigue
Research shows that men and women can have different heart attack symptoms. The Australian Heart Foundation says that just over half of women who have a heart attack experience chest pain. Many other women will only experience non-typical symptoms like breathlessness, nausea and arm or jaw pain.
The American Heart Association agrees. According to their 2016 statement published in the journal Circulation, women can report shortness of breath, muscle weakness and fatigue, anxiety, loss of appetite, and profuse, cold sweating.
Women are more likely to put down their symptoms to less life-threatening conditions like acid reflux, the flu or normal ageing and as a consequence will take longer to reach a hospital and get treatment.
By knowing the warning signs and acting quickly you can reduce the damage to your heart muscle and increase your chance of survival. If you experience any symptoms you suspect might be a heart attack, stop, rest and call emergency services.
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Ch 23: The Eye Section: Special Sense Organs Flashcards Preview
SUM: Histology I > Ch 23: The Eye Section: Special Sense Organs > Flashcards
Flashcards in Ch 23: The Eye Section: Special Sense Organs Deck (40)
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1
EYES: THE PHOTORECEPTOR
SYSTEM
Each eye is composed of three concentric tunics or layers:
A tough external fibrous layer consisting of the sclera
and the transparent cornea
■ A middle vascular layer that includes the choroid , ciliary
body, and iris; and
■ An inner sensory layer, the retina , which communicates
with the cerebrum through the posterior optic nerve.
2
Not part of these layers, the lens is a perfectly transparent biconvex structure held in place by a circular system of zonular
fibers
that attach to the ciliary body and by close apposition
to the posterior vitreous body.
Partly covering the
anterior surface of the lens is an opaque pigmented extension of
the middle layer called the iris , which surrounds a central opening,
the pupil.
3
Located in the anterior portion of the eye, the iris and lens
are bathed in clear aqueous humor that fills both the anterior
chamber between the cornea and iris and the posterior chamber
between the iris and lens.
Aqueous humor flows through the pupil that connects these two chambers. The posterior vitreous chamber, surrounded by the retina, lies behind the lens and its zonular fibers and contains a large gelatinous mass of transparent connective tissue called the
vitreous body.
4
In the 4-week embryo, epithelial optic vesicles bulge
bilaterally from the forebrain, then turn into the optic
stalks
bearing optic cups.
Inductive interactions between the optic cups and the
overlying surface ectoderm cause the latter to invaginate
and eventually detach as the initially hollow lens vesicles.
5
The optic stalk develops as the optic nerve and in an
inferior groove called the choroid fissure encloses the
hyaloid vessels that supply blood for the developing lens
and optic cup.
In the ensuing weeks, head mesenchyme differentiates to
form most of the tissue in the eye’s two outer layers and the
vitreous. Ectoderm of the optic cup differentiates as the
retina and surface ectoderm creates the corneal epithelium.
When the lens is fully formed, the distal
hyaloid artery and vein disappear, leaving only the blood
supply to the retina.
6
Fibrous Layer: Has 2 parts
1. Sclera: Mainly dense irregular connective tissue with flat bundles of type I collagen parallel to to the organ surface.
Protects delicate internals, supports shape.
Extrinsic eye muscles attachment site.
Tendons of the extraocular muscles which move the eyes
insert into the anterior region of the sclera. Posteriorly the sclera
thickens to approximately 1 mm and joins with the epineurium
covering the optic nerve. Where it surrounds the choroid, the
sclera includes an inner suprachoroid lamina, with less collagen,
more fibroblasts, elastic fibers, and melanocytes.
7
Fibrous Layer: 2 parts
In contrast to the sclera, the anterior one-sixth of the eye—the
cornea—is transparent and completely avascular.
Protects anterior surface of the eye
refracts (bends) incoming light.
A section of the cornea shows five distinct layers:
■■ An external stratified squamous epithelium;
■■ An anterior limiting membrane (Bowman’s membrane),
which is the basement membrane of the external
stratified epithelium;
■■ The thick stroma;
■■ A posterior limiting membrane (Descemet’s membrane),
which is the basement membrane of the endothelium;
and
■■ An inner simple squamous endothelium.
8
Vascular Tunic (Middle Layer) of eye.
Choroid
Areolar connective tissue;
highly vascularized.
Supplies nourishment to retina
Pigment absorbs extraneous light
9
Vascular Tunic (Middle Layer) of eye.
Ciliary body
Ciliary smooth muscle and ciliary processes;
covered with a secretory epithelium.
Epithelium secretes aqueous humor
Holds suspensory ligaments that
attach to the lens and change lens
shape for far and near vision.
10
Vascular Tunic (Middle Layer) of eye.
Iris:
Two layers of smooth muscle (sphincter pupillae
and dilator pupillae
) and connective tissue, with a
central pupil.
Controls pupil diameter and thus
the amount of light entering the
eye.
11
Retina (Internal Layer) of the eye.
Pigmented layer
Pigmented epithelial cells
Absorbs extraneous light.
Provides vitamin A for
photoreceptor cells.
12
Retina (Internal Layer) of the eye.
Neural layer
Photoreceptors, bipolar neurons, ganglion cells,
and supporting Müller cells.
Detects incoming light rays; light
rays are converted to nerve signals
and transmitted to the brain
13
The basal cells have a high proliferative
capacity important for renewal and repair of the corneal surface
and emerge from stem cells in the corneoscleral limbus that
encircles the cornea.
As another protective adaptation, the corneal epithelium
also has one of the richest sensory nerve supplies of any tissue.
14
has one of the richest sensory nerve supplies of any tissue.
Th e basement membrane of this epithelium, often called
Bowman’s membrane,
contributes to the stability and strength of the cornea, helping to protect
against infection of the underlying stroma.
15
The stroma, or substantia propria, makes up 90% of
the cornea’s thickness and consists of approximately 60 layers
of parallel collagen bundles aligned at approximately right
angles to each other and extending almost the full diameter
of the cornea.
Between the collagen lamellae are cytoplasmic extensions
of flattened fibroblast-like cells called keratocytes.
The ground substance around these cells contains proteoglycans
such as lumican, with keratan sulfate and chondroitin
sulfate, which help maintain the precise organization and
spacing of the collagen fibrils.
16
The posterior surface of the stroma is bounded by another
thick basement membrane, called Descemet’s membrane,
which supports the internal simple squamous corneal endothelium.
This endothelium maintains Descemet’s membrane and
includes the most metabolically active cells of the cornea.
*responsible for regulating the proper hydration state
of the corneal stroma to provide maximal transparency and
optimal light refraction.
17
Encircling the cornea is the limbus, a transitional area
where the transparent cornea merges with the opaque sclera.
Here Bowman’s membrane ends
and the surface epithelium becomes more stratified as the conjunctiva that covers the anterior part of the sclera.
Also at the limbus Descemet’s membrane and its simple
endothelium change into a system of irregular endothelium-
lined channels called the trabecular meshwork.
they allow slow, continuous drainage of aqueous
humor
from the anterior chamber. This fluid moves from
these channels into the adjacent larger space of the scleral
venous sinus
, or canal of Schlemm.
18
Vascular Layer
The eye’s more vascular middle layer, known as the uvea, consists
of three parts:
from posterior to anterior:
the choroid,
the
ciliary body,
and the iris
19
Located in the posterior two-thirds of the eye, the choroid consists
of loose, well-vascularized connective tissue and contains
numerous melanocytes.
These form a characteristic
black layer in the choroid and prevent light from entering the
eye except through the pupil. Two layers make up the choroid
The inner choroido-capillary lamina has a rich microvasculature
important for nutrition of the outer retinal layers.
■■ Bruch’s membrane, a thin extracellular sheet, is composed
of collagen and elastic fibers surrounding the
adjacent microvasculature and basal lamina of the retina’s
pigmented layer.
20
The ciliary body, the anterior expansion of the uvea that encircles
the lens, lies posterior to the limbus.
Like the choroid, most of the ciliary body rests on the sclera.
Important structures associated with the ciliary body include
the following:
Ciliary muscle makes up most of the ciliary body’s
stroma and consists of three groups of smooth muscle
fibers. Contraction of these muscles affects the shape of
the lens and is important in visual accommodation.
Ciliary processes: Cells of this dual epithelium have extensive basolateral folds with Na+/K+-ATPase activity and are
specialized for secretion of aqueous humor.
The ciliary zonule: is a system of many radially oriented
fibers composed largely of fibrillin-1 and 2 produced by
the nonpigmented epithelial cells on the ciliary processes. The fibers extend from grooves between the ciliary processesand attach to the surface of the lens,
holding that structure in place.
21
The iris is the most anterior extension of the middle uveal layer
which covers part of the lens, leaving a round central pupil.
The posterior surface of the iris has a two-layered epithelium
continuous with that covering the ciliary processes, but
very heavily filled with melanin. The highly pigmented posterior
epithelium of the iris blocks all light from entering the
eye except that passing through the pupil.
Myoepithelial cells form a partially pigmented epithelial layer and extend contractile processes radially as the very thin dilator pupillae muscle.
Smooth muscle fibers form a circular bundle
near the pupil as the sphincter pupillae muscle.
The dilator and sphincter muscles of the iris have sympathetic and parasympathetic
innervation, respectively, for enlarging and constricting the pupil.
Melanocytes of the iris stroma provide the color of one’s
eyes.
22
Lens
The lens is a transparent biconvex structure suspended immediately
behind the iris, which focuses light on the retina.
the lens is a unique avascular
tissue and is highly elastic, a property that normally decreases
with age. The lens has three principal components:
23
Lens:
A thick (10-20 μm), homogeneous lens capsule composed
of proteoglycans and type IV collagen surrounds
the lens and provides the place of attachment
for the fibers of the ciliary zonule.
subcapsular lens epithelium consists of a single layer
of cuboidal cells present only on the anterior surface
of the lens. Area here allows for growth of the
lens and continues at a slow,
decreasing rate near the
equator of the lens throughout adult life.
Lens fibers are highly elongated, terminally differentiated
cells that appear as thin, flattened structures. Its cytoplasm
becomes filled with a group of proteins called crystallins,
and the organelles and nuclei undergo autophagy. Lens
fibers are packed tightly together and form a perfectly
transparent tissue highly specialized for light refraction.
24
The lens is held in place by fibers of the ciliary zonule,
which extend from the lens capsule to the ciliary body. Together with the ciliary muscles....
this structure allows the process of visual accommodation, which permits focusing on near and far objects by changing the curvature of the lens.
In the fourth decade of life presbyopia
normally causes the lenses to lose elasticity and their ability to undergo
accommodation.
25
The vitreous body occupies the large vitreous chamber behind
the lens. It is 99% water gel like.
Its only...
T cells in the vitreous body are a small mesenchymal population near the membrane
called hyalocytes, which synthesize the hyaluronate and collagen,
and a few macrophages.
26
The retina, the innermost tunic of the eye, develops with
two fundamental sublayers from the inner and outer layers of
embryonic optic cup.
1. The outer pigmented layer is a simple cuboidal epithelium
attached to Bruch’s membrane and the choroidocapillary
lamina of the choroid.
2. The inner retinal region, the neural layer, is thick and
stratified with various neurons and photoreceptors.
27
Retina Pigmented Epithelium:
This cellular region also contains numerous
phagocytic vacuoles and secondary lysosomes, peroxisomes,
and abundant smooth ER (SER) specialized for retinal
(vitamin A) isomerization.
Some functions of the Retina Pigmented Epithlium are:
1. The pigmented layer absorbs scattered light that passes
through the neural layer, supplementing the choroid in
this regard.
2. With many tight junctions, cells of the pigmented epithelium
form an important part of the protective blood-retina
barrie
r isolating retina photoreceptors from the highly
vascular choroid and regulating ion transport between
these compartments.
28
More Retina Pigmented Epithelium Functions:
3. After Phagocytosis of coponents,
The cells play key roles in the visual cycle of retinal
regeneration
, making
all-trans-retinal released from photoreceptors and produce
11-cis-retinal that is then transferred back to the photoreceptors.
5. Cells of pigmented epithelium remove free radicals by
various protective antioxidant activities and support the
neural retina by secretion of ATP, various polypeptide
growth factors, and immunomodulatory factors.
29
Neural retina functions as
an outpost of the CNS with glia and several interconnected
neuronal subtypes in well-organized strata. Nine distinct layers comprise the neural retina.
1. Near the pigmented epithelium, the outer nuclear layer
(ONL) contains cell bodies of photoreceptors (the rod and
cone cells).
2. The inner nuclear layer (INL) contains the nuclei of various
neurons, notably the bipolar cells, amacrine cells, and
horizontal cells, all of which make specific connections
with other neurons and integrate signals from rods and
cones over a wide area of the retina.
3. Near the vitreous, the ganglionic layer (GL) has neurons
(ganglion cells) with much longer axons. These
axons make up the nerve fiber layer (NFL) and converge
to form the optic nerve which leaves the eye and
passes to the brain.
30
Neural Retina other layers
4. The outer plexiform layer (OPL) includes axons of the
photoreceptors and dendrites of association neurons in the
INL.
5. The inner plexiform layer (IPL) consists of axons and
dendrites connecting neurons of the INL with the ganglion
cells.
The rod and cone cells, named for the shape of their outer
segments, are polarized neurons with their photosensitive portions
aligned in the retina’s rod and cone layer (RCL) and their
axons in the IPL.
All neurons of the retina are supported physically by glial
cells called Müller cells.
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5eff3d1f6f98e57329caed0ceb9053d3
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7,398,229,422,259,388,000
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@article {Sj{\"o}gren47, author = {Sj{\"o}gren, Erik and Lennern{\"a}s, Hans and Andersson, Tommy B. and Gr{\r a}sj{\"o}, Johan and Bredberg, Ulf}, title = {The Multiple Depletion Curves Method Provides Accurate Estimates of Intrinsic Clearance (CLint), Maximum Velocity of the Metabolic Reaction (Vmax), and Michaelis Constant (Km): Accuracy and Robustness Evaluated through Experimental Data and Monte Carlo S{\textellipsis}}, volume = {37}, number = {1}, pages = {47--58}, year = {2009}, doi = {10.1124/dmd.108.021477}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The use of multiple depletion curves for the estimation of maximum velocity of the metabolic reaction (Vmax), the Michaelis constant (Km), and intrinsic clearance (CLint) was thoroughly evaluated by means of experimental data and through a series of Monte Carlo simulations. The enzyme kinetics of seven compounds were determined using the multiple depletion curves method (MDCM), the traditional initial formation rate of metabolite method (IFRMM), and the {\textquotedblleft}in vitro t{\textonehalf}{\textquotedblright} method, and the parameter estimates that were derived from the three methods were compared. The impact of a change in enzyme activity during the incubation period on the parameter estimates and the possibility to correct for this were also investigated. The MDCM was in good overall agreement with the IFRMM. Correction for a change in enzyme activity was possible and resulted in a better concordance in CLint estimates. The robustness of the method in coping with different rates of substrate turnover and variable starting concentrations were also demonstrated through Monte Carlo simulations. Furthermore, the limitations imposed by assumptions inherent in the in vitro t{\textonehalf} method were demonstrated both experimentally and by simulations. This study demonstrates that the MDCM is a robust and efficient method for estimating enzyme kinetic variables with high accuracy and precision. The method may potentially be used in a wide range of applications, from pure enzyme kinetics to in vitro-based predictions of the pharmacokinetics of compounds with multiple and/or unknown metabolic pathways. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/37/1/47}, eprint = {https://dmd.aspetjournals.org/content/37/1/47.full.pdf}, journal = {Drug Metabolism and Disposition} }
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5eff3d1f6f98e57329caed0ceb9053d3
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Uncategorized
peyronie’s disease incidence
Peyronie’s disease (PD) is an acquired inelastic scar. contemporary data suggest an incidence of one in 20 men, with peak occurrence between ages of 50-55 years. Initial diagnosis of PD.
Franois Gigot de Peyronie is widely credited for first describing penile curvature, now known as Peyronie disease (PD), in 1743. However, the.
Peyronie's disease: a literature review on epidemiology, genetics, pathophysiology, diagnosis and work-up. Sultan Al-Thakafi and Naif Al-.
peyronie’s disease no pain
Medindia provides you with the latest news and research breakthroughs on Peyronie´s Disease. Please find 253 such items on this topic. Two Commonly Used Drugs for Erectile Dysfunction Could Treat.
However, based on studies of men who reported having symptoms of Peyronie’s disease, researchers estimate that the actual number of men who have Peyronie’s disease is more than 1 in 10. 2,3. The chance of developing Peyronie’s disease increases with age. 1 It is less common for men in their 20s and 30s to have Peyronie’s disease. 1
peyronie’s disease in hands peyronie’s disease no pain Causes. In Peyronie disease, fibrous scar tissue develops in the deep tissues of the penis.. This is a cord-like thickening across the palm of one or both hands.
The true prevalence of PD is unknown; it is estimated as between 3.7% and 7.1% , but the actual prevalence of this disease may be higher because of patients'.
The survey had a high response rate, and the participant responses provided the first available population-based prevalence and incidence estimates for PD in the .
In many countries, Peyronie’s Disease is considered a “rare” disease because it can only be tracked by the number of reported new cases and known cases. If significantly more men are affected and would be diagnosed, then the categorization of “rare” as it applies to this disease would change.
Feelings of anxiety and isolation can be prevalent in individuals over the age of 65. For this older group, shelter-in-place orders during the COVID-19 pandemic can make the feelings of being.
Peyronie's disease (PD) is a connective tissue disorder of the penis. Despite several studies, the incidence and prevalence rates of PD are still unclear.
However, this technique does not allow direct visualization of the kidney or cyst, does not provide a large sampling of tissue, does not allow for high-resolution ultrasound guidance, and is.
TORONTO–(BUSINESS WIRE)–The first-ever Canadian study to forecast the growing burden of nonalcoholic fatty liver disease.
Peyronie's disease (PD) is a connective tissue disorder which can result. The incidence of Peyronie's Disease in Rochester, Minnesota, 1950.
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Thu. Feb 9th, 2023
Contemplating a cosmetic touch up? There are numerous elective medicines to restorative medical procedure, which give a non-careful cosmetic touch up, lessen kinks and assist you with looking 10 years more youthful. Over the most recent couple of years, Botox has turned into an extremely well known treatment. There is a long history of protected, powerful utilization of Botox to treat solid issues, and presently it is utilized to eliminate lines and kinks on the face brought about by everyday muscle withdrawal of your normal looks. How Does Botox Work? Botox (Botulinum Toxin) keeps muscles from contracting. When infused into the face, it loosens up the muscles and in this way eliminates facial lines and kinks brought about by muscle constriction. It is a transitory enemy of maturing treatment, going on for a considerable length of time. The impacts of botox can make you look years more youthful, and support your self-assurance and self esteem.Which region of the Face can be Treated with Botox? Lines on the face brought about by muscle withdrawal can be treated by Botox. Lines on the brow, glare lines at the extension of the nose (glabella lines), eye kinks and crows feet (giggling lines) can be generally treated with Botox.
When Will I See Results After a Botox Treatment?
The full impacts of Botox infusions should be visible in 5-7 days. Results might change on people, contingent upon the seriousness of kinks and the strength of muscles treated.
What are the Side Effects of Botox Injections?
Swelling can happen around the infusion site, and Charlotte Botox infrequently on the off chance that a vein is harmed, a patient might get “bruised eye” swelling. The utilization of an ice pack when botox infusions will limit any swelling.
Infrequently, an impermanent hanging of the eyelid might happen. The dangers of this can be limited assuming infusions to the temple are restricted to the upper and focal region of the brow. This additionally has a helpful impact of lifting the eyebrows, which works on the presence of the upper eyelids and diminishes any hanging skin around the upper eyes, giving a more young, more extensive peered toward look.
Assuming you are thinking about Botox infusions to put your best self forward for a unique occasion, it is suggested that you have your Botox treatment something like 7 days before the occasion, to take into consideration the full impacts of botox and to take into account any swelling to disappear.
Any infusion conveys a little gamble of contamination, so Botox medicines are not suggested in the event that you are pregnant or bosom taking care of.
What number of Botox Treatments are Required?
Botox infusions ought to be rehashed each 3-4 months. Patients who have had Botox medicines north of a year may just require further medicines at regular intervals.
Where Can I Get Botox Injections? There are numerous centers and beauty parlors offering botox medicines. Numerous beauty parlors have a meeting specialist who does the infusions, so the medicines may just be accessible on a set number of days for a specific beauty parlor. Assuming you live in a very much populated region, you ought to have the option to seek botox medicines without voyaging excessively far from home. A web look for “botox” and the name of your town ought to assist you with observing a nearby facility or beauty parlor which offers the help.
By Eshan
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Posted .
The recent documentary on Netflix,Root Cause, is causing quite a stir. Many are questioning the safety of root canals that have been done and their possible connection to cancer.Many Periodontists and Endodontists discuss the validity of these accusations made in this film.
Do Root Canals Cause Cancer?
This is a genuine question many patients are asking after this film was aired and made a case for endodontic therapy being linked to an increase in cancer rates. This will attempt to debunk the accusations made in this documentary on three levels, so that an intelligent conversation can be had with your current and potential dental patients. A tooth saved by typical nonsurgical root canal treatment. No peer-reviewed studies have shown this type of treatment being linked to cancer or heart attacks.
Focal infection theory
The theory discussed in the Root Cause documentary—the focal infection theory—suggests that chronic diseases are caused by localized infections. In the documentary, this theory was used as a basis to state that because we cannot remove all of the bacteria in a root canal-treated tooth, a chronic inflammatory response is induced. Claims were made that the chronic inflammation associated with these root canal-treated teeth led to systemic diseases such as cancer, arthritis, heart disease, chronic fatigue, and male impotence.
Why the focal infection theory is false
The focal infection theory was devised by a dentist named Weston Price in 1922. That was 100 years ago. The true science behind root canals and the techniques used to treat apical periodontitis were not developed until 1965, 45 years after the focal infection theory was promulgated. (1) Because the cause of the etiology of apical periodontitis was unknown 100 years ago, root canal treatments were highly variable, no protocols were established, and root canals performed at that time cannot be compared to root canals performed today. The modern concepts of endodontics that dentists perform today—such as irrigation, medication, and microscopic debridement—wouldn’t have been mainstream practice 100 years ago. The theory of focal infection was found to be flawed, as the studies performed by Dr. Price lacked control groups, were found to have bias, and, overall, had poor experimental design. (2) However, even if you still believe in this 100-year-old theory, modern-era root canal techniques would not leave the same bacteria in the tooth as the root canals that were performed a century ago.
Cause and effect
The definition of cause and effect is a relationship between events or things, where one is the result of the other or others. This is a combination of action and reaction. Correlation, on the other hand, is defined as a mutual relationship between two or more things. A confounding variable is defined as an extra variable that was not accounted for in a study that can ruin an experiment and suggest correlation, when in fact there is none.
How the documentary incorrectly uses cause and effect
In this documentary, the case is made by one osteopathic physician that 97% of terminal cancer patients (breast cancer) previously had root canal procedures. Because of this percentage, the claim is made that root canals cause cancer. Cause and effect, clear and simple. The problem with this rationale is that the highest incidence of women with breast cancer are in the age range of 50–75. (3) Similarly, the age range that exhibits the highest prevalence of root canal-treated teeth are in this same age range. (4) The statement that people with breast cancer had root canal therapy so root canal therapy causes breast cancer is not a logical statement. This is not cause and effect. This correlation is further proved false by the confounding variable of age. In other words, this statement would be similar to a statement that says 97% of the people who had breast cancer had skin wrinkles so skin wrinkles cause breast cancer.
Oral-systemic connection
The oral-systemic connection is a thought process that the mouth is not a separate part of the body but intrinsically linked. The oral cavity is often called the window into the body as many systemic problems manifest themselves in the mouth. Unfortunately, a strong mouth-body disconnect sentiment still exists in medicine. An article written this month explains the history behind this divide and how studies have shown that dental conditions can contribute to systemic conditions. (5) Chronic inflammation of tissues in the mouth, especially periodontal disease, has been linked to systemic issues such as diabetes, cardiovascular disease, respiratory diseases, Alzheimer’s disease, low-birth-weight babies, pancreatic cancer, and rheumatoid arthritis. (6) Many studies have shown the benefits of treating inflammation in the mouth as a means of treating systemic illness. One recent study shows how nonsurgical treatment of periodontal disease lowered HbA1c levels in individuals with prediabetes. (7) This is a classic example of how dental treatment can decrease inflammatory cytokines and is thought to have an impact on systemic illness. On the other hand, there are many reports of adverse effects of untreated dental disease, especially in the case of acute abscess infections. (8)
How the documentary incorrectly uses the oral-systemic connection
Although this documentary does address how the mouth is linked to the rest of the body, the conclusions drawn are not supported by research and are wildly inaccurate. Root canal therapy is not the cause of cancer or heart attacks. Root canals do not leave areas of necrotic bone in your jaw that are filled with bacteria and lead to chronic inflammation and illness.
Conclusion
In the words of Marcus Johnson, DDS, MSD, a board-certified endodontist:
Misinformation presents a threat to public health without sound facts and data based within peer-reviewed science and verified studies. In these times where from the palm of your hand correct information is as easy to access as false and outlandish rubbish, identifying truthful resources can be a challenge. There is no valid scientific knowledge linking root canal treatment to any health problems, and with the backing of 8,000 endodontists—”the specialists in saving natural teeth”—163,000 dentists, and 3,300 dental researchers, it becomes clearer that fear-based platforms of fallacy are doing a disservice, are disingenuous to the public, and will be silenced by sound research! As an evidenced-based board-certified endodontist, I welcome any questions concerning root canal treatment and its safety and would be happy to answer them and direct inquiring minds to the appropriate resources at the American Association of Endodontists and our parent entity, the American Dental Association. I can honestly say if there were ever any concerns about the safety of this procedure, which is performed millions of times a year, I would have been the first to object. Natural teeth are worth saving!
The American Association of Endodontists offers a wealth of resources to help combat misinformation and reassure patients and dental professionals about root canal safety.
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5eff3d1f6f98e57329caed0ceb9053d3
|
1,886,929,064,587,668,700
|
John S. Lam
Learn More
Dendritic cells (DCs) are bone marrow-derived leukocytes that function as potent antigen presenting cells capable of initiating T cell-dependent responses from quiescent lymphocytes. DC pulsed with tumor-associated antigen (TAA) peptide or protein have recently been demonstrated to elicit antigen-specific protective antitumor immunity in a number of murine(More)
Dendritic cells (DCs) are potent antigen-presenting cells that can activate quiescent T lymphocytes. When pulsed with tumor-associated antigen (TAA) peptide or protein, murine DCs can provide antitumor immunity. We reasoned that DCs retrovirally transduced with TAA genes might have important advantages over peptide- or protein-pulsed DCs, including(More)
• 1
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5eff3d1f6f98e57329caed0ceb9053d3
|
4,112,261,105,014,211,600
|
Iron improve memory
Does iron improve memory?
Effectiveness Rating for Iron's Ability to Improve Memory
The effectiveness rating is a measure of how well iron is able to improve memory. The overall rating for this claim is 3 out of 3. The research shows the supplement's ability to deliver on this particular claim is warranted. Using Iron to improve memory will most likely lead to positive results.
Confidence Rating for Iron's Ability to Improve Memory
The confidence rating is a mesure of how valid the effectiveness rating is. This rating is based on how many studies are included in the database on this topic.
There is one study in the database on iron; the confidence rating is 20. A score above 80 means the effectiveness rating for this supplement is reliable. A score under 80 means there is insufficient evidence to ensure a reliable effectiveness rating.
References
Title of Study
Effects of iron and n-3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa
Back to iron reviews
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5eff3d1f6f98e57329caed0ceb9053d3
|
-2,989,548,675,285,086,000
|
Muscle Structure Influences Utrophin Expression in Mice
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in the dystrophin gene. Utrophin is structurally similar to dystrophin and improving its expression can prevent skeletal muscle necrosis in the mdx mouse model of DMD. Consequently, improving utrophin expression is a primary therapeutic target for treating DMD. While the downstream mechanisms that influence utrophin expression and stability are well described, the upstream mechanisms are less clear. Here, we found that perturbing the highly ordered structure of striated muscle by genetically deleting desmin from mdx mice increased utrophin expression to levels that prevented skeletal muscle necrosis. Thus, the mdx:desmin double knockout mice may prove valuable in determining the upstream mechanisms that influence utrophin expression to develop a therapy for DMD.
Published in the journal: . PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004431
Category: Research Article
doi: 10.1371/journal.pgen.1004431
Summary
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in the dystrophin gene. Utrophin is structurally similar to dystrophin and improving its expression can prevent skeletal muscle necrosis in the mdx mouse model of DMD. Consequently, improving utrophin expression is a primary therapeutic target for treating DMD. While the downstream mechanisms that influence utrophin expression and stability are well described, the upstream mechanisms are less clear. Here, we found that perturbing the highly ordered structure of striated muscle by genetically deleting desmin from mdx mice increased utrophin expression to levels that prevented skeletal muscle necrosis. Thus, the mdx:desmin double knockout mice may prove valuable in determining the upstream mechanisms that influence utrophin expression to develop a therapy for DMD.
Introduction
Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder that affects approximately 1∶4000 boys [1]. DMD is caused by mutations in the large 2.2 Mb dystrophin gene [2], [3]. The dystrophin protein functions as a large molecular spring that connects the skeletal muscle cytoskeleton to the transmembrane dystrophin glycoprotein complex (DGC) [4][9]. The lack of dystrophin in DMD is accompanied by a significant reduction in the expression of the DGC leaving the membrane highly susceptible to contraction-induced injury and hypoxic stress [10][18]. DMD patients develop severe cardiorespiratory distress and generally live into their third decade with the help of palliative care.
The absence of dystrophin leads to various molecular and cellular homeostatic responses that slow the loss of skeletal muscle [19]. For instance, the dystrophin paralog, utrophin is expressed on the sarcolemma of dystrophic fibers acting to mitigate necrosis [20][25]. Skeletal muscle necrosis in the mdx mouse model of DMD is prevented by the expression of a full-length utrophin transgene when expressed at twice the levels of the endogenous utrophin [26]. Utrophin expression in DMD patients correlates with the severity of disease and time to wheelchair demonstrating the therapeutic potential of utrophin in humans [25], [27][31]. An utrophin therapy would benefit all DMD patients and circumvent a potential T-cell mediated immune response that could impair the long-term benefit of prospective dystrophin replacement strategies [32][34]. Accordingly, increasing the expression of utrophin is a primary target for therapy of DMD [33]. While promising utrophin-mediated therapies are being tested in clinical trials [33], [35], the mechanisms that influence utrophin expression are not fully understood.
Utrophin is normally expressed on the sarcolemma of developing and regenerating muscle fibers [21], [22], [36]. Utrophin is ultimately replaced by dystrophin in the sarcolemma of normal maturing fibers and remains concentrated at the neuromuscular and myotendinous junctions. However, low levels of utrophin can remain on the sarcolemma of dystrophin-deficient mdx mouse skeletal muscle fibers independent from muscle regeneration [37]. While various factors that influence utrophin expression and stability within the sarcolemma are well described [33], [38], [39], the upstream mechanisms are less clear. We recently discovered an increase in utrophin expression in mdx4cv mice expressing the microdystrophinΔR4–R23 transgene [40]. The polyproline site within hinge 2 of microdystrophinΔR4–R23 led to myotendinous strain injury and the formation of ringed fibers where the peripheral sarcomeres surround the central sarcomeres [40], [41]. Notably, we found a significant increase in utrophin expression within the limb muscles that contained ringed fibers, but not in the diaphragm muscles that did not contain ringed fibers [40]. Accordingly, we hypothesize that structural changes within skeletal muscle can influence utrophin expression, independent from muscle regeneration.
To examine the role of muscle structure on the pathogenesis of DMD we generated mdx:desmin double knockout (dko) mice. Desmin is an intermediate filament protein that maintains the highly ordered structure of striated muscles by connecting the sarcomeres to the sarcolemma and organelles [42][45]. Desmin influences the organization of dystrophin and ankyrin in a costameric lattice that connects the Z-disks of peripheral sarcomeres to the sarcolemma [46], [47]. Desmin−/− mice develop a severe dilated cardiomyopathy with a mild skeletal myopathy [45], [48]. The skeletal myopathy is associated with misaligned sarcomeres and changes to the distribution and function of mitochondria [45], [48]. Here, we report that a ∼2.5-fold increase in utrophin expression in dko skeletal muscle fibers prevented necrosis in a fiber-type specific manner.
Results
Premature death of dko mice
We initially found that desmin expression was increased in mdx4cv mouse skeletal muscles by western analysis of whole muscle lysates (Fig. 1A), confirming previous reports in mdx mice [49], [50]. To examine the role of desmin in the pathogenesis of DMD we bred mdx4cv:desmin+/− mice to generate the dko pups (N = 5, F>4). The dko pups were born in the expected Mendelian ratios [71 (25%) +/+; 144 (51%) +/−; 67 (24%) −/−]. We examined only the male mice for this study, as DMD patients are males. The dko mice developed a mild kyphosis (Fig. 1B). The genotype was confirmed by immunohistological analyses of dystrophin and desmin expression in skeletal muscle (Fig. 1C). The dko mice gained less body mass than the wild-type (24%), desmin−/− (18%), and mdx4cv controls (36%; P<0.001 one way ANOVA; Fig. 1D). The desmin−/− and dko mice were euthanized when they lost body mass and/or exhibited labored breathing and reduced mobility consistent with cardiorespiratory failure. Kaplan-Meyer survival analyses demonstrated a significantly reduced lifespan in the dko mice with a median survival of 76 days for males compared to a median survival of 609 days for the desmin−/− males (Fig. 1E, P<0.001). The average lifespan for mdx4cv males is 21.5 months [51]. We chose a time point of 11 weeks for the experiments in this study, unless otherwise stated. Approximately a quarter of the dko mice (22%) developed malocclusion, which contributed to the reduced body mass and increased mortality rate particularly in mice younger than 8 weeks of age. The malocclusion was treated with trimming the teeth every week and feeding the mice crushed food pellets mixed with hydrated gel. Malocclusion consistently presented in dko mice through various backcrosses suggesting that this was likely a phenotype of the dko mice and not a separate genetic defect. Furthermore, none of the wild-type, desmin−/− or mdx4cv mice developed malocclusion during the course of this study. The dko mice that developed malocclusion were included for body mass and survival analysis, but not for further analyses.
The genetic deletion of desmin from <i>mdx<sup>4cv</sup></i> mice reduces body mass and survival.
Fig. 1. The genetic deletion of desmin from mdx4cv mice reduces body mass and survival.
A) Desmin expression was significantly increased in the mdx4cv skeletal muscles. Bars represent the mean +/− S.D. densitometry of desmin expression from n = 7 wild-type and n = 6 mdx4cv gastrocnemius muscles. B) Photograph of representative wild-type and dko mice. Note that the dko mice develop a mild kyphosis at 11 weeks of age. C) Confirmation of genotype by immunostaining of frozen gastrocnemius muscle sections with antibodies to dystrophin and desmin. Scale bar = 50 µm D) Mean +/− S.D. body mass of wild-type (n = 5), mdx4cv (n = 4), desmin−/− (n = 5) and dko mice (n = 9). E) Kaplan-Meyer survival analyses demonstrating the significantly shortened lifespan of dko mice (n = 13) compared with desmin−/− mice (n = 16). *P<0.05, **P<0.01 compared with wild-type. @@@P<0.001 compared to desmin−/−.
Profound reduction in dystrophic histopathology in dko mice
We next examined the gross dystrophic histopathology in various limb and respiratory muscles. Wild-type mice had few central nuclei (<1%), and no detectable calcified or necrotic fibers (Fig. 2A-D). Desmin−/− mice had a mild skeletal myopathy with a low level of central nuclei (∼5%) and rare necrotic fibers (Fig. 2AD), but no calcification was evident (Fig. 2A,C), as previously described [45], [48], [52]. The mdx4cv skeletal muscles were highly dystrophic with predominantly centrally nucleated fibers (Fig. 2A,B). Of the different limb and respiratory muscles we examined, only the mdx4cv diaphragms consistently contained calcified fibers (Fig. 2A,C), whereas all mdx4cv muscles contained patches of necrotic fibers (Fig. 2A,D). The proportion of dko limb and respiratory skeletal muscles with central nuclei was significantly reduced when compared to the mdx4cv muscles (Fig. 2A,B). None of the dko skeletal muscle fibers were calcified and there were 96% fewer necrotic fibers than the mdx4cv gastrocnemius muscles (P<0.001; Fig. 2A,C,D). Inflammation was also reduced in the dko gastrocnemius muscle with a 93% reduction in macrophages (P<0.01; Fig 2A,E) and an 82% reduction in CD3 positive T-lymphocytes (P<0.001; Fig. 2A,F) when compared to the mdx4cv controls. Thus, multiple indices of dystrophic histopathology in the mdx4cv mice were improved by the absence of desmin.
The dystrophic histopathology in <i>mdx<sup>4cv</sup></i> mice was profoundly improved by the absence of desmin.
Fig. 2. The dystrophic histopathology in mdx4cv mice was profoundly improved by the absence of desmin.
A) Frozen sections demonstrating the histopathology of skeletal muscles. Note that the extensive central nucleation and mononuclear cell infiltrate, calcification, necrosis and inflammation in mdx4cv muscles were significantly diminished in the dko skeletal muscles. All panels are representative sections of gastrocnemius muscle except the second row, which are sections of the diaphragm. Scale bars = 100 µm. B) The number of centrally nucleated fibers was significantly diminished in hind-limb and respiratory muscles in the dko mice when compared with the mdx4cv muscles C) Calcified fibers were found in the mdx4cv diaphragm muscle but not in the dko muscles. D) Quantitation of the total number of necrotic fibers in the gastrocnemius muscles. E) Quantitation of macrophages in the gastrocnemius muscles. F) Quantitation of the CD3 positive T-lymphocytes in the gastrocnemius muscles. N = 4 for all experiments. All bars in the graphs represent mean +/− S.D. *P<0.05, **P<0.01 and ***P<0.001 compared to wild-type; #P<0.05, ##P<0.01 and ###P<0.001 compared to mdx4cv.
Increased expression of utrophin prevented necrosis of dko skeletal muscle fibers
We next examined whether the dystrophic pathology in the dko muscles was improved by an increase in utrophin expression. We examined the gastrocnemius muscle because of its distinct fiber-type distribution. Utrophin was restricted to the neuromuscular junctions in mature (11 week) wild-type and desmin−/− skeletal muscle fibers (Fig. 3A). Utrophin was expressed at low levels on the extrasynaptic sarcolemma in mdx4cv muscles (Fig. 3A), as previously described in mdx mice [21], [22], [36]. Utrophin was highly expressed in the dko extrasynaptic sarcolemma in some, but not all of the gastrocnemius muscle fibers (Fig. 3A). We next performed a titration of dko utrophin by western analyses to generate a non-linear regression to quantitate the changes in utrophin expression (Fig. S1). The significant increase in utrophin expression in mdx4cv mice compared to wild-type mice was confirmed by western analysis of total gastrocnemius muscle lysates (Fig. 3B; P<0.001). Importantly, we found a 2.54-fold increase in utrophin expression in the dko when compared with the mdx4cv controls (Fig. 3B; P<0.001). Because not all myofibers express utrophin in the dko we next quantitated the level of utrophin fluorescence intensity on the sarcolemma. We quantitated utrophin fluorescence in the wild-type sarcolemma as the negative control and the wild-type neuromuscular synapse as the peak of detection to ensure our quantitation is not beyond the limits of detection. The fluorescence intensity of utrophin was significantly increased in mdx4cv muscles compared to wild-type muscles (P<0.001; Fig. 3C). The utrophin fluorescence intensity increased by 2.86-fold in the dko sarcolemma when compared to the mdx4cv (P<0.001). To test whether this increase in fluorescence intensity in the dko reached therapeutic levels, we compared mdx:utrophin double knockout muscles treated with microutrophinΔR4–R21 using the same gastrocnemius muscles from our previous study [53], which demonstrated that microutrophinΔR4–R21 prevented skeletal muscle necrosis. We found that the sarcolemmal fluorescence intensity of utrophin was increased by 22% in the dko muscles when compared to the mdx:utrophin double knockout muscles expressing microutrophinΔR4–R21 (P<0.01). We found no change in utrophin mRNA in the gastrocnemius muscles of wild-type, desmin−/−, mdx4cv and dko mice, when measured by qPCR (Fig. 3D). Upregulation of utrophin was associated with a reduction in necrosis and regeneration in the dko, as only 9% of the fibers with extrasynaptic utrophin had central nuclei compared with 46% central nuclei in fibers without extrasynaptic utrophin (P<0.001; Fig. 3E). Thus, an increase in utrophin expression in a fraction of the dko muscle fibers prevented cycles of necrosis and regeneration.
Expression and localization of utrophin in wild-type, desmin<sup>−/−</sup>, <i>mdx<sup>4cv</sup></i> and dko muscles at 11 weeks of age.
Fig. 3. Expression and localization of utrophin in wild-type, desmin−/−, mdx4cv and dko muscles at 11 weeks of age.
A) Frozen sections of the gastrocnemius muscles immunolabelled with antibodies to utrophin A and α-bungarotoxin (α-BTX). Utrophin was restricted to the neuromuscular junctions in wild-type and desmin−/− muscles. Utrophin was expressed on the extrasynaptic sarcolemma in the mdx4cv and dko muscles. Note the increased utrophin expression on the sarcolemma of dko fibers compared with the mdx4cv muscles. Scale bar = 50 µm. B) Western blot analyses of utrophin A expression in whole gastrocnemius muscle lysates from wild-type (n = 3), desmin−/− (n = 3), mdx4cv (n = 7) and dko (n = 6) mice. Quantitation of utrophin expression in whole muscle lysates is shown below the immunoblots. C) Maximal utrophin fluorescence intensity was significantly increased on the sarcolemma of dko fibers compared with mdx4cv fibers. Furthermore, maximal fluorescence intensity was significantly increased in dko fibers compared to mdx:utrophin double knockout fibers expressing microutrophinΔR4–R21. N = 4. D) We found no change in utrophin mRNA when comparing whole gastrocnemius muscle lysates when utrophin mRNA was normalized to the housekeeping gene Ywhaz. N = 4. E) Utrophin prevents muscle degeneration and regeneration in dko gastrocnemius muscles as demonstrated by the reduced proportion of fibers with central nuclei. N = 4. All bar graphs show the mean +/− S.D. *P<0.05 and ***P<0.001 compared to wild-type; #P<0.05 and ###P<0.001 compared to mdx4cv.
Utrophin expression on the sarcolemma of maturing 1a, 2a and 2d/x fiber types
Utrophin expression is found on the sarcolemma of all developing wild-type muscle fibers and subsequently becomes restricted to the neuromuscular junctions [21], [54]. The prevention of skeletal muscle necrosis in the dko mice implied that the developmental loss of utrophin expression from the extrasynaptic sarcolemma did not occur. Furthermore, the expression of utrophin on the extrasynaptic sarcolemma of a portion of dko fibers suggests that utrophin may be expressed in certain muscle fiber types. To test this, we compared the expression of the utrophin A isoform relative to muscle fiber types at 3 weeks of age (Fig. 4). We found that utrophin was near absent from the extrasynaptic sarcolemma of wild-type gastrocnemius muscles by 3 weeks of age (Fig. 4). We found utrophin in the cytoplasm of a portion of the wild-type fast 2b fibers (Fig. 4). Furthermore, antibodies to the utrophin A isoform labeled blood vessels in wild-type muscles at 3 weeks of age (Fig. 4), but not at 11 weeks of age (Fig. 3), which was similar to the immunohistochemical staining pattern of the utrophin A isoform in humans [55]. Utrophin expression was absent from the extrasynaptic sarcolemma in most fast 2b fibers in desmin−/−, mdx4cv and dko muscles (Fig. 4). However, utrophin remained at low levels on the sarcolemma of 1a, 2a and 2d/x fiber types in desmin−/− and mdx4cv gastrocnemius muscles. The reduced utrophin expression in the extrasynaptic sarcolemma of mdx4cv muscles coincided with the appearance of patches of necrotic fibers (Fig. 4). In contrast, utrophin prevented skeletal muscle necrosis in the dko muscles by remaining on the extrasynaptic sarcolemma of maturing 1a, 2a and 2d/x fiber-types (Fig. 4). We next performed a titration of utrophin by western analyses of the 3-week-old dko muscles to generate a non-linear regression to quantitate the changes in utrophin expression (Fig. S2). We found a 29.6% increase in utrophin in the mdx4cv muscles compared to wild-type controls (Fig. 4B; P<0.05). Utrophin in the dko was increased by a further 60.9% compared to the mdx4cv muscles (P<0.001). Similar to 11 weeks of age (Fig. 3D), we found no change in the relative amounts of mRNA at 3 weeks of age when comparing all genotypes (Fig. 4C). Thus, utrophin expression was increased in the dko in a fiber-type specific manner to prevent necrosis.
Expression and localization of utrophin in wild-type, desmin<sup>−/−</sup>, <i>mdx<sup>4cv</sup></i> and dko muscles at 3 weeks of age.
Fig. 4. Expression and localization of utrophin in wild-type, desmin−/−, mdx4cv and dko muscles at 3 weeks of age.
A) Utrophin expression in gastrocnemius muscles compared to adjacent sections labeled for the different skeletal muscle fiber-types. Note that utrophin expression is restricted to the neuromuscular junctions and non-muscle cells in the wild-type muscles. Utrophin is also restricted to the neuromuscular junctions in most fast 2b fibers in desmin−/− muscles, but remains on the sarcolemma of the type 1a, 2a and 2d/x fiber types. Utrophin is found on the extrasynaptic sarcolemma of mdx4cv muscles, irrespective of fiber-type at 3 weeks of age. Regions where utrophin is lost from the extrasynaptic sarcolemma in mdx4cv muscles have necrotic fibers (arrows). Utrophin expression is lost from most of the fast 2b fibers in the dko by 3 weeks of age, but is retained on the sarcolemma of 1a, 2a and 2d/x fiber types. Scale bar = 50 µm. B) Western blot analyses of utrophin A expression in whole gastrocnemius muscle lysates from (n = 4), desmin−/− (n = 4), mdx4cv (n = 8) and dko (n = 8) mice. Quantitation of utrophin expression in whole muscle lysates is shown below the immunoblots. C) We found no change in utrophin mRNA when comparing whole gastrocnemius muscle lysates, when utrophin mRNA was normalized to the housekeeping gene Ywhaz. N = 4. *P<0.05, P<0.001 compared to wild-type. ###P<0.001 compared to mdx4cv.
Utrophin protects the sarcolemma of 1a, 2a and 2d/x dko skeletal muscle fiber types
To examine whether utrophin prevented necrosis by maintaining the integrity of the muscle membrane, we systemically delivered 200 µl of 1% (w/v) Evan's blue dye (EBD) into the mdx4cv and dko mice and looked for permeable skeletal muscle fibers (Fig. 5A). We found large patches of skeletal muscle fibers in the mdx4cv mice that were permeable to EBD (Fig. 5A), as previously described [40]. Utrophin was selectively expressed in the dko 1a, 2a and 2d/x fiber types and prevented the infiltration of EBD into these fibers (Fig. 5A). This correlated with an ∼80% reduction in centrally nucleated 1a, 2a and 2d/x fiber types in the dko compared to the corresponding mdx4cv muscles (P<0.001; Fig. 5B). Only the fast 2b fibers in the dko were permeable to EBD, which correlated with an ∼5 fold increase in centrally nucleated 2b fibers when compared with the other fiber-types in the dko (P<0.001; Fig. 5B). The total number of permeable fibers in the dko gastrocnemius muscles was ∼91% less than the mdx4cv muscles (Fig. 5C; P<0.001). Thus, utrophin prevented necrosis in the dko 1a, 2a and 2d/x fiber types by maintaining the integrity of the membrane.
Utrophin maintains the integrity of the dko muscle membrane in a fiber-type specific manner.
Fig. 5. Utrophin maintains the integrity of the dko muscle membrane in a fiber-type specific manner.
A) Shown are frozen sections of the lateral portion of the gastrocnemius muscle immunolabeled with monoclonal antibodies to fiber types 1a (blue), 2a (red), 2d/x (black) and 2b (green; left panel) or utrophin (green; right panel) and Evan's blue dye (EBD; red; right panel). Note that the uneven distribution of utrophin expression in the mdx4cv muscles correlated with patches of adjacent membrane permeable fibers that labeled with EBD. However, an increase in utrophin expression in the dko myofibers excluded EBD from the 1a, 2a and 2d/x fiber types. The dko fast 2b fibers, which lacked utrophin, were permeable to EBD. Scale bar = 500 µm. B) Bars show the mean +/− S.D. percentage of centrally nucleated fibers in distinct fiber types. Note that all dko muscle fiber types had significantly less myonuclei than the mdx4cv fibers (##P<0.01 and ###P<0.001). The dko fast 2b fibers had more central nuclei than the 1a, 2a and 2d/x fiber types (@@@P<0.001). The mdx4cv fast 2b fibers had more central nuclei than the 1a, 2a and 2d/x fiber types (**P<0.01). C) Bars show the mean +/− S.D. total number of EBD positive fibers in the gastrocnemius muscles. ***P<0.001 compared with mdx4cv myofibers. D) Bars show the mean +/− S.D. area of type 1a, 2a, 2d/x and 2b muscle fiber types. ***P<0.001 compared with wild-type myofibers. ###P<0.001 compared with mdx4cv myofibers. @@@P<0.001 compared with desmin−/− myofibers. All experiments were from n = 4 mice.
We found a distinct separation of the fast 2b fibers from the 1a, 2a and 2d/x fiber types in the dko gastrocnemius muscles suggestive of a fiber-type switch in the dko muscles (Fig. 5A). We examined the fiber-type proportions in the smaller soleus muscle that contains all fiber-types in wild-type C57Bl/6mice. Analysis of fiber-type proportions in the soleus muscles at 11 weeks of age revealed a significant shift from the 2a fibers in the wild-type toward the slow 1a fibers in the desmin−/−, mdx4cv and dko muscles (P<0.001; Fig. S3). However, we found no significant change in fiber-type proportions when comparing between the desmin−/−, mdx4cv and dko muscles (Fig. S3). Thus, the skeletal muscle fiber-types were redistributed in the dko muscles, but we found no evidence of a fiber-type switch.
The increase in utrophin on the dko sarcolemma (Fig. 3C) may have resulted from reduced surface area of the 1a, 2a and 2d/x fibers compared with the corresponding mdx4cv muscles. However, the fiber area of 1a, 2a and 2d/x fiber types within the gastrocnemius muscles was unchanged when comparing wild-type, desmin−/−, mdx4cv and dko muscles (Fig. 5D). The fast 2b fibers in the desmin−/− and mdx4cv gastrocnemius were hypertrophic when compared to wild-type muscles (Fig. 5D). In contrast, the fast 2b fibers in the dko muscles were selectively atrophic. The desmin−/− muscles contained some smaller caliber fibers that increased the overall variability in muscle fiber area. The muscle fiber areas were highly variable in the mdx4cv muscles. Thus, the increase in utrophin expression on the dko sarcolemma did not result from changes in the average area of 1a, 2a and 2d/x fiber types.
Utrophin-independent mechanisms influence dystrophic pathology in the dko muscles
We also found a 36% reduction in the proportion of centrally nucleated fast 2b fibers in the dko when compared to the mdx4cv fast 2b fibers (P<0.01; Fig. 5B), which was consistent with the low level of central nuclei in utrophin negative fibers in the dko (46%) compared to all mdx4cv control fibers (76%) (Fig. 3E). To directly test whether utrophin-independent mechanisms were influencing the dystrophic pathology we performed a more detailed examination of the most superficial region of the gastrocnemius muscles that contained a near pure population of fast 2b fibers (Fig. 6). We found a significant reduction in the extrasynaptic utrophin expression on the fast 2b fibers in the dko compared with mdx4cv muscles (Fig. 6A,B; P<0.001). Moreover, there was a significant reduction in the number of fast 2b fibers expressing extrasynaptic utrophin in the dko when compared to the mdx4cv fast 2b fibers (Fig. 6A,C; P<0.05). Utrophin was expressed on the extrasynaptic sarcolemma in groups of regenerating mdx4cv 2b fibers as the myofibers expanded toward the basal lamina shell (Fig. 6D). Utrophin expression was maintained on the mdx4cv sarcolemma as the muscles matured and developmental myosin heavy chain dissipated (Fig. 6D). In contrast, examination of four dko gastrocnemius muscles revealed that the regenerating 2b fibers were directly enveloped by the basal lamina rather than utrophin (Fig. 6D). Together, these results demonstrate that utrophin expression was reduced in the extrasynaptic sarcolemma of dko fast 2b fibers. Thus, utrophin-independent mechanisms were also mitigating the dystrophic pathology of dko muscles.
Utrophin expression was reduced on the extrasynaptic sarcolemma of dko fast 2b fibers.
Fig. 6. Utrophin expression was reduced on the extrasynaptic sarcolemma of dko fast 2b fibers.
A) Utrophin expression in transverse sections of the near pure population of fast 2b fibers in the most superficial region of the gastrocnemius muscles. Shown are single sections from mdx4cv or dko gastrocnemius fast 2b fibers labeled with utrophin in red, α2-laminin in magenta, DAPI in cyan and fast 2b fibers in green. B) Quantitation of maximal extrasynaptic utrophin fluorescence intensity in fast 2b fibers and C) the proportion of fast 2b fibers expressing extrasynaptic utrophin in the mdx4cv and dko. All bars represent the mean +/− S.D. from n = 4 mice. #P<0.05 and ###P<0.001 compared with mdx4cv fibers. D) Regenerating fibers expressed utrophin in the mdx4cv fibers, but not in the dko. Shown are single sections from mdx4cv or dko superficial gastrocnemius muscles labeled with utrophin in red, developmental myosin heavy chain in green, α2-laminin in yellow and DAPI in cyan. Note that utrophin is on the expanding sarcolemma in mdx4cv muscles, but not in the dko (arrows). Scale bars = 50 µm.
Regenerative potential of skeletal muscles
The regenerative capacity of skeletal muscles depleted of desmin is profoundly impaired in cell culture [56], [57]. However, muscle generation in desmin−/− skeletal muscles in vivo is apparently normal [58]. Desmin−/− muscles injured with cardiotoxin can lead to persistent expression of developmental myosin heavy chain [59]. We found that regenerating fibers in uninjured gastrocnemius muscles were rare (up to 2 fibers) in the wild-type and desmin−/− mice (Fig. 7A,B). The mdx4cv muscles contained patches of regenerating fibers (Fig. 7). However, the dko muscles contained 47% fewer regenerating fibers than the mdx4cv muscles (P<0.01; Fig. 7A,B). To examine whether the regenerative capacity of muscles was impaired in the dko we delivered notexin to injure the gastrocnemius muscles and examined the muscles 4 and 6 days post injury. We found that regenerating fibers were expressing developmental myosin in wild-type, desmin−/−, mdx4cv and dko treated muscles at 4 days post injury (Fig. 7). At 6 days post injury we found that half (2 out of 4) of the injured wild-type muscles expressed developmental myosin (Fig. 7). Neither the desmin−/−, mdx4cv or dko muscles expressed developmental myosin 6 days post notexin injury (Fig. 7). We found no other overt changes in the regenerative capacity of the muscles when comparing the different strains of mice (Fig. 7). Thus, the improved dystrophic pathology in the dko muscles did not result from overt changes to the regenerative capacity of the skeletal muscles.
Regenerative capacity of muscle.
Fig. 7. Regenerative capacity of muscle.
A) Transverse sections of uninjured (Day 0) or injured gastrocnemius muscles 4 days and 6 days post notexin administration. Sections stained with hematoxylin and eosin are shown in the left columns and developmental myosin heavy chain (green), α2-laminin (red) and DAPI (blue) are shown in the right columns. Scale bar = 50 µm. B) Bars represent the mean +/− S.D. of the total number of regenerating fibers in the uninjured gastrocnemius muscles (Day 0). ***P<0.001 compared with wild-type muscles and ##P<0.01 compared with mdx4cv muscles. N = 4 mice for all experiments.
Utrophin concentrated β-dystroglycan in the sarcolemma, but not the nNOS, α-dystrobrevin and α1-syntrophin (NODS) complex in the dko mice
We next examined whether the significant increase in utrophin expression in the dko muscles restored the expression of β-dystroglycan and the NODS complex to the sarcolemma. Adjacent sections of gastrocnemius muscles revealed that β-dystroglycan and members of the NODS complex were concentrated within the sarcolemma of wild-type and desmin-/- skeletal muscles (Fig. 8A). The expression of β-dystroglycan and the NODS complex were increased in the desmin-/- mice (Fig. 8B,C), as previously described [60]. The expression of β-dystroglycan and the NODS complex at the sarcolemma of mdx4cv skeletal muscles were significantly diminished (Fig. 8), as previously described [40], [61] (Fig. 8). The increase in utrophin expression in the dko sarcolemma was accompanied by the increased concentration of β-dystroglycan (Fig. 8A). Immunoblots of whole muscle lysates revealed no significant difference in β-dystroglycan expression when comparing the wild-type or the mdx4cv controls with the dko (Fig. 8B,C). However, the expression of the NODS complex on the sarcolemma of dko muscles was not restored (Fig. 8).
Localization and expression of β-dystroglycan and the NODS complex in skeletal muscles.
Fig. 8. Localization and expression of β-dystroglycan and the NODS complex in skeletal muscles.
A) Adjacent sections of gastrocnemius muscles showing the localization of β-dystroglycan and the NODS complex at the sarcolemma of wild-type, desmin-/-, mdx4cv and dko skeletal muscles. Scale bar = 50 µm. B) Western analysis of quadriceps muscles reveals an increase in expression of DGC proteins in the desmin-/- and a reduction in the mdx4cv and dko muscles. α-DB is α-dystrobrevin and α-sarc. actin is the α-sarcomeric actin loading control. C) Bars show mean +/− S.D. densitometric quantitation of protein expression graphed as a percentage of wild-type. *P<0.05, **P<0.01 compared to wild-type. N = 4–8 for all experiments.
Desmin can interact with α-dystrobrevin in the NODS complex indirectly through synemin, syncoilin and dysbindin [46]. Therefore, we examined whether desmin expression influenced the restoration of the NODS complex (Fig. S4). We found that utrophin was expressed on the sarcolemma of 4-week-old mdx4cv soleus muscles with minimal expression of the NODS complex (Fig. S4). Thus, the lack of the NODS complex on the sarcolemma of dko skeletal muscle fibers did not result from the absence of desmin.
Structural/functional changes in dko skeletal muscles
We next examined whether diaphragm function in the dko was influenced by structural defects within and around the muscles. We measured the specific contractile force of diaphragm strips in vitro. We found that the specific force production of the desmin−/− diaphragm was similar to wild-type at 11 weeks of age (Fig. 9A). In contrast, the specific force production of both mdx4cv and dko diaphragms were significantly diminished (Fig. 9A; P<0.001). Detailed histological analyses of the mdx4cv and dko diaphragms revealed that utrophin colocalized with α-sarcomeric actin in a costameric lattice (Fig. 9B). However, the alignment of α-sarcomeric actin in the dko was severely perturbed similar to the rectilinear pattern of utrophin (Fig. 9B). Electron microscopy analyses revealed that the sarcomeres aligned in wild-type muscles, but this alignment was impaired in desmin−/− muscles (Fig. 9C), as previously described [44], [45]. The alignment of sarcomeres in mdx4cv myofibers was similar to wild-type (Fig. 9C). However, the alignment of sarcomeres in the dko was severely impaired within and between individual muscle fibers (Fig. 9C). Gross histological analyses of the diaphragm revealed a 1.83-fold increase in the deposition of collagen in desmin−/− compared to wild-type (P<0.05; Fig. 9D,E). The mdx4cv diaphragms were significantly larger and contained proportionally more collagen than wild-type (4.05-fold increase; P<0.001) and desmin−/− controls (2.21-fold increase; P<0.001; Fig. 9D,E). The dko diaphragm was similar in size to the wild-type and desmin−/− controls (Fig. 9D), but contained proportionately similar amounts of collagen as the mdx4cv diaphragm (28% in the dko compared to 29% in mdx4cv; Fig. 9D,E). Together, these results demonstrate that the impaired respiratory function in the dko mice resulted, at least in part, from the impaired alignment of sarcomeres and deposition of collagen between the myofibers in the diaphragm.
Impaired diaphragm function in the dko correlates with loss of sarcomere alignment and deposition of collagen.
Fig. 9. Impaired diaphragm function in the dko correlates with loss of sarcomere alignment and deposition of collagen.
A) Mean +/− S.D. specific force of diaphragm strips in vitro from wild-type (n = 6), desmin−/− (n = 5), mdx4cv (n = 5) and dko (n = 5) mice. B) Utrophin A colocalizes with α-sarcomeric actin in longitudinal sections. Note the misalignment of α-sarcomeric actin and utrophin A in the dko myofiber. Scale bar = 6 µm. C) Electron microscopy of longitudinal sections of diaphragm muscle demonstrating the alignment of sarcomeres in wild-type and mdx mice (arrows). Note the alignment of sarcomeres is perturbed in desmin−/− muscles (arrows) and severely impaired in the dko muscles (arrows point to misalignment of sarcomeres while the arrow head points toward a hyper-contracted myofiber). Scale bars = 2 µm. D) Sirius red staining of collagen in transverse frozen sections of the wild-type (n = 8), desmin−/− (n = 9), mdx4cv (n = 5) and dko (n = 5) diaphragms. Scale bar = 100 µm. E) Mean +/− S.D. of Sirius red staining as a proportion of the muscle area. *P<0.05, ***P<0.001 compared to wild-type, @@@P<0.001 compared to desmin−/−.
Discussion
Increasing utrophin expression is a promising target for treatment of DMD [33]. While the downstream signaling pathways that influence utrophin expression are well described [33], [38], [39], the upstream mechanisms are less clear. Here, we found that perturbing the highly ordered structure of striated muscle by genetically deleting desmin from mdx4cv mice increased utrophin expression to levels that prevented skeletal muscle necrosis. We report a ∼2.5-fold increase in utrophin expression in the dko sarcolemma of 1a, 2a and 2d/x fiber types, which prevented necrosis by maintaining the integrity of the sarcolemma. Understanding the structural mechanisms that influence utrophin expression in the dko skeletal muscles may contribute to development of a therapy for DMD.
Potential mechanisms that influence utrophin expression in the dko muscles
We found that the onset of necrosis in the mdx4cv gastrocnemius muscles was coincident with the loss of utrophin expression from the maturing fibers (Fig. 4), as previously described [22], [36]. MyoD initiates skeletal muscle differentiation and maturation by activating many skeletal muscle genes and suppressing others [62]. MyoD activates the transcription of miR-206, which targets the utrophin mRNA for degradation leading to the loss of utrophin expression from the sarcolemma and its replacement by dystrophin [63]. Analysis of C2C12 cells suggests that several other miRNAs may also repress the expression of utrophin [64]. The loss of utrophin expression from the sarcolemma of maturing fibers was delayed in desmin−/− muscles and prevented in the dko muscles. It will be interesting to test whether desmin can influence the expression, trafficking, or function of miRNA's that knock-down utrophin expression.
An alternate possibility is that an early pulse in utrophin transcription [65] increased utrophin expression to levels that could overcome the knockdown effects of the miRNA's. Muscle contraction can change the shape of nuclei [66], which can change gene expression [67][69]. Desmin interacts with myonuclei via plectin and lamin A/C [70][72]. The myonuclei in the desmin−/− muscles remain oval shaped in response to muscle contraction [66]. This could potentially lead to the persistence of a developmental gene expression program that underlies the increased utrophin expression in the dko.
Utrophin is normally expressed at low levels on the sarcolemma of the slower oxidative fibers in wild-type mice [73]. Inducing the oxidative myogenic program can alleviate the dystrophic pathology in mdx mice by stimulating utrophin expression. For instance, activation of PGC1α [74][76], calcineurin A/NFAT [77][80], GA binding protein [74], Ca2+/calmodulin [81], AMP activated protein kinase [82], and the transcriptional activator PPARβ/δ [83] can each induce the slow oxidative program in mdx muscle and increase utrophin expression. Metabolic changes to the muscle can also influence utrophin expression [84]. While we found no significant change in fiber-types when comparing mdx, desmin−/− and dko soleus muscles (Fig. S3), we did find utrophin expression on the extrasynaptic sarcolemma of 1a, 2a and 2d/x fiber-types, but not in the fast 2b fibers. Thus, our results are consistent with the activation of the slower oxidative myogenic pathways that can induce utrophin expression.
The absence of desmin in stressed muscle is associated with a shift in the expression of muscle proteins to those found in slow-twitch fibers [85], [86]. These changes may be mediated in part by changes in the activity of calcineurin linked to alter myoplasmic Ca2+ levels, which could result from a loss of local protein kinase A (PKA) signaling linked to the loss of desmin. The copolymerization of desmin with synemin in the intermediate filament reticulum contributes to synemin's localization around Z-disks [87], [88]. As synemin is an A kinase anchor protein (AKAP) [89] the absence of desmin in the dko is likely to alter local PKA activity associated with the sarcomere. Calcium homeostasis is likely to be affected locally as PKA can regulate many channels and transporters essential for normal excitation-contraction coupling [90][93]. However, our finding that the mRNA levels for utrophin do not change in extracts of dko gastrocnemius muscle, compared to age-matched wild-type, desmin−/− and mdx4cv muscles, argue against this mechanism.
While there are various signaling pathways that can activate utrophin transcription in mdx mice, we found no changes in utrophin mRNA in the dko total gastrocnemius muscle lysates when compared to the mdx4cv, desmin−/− or wild-type muscles. The persistence of utrophin on the dko sarcolemma of maturing skeletal muscle fibers is consistent with increased utrophin stability and post-transcriptional mechanisms. Proteins experimentally over-expressed within the mdx extrasynaptic sarcolemma such as sarcospan [94], [95], cytotoxic T cell GalNac transferase [96] and biglycan [35] can stabilize utrophin to prevent skeletal muscle necrosis. RhoA, a small GTPase also increases utrophin expression without apparently influencing transcription [97]. Stabilizing RNA, a known function for the type III intermediate filament protein vimentin [98], is another potential mechanism that can increase utrophin expression without changing transcription [99], [100]. Desmin may also influence protein degradation pathways by trafficking lysosomes through the muscle via its interaction with myospryn [101], [102].
The lack of NODS expression may impair the therapeutic efficacy of utrophin in the dko
Increasing utrophin expression by increasing utrophin transcription or stabilization can restore the expression of the DGC to the sarcolemma [53], [96], [103][105], except for nNOS [106]. We found that utrophin was able to concentrate β-dystroglycan to the sarcolemma in the dko 1a, 2a and 2d/x fiber types. However, the expression of the NODS sub-complex was not restored in the dko muscles. nNOS influences blood flow to the skeletal muscles and can lead to hypoxic stress injury post-exercise [12]. However, the long-term effects of the lack of nNOS are difficult to predict considering Becker muscular dystrophy patients expressing truncated dystrophins can have a mild phenotype without restoring nNOS to the sarcolemma [12], [107]. The low level of α-dystrobrevin on the sarcolemma may have contributed to the low level of central nuclei in the dko mice, as α-dystrobrevin−/− mice have a mild dystrophy and residual expression of α2-dystrobrevin mitigates the dystrophic pathology in mdx muscles [13]. While α1-syntrophin is an important adapter protein that is required for the localization of nNOS and aquaporin to the sarcolemma of striated muscle [108], [109], its role in the pathogenesis of DMD is unclear. The low level of the NODS complex in the dko muscles did not result from the lack of desmin (Fig. S4). Thus, the low level of central nuclei (∼9%) in the dko muscle fibers with extrasynaptic utrophin likely resulted from the lack of desmin in combination with the reduced expression of the NODS complex from the extrasynaptic sarcolemma.
Utrophin-independent mechanisms influence dystrophic pathology
We found that the dystrophic pathology in the fast 2b fibers was also improved in the dko despite a significant reduction in extrasynaptic utrophin expression when compared with mdx4cv fast 2b fibers. Most striking was the fact that utrophin expression was reduced in the extrasynaptic sarcolemma of regenerating fast 2b fibers in the dko. However, we found no overt change in the regenerative capacity of the muscle stem cells in the dko gastrocnemius muscles injured with notexin. In contrast, Agbulut and colleagues found that desmin−/− muscles injured with cardiotoxin displayed persistent expression of developmental myosin, small caliber fibers and the infiltration of adipocytes [59]. Here, we found no evidence of increased adipocytes in the desmin−/− or dko muscles. Therefore, the discrepancy between our studies may have resulted from the different myotoxins. In any case, we found a significant reduction in the number of necrotic fibers in the dko supporting a mechanism that prevents dystrophy rather than influencing regeneration. Desmin is also likely to play a structural role in linking the contractile apparatus to the sarcolemma [47], [52], [101] and in regulating the passive mechanical properties of skeletal muscle [66], [110]. We found that utrophin could form costameric striations with α-sarcomeric actin in dko mice, but the rectilinear pattern was severely impaired. The exacerbated loss of sarcomere alignment in dko diaphragms suggests the absence of desmin and potentially the NODS complex could weaken the sarcomeric connections to the membrane. However, it is important to note that the specific force production of mdx4cv and dko diaphragms was comparable. The mdx4cv mice have a compensatory hypertrophy that can potentially maintain peak force production [111]. However, the dko diaphragms lack this cellular hypertrophy suggesting that the impaired diaphragm function could contribute to the respiratory distress and shortened lifespan. Considering the dko mice die prematurely from apparent cardiorespiratory failure, it is possible that reduced mobility in the cage could mitigate contraction-induced injury to the muscles. We are currently investigating whether desmin influences contraction-induced injury to the sarcolemma in mdx4cv muscles.
Conclusion
In conclusion, we report a significant increase in utrophin expression in dko skeletal muscles that prevented necrosis in a fiber-type specific manner. The fact that utrophin expression was elevated ∼2.5-fold on the dko sarcolemma when compared with mdx4cv muscles is of considerable interest for developing treatments for DMD [26]. Clearly, deleting desmin is not a therapeutic option for DMD as the dko mice die from apparent cardiorespiratory distress, but understanding the upstream mechanisms that influence utrophin expression may lead to novel treatment strategies for DMD. Furthermore, an utrophin-mediated therapy developed from the dko mice would treat all muscle fiber-types in the human as humans lack the fast 2b fiber types. Considering desmin functions to maintain the highly ordered structure of striated muscles [44], [45], it is likely that utrophin expression in the dko is initiated by changes to muscle structure/signaling relationships. We also found that utrophin-independent mechanisms were improving the dystrophic pathology in dko fast 2b fibers, which will be of interest for understanding the pathophysiology of DMD. Thus, the dko mice may provide new insights into the regulation of utrophin expression that are relevant for the treatment of DMD.
Materials and Methods
Mice and ethics statement
We utilized C57Bl/6 wild-type mice, desmin−/− mice, mdx4cv mice and mdx:desmin dko mice. All experiments were in accordance with the Institute of Animal Care and Use Committee of the University of Washington. The desmin−/− mice were a kind gift from Professor Yassemi Capetanaki. We generated the dko mice by first backcrossing the desmin−/− mice from the FVB strain to the wild-type C57Bl/6 strain for five generations (N5). The resulting desmin−/− mice on the C57Bl/6 strain were then inbred for at least four generations to obtain desmin−/− controls (>F4) or they were crossed with the mdx4cv strain on the C57Bl/6 background and inbred for at least four generations to obtain the dko mice (>F4). Therefore, the mice generated for this study were B6.FVB-Desmin and B6.FVB-Desmin-mdx4cv incipient congenic with ∼96.9% homozygosity with the C57Bl/6 background. We genotyped the mice using standard PCR for desmin and performed sequence analysis of the mdx4cv genomic DNA to avoid potential false positives as previously described [112]. The desmin−/− and dko mice were sacrificed if they lost body mass or exhibited signs of cardiorespiratory distress. Kaplan-Meyer survival analysis was performed with 16 desmin−/− male mice and 13 dko male mice.
Diaphragm function
The diaphragm physiology was performed as previously described [113]. Briefly, the diaphragm from wild-type (n = 6), desmin−/− (n = 5), mdx4cv (n = 5) and dko (n = 5) was placed in oxygenated KREBS (2 mM Ca2+, 24 mM NaHCO3, 137 mM NaCl, 5 mM KCl, 1 mM MgSO4, 1 mM NaH2PO4, D-Glucose). Strips of the diaphragm were dissected and the optimum length and peak tetanic contractile force was measured over 350 ms. Because the diaphragm strips vary in size, a direct comparison of peak contractile force is not plausible. After contraction, the diaphragm strip is weighed and specific force was calculated as peak tetanic force production × length × density (1.04) × pennation (1 for the diaphragm)/muscle mass.
Costamere analysis
Costamere analysis was performed as previously described [52]. Briefly, the mice were anaesthetized with 2,2,2-tribromoethanol (Sigma) and perfused with 2% paraformaldehyde (Electron microscopy sciences). The muscles were incubated in 2% paraformaldehyde for 2 hours at 4°C, then washed 3 times with 1× PBS, and incubated in 10% sucrose for 1 hour at 4°C, and then 20% sucrose overnight at 4°C. The muscles were then placed in cryovials and flash frozen in liquid N2. The frozen samples were placed on a frozen chuck with OCT and 40 µm thick sections were cut using a cryostat. The sections were immunostained with 1∶800 utrophin A polyclonal antibody (kind gift from Stanley Froehner) and 1∶500 α-sarcomeric actin monoclonal antibody (SIGMA). The thick sections were imaged using a Leica SP5 confocal microscope.
Electron microscopy
The electron microscopy was performed on longitudinal sections of diaphragm muscle as previously described [114].
Histology
Muscles were frozen directly in OCT cooled in 2-methylbutane in liquid N2. Ten micrometer transverse sections of skeletal muscles were stained with hematoxylin and eosin, alizarin red and Sirius red using manufacturer protocols (Electron Microscopy Sciences; Hatfeild, PA). The Sirius red staining of collagen was measured using the manufacturers protocols in Image J analyses software. Transverse frozen sections were also immunostained as previously described [40]. Briefly, the sections were incubated in blocking buffer (1% BSA, 0.05% Triton X-100 in 1× phosphate buffered saline (PBS)) for 30 minutes and immunostained with antibodies to desmin (1∶50; DAKO Corp), N-terminal dystrophin antibody (1∶800), utrophin (1∶800), α-dystrobrevin 1 (1: 500), α-dystrobrevin 2 (1∶1000), α1-syntrophin (1∶500; the latter four antibodies were kind gifts from Stanley C. Froehner), β-dystroglycan (1∶100; Transduction Laboratories), MHCd (1∶40; Novocastra), α2-laminin (1∶800; Sigma) or nNOS (Zymed; 1∶100) for 1 hour. The sections were washed 3 times in 1× PBS for 10 minutes each and incubated in Alexa-488, Alexa-555, Alexa-594 or Alexa-647 secondary antibodies for 30 minutes (1∶800; Invitrogen). To label necrotic fibers we immunostained the muscles with mouse IgG1 antibodies conjugated to Alexa 488 (1∶800; Invitrogen). For labeling of acetylcholine receptors we incubated the sections in α-bungarotoxin conjugated to TRITC for 1 hour (1∶800; Invitrogen). The sections were washed 3 times for 10 minutes each and coverslipped with ProLong Gold mounting medium containing DAPI (Invitrogen). Muscle fiber typing was performed using conjugated monoclonal antibodies as previously described [115]. Sections were imaged with either a Leica SP5 confocal (Fig. 1, 3, 6), Nikon eclipse E1000 (Fig. 2, 7, 8) or an Olympus SZX16 dissection fluorescent microscope (Fig. 4, 5).
Quantitation of utrophin staining of muscle sections
Quantitation of maximal sarcolemmal utrophin fluorescence intensity was performed as previously described for dystrophin [116]. Briefly, gastrocnemius muscle sections and images were processed identically for quantitation. We utilized the FIJI analyses software to quantitate maximal fluorescence intensity. The utrophin fluorescence intensity on the wild-type sarcolemmal was used as a negative control and the utrophin fluorescence intensity at the wild-type synapse was used as the peak of detection. We drew a line across the images to ensure unbiased quantitation and measured the peak fluorescent intensity that coincided with extrasynaptic sarcolemma staining. The sarcolemmal utrophin fluorescence intensity from mdx4cv, dko and microutrophinΔR4–R21 treated mdx∶utrophin double knockout muscles all fell within these limits. The mean +/− S.D. fluorescence intensity from n = 4 mice from 92 wild-type, 99 desmin−/−, 100 mdx4cv, 112 dko, and 77 microutrophinΔR4–R21 treated mdx:utrophin double knockout myofibers were compared.
Evans blue dye
The mdx4cv and dko mice (n = 4) were administered 200 µl of 0.22 µm filter sterilized 1% (w/v) EBD solution in HBSS intravenously by retro-orbital injection. Mice were sacrificed 3 hours after EBD administration. The gastrocnemius muscles were frozen in OCT in 2-methylbutane in liquid N2. Ten micrometer sections were cut and stained for utrophin (1∶800; kind gift from Stanley Froehner). Utrophin was labeled with Alexa-488 goat anti-rabbit secondary antibody (Invitrogen). The sections were viewed and imaged using the Olympus SZX16 dissection fluorescent microscope.
Muscle fiber regeneration
The gastrocnemius muscles of wild-type, desmin−/−, mdx4cv and dko (n = 8) were administered 30 µl of 1 µg/ml notexin in PBS at 11 weeks of age. The mice were sacrificed 4 days (n = 4) and 6 days (n = 4) post-injury. The gastrocnemius muscles were frozen in OCT. Ten micrometer sections were immunostained with α2-laminin (1∶800; Sigma) and developmental myosin heavy chain (1∶40; Novocastra) and directly compared to adjacent sections stained with hematoxylin and eosin. Considering monoclonal antibodies can label necrotic fibers, we defined regenerating fibers as those fibers that expressed developmental myosin heavy chain and contained centrally located nuclei.
Immunoblotting
Western blots were performed on whole muscle lysates as previously described [40]. Briefly, the gastrocnemius muscles of 3 and 11-week-old wild-type, desmin−/−, mdx4cv and dko (n = 6) were ground in liquid N2 and homogenized in extract buffer (50 mM Tris-HCl, 150 mM NaCl, 0.2% SDS, 24 mM Na Deoxycholate, 1% NP40, 47.6 mM Na Fluoride, 200 mM Na Orthovanadate, Roche). Protein concentration of whole muscle was determined by Coomassie Plus Bradford Assay (Pierce). Equal amounts of protein (10 µg) were resolved on a 4–12% SDS polyacrylamide gel. The blots were incubated in utrophin (1∶1000; kind gift from Stanley C. Froehner) overnight at 4°C. The α-sarcomeric actin primary antibody (1∶500; Sigma) was used as a loading control as its expression was unchanged when comparing the different strains of mice, as previously described for wild-type versus mdx4cv [40], [117]. We also loaded 20 µg of total protein to compare the expression of desmin, β-dystroglycan (1∶100; BD Transduction laboratories), α1-syntrophin (1∶500; kind gift from Stanley C. Froehner), pan α-dystrobrevin (1∶1000; BD Transduction laboratories) primary antibodies. The primary antibodies were detected with IgG HRP secondary antibodies (1∶6000; Jackson ImmunoResearch Labs). The blots were developed with ECL plus (Pierce) and scanned with the Storm 860 imaging system (Amersham Biosciences). The band intensity was measured using Image J software (NIH). The relative amount of utrophin in each blot was determined using a non-linear regression generated by a titration of utrophin from the dko from 1.25 µg up to 20 µg of total loaded protein and examined using the PRISM statistics software (Figures S1, S2; n = 4 for wild-type and desmin−/− and n = 8 for mdx4cv and dko samples).
Real time PCR
To isolate the RNA, approximately 20 µg of gastrocnemius muscle previously ground by mortar and pestle in liquid N2 was used to extract total RNA following manufacturers instructions (TRI Reagent, Molecular Research Center). We used gastrocnemius muscles from 11 week old (Fig. 3D) or 3 week old mice (Fig. 4C). The pelleted RNA was suspended in 50 µl nuclease free elution solution (Ambion, Austin, TX). Five µg of total RNA was treated with Turbo DNA-free (Ambion, Austin, TX) in order to remove trace amounts of contaminating DNA. The DNAase Treated RNA (0.5 µg) was diluted to 8 µl with nuclease free water followed by use of the SuperScript™ III First-Strand Synthesis kit (Invitrogen, Carlsbad, CA) to generate cDNA. Subsequently 2 µl of the cDNA was used for qPCR with utrophin primer-probe sets. The mouse utrophin primers sequences were: Forward 5′- ACCAGCTGGACCGATGGA-3′, Reverse 5′- CTCGTCCCAGTCGAAGAGATCT-3′, Probe 5′-6FAM- CGTTCAACGCCGTGCTCCACC-3′-BHQa1-Q. As a reference gene the oligonucleotide set was used to target the mouse Ywhaz gene sequence (Tyrosine 3-monooxygenase; [118]): Forward 5′- GCTGGTGATGACAAGAAAGGAAT-3′, Reverse 5′- GGTGTGTCGGCTGCATCTC-3′, Probe 5′-6FAM- TGGACCAGTCACAGCAAGCATACCAAGA-3′-BHQa1-Q.
Statistics
The data were compared using a one-way ANOVA with a Tukey post-test that compares all data sets with a Student's t-test. The relative amounts of utrophin in western analyses were determined using a non-linear regression generated from a titration of utrophin in the dko gastrocnemius muscles (from 1.25 µg–20 µg of total added protein). All data analyses were performed using the PRISM software.
Supporting Information
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Zdroje
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Oesophagectomy
What is a Oesophagectomy?
There are many techniques available in the removal of the oesophagus (key-hole or open) and as many techniques available in the reconstruction. Instead of describing each technique individually, it is important to understand the rationale behind the operation.
The surgeon needs to remove the cancer together with some normal tissue (known as clear margins of resection). This often means that a variable degree of the normal oesophagus and stomach is removed. Most lymph nodes draining the cancer are removed. Cancers spread commonly through the lymph nodes and less commonly via the blood stream. By removal of these lymph nodes, it will tell us if the patient has responded well to chemotherapy and the extent of the disease. It may help control the disease process locally.
In reconstructing the oesophagus, the stomach is often used as a new food pipe. This is known as the “neo-oesophagus” or new-oesophagus. Depending on the location of the tumor and the operative techniques used, the joint (known as anastomosis) may occur in the neck or in the chest.
Often, the stomach is re-fashioned like a tube/ pipe before it is stitched or stapled to the non-diseased portion of the old oesophagus. Occasionally, the stomach is not suitable and other alternatives such as the small bowel or colon have been used. Often, but not always, temporary route of feeding is established.
This is usually known as a “feeding jejunostomy”. A suitable tube is placed inside the small bowel, which would provide adequate nutrition, energy and fluids while healing takes place. This feeding tube is left for a couple of weeks even if not used. It is easily removed and can be blocked, therefore must be well cared for. All of this will take approximately 6 to 8 hours. Expect to be in hospital for an average of 7 to 14 days.
The patient recovers initially in intensive care, before being moved to the ward. It would also involve two or three incisions (cuts). There will be a few drain tubes that draw unwanted fluids away and re-expand the lungs.
Recovery from Esophageal Cancer Surgery
After the operation, the patient plays a crucial role in recovery. It is an uncomfortable operation. With pain relief, the patient will still have some discomfort but should be able to take deep breaths and cough gently.
The discomfort in the tummy (abdominal) cut would feel like a belly-ache. The discomfort in the chest cut (thoracotomy) if done, feels like broken-ribs. Despite this, patients must actively participate and take the initiative in chest exercises to clear all secretions. Otherwise, the lung secretions accumulate and can lead to lung infections.
The physiotherapist will insist and assist with your recovery. The discomfort will improve with time and most patients would not need strong pain relief on discharge.
Recovery in the Long Term
All patients undergoing this operation require adapting to a new lifestyle. Essentially two crucial things have changed. This results in two mechanical issues. The first is a small stomach and the second is reflux.
As the stomach has been reduced into a circular tube, the amount of food stored at any time is reduced. As a result, patients need to have frequent but small nourishing meals. Reflux can be a problem. Prior to the operation, the body has inbuilt anti-reflux valve and anti-reflux mechanism. These have been disrupted with the operation. We will try to re-construct and rebuild some anti-reflux mechanism. However, it is easier to assume that reflux will occur and if none occurs, it would be a bonus.
Simple lifestyle adjustments are required. These include sleeping on 1 or 2 pillows (known as head elevation) and not having a meal late at night. During the evening, it is best to have food or fluids that would not hang around the stomach for long. Often this means having your heaviest meals in the afternoon (when you are on your feet) and possibly having soups or drinks in the evening.
Plan to stay upright for a couple of hours to allow the stomach to empty before going to bed. Nutrition in the long term is usually not a problem especially if the stomach is used in the reconstruction. Initial weight loss is expected but minimized. Most patients will regain some of this weight. In the longer term, most patients adjust well.
Oesophagectomy
MELBOURNE LOCATIONS
BULLEEN
Suite 3/195 Thompsons Rd,
Bulleen, VIC 3105
Tel: (03) 9852 3777
Fax: (03) 9852 0014
BUNDOORA
1a/445 Grimshaw St,
Bundoora, VIC 3083
Tel: (03) 9852 3777
Fax: (03) 9852 0014
MARIBYRNONG
Suite 104, 1 Thomas Holmes St,
Maribyrnong, VIC 3032
13 + 4 =
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Categories
Back Pain
How To Better Handle Your Back Pain
Nobody has the same back pain symptoms. Some people may just have stiffness in their back, while other people will have stabbing pain. Back pain isn’t a walk in the park for anyone, but using the advice that follows can make it far easier to deal with.
There are a number of fitness workouts that reduce back injury and pain that work effectively. For instance, yoga helps increase muscle flexibility and can stave off injury. Likewise, exercises that focus on strengthening your core muscles can help people that regularly do heavy lifting to better endure the demands of their job by fortifying the most frequently used back muscles.
Do not lift anything that is too far away from you. Always move closer to the object and do not twist around to grab something like in the back seat of a car for example. Do not extend from the couch and reach for things that are too far away either.
In order to minimize back pain cause by injured or strained muscles, apply ice to the injured area. Although heat may feel better on the skin, it does nothing to reduce the inflammation, which is what is causing the back pain. Ice, however, will help reduce the swelling and inflammation. Reducing the inflammation relieves back pain.
In order to avoid back pain, avoid sitting for extended periods of time. Sitting is bad for your back. If you must sit at a desk all day, get up every so often and stretch or walk around. Likewise, if you spend a lot of time in the car, take frequent breaks so that you can stretch your legs.
High stress and fast-paced living can easily lead to both acute and chronic back pain. As well, it is important to alleviate stress and be aware of different surroundings and practices, especially if you already have been suffering from back pain. While life moves fast and mental stress is hardly unavoidable, it is important to pay attention to ways to improve your way of life.
As trivial as it may seem, it is important that you do not have your wallet in your back pocket when you are going to be sitting for long periods of time. By having your wallet in your back pocket, you could be putting unnecessary strain on your back, which can cause pain.
A great way you can work to fight back against back pain is to eliminate caffeine from your diet. Caffeine can inflame muscles and bring on spasms. Drink less caffeine and you may notice less pain.
Being overweight is one of the biggest causes of back pain in the world, so always attempt to maintain a healthy weight if you’re fighting back pain. You will find as an overweight individual that as you begin to lose the weight, your back pain will lessen. The goal should be to keep fighting to lose the weight.
What you’re sleeping on might be responsible for the back pain you’re dealing with, so always thoroughly check your mattress to see if you should make a change. Maybe you can get by with a memory foam mattress pad, or maybe you will have to replace the entire mattress. Either way, it’s important to take care of the issue to take care of your back.
Get a back massage at a parlor or at home from a loved one on a regular basis to prevent and treat back pain. Regular back massages can increase blood flow to promote healing and keep your muscles healthy. It also keeps your stress level low, which can also help to prevent back pain.
Realize that low back pain is common and may not need any treatment at all. Nearly everyone misses work or an important engagement due to back pain at some point during his or her life, but it is usually neither serious nor lasting. Most backaches relieve themselves in about six weeks time, and the only thing necessary is to ride them out.
A tried-and-true way to relieve back pain is to use a heating pad. By using an electric heating pad, you can work to soothe the muscles and pain associated with moderate and even severe back pain. Also, heating pads have various settings to allow you to control the level of heat you desire.
To relieve back pain caused from working at the computer, try adjusting your chair. Adjust your chair’s height to the point that the computer screen is below your eye level and you don’t need to reach up to gain access to your keyboard. Then, move your chair closer to the screen, so you aren’t hunching over while working. This will keep your spine straight and help keep you from worse problems later on.
Frequent walking is very effective at alleviating chronic back pain. Your back will benefit from this motion.
Wearing properly fitting jeans will save you from back pain now and later! Jeans that are too tight exert unnecessary downward pressure on your lower back and that will leave you with a tired, aching back by the end of the day and can lead to long term damage so be smart about the way you wear your jeans!
To help to minimize back pain, you should avoid sitting with a wallet or other purse in your back pocket. This could force the sacrum out of alignment, or force you to sit at an angle to relieve the pressure. Keep items out of your back pockets when sitting to avoid back pain.
If you are suffering from back pain, look into acupuncture as a possible treatment. More and more medical practitioners are using this method to treat patients effectively. Upon insertion, the needles stimulate specific nerves that trigger the brain and spinal cord to release chemicals that can help to reduce pain. Many back pain sufferers have found relief using this method.
Knowing that there are different types of symptoms of back pain does not mean that any one symptom is less painful than another. Pain in the mid and lower back can ruin entire days or weeks in a casual sense. On a more serious note, it’s been known to immobilize patients and put entire lives in despair. Use the strategies given in this guide when experiencing back pain, so you can continue living a great life.
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By Mayo Clinic Staff
Avascular necrosis is the death of bone tissue due to a lack of blood supply. Also called osteonecrosis, avascular necrosis can lead to tiny breaks in the bone and the bone's eventual collapse.
The blood flow to a section of bone can be interrupted if the bone is fractured or the joint becomes dislocated. Avascular necrosis is also associated with long-term use of high-dose steroid medications and excessive alcohol intake.
Anyone can be affected by avascular necrosis. However, it's most common in people between the ages of 30 and 60. Because of this relatively young age range, avascular necrosis can have significant long-term consequences.
Many people have no symptoms in the early stages of avascular necrosis. As the condition worsens, your affected joint may hurt only when you put weight on it. Eventually, the joint may hurt even when you're lying down.
Pain can be mild or severe and usually develops gradually. Pain associated with avascular necrosis of the hip may be focused in the groin, thigh or buttock. In addition to the hip, the areas likely to be affected are the shoulder, knee, hand and foot.
Some people develop avascular necrosis bilaterally — for example, in both hips or in both knees.
When to see a doctor
See your doctor if you have persistent pain in any joint. Seek immediate medical attention if you believe you have a broken bone or a dislocated joint.
Avascular necrosis occurs when blood flow to a bone is interrupted or reduced. Reduced blood supply can be caused by:
• Joint or bone trauma. An injury, such as a dislocated joint, might damage nearby blood vessels. Cancer treatments involving radiation also can weaken bone and harm blood vessels.
• Fatty deposits in blood vessels. The fat (lipids) can block small blood vessels, reducing the blood flow that feeds bones.
• Certain diseases. Medical conditions, such as sickle cell anemia and Gaucher's disease, also can cause diminished blood flow to bone.
For about 25 percent of people with avascular necrosis, the cause of interrupted blood flow is unknown.
Risk factors for developing avascular necrosis include:
• Trauma. Injuries, such as hip dislocation or fracture, can damage nearby blood vessels and reduce blood flow to bones.
• Steroid use. High-dose use of corticosteroids, such as prednisone, is the most common cause of avascular necrosis that isn't related to trauma. The exact reason is unknown, but one hypothesis is that corticosteroids can increase lipid levels in your blood, reducing blood flow and leading to avascular necrosis.
• Excessive alcohol use. Consuming several alcoholic drinks a day for several years also can cause fatty deposits to form in your blood vessels.
• Bisphosphonate use. Long-term use of medications to increase bone density may be a risk factor for developing osteonecrosis of the jaw. This complication has occurred in some people treated with these medications for cancers, such as multiple myeloma and metastatic breast cancer. The risk appears to be lower for women treated with bisphosphonates for osteoporosis.
• Certain medical treatments. Radiation therapy for cancer can weaken bone. Organ transplantation, especially kidney transplant, also is associated with avascular necrosis.
Medical conditions associated with avascular necrosis include:
• Pancreatitis
• Diabetes
• Gaucher's disease
• HIV/AIDS
• Systemic lupus erythematosus
• Sickle cell anemia
Untreated, avascular necrosis worsens with time. Eventually the bone may become so weakened that it collapses. Avascular necrosis also causes bone to lose its smooth shape, potentially leading to severe arthritis.
You may be referred to a doctor who specializes in disorders of the joints (rheumatologist) or to an orthopedic surgeon.
What you can do
• Write down your symptoms, including any that may seem unrelated to the reason why you scheduled the appointment.
• Write down your key medical information, including other conditions and any history of injury to the painful joint.
• Write down key personal information, including any major changes or stressors in your life.
• Make a list of all your medications, vitamins or supplements.
• Ask a relative or friend to accompany you, to help you remember what the doctor says.
• Write down questions to ask your doctor.
Questions to ask your doctor
• What's the most likely cause of my symptoms?
• What kinds of tests do I need?
• What treatments are available?
• I have other health conditions. How can I best manage them together?
In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask other questions.
What to expect from your doctor
Your doctor is likely to ask you a number of questions. Being ready to answer them may make time to go over points you want to discuss in-depth. You may be asked:
• Where exactly does it hurt?
• How long have you had this pain?
• Does any particular joint position make the pain better or worse?
• Have you ever taken steroids, such as prednisone?
• How much alcohol do you drink?
During a physical exam your doctor will likely press around your joints, checking for tenderness. Your doctor may also move the joints through a variety of positions to see if your range of motion has been reduced.
Imaging tests
Many disorders can cause joint pain. Imaging tests can help pinpoint the source of pain. The options include:
• X-rays. They can reveal bone changes that occur in the later stages of avascular necrosis. In the condition's early stages, X-rays usually appear normal.
• MRI and CT scan. These tests produce detailed images that can show early changes in bone that may indicate avascular necrosis.
• Bone scan. A small amount of radioactive material is injected into your vein. This tracer travels to the parts of your bones that are injured or healing and shows up as bright spots on the imaging plate.
The goal is to prevent further bone loss. Specific treatment usually depends on the amount of bone damage you already have.
Medications and therapy
In the early stages of avascular necrosis, symptoms can be reduced with medication and therapy. Your doctor might recommend:
• Nonsteroidal anti-inflammatory drugs. Medications, such as ibuprofen (Advil, Motrin IB, others) or naproxen sodium (Aleve, others) may help relieve the pain and inflammation associated with avascular necrosis.
• Osteoporosis drugs. Medications, such as alendronate (Fosamax, Binosto), may slow the progression of avascular necrosis, but the evidence is mixed.
• Cholesterol-lowering drugs. Reducing the amount of cholesterol and fat in your blood may help prevent the vessel blockages that can cause avascular necrosis.
• Blood thinners. If you have a clotting disorder, blood thinners, such as warfarin (Coumadin, Jantoven), may be recommended to prevent clots in the vessels feeding your bones.
• Rest. Reducing the weight and stress on your affected bone can slow the damage. You might need to restrict your physical activity or use crutches to keep weight off your joint for several months.
• Exercises. You may be referred to a physical therapist to learn exercises to help maintain or improve the range of motion in your joint.
• Electrical stimulation. Electrical currents might encourage your body to grow new bone to replace the area damaged by avascular necrosis. Electrical stimulation can be used during surgery and applied directly to the damaged area. Or it can be administered through electrodes attached to your skin.
Surgical and other procedures
Because most people don't start having symptoms until avascular necrosis is fairly advanced, your doctor may recommend surgery. The options include:
• Core decompression. The surgeon removes part of the inner layer of your bone. In addition to reducing your pain, the extra space within your bone stimulates the production of healthy bone tissue and new blood vessels.
• Bone transplant (graft). This procedure can help strengthen the area of bone affected by avascular necrosis. The graft is a section of healthy bone taken from another part of your body.
• Bone reshaping (osteotomy). In this procedure, a wedge of bone is removed above or below a weight-bearing joint, to help shift your weight off the damaged bone. Bone reshaping might allow you to postpone joint replacement.
• Joint replacement. If your diseased bone has already collapsed or other treatment options aren't helping, you might need surgery to replace the damaged parts of your joint with plastic or metal parts. An estimated 10 percent of hip replacements in the United States are performed to treat avascular necrosis of the hip.
• Regenerative medicine treatment. Bone marrow aspirate and concentration is a novel procedure that in the future might be appropriate for early stage avascular necrosis of the hip. Stem cells are harvested from your bone marrow. During surgery a core of dead hip bone is removed and stem cells inserted in its place, potentially allowing for growth of new bone.
To reduce your risk of avascular necrosis and improve your general health:
• Limit alcohol. Heavy drinking is one of the top risk factors for developing avascular necrosis.
• Keep cholesterol levels low. Tiny bits of fat are the most common substance blocking blood supply to bones.
• Monitor steroid use. Make sure your doctor knows about any past or present use of high-dose steroids. Steroid-related bone damage appears to worsen with repeated courses of high-dose steroids.
March 21, 2015
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Low-Fat vs Low-Carbohydrate [NEW STUDY]
Low-Fat vs Low-Carbohydrate.........I honestly love it when a study like this is released!
Low-Fat vs Low-Carb - Online Personal Trainer
This study is particularly interesting due to its large group of participants, a staggering 12 month duration and the careful dietary monitoring. Also, it was partially funded by NuSI, an organisation co-founded by low-carb advocates.
They randomly assigned 609 participants to either a healthy low-fat diet or a healthy low-carb diet for 12 months. During those 12 months, everyone was instructed to attend 22 dietary counselling sessions with a dietitian. While no calories targets were given, both groups were instructed to consume high-quality whole foods and drinks. They were told to maximise intake of vegetables and minimise intake of added sugars, refined flours and and trans fats, also to focus on whole foods that were minimally processed, nutrient dense, and prepared at home when possible.
The researchers looked to see if genotype or insulin production could predict weight loss on either a low-fat or a low-carb diet. Other health outcomes measured were weight change, body fat (DXA), cholesterol, blood pressure and fasting glucose.
Main findings were...
- No significant weight-loss differences were observed between the low-fat and low-carb groups!
- Neither genetics nor insulin production could predict weight-loss success on either diet!
- There were also no significant differences between groups for most other health markers tested!
Yes....triple shock!
Low-Fat vs Low-Carbohydrate - Online Personal Trainer
The DIETFITS study replicates the results of numerous other studies, showing that when calorie intake and protein intake are consistent the amount of carbs or fat doesn't matter too much.
Summary
There will always be diet trends, people will always say "I have the diet for you!!" but.......in the end......it comes down to having a diet that you can stick with! Also, one that is abundant with whole and nutrient dense foods whilst rich in protein.
References:
The DIETFITS Randomised Clinical Trial
- https://www.ncbi.nlm.nih.gov/pubmed/29466592
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Scabies: a review of diagnosis and management based on mite biology.
Abstract
Scabies is a contagious parasitic dermatitis that is a significant cause of morbidity, especially outside of the United States. Scabies is diagnosed most often by correlating clinical suspicion with the identification of a burrow. Although scabies should be on the differential for any patient who presents with a pruritic dermatosis, clinicians must consider… (More)
DOI: 10.1542/pir.33-1-e1
Topics
11 Figures and Tables
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Cinnamon’s side effects?
Cinnamon has long been known for its wide range of health benefits. However, did you know that this food can cause some cinnamon’s side effects if consumed in high doses?
In fact, Cassia cinnamon is completely harmless and safe to eat in small or medium doses. However, if you eat cinnamon in high doses, this can cause health problems. This is because cinnamon contains high levels of coumarin compounds.
Research has proven that consuming too much coumarin will damage the liver and increase the likelihood of cancer. In addition, there is ample evidence to suggest that excessive consumption of Cassia cinnamon is associated with many other side effects.
Cinnamon's side effects 1
Cinnamon’s side effects 1
Cinnamon’s side effects:
Causes damage to the liver
As mentioned above, Cassia cinnamon – common cinnamon, is a rich source of coumarin compound. It contains approximately 5 mg of coumarin / tablespoon (2g of cinnamon) – while star anise contains only a small amount.
The recommended daily limit of coumarin is approximately 0.1 mg / kg of total body weight, such as you can only consume up to 5 mg of coumarin per day if you weigh 60 kg. This means you cannot eat more than 1.5 tablespoons of cinnamon every day. In addition, several studies have also found that consuming too much coumarin will cause toxins to accumulate in the liver, thereby damaging the organ.
Increased risk of cancer – Cinnamon’s side effects
Animal studies have shown that consuming too much coumarin – the compound in Cassia cinnamon – increases the risk of some forms of cancer.
An additional example of this result is that studies in rodents have shown that excessive consumption of coumarin can cause the formation of cancerous tumors in vital organs such as the lungs, liver and kidney. The form of coumarin causing tumors is currently unknown.
However, some scientists believe that coumarin can cause repeated damage to some organs. Over time, damage can cause healthy cells to be replaced by tumor cells, which can lead to cancer. Most animal studies have shown coumarin results in carcinogenic effects. However, we still need more human studies to understand the relationship between cancer and coumarin consumption in humans.
Cause mouth sores – Cinnamon’s side effects
Some people have experienced mouth ulcers due to eating too much cinnamon. Cinnamon contains cinnamaldehyde – the compound that causes allergic reactions when you absorb in large doses. Consumption of cinnamon in small amounts does not seem to cause this kind of reaction because saliva will help you prevent chemicals from coming into contact with the oral cavity for a long time.
In addition to causing mouth ulcers, cinnamaldehyde can cause allergic symptoms including swelling of the tongue or gums, a burning sensation, itching in the mouth and the appearance of white patches in the oral cavity. Although these symptoms are usually not serious and require medical intervention, they will make you feel uncomfortable.
However, it’s important to remember that cinnamaldehyde only causes mouth sores if you are allergic to this compound. You can go to the hospital for a test to see if you have this allergy through a skin patch test (Skin patch test).
In addition, mouth ulcers can affect most people who consume too much cinnamon oil or cinnamon-flavored gum, because these products may contain fairly high levels of cinnamaldehyde.
Cinnamon's side effects 2
Cinnamon’s side effects 2
Lowers blood sugar levels – Cinnamon’s side effects
Chronic high blood pressure is a serious health problem. If left untreated, it can lead to diabetes, heart disease and a host of other health problems. Cinnamon has long been prized for its ability to lower blood sugar levels. Studies have shown that this food may play a similar role to insulin – the hormone that helps remove sugar from the blood stream.
Although eating cinnamon in moderation may lower blood sugar levels, if you consume it too much, this can lead to very low blood sugar. This is a hypoglycemia – a condition that leads to fatigue, dizziness and even fainting. Most people who are at high risk of hypoglycemia are those who often take diabetes medications. This is because cinnamon can enhance the effectiveness of these drugs, causing blood sugar levels to drop too low.
Causes respiratory problems – Cinnamon’s side effects
Consuming too much cinnamon at one meal can cause breathing problems. This is because the food has a special texture that makes it easy to inhale through the nasal cavity into the lungs. Accidental inhalation of cinnamon powder or the smell of cinnamon can cause symptoms such as coughing, vomiting and shortness of breath.
In addition, cinnamaldehyde contained in cinnamon is a throat irritant and may cause other respiratory problems. People with asthma or other medical conditions affecting the respiratory system should pay special attention to avoiding inhaling the scent of cinnamon. This is because they tend to develop respiratory problems easily after breathing in cinnamon powder.
When using the above foods, remember to pay attention to the conditions happening in your body to have timely remedies.
– Cinnamon’s side effects:
The articles are for reference only, not a substitute for medical diagnosis or treatment.
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The Scientific Scoop on Vitamins
By Dagmar Gross
Vitamins and minerals are essential to our good health. They build immunity against colds and flus, protect the heart, keep our bones strong, and prevent neural tube birth defects. A group of vitamins called "antioxidants" may help fight heart disease and cancer, by preventing "bad" cholesterol (LDL) from attaching to and damaging arteries, and by fighting free radicals, which may injure cells and harm the body's natural healing ability. But which vitamins do we need, and at what levels?
Vitamin C, or ascorbic acid, is an antioxidant that keeps the immune system strong and responsive, and many people faithfully consume large daily quantities to ward off colds. In fact, recent studies indicate that a daily dose of up to 250 mg of vitamin C is sufficient to strengthen the immune system and lower the risk of developing heart disease, cancer or cataracts.1,2,3 However, smokers require almost double that amount to receive the same benefits.2,4 Doses of up to 2,000 mg per day of vitamin C appear to be safe and have been shown to reduce allergy and cold symptoms and result in fewer workdays lost due to illness.2,5,6 One orange contains 70 mg of vitamin C, a cup of cranberry juice provides 108 mg, and a single half-cup serving of broccoli contains 60 mg. Other good sources of vitamin C include lemons, grapefruits, strawberries, peaches, raspberries, red and yellow peppers, tomatoes, cauliflower, Brussels sprouts and baked potatoes.
Vitamin E is another antioxidant that strengthens the immune system and may cut the risk of heart disease. Growing evidence suggests that the optimal daily intake of vitamin E is around 100 mg, or 100 IU.7,8 But avoid taking high daily doses of vitamin E, since they can depress the immune system,9 and excess quantities are stored in the liver. Good sources of vitamin E include vegetable oils, nuts, green leafy vegetables, apricots, peaches, seafood, wheat germ and whole grains.
Beta-carotene, also an antioxidant, benefits the immune system and may protect against some cancers.10,11 A daily intake of 25,000 IU (or 16 mg) appears to be optimal to strengthen immunity.7 However, higher daily doses of 30,000 to 50,000 IU of beta-carotene are shown to raise the risk of cancer in heavy smokers.12,13 Clearly, the potential dangers of taking large amounts of beta-carotene require further study. Beta-carotene is found primarily in deep yellow-orange and dark green fruits and vegetables, including carrots, spinach, broccoli, tomatoes, squash, sweet potato, pumpkin, beets, papaya, cantaloupe, mango, apricots and watermelon.
Calcium and vitamin D work together to maintain the body and bone mass. Women under 25 require 1,200 mg of calcium daily to maximize their bone mass and reduce the risk of osteoporosis later in life. Adults require about 1,000 mg of calcium per day, but women over 50 not taking estrogen, pregnant women, and women who are breast-feeding need at least 1,500 mg to maintain their bone mass. Calcium is also necessary for the functioning of the brain, lungs, muscles and heart. When calcium intake is insufficient, it is removed from the bones to ensure the rest of the body functions properly. Dairy products such as milk, yogurt, cheese and ice cream are the best sources of calcium, with 300 mg found in a single 8-ounce glass of milk. Other good sources of calcium include spinach, broccoli, canned salmon with the bones, tofu made with calcium sulphate, almonds, brazil nuts and sunflower seeds.
It is equally important to get enough vitamin D, which maintains the blood calcium levels critical for the normal functioning of the other organs. Several studies indicate that we get insufficient vitamin D, particularly in the winter when there is less sunlight, which is required to activate our body's vitamin D.14,15,16 This deficiency produces rickets in children and accelerates bone loss in adults, which leads to osteoporosis and a greater risk of bone fractures. The data indicates that people under 70 require 400 IU of vitamin D daily, and those over 70 require 600 IU.14,15 Vitamin D toxicity occurs only if taking more than 2,000 IU a day, for half a year or more, with resulting symptoms of confusion, fatigue, constipation, and possibly kidney stones. A glass of milk contains approximately 100 IU of vitamin D. Some Vitamin D is also found in butter, cottage cheese, carrots, clams, cod livers and cod liver oil, egg yolk, salmon and some cereals.
Finally, folic acid is particularly important for women of child-bearing age. Folic acid deficiencies have been linked to the development of neural tube defects in the fetus, which occur during the first few weeks of pregnancy, before the woman is even aware that she is pregnant. Therefore, it is vital that women ensure they get sufficient folic acid, about 400 micrograms (mcg) a day. Folic acid has also been implicated in the prevention of cancer and heart disease in both men and women.17,18 Fruits and vegetables, particularly romaine lettuce, spinach, and broccoli are good sources of folic acid.
Dagmar Gross, M.Sc., is president of MedSci Communications & Consulting Co., which specializes in technical writing and meeting planning services for the medical, scientific, and health communities. Ms. Gross may be contacted at: 2 Bloor St. West, Suite #100-385, Toronto, ON, M4W 3E2, Tel: 416-968-9414, Fax: 416-968-9417, E-mail: [email protected]
Copyright © 1997 WOMAN Newsmagazine. Reprinted by permission.
References:
1. Amer J Optimal Nutr 66: 911, 1997
2. Int J Vitam Nutri Res 66:19, 1996
3. Age and Ageing 20:169, 1991
4. Circulation 94:6, 1996
5. Can Med Assoc J 107:503, 1972
6. Scottish Med J 18:3, 1973
7. Lancet 340:1124, 1992
8. J Amer Med Assoc 277:1380, 1997
9. Bogden and Louria, "Micronutrients and Immunity in Older People", in Preventive Nutrition, eds Bendich & Deckelbaum,Totawa, New Jersey: Human Press, 1997
10. J Clin Oncol 8:1715, 1990
11. Nutr Cancer 12:321, 1989
12. New Engl J Med 330:1029, 1994
13. Cancer Res 1;54:2038s, 1994
14. Amer J Clin Nutr 61:1140, 1995
15. Bone and Mineral 25:83, 1994
16. J Clin Endocrin Metab 67:373, 1988
17. Cancer Causes & Controls 7:3, 1996
18. J Amer Med Assoc 274:1049, 1995
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Reasons why diagnosis of diabetes mellitus in a person cannot be a death sentence again
For the Okons, a huge cloud fell over their household when 60 year old Mrs Okon was found to have diabetes mellitus on a routine medical visit. Her first reaction was to reject the doctor’s pronouncement. “It is not my portion”, Mrs Okon replied the doctor. At home, Mr Okon and the children concurred that “it’s not our portion”.
For several weeks, Mrs Okon refused to take the oral medications which she thought was for the newly diagnosed diabetes mellitus. She, also, refused to adhere to the dietary restrictions prescribed by the doctor.
In the next couple of weeks, the symptoms of diabetes mellitus were becoming more and more obvious in her. It was after a visit to another medical consultant who, also, confirmed the ailment that she decided to accept the diagnosis. When it dawned on the household that the situation is real, she was depressed, worried and anxious. She asked several questions which included:
“God, why me? “.
“When will it be over? “.
“Don’t eat this, don’t eat that, for how long? “.
“I do not take sugar much, how come diabetes for me? ”
“My parents never had diabetes mellitus, where did this one come from?”
These were some of her numerous unanswered questions. This reaction of the Okons to the diabetes mellitus challenge was not out of place. Most people living with diabetes reacted in similar way at the onset of their illnesses.
The question now goes: is the diagnosis of diabetes mellitus a death sentence? Is it the end of the road for someone diagnosed with the illness?
Diagnosis of diabetes mellitus is, definitely, NOT a death sentence! Reasons abound to support this stand.
Firstly, diabetes mellitus is just one of several diseases like hypertension, obesity, cancers, osteoarthritis, rheumatoid arthritis, senile dementia and so on. They are not curable but people live with them and age gracefully. People have lived with diabetes for 20, 30, 40 or more years. It, rather, calls for some discipline, cost burden and some bodily inconveniences.
A second reason why diagnosis of diabetes mellitus is not a death sentence is because with the current advances in medical sciences and surgical procedures coupled with the current understanding of diabetes mellitus as a metabolic disease, many patients with type 2 diabetes have it reversed or “cured” after bariatric surgery is performed especially for those who are obese. Again, some dietary manipulations such as use of low-carb diets, intermittent fasting or use of ketotic diets have been promising in people living with type 2 diabetes. For type 1 diabetes mellitus, bio-engineered pancreatic B-cells have been used to cure it when implanted on someone. More so, many scientists are currently in the laboratories in many parts of the world working assiduously to get a cure for diabetes. This could happen any day from now!
Finally, with a positive mental attitude. one soon realizes that one can live and age gracefully with diabetes mellitus. It’s just a cross one may be called upon to carry. Just imagine the case of someone living with diabetes who confessed recently that having diabetes is one of the best things that ever happened to her. Because of her understanding of the disease, she has been invited to many countries of the world and at different fora to make speeches and give lectures on diabetes. That’s positive living with diabetes!”.
On the contrary, if one decides to see only the ugly side of diabetes, then, it can be so. The choice is ours…..to view diabetes with a positive or negative mental attitude.
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Research Paper Volume 13, Issue 13 pp 17789—17817
Bioinformatics analysis of the role of CXC ligands in the microenvironment of head and neck tumor
class="figure-viewer-img"
Figure 4. Protein–protein interaction network. The relationships between CXCLs and the top 50 similar genes were visualized using the STRING database (see Supplementary Table 3 for a detailed gene list).
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How Do Muscles Grow?
by Young sub Kwon, MS and Len Kravitz, PhD on Feb 01, 2006
Charge, S.B.P., & Rudnicki, M.A. 2004. Cellular and molecular regulation of muscle regeneration. Physiological Reviews, 84, 209–38.
Fitness professionals spend countless hours reading articles and research on new training programs and exercise ideas for developing muscular fitness. However, largely because of the topic’s physiological complexity, few personal trainers or instructors are thoroughly informed about how muscles actually adapt to, and grow to meet, the progressively increasing overload demands of exercise. In fact, skeletal muscle is the most adaptable tissue in the human body. Already a widely studied topic, muscle hypertrophy is still considered a fertile research area. This column will provide a brief update on some of the intriguing cellular changes that lead to muscle growth, also known as the satellite cell theory of hypertrophy.
Muscle Trauma: Activating Satellite Cells
When muscles undergo intense exercise, as from a resistance training bout, the muscle fibers undergo trauma that is referred to scientifically as “muscle injury” or “muscle damage.” This disruption of the fibers also causes damage to the muscle cell proteins within the muscle fibers, thus activating satellite cells. These cells, located on the outside of the muscle fibers between the basal lamina (basement membrane) and the plasma membrane (sarcolemma) of muscle fibers, proliferate to the injury site (Charge & Rudnicki 2004). In essence, a biological effort to repair or replace damaged muscle fibers begins with the satellite cells fusing together and to the muscle fibers, often leading to increases in muscle fiber cross-sectional area or hypertrophy. The satellite cells have only one nucleus and can replicate by dividing. As the satellite cells multiply, some remain as organelles on the muscle fiber, whereas the majority differentiate (the process that cells undergo as they mature into normal cells) and fuse to muscle fibers to form new muscle protein strands (or myofibrils) and/or to repair damaged fibers. Thus, the muscle cells’ myofibrils increase in thickness and number. See Figure 1.
After fusing with muscle fibers, some satellite cells serve as a source of new nuclei to supplement the growing fibers. With these additional nuclei, muscle fibers can synthesize more proteins and create more contractile myofilaments, known as actin and myosin, in skeletal muscle cells. Higher numbers of satellite cells are found in slow-twitch muscle fibers than in fast-twitch muscle fibers within the same muscle, because the slow-twitch fibers are regularly going through cell maintenance repair from daily activities.
Growth Factors
Growth factors are hormones or hormone-like compounds that stimulate satellite cells to produce gains in muscle fiber size. These growth factors have been shown to affect muscle growth by regulating satellite cell activity.
Hepatocyte growth factor (HGF) is a key regulator of satellite cell activity. It has been shown to be the active factor in repairing muscle damage and may also be responsible for directing satellite cells to migrate to the damaged muscle area (Charge & Rudnicki 2004).
Fibroblast growth factor (FGF) is another important growth factor in repairing muscle following exercise. The role of FGF may be in the revascularization process (formation of new blood capillaries) during muscle regeneration (Charge & Rudnicki 2004).
A great deal of research has been focused on the role of insulin-like growth factors-I and -II (IGFs) in muscle growth. The IGFs play a primary role in regulating the amount of muscle mass growth, promoting changes occurring in the DNA for protein synthesis and promoting muscle cell repair. Insulin also stimulates muscle growth by enhancing protein synthesis and facilitating the entry of glucose into cells. The satellite cells use glucose as a fuel substrate, thus enabling their cell growth activities. Glucose is used for intramuscular energy needs as well.
Growth hormone is also highly recognized for its role in muscle growth. Resistance exercise stimulates the release of growth hormone from the anterior pituitary gland, with released levels being very dependent on exercise intensity. Growth hormone helps trigger fat metabolism for energy use in the muscle growth process. In addition, growth hormone stimulates the uptake and incorporation of amino acids into protein in skeletal muscle.
Testosterone also affects muscle hypertrophy. This hormone can stimulate growth hormone responses in the pituitary, thereby enhancing cellular amino acid uptake and protein synthesis in skeletal muscle. Testosterone can increase the presence of neurotransmitters at the fiber site, which can help activate tissue growth. As a steroid hormone, testosterone can interact with nuclear receptors on the DNA, resulting in protein synthesis. Testosterone may also have some type of regulatory effect on satellite cells.
Muscle Growth: The “Bigger” Picture
This discussion clearly shows that muscle growth is a complex molecular biology cell process involving the interplay of numerous cellular organelles and growth factors, occurring as a result of resistance exercise. However, for client education some important applications need to be summarized:
• Muscle growth occurs whenever the rate of muscle protein synthesis is greater than the rate of muscle protein breakdown.
• Both the synthesis and the breakdown of proteins are controlled by complementary cellular mechanisms.
• Resistance exercise can profoundly stimulate muscle cell hypertrophy and the resultant gain in strength. However, the development for this hypertrophy is relatively slow, generally taking several weeks or months to be apparent (Rasmussen & Phillips 2003). Interestingly, a single bout of exercise stimulates protein synthesis within 2–4 hours after the workout, and the rate of synthesis may remain elevated for up to 24 hours (Rasmussen & Phillips 2003).
Highlighting some specific factors that influence these adaptations will be helpful to your clients:
All studies show that men and women respond to a resistance training stimulus very similarly. However, owing to gender differences in body size, body composition and hormone levels, gender will have a varying effect on the extent of hypertrophy one may possibly attain. Although the upper limit of muscle growth is truly unknown, most resistance training studies report increases in cross-sectional muscle area of 30%–70% (Gardiner 2001).
Aging also mediates cellular changes in muscle, decreasing the actual muscle mass. This loss of muscle mass is referred to as sarcopenia. Happily, the detrimental effects of aging on muscle have been shown to be restrained or even reversed with regular resistance exercise. What’s more, resistance exercise also improves the connective tissue harness surrounding muscle, thus being most beneficial for injury prevention and in physical rehabilitation therapy.
Heredity differentiates the percentage and amount of the two markedly different fiber types. In humans the cardiovascular-type fibers have at different times been called red, tonic, type I, slow-twitch or slow-oxidative fibers. By contrast, the anaerobic-type fibers have been called white, phasic, type II, fast-twitch or fast-glycolytic fibers. Further subdivisions of type II fibers are the IIa (fast-oxidative-glycolytic) and IIb (fast-glycolytic) fibers. It is noteworthy that the soleus, a muscle involved in standing posture and gait, generally contains 25%–40% more type I fibers, while the triceps has 10%–30% more type II fibers than the other arm muscles (Foss & Keteyian 1998).
The proportions and types of muscle fibers vary greatly between adults. It is suggested that the new, popular periodization models of exercise training, which include light, moderate and high-intensity training phases, satisfactorily overload the different muscle fiber types of the body while also providing sufficient rest for protein synthesis to occur.
figure 1: structure of skeletal muscle and satellite cell activation
Figure 1 shows the structural layers of muscle to muscle fibers. Satellite cells on the outside of the muscle fibers proliferate to the “trauma” site from an overload training stimulus, leading to repair and replacement of damaged muscle fibers.
This section of the article is still in the process of conversion to the web.
muscle hypertrophy summary
• Resistance training leads to trauma or injury of the cellular proteins in muscle. This prompts cell-signaling messages to activate satellite cells to begin a cascade of events leading to muscle growth and repair.
• Several growth factors are involved that regulate the mechanisms of change in protein number and size within the muscle.
• The adaptation of muscle to the overload stress of resistance exercise begins immediately after each exercise bout, but the effect often takes weeks or months to physically manifest itself.
• The most adaptable tissue in the human body is skeletal muscle, and it is remarkably remodeled after continuous and carefully designed resistance exercise training programs.
Want more from Len Kravitz?
Muscle Growth References
Foss, M.L., & Keteyian, S.J. 1998. Fox’s Physiological Basis for Exercise and Sport. Boston: WCB McGraw-Hill.
Gardiner, P.F. 2001. Neuromuscular Aspects of Physical Activity. Champaign, IL: Human Kinetics.
Rasmussen, R.B., & Phillips, S.M. 2003. Contractile and nutritional regulation of human muscle growth. Exercise and Sport Sciences Reviews, 31 (3), 127–31.
Fitness Journal, Volume 3, Issue 2
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© 2006 by IDEA Health & Fitness Inc. All rights reserved. Reproduction without permission is strictly prohibited.
About the Authors
Young sub Kwon, MS
Young sub Kwon, MS IDEA Author/Presenter
Len Kravitz, PhD
Len Kravitz, PhD IDEA Author/Presenter
Len Kravitz, PhD, is the program coordinator of exercise science and a researcher at the University of New Mexico in Albuquerque, where he recently won the Outstanding Teacher of the Year award. Len was also honored as the 2006 Fitness Educator of the Year by the American Council on Exercise.
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Maestro Biofilm: Orchestrating an anti-inflammatory immune response through bacterial metabolites
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Staphylococcus aureus (S. aureus) encodes a vast array of virulence factors that target host immune defenses (1, 2), and the ability to form a biofilm is another example of how this bacterium is able to circumvent immune-mediated clearance (3, 4). Bacterial biofilms are microbial communities that exhibit metabolic diversity within a matrix composed of extracellular DNA, protein, and polysaccharide (2). S. aureus is a leading cause of prosthetic joint infection (PJI) that is characterized by biofilm formation (5). Eradication of established S. aureus PJI in situ is considered the “Holy Grail” of orthopaedic surgery, as current treatment typically requires surgical intervention (5). This is because antibiotics alone are usually ineffective at clearing infection due to the metabolic dormancy of a sub-population of bacteria within the biofilm, referred to as “persisters” (6). Our laboratory’s approach to this problem over the past 12 years is to understand why the innate immune response is not capable of eradicating S. aureus biofilm, particularly given the fact that innate immunity is the first line of defense against bacterial infection and is usually successful at eliminating pathogens in a healthy immune competent host.
The first clue came in 2014, when our laboratory was the first to discover that S. aureus biofilm preferentially recruits myeloid-derived suppressor cells (MDSCs) (7), which was subsequently confirmed by other groups (8, 9). We found that MDSCs are critical for attenuating monocyte/macrophage pro-inflammatory activity during S. aureus biofilm infection and earlier work from our group characterized the anti-inflammatory properties of biofilm-associated macrophages (7, 10-14). However, although the leukocyte infiltrates and their inflammatory bias during S. aureus PJI are defined, what was lacking is the signals that are responsible for organizing the anti-inflammatory cellular milieu that is typical of biofilm infection.
In 2017, we set out to investigate whether we could identify biofilm-derived factors that were responsible for polarizing the immune response towards an anti-inflammatory state, since our studies had led us to hypothesize that the biofilm was acting as a “maestro” with leukocytes as its obedient orchestra (Figure 1)
Figure 1. Maestro biofilm directs leukocyte anti-inflammatory activity.
We knew that IL-10 production by MDSCs and monocytes/macrophages was critical for biofilm persistence (11), so we focused our efforts on screening the S. aureus Nebraska Transposon Mutant Library (NTML) (15) for mutants that failed to induce IL-10 in MDSCs. Several hits were identified in pathways responsible for bacterial lactic acid biosynthesis, including D- and L-lactate (16). We generated transposon mutants that were unable to synthesize D- (Δddh) or L-lactate (Δldh1/ldh2) as well as a triple mutant (Δddh/ldh1/ldh2) that was defective in producing both lactate stereoisomers.
Our studies found that both D- and L-lactate production by S. aureus biofilm was critical for inducing maximal IL-10 release from MDSCs and macrophages in vitro and in vivo (16). This was demonstrated by reduced IL-10 levels when MDSCs or macrophages were co-cultured with lactate mutant biofilm, and using pharmacological inhibitors of a major mammalian lactate transporter (MCT1), we demonstrated that biofilm-derived lactate was imported into leukocytes to increase IL-10 production. Using a mouse model of PJI, biofilm burden was significantly lower in Δddh/ldh1/ldh2-infected mice concomitant with decreased IL-10 levels and a transformation of the leukocyte infiltrate as typified by less inhibitory MDSCs and increased anti-bacterial effectors (monocytes and neutrophils). Confirmation that these phenotypes resulted from S. aureus-derived lactate was demonstrated by the fact that co-infection of mice with wild type (WT) and Δddh/ldh1/ldh2 S. aureus reversed the immune phenotypes associated with Δddh/ldh1/ldh2 monoinfection, with a restoration of IL-10 production equal to that elicited by WT bacteria (16).
Next, we aimed to elucidate the mechanism of S. aureus lactate action on IL-10 production by MDSCs and macrophages. We focused on the possibility that biofilm-derived lactate induced epigenetic changes in leukocytes, by linking independent observations that lactate can inhibit histone deacetylases (HDACs) (17, 18) and that the IL-10 promoter is regulated by the antagonistic actions of HDAC11 and HDAC6 (negative vs. positive regulation, respectively) (19, 20). Histones are a class of highly conserved proteins (H3, H4, H2A, H2B, and H1) that regulate gene transcription through post-translational modifications of N-terminal histone tails (21, 22). Histone acetylation is mediated by histone acetyltransferases that transfer an acetyl group to a lysine residue on the histone tail, which relaxes chromatin structure and increases promoter accessibility and gene transcription. Deacetylation is mediated by HDACs, which condense chromatin and favor gene silencing (23). We first demonstrated that leukocytes recovered from WT S. aureus-infected animals in the mouse PJI model had reduced HDAC activity that coincided with increased total H3Ac compared to Δddh/ldh1/ldh2, the first piece of evidence that S. aureus-derived lactate was acting as an HDACi. Chromatin immunoprecipitation sequencing (ChIP-seq) confirmed the increased in H3Ac, including at the Il-10 promoter, as well as the promoters of other genes (16). This indicated that S. aureus-derived lactate induces epigenetic changes extending beyond Il-10.
To investigate the functional importance of HDAC11 vs. HDAC6 in response to S. aureus biofilm, we had to get creative, since no selective pharmacological inhibitors of HDAC11 exist. Therefore, we leveraged HDAC11 knockout (KO) mice for our studies combined with tubastatin A, which is a selective HDAC6i. The premise that we tested was based on earlier reports demonstrating that HDAC6 is a positive regulator of IL-10, whereas HDAC11 physically binds and inhibits HDAC6 action, and hence, IL-10 production (Figure 2) (19, 20).
Figure 2. S. aureus-derived lactate inhibits HDAC11, resulting in unchecked HDAC6 activity that drives IL-10 production.
This made our studies technically challenging, since we were trying to determine if S. aureus-derived lactate inhibited a negative regulator of Il-10 transcription (i.e. HDAC11)- a double negative! Infection of WT and HDAC11 KO mice with WT S. aureus showed no significant differences in IL-10 production or bacterial burden. This was expected if S. aureus-derived lactate inhibits HDAC11, making the loss of HDAC11 irrelevant, since nothing is inhibiting HDAC6 and thus, IL-10 is already maximally expressed. In contrast, IL-10 production was significantly higher in HDAC11 KO mice infected with Δddh/ldh1/ldh2 compared to WT animals, likely due to the lack of negative regulation of HDAC11 on HDAC6 activity that drives IL-10 production, which translated into increased bacterial burden in implant-associated tissue. To demonstrate HDAC6 action in vivo, WT mice were treated with the HDAC6i tubastatin A. Bacterial burden and IL-10 production were reduced in animals infected with WT S. aureus following tubastatin A treatment, a phenotype equivalent to when no S. aureus lactate is produced (Δddh/ldh1/ldh2). Moreover, tubastatin A had no effect in Δddh/ldh1/ldh2-infected WT mice, since HDAC6 was already being inhibited by HDAC11 in the absence of S. aureus-derived lactate. Collectively, these findings support the action of bacterial-derived lactate as an HDAC11i that augments IL-10 production during S. aureus biofilm infection, by alleviating the negative feedback on HDAC6 (Figure 2) (16).
Finally, we showed that IL-10 was significantly increased in the synovial fluid of patients with PJI compared to aseptic joints and this coincided with elevated D-lactate levels in the former. Furthermore, human monocyte-derived macrophages exposed to Δddh/ldh1/ldh2 biofilm-conditioned medium produced less IL-10 than in the presence of lactate (i.e. WT biofilm), which was HDAC6-dependent (16). This human data corroborated the mouse model, supporting the translational relevance that biofilm-derived lactate is a critical inducer of IL-10 during PJI and contributes to infection persistence. The finding that IL-10 levels were elevated in the synovial fluid of human PJIs caused by distinct gram-positive pathogens, this highlights the potential broader implications of lactate as a regulator of leukocyte gene expression during infectious caused by diverse bacterial species.
Although host cells can also produce lactate, our studies suggest that bacterial-derived lactate is the major regulator of IL-10 production during biofilm infection. This was supported by two major findings in our work. First, inhibition of host LDH by sodium oxamate had no effect on IL-10 production in the mouse PJI model and second, co-infection of mice with WT and Δddh/ldh1/ldh2 reversed the reduction in IL-10 associated with Δddh/ldh1/ldh2 monoinfection. Although a role for host-derived lactate cannot be definitively ruled out, the main driver of IL-10 production during PJI appears to be bacterial-derived lactate (16). Although our report was focused on IL-10, ChIP-seq revealed that the H3Ac status of numerous genes is affected by S. aureus-derived lactate. Investigating the functional implications of bacterial lactate beyond IL-10 and how this contributes to infection persistence will be interesting topics for future research.
This work was made possible by contributions from our collaborators Drs. Adam Karpf, Dave Klinkebiel, and Ed Seto (epigenomics) and Drs. Vinai Thomas and Sujata Chaudhari (microbiology). It was a pleasure working with scientists who were excited to join the project and were generous with their time and resources.
References:
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2. Askarian F, Wagner T, Johannessen M, Nizet V. Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol Rev. 2018;42(5):656-71.
3. Scherr TD, Heim CE, Morrison JM, Kielian T. Hiding in Plain Sight: Interplay between Staphylococcal Biofilms and Host Immunity. Front Immunol. 2014;5:37.
4. Seebach E, Kubatzky KF. Chronic Implant-Related Bone Infections-Can Immune Modulation be a Therapeutic Strategy? Front Immunol. 2019;10:1724.
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7. Heim CE, Vidlak D, Scherr TD, Kozel JA, Holzapfel M, Muirhead DE, et al. Myeloid-derived suppressor cells contribute to Staphylococcus aureus orthopedic biofilm infection. J Immunol. 2014;192(8):3778-92.
8. Tebartz C, Horst SA, Sparwasser T, Huehn J, Beineke A, Peters G, et al. A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immunosuppression during Staphylococcus aureus infection. J Immunol. 2015;194(3):1100-11.
9. Skabytska Y, Wolbing F, Gunther C, Koberle M, Kaesler S, Chen KM, et al. Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity. 2014;41(5):762-75.
10. Hanke ML, Heim CE, Angle A, Sanderson SD, Kielian T. Targeting macrophage activation for the prevention and treatment of Staphylococcus aureus biofilm infections. J Immunol. 2013;190(5):2159-68.
11. Heim CE, Vidlak D, Kielian T. Interleukin-10 production by myeloid-derived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection. J Leukoc Biol. 2015;98(6):1003-13.
12. Heim CE, Vidlak D, Scherr TD, Hartman CW, Garvin KL, Kielian T. IL-12 promotes myeloid-derived suppressor cell recruitment and bacterial persistence during Staphylococcus aureus orthopedic implant infection. J Immunol. 2015;194(8):3861-72.
13. Heim CE, West SC, Ali H, Kielian T. Heterogeneity of Ly6G(+) Ly6C(+) Myeloid-Derived Suppressor Cell Infiltrates during Staphylococcus aureus Biofilm Infection. Infect Immun. 2018;86(12).
14. Thurlow LR, Hanke ML, Fritz T, Angle A, Aldrich A, Williams SH, et al. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J Immunol. 2011;186(11):6585-96.
15. Fey PD, Endres JL, Yajjala VK, Widhelm TJ, Boissy RJ, Bose JL, et al. A genetic resource for rapid and comprehensive phenotype screening of nonessential Staphylococcus aureus genes. mBio. 2013;4(1):e00537-12.
16. Heim CE, Bosch ME, Yamada KJ, Aldrich AL, Chaudhari SS, Klinkebiel D, et al. Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection. Nat Microbiol. 2020.
17. Latham T, Mackay L, Sproul D, Karim M, Culley J, Harrison DJ, et al. Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acids Res. 2012;40(11):4794-803.
18. Wagner W, Ciszewski WM, Kania KD. L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation. Cell Commun Signal. 2015;13:36.
19. Cheng F, Lienlaf M, Perez-Villarroel P, Wang HW, Lee C, Woan K, et al. Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol. 2014;60(1):44-53.
20. Villagra A, Cheng F, Wang HW, Suarez I, Glozak M, Maurin M, et al. The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol. 2009;10(1):92-100.
21. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41-5.
22. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574(7779):575-80.
23. Shakespear MR, Halili MA, Irvine KM, Fairlie DP, Sweet MJ. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 2011;32(7):335-43.
Tammy Kielian
Professor, University of Nebraska Medical Center
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How much sugar is too much sugar?
With most people looking forward tucking into a few chocolatey treats over Easter, we thought we’d take a closer look at sugar. We spoke to Dr Tessa Young, who specialises in weight loss and bariatric medicine at Illawarra Medical Centre, about the health risks associated with eating too much sugar and simple ways to avoid overindulging.
We are starting to see a growing number of people advocate for a low sugar diet. How bad is sugar really and, if it is so bad, why is it so easily available and not forced to come with warning labels?
We are starting to understand that excess sugar is the cause of many health problems. This can start with poor teeth development in children and lead to obesity, diabetes, heart disease, cancers and more health problems later in life.
lump_sugar_diet
In the 1950’s and 1960’s, they started researching why there was such a rise in obesity and heart disease with the introduction of processed foods and supermarkets. There were two main schools of thought on this – the first was that it was due to the amount of fat in people’s diets, while others believed it was due to the amount of sugar. The anti-fat group won the debate at the time, and so the “low fat” message spread. As with any consumer driven product, we saw supermarkets and food producers respond to the public demand for low fat foods by stocking their shelves with products that described themselves in that way. In order to remove fat from many of these products, however, it meant that the sugar content actually went up. As a result, obesity continued to rise, as did heart disease and many other illnesses. That does not mean fat is good and sugar is the cause of everything, but there is probably a message in there somewhere – and one that I’m sure we all heard from our grandparents and don’t adhere to – and that is to eat “everything in moderation”.
One of the other major changes we have seen since that time is that people can now afford to buy in excess and eat in excess, and no doubt that has contributed significantly to a rise in these health issues associated with too much sugar. When our grandparents were young, “treat” foods like cakes and soft drinks were exactly that – a treat, eaten only a few times a year on special occasions. It is now normal for people to eat something every day and still call it a treat, when it is really part of their regular diet.
With a growing number of sugar-free advocates and people now becoming more aware about the impact of too much sugar in their diet, supermarkets are starting to respond to consumer pressure for low sugar and no-sugar products. It’s important to remember, however, that supermarkets are still driven by profit, not health, so they will continue to stock what people will buy and this can result in large differences in what is available from suburb to suburb, depending on the patterns of community spending.
In Australia, the nutrition labels on foods do tell you how much is in a serve, however, this serve is normally based on the recommendation for an average male and assumes that you will only eat that one high fat/high salt/high sugar product in the day. What we know, though, is that most people don’t adhere to serving suggestions and/or they have more than just that one serving suggestion throughout the day.
If we were to take our grandparents’ advice and eat everything in moderation, what does that mean for sugar? How do we know what moderation looks like?
The World Health Organisation (WHO) looks at and compares research available from all over the world to come up with recommendations to improve world health. Their current advice about sugar is that free sugars should make up less than 10% of someone’s daily intake and optimum health benefits occur when adults stick to less than 25g of sugar per day.
What are free sugars?
Free sugar basically means the sugars from anything in a packet, so you don’t need to count the sugar in your vegetables or your two serves of fruit in a day, but you do need to count anything that you drink or consume throughout the day that comes in a packet. As mentioned, all food labels will tell you the amount of sugar contained in that particular food, as per the example to the right.
So what does 25g of sugar look like?
There is a fabulous Australian film that talks about this in an entertaining way – That Sugar Film. It is well worth watching because it helps people to see that the “healthy” foods they thought they could eat in any volume are often the cause of hidden high sugar intake.
Most people know that when they eat cakes, sweets, biscuits, chocolates etc, they are eating foods that aren’t good for them but it is often the hidden sugars found in cereals, yoghurt, juices, marinades, pasta sauces and other foods that are not considered in their overall sugar intake.
To give you an idea of how much 25g of sugar actually is:
nutrition_label_sugar_content_food_packagin
• One teaspoon of sugar is 5g, for those who have sugar in their tea/coffee. Any flavoured coffee that you buy is flavoured with syrup and the sugar levels in these drinks are usually substantially higher.
• A 355ml can of coke has 45g of sugar – more than a full day’s recommendation, and that is assuming no other free sugar is eaten or drunk that day.
• A low fat, fruit yoghurt can be 19-25g of sugar, or a whole day’s worth of recommended sugar. The best yoghurt to have is a tablespoon of plain greek yoghurt, which generally has less sugar in it.
You can also take this quiz to get more of an idea of how much sugar is contained in some of the food and drinks consumed in Australia every day:
ABC QUIZ – What Does Six Teaspoons of Sugar Look Like?
Is it better to have artificial sweeteners, sugar substitutes or things like honey?
When artificial sweeteners are consumed, our bodies respond to the sweet taste and release insulin to break down the sugar. When there is no sugar to break down, they tend to make us crave more carbohydrate or sugar-based foods, so that we can use up the insulin that has been released. This basically means that artificial sweeteners can be just as bad, if not worse, for your health than the real thing. They can, however, be useful for people who need to reduce their sugar intake urgently (for example, diabetics) and who need to have an alternative as they wean their taste buds off sugar, but in general they are best avoided.
Sugar based foods that have been minimally processed, like raw sugars or honey are better than more refined sugars, but they are still sugar based products, so the same rules apply.
easter_eggs_colourful
With an abundance of chocolate stacking the shelves at this time of year, what are your recommendations over Easter to help us avoid eating too much sugar?
1.
Try not to go too crazy with Easter eggs for your children. Rather than giving the kids huge eggs, why not give them smaller ones or a different gift all together? If they have received lots of chocolate, try to spread the intake out rather than allowing them to gorge all at once and explain the reasons why, so that they start to develop a good understanding of how sugar fits into an overall balanced diet.
2. Reduce your other free sugar intake. Look at the rest of your day and keep it as clean as possible, so that the only sugar intake is coming from chocolate. Maybe have eggs (real , not chocolate!) for breakfast, rather than cereal and avoid having any yoghurt that day. Stick to water to drink and eat your veggies.
3. Encourage children to eat their healthy food first, before they have any chocolate, so that they physically can’t get as much food in.
4. Increase exercise. Sugar is an immediate energy source for exercise and the recommendations assume that we are all doing our heart health minimum of 10,000 steps in a day to burn off the sugar that we eat. So, over Easter, I would recommend increasing your exercise on the days when your sugar intake has increased.
5. Opt for dark or raw chocolate. For adults, I suggest trying to pick lower sugar chocolates, like dark chocolate (the darker the better) or raw chocolate when indulging that sweet tooth over Easter.
To find out more about the impact of sugar on your health, visit:
To book in an appointment with one of our GPs to discuss any health concerns you have regarding your diet or overall health and wellbeing, book online or contact us on (08) 9208 6400.
About the Author: Dr Tessa Young
Tessa is a GP at Illawarra Medical Centre, with special interests in women’s health, weight loss, paediatrics and bariatric medicine. As a former professional dancer, Tessa enjoys anything dance-related outside of her work as a GP. She is also a fitness instructor and enjoys anything to do with fitness, particularly acrobatic yoga.
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Cow's Milk Protein Allergy and Fussiness
It's hard being a Mom when your baby keeps crying. It's even harder when you don't know whether your baby's behavior is due to his temperament or a potential health issue.
Trusting your mother's intuition is always a good idea when it comes to fussiness in babies, as is seeing your doctor any time that you are concerned about your baby's well-being. Your baby’s doctor can help figure out what's going on and provide solutions to ensure your little one stays healthy and happy.
Pinpointing a Cause
One way to gauge whether there is something more behind your baby's discomfort is to observe how he acts when you feed him or shortly afterward. Notice if he gets upset when you try to nurse or offer a bottle, or whether he seems uninterested in eating even when you know he's hungry. You'll want to pay attention to these potential signs of trouble too.
Baby reflux. All infants experience some degree of gastroesophageal reflux. It's what causes stomach contents to occasionally flow back into your baby's esophagus or mouth (in other words, baby spit-up). But some babies have more severe reflux problems. They may frequently spit up lots of liquid, forcefully vomit, choke or gag, arch away from the bottle or breast, seem irritable during or after feedings, or have trouble putting on weight.
Gassiness. Your little one's stomach may look bloated or feel hard or tense. He may pull up his legs or lock them out straight, clench his fists, and pass gas.
Signs of colic. If your baby keeps crying even though he isn't hungry, tired, or in need of a diaper change, he could have colic. Colic tends to follow a pattern of threes: crying for more than three hours per day (usually in the evening), for more than three days per week, and for more than three weeks. Up to 25 percent of newborns suffer from these crying jags, which generally start a few weeks after birth1. Colic often improves by the third or fourth month.
Itchy rash. Tiny red bumps on your baby's face, scalp, hands or feet may be a sign of eczema. The bumps may itch, ooze and crust over, or feel like dry, scaly skin.
Hives. Raised red welts or hives on your infant's skin suggest that your baby is having an allergic reaction, possibly to something in his diet or to pet dander, a medication, plant pollen, or any number of things. Hives typically occur soon after exposure to an allergen.
Respiratory problems. A chronic cough, persistent runny nose, and raspy, wheezy breathing may indicate allergies.
Constipation. Your baby's stool might look like little rabbit pellets or a hard ball. You also may notice some blood. Don't judge whether your baby is constipated by how frequently he has a bowel movement. Sometimes, healthy infants may go several days without one.
Infant diarrhea. The stools of breastfed babies are typically runny and seedy. Stools of formula-fed infants tend to be a little thicker. If your baby has diarrhea, you will notice frequent watery, foul-smelling loose stools. Because infants who have diarrhea may become dehydrated, you should call your baby’s doctor. In fact, if your baby is experiencing any of the symptoms above, talk to your doctor.
What's going on?
If your baby keeps crying, it is important to determine the cause. Any number of things could be affecting your baby's behaviour, which is why it's important to see your doctor. One condition to consider is cow's milk protein allergy. You might not be familiar with this health issue, yet it affects 2.2-2.8% of infants and is a common childhood food allergy2-4. Infants who have a cow's milk protein allergy may react in many different ways to the protein found in cow's milk. Most babies experience mild-to-moderate allergic reactions like colic, reflux, diarrhea, constipation, gas, skin rashes and upper respiratory problems. A smaller number have more severe problems, such as breathing difficulties, failure to thrive and anemia5. The most serious allergic reaction, anaphylactic shock or anaphylaxis, causes a mix of potentially life-threatening health issues—low blood pressure, irregular heartbeat, distressed breathing, intense stomach pain, vomiting and hives—within minutes or hours of exposure to an allergen. Fortunately, this sort of allergic reaction is rare.
Related article :
cow's Milk Protein Allergy in Babies
1. Roberts DM, et al. Am Fam Physician. 2004; 70: 735-40. 2. Sicherer SH et al. J Allergy Clin Immunol. 2006; 117(Suppl 2): S470-5. 3. Schrander JJ et al. Eur J Pediatr. 1993; 152: 640-4. 4. Høst A et al. Pediatr Allergy Immunol . 2002; 13(Suppl 15): 23-8. 5. De Greef et al. World J Pediatr. 2012; 8 (1)19-24.
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• Research article
• Open Access
Extensive proteomic screening identifies the obesity-related NYGGF4 protein as a novel LRP1-interactor, showing reduced expression in early Alzheimer's disease
• 1, 2, 3,
• 1, 2,
• 1, 2,
• 1, 2,
• 2,
• 4, 5,
• 2, 6,
• 1, 2,
• 7,
• 4,
• 2, 7 and
• 1, 2, 3, 8Email author
Contributed equally
Molecular Neurodegeneration20105:1
https://doi.org/10.1186/1750-1326-5-1
• Received: 15 October 2009
• Accepted: 14 January 2010
• Published:
Abstract
Background
The low-density lipoprotein receptor related protein 1 (LRP1) has been implicated in Alzheimer's disease (AD) but its signalling has not been fully evaluated. There is good evidence that the cytoplasmic domain of LRP1 is involved in protein-protein interactions, important in the cell biology of LRP1.
Results
We carried out three yeast two-hybrid screens to identify proteins that interact with the cytoplasmic domain of LRP1. The screens included both conventional screens as well as a novel, split-ubiquitin-based screen in which an LRP1 construct was expressed and screened as a transmembrane protein. The split-ubiquitin screen was validated in a screen using full-length amyloid protein precursor (APP), which successfully identified FE65 and FE65L2, as well as novel interactors (Rab3a, Napg, and ubiquitin b). Using both a conventional screen as well as the split-ubiquitin screen, we identified NYGGF4 as a novel LRP1 interactor. The interaction between LRP1 and NYGGF4 was validated using two-hybrid assays, coprecipitation and colocalization in mammalian cells. Mutation analysis demonstrated a specific interaction of NYGGF4 with an NPXY motif that required an intact tyrosine residue. Interestingly, while we confirmed that other LRP1 interactors we identified, including JIP1B and EB-1, were also able to bind to APP, NYGGF4 was unique in that it showed specific binding with LRP1. Expression of NYGGF4 decreased significantly in patients with AD as compared to age-matched controls, and showed decreasing expression with AD disease progression. Examination of Nyggf4 expression in mice with different alleles of the human APOE4 gene showed significant differences in Nyggf4 expression.
Conclusions
These results implicate NYGGF4 as a novel and specific interactor of LRP1. Decreased expression of LRP1 and NYGGF4 over disease, evident with the presence of even moderate numbers of neuritic plaques, suggests that LRP1-NYGGF4 is a system altered early in disease. Genetic and functional studies have implicated both LRP1 and NYGGF4 in obesity and cardiovascular disease and the physical association of these proteins may reflect a common mechanism. This is particularly interesting in light of the dual role of ApoE in both cardiovascular risk and AD. The results support further studies on the functional relationship between NYGGF4 and LRP1.
Keywords
• Amyloid Protein Precursor
• Brodmann Area
• Braak Stage
• Human APOE
• NPXY Motif
Background
The low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) is a multifunctional receptor that mediates the internalization and degradation of ligands involved in diverse metabolic pathways [1]. LRP1, which is expressed by many cells in the central nervous system, including neurons and astrocytes [2, 3], is synthesized as a 600-kDa polypeptide that is subsequently cleaved by furin in the trans-Golgi compartment into two subunits of 515 and 85 kDa [4, 5]. The 515-kDa subunit contains the ligand binding domains and remains noncovalently associated with the 85-kDa subunit, which includes the transmembrane domain and a short cytoplasmic tail. LRP1 plays an important role in several physiological processes including embryonic development [6].
LRP1 recognizes and internalizes numerous extracellular ligands, including protease/protease inhibitor complexes and apolipoprotein particles such as apolipoprotein E (ApoE), and has an important role in intracellular signaling pathways, some being mediated through tyrosine phosphorylation sites in the cytoplasmic domain [1, 79]. The binding of the AD-associated apolipoprotein ApoE to LRP1 has been shown to be neuroprotective [10]. LRP1 also interacts with other AD-related proteins including APP, BACE1 and presenilin 1 [1113]. The cytoplasmic tail of LRP1 contains two NPXY motifs and two dileucine-based motifs and may interact with multiple adaptor and scaffolding proteins, include PSD-95, Shc, Mint2, disabled-1 (Dab1), JIP-1, JIP-2 and Fe65 [1416]. Signaling pathways associated with LRP1 include intracellular cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), calcium signaling via N-methyl-D-aspartate (NMDA) receptors [17] and mitogen-activated protein (MAP) kinase pathway [18].
LRP1 has been shown to be associated with late onset AD in some studies but not in others [1921]. Age of onset and severity of AD has also been shown to be associated with LRP1 [19, 22]. In addition, LRP1 signaling pathways have been functionally implicated in AD since LRP1 has been found to be associated with senile plaques in AD brains along with the LRP1 ligands ApoE, α-2 macroglobulin and APP, which themselves are genetically and functionally associated with AD [2325]. LRP1 has been implicated as a receptor for cellular uptake of Aβ [22, 26, 27] as well as in the efflux of Aβ at the blood brain barrier [28]. Furthermore, LRP1 has also been shown to promote the generation of Aβ through an interaction of the Kunitz protease inhibitor domain (KPI) and cytoplasmic tail with APP [29, 30]. The cytoplasmic tail alone has also been shown to promote delivery of APP to lipid raft microdomains that are enriched with BACE1 activity [31]. These results indicate that LRP1 plays a role in Aβ generation, uptake into cells and removal from the CNS.
LRP1 contains four putative ligand binding domains (I, II, III and IV). The furin endopeptidase processing site is found between the fourth ligand binding domain and the transmembrane region. The cytoplasmic tail of LRP1 contains at least five motifs: two NPXY motifs, two dileucine motifs, and one YXXL motif, each of which can have a role in LRP1 trafficking and signaling. The YXXL motif has been shown to serve as the dominant endocytosis signal for LRP1 [32], whereas the two NPXY motifs have been shown to be subject to tyrosine phosphorylation and constitute binding sites for proteins with phosphotyrosine binding (PTB) domains. One of the NPXY motifs interacts with the transcription factor Fe65 [14].
In this study, we used conventional yeast two-hybrid screens and a novel split-ubiquitin yeast two-hybrid screen to identify novel interactors of LRP1. NYGGF4 was found to be a novel, and specific, interactor of LRP1, whose expression is regulated by ApoE allele in a mouse model is decreased during AD progression. These results further implicate LRP1 as well as of the novel LRP1 interactor, NYGGF4, in AD pathogenesis as well as obesity and cardiovascular disease.
Results
Yeast two-hybrid analysis with cytoplasmic domains of LRP1
Baits derived from two different cytoplasmic domain sequences of LRP1 (Fig. 1), containing either the first or second NPXY motif, were used to screen for interacting proteins in a mouse brain library. One bait (LRP1-C1) consisted of amino acids 4455-4476 of the LRP1 cytoplasmic domain and the other of amino acids 4497-4533 (LRP1-C2). After validating that the fusion proteins were expressed in yeast and that each by itself did not activate reporter gene expression, 1.1 × 107 colonies (for LRP1-C1) and 2.8 × 107 colonies (for LRP1-C2) from an adult mouse brain cDNA library (complexity 1 × 106; Clontech) were screened. Clones identified in the screen were re-assayed with an X-Gal filter test and those passing this test were further analyzed by retransformation with either the LRP1 bait or with a control bait. Restriction analysis and sequencing of all specific clones was then carried out (Table 1). The results for LRP1-C2 include previously identified and validated LRP1 interactors (EB-1, JIP1b) as well as novel interactors (Nyggf4, Hnrpdl). The overlap with prior results for LRP1-C2 confirm the approach, while results for LRP1-C1 represent the first successful published screen with this domain and identified Ric-8b, Freud-1 and the ribonucleoprotein U1 as interactors.
Figure 1
Figure 1
Schematic of LRP1. The 515-kDa extracellular region of LRP1 consists of four domains: I, II, III and IV. The 85-kDa intracellular region of LRP1 includes two NPXY motifs.
Table 1
Results of traditional yeast two-hybrid screens
Prey
Number of clones
Accession number
Using LRP1-C1 as bait
Ric-8b
3
NM_001013441
Freud-1
1
NM_145970
Small nuclear ribonucleoprotein U1
1
NM_009224
Using LRP1-C2 as bait
JIP1b
22
NM_011162
EB-1
3
XM_001003394
Nyggf4
3
NM_001003948.1
Hnrpdl
1
NM_016690
Split-ubiquitin yeast two-hybrid analyses
A novel two-hybrid method has been developed to allow screening transmembrane proteins for interactors [33]. We first carried out this split-ubiquitin, yeast two-hybrid screen for full-length APP695 to determine whether this approach would identify previously validated, as well as possibly novel, APP interactors. Because of the nature of the screen (transmembrane bait but soluble prey), we focused on soluble proteins and identified five specific, unique clones (Table 2), including Fe65 and Fe65L2, as well as rab3a, Napg, and ubiquitin b. The identification of Fe65 proteins in this screen validated the approach and justified its use with LRP1.
Table 2
Results of the split-ubiquitin yeast two-hybrid screens
Prey
Number of clones
Accession number
Using APP695 as bait
Fe65
1
NM_009685
Fe65l2
1
NM_146085
Rab3a
1
NM_009001
Napg
1
NM_028017.1
Ubiquitin b
1
NM_011664.3
Using mLRP4 as bait
Nyggf4
2
NM_001003948.1
Screening the same mouse brain library with the LRP1 transmembrane mini-receptor mLRP4, we identified 1 unique soluble clone, Nyggf4 (Table 2). The specificity of the interaction was validated, showing no interaction in a follow up screen with irrelevant baits (p53 and lamin A/C). It was exciting to note that Nyggf4 was identical to the protein we previously identified with conventional yeast two-hybrid screen using the LRP1-C2 bait (Table 1). The identification of Nyggf4 in two very different yeast two-hybrid assays provided evidence that this protein may be an important LRP1-interacting protein.
Validation of the LRP1-Nyggf4 interaction
The interaction between LRP1 and Nyggf4 was confirmed by four additional methods. We first used a mammalian two-hybrid system to confirm that LRP1 and Nyggf4 interact in mammalian cells (Fig. 2A). Nyggf4 showed significant interaction with the LRP1 cytoplasmic domain in this assay. For comparison, we included additional potential LRP1 interactors, identified in the screen with the LRP1-C2 bait. From these latter studies, we confirmed that both EB-1 and JIP1b were LRP1 interactors in this system (Fig. 2A).
Figure 2
Figure 2
Mammalian two-hybrid assays with the LRP1 or APP cytoplasmic domains. H4 human neuroglioma cells were transfected with the indicated constructs, and luciferase activity measured. A. The LRP1 cytoplasmic domain was cloned into the pBIND vector while the interactors JIP-1b, EB-1 and Nyggf4 were cloned into the pACT vector. Strong interactions between LRP1 and JIP-1b, EB-1 or Nyggf4 were observed, confirming results with yeast two hybrid studies. B. The APP cytoplasmic domain (known as APP intracellular domain/AICD) was cloned into pBIND, while the interactors JIP-1b, EB-1 and Nyggf4 were cloned into pACT. Strong interactions between JIP-1b or EB-1 with the APP intracellular domain were observed but no interaction was observed with Nyggf4 and the APP intracellular domain. ***, P < 0.0001.
It was of interest to us that some of the LRP1-C2 domain interacting proteins identified by us and by others (e.g., JIP1b and EB-1, [34, 35]) have also been reported to interact with APP. We therefore sought to determine whether Nyggf4 could interact with APP (Fig. 2B). Using the mammalian two-hybrid system, we observed that under conditions where JIP1b and EB-1 could bind the cytoplasmic domain of APP, Nyggf4 could not. The Nyggf4 interaction shows specificity to LRP1 in these studies, while JIP1b and EB-1 do not, as they bind both LRP1 and APP.
We also confirmed an interaction between LRP1 and NYGGF4 using GST pulldown, coimmunoprecipitation and colocalization studies. For the GST pulldowns, a fusion protein comprised of GST and the LRP1-intracellular domain (GST-LICD), but not GST alone, could precipitate NYGGF4, when it was expressed in COS-7 cells (Fig. 3A).
Figure 3
Figure 3
Interaction of LRP1 and NYGGF4 expressed in mammalian cells. A. COS-7 cells were transfected with vector (pcDNA3) or NYGGF4-V5 cloned into pcDNA3.1V5/His and resultant cell lysates were subjected to GST-pulldown with either GST or with GST-LRP1 (cytoplasmic domain only), as indicated by the scheme at the base of the figure. Aliquots of cell lysates (right most lanes) and aliquots of the GST-pulldowns were probed by immunoblotting with anti-V5 antibody for NYGGF4. NYGGF4 is precipitated with GST-LRP1, but not with GST alone. B. FLAG-tagged mLRP4 and V5-tagged NYGGF4 were cotransfected into H4 neuroglioma cells, and immunoprecipitation (IP) of either protein by FLAG or V5 antibody successfully coprecipitated the other protein as detected by immunoblot (IB). Lysate was also blotted to show expression in transfected cells (Input) and control immunoprecipitations were carried out with purified control immunoglobulin (IgG). C. FLAG-tagged mLRP4 and V5-tagged NYGGF4 were cotransfected into either H4 (upper) or Neuro 2A (lower) cells, and detected by immunocytochemistry. Both proteins showed extensive colocalization, especially in the perinuclear region. Results are representative of three independent experiments.
Subsequently, FLAG-mLRP4 and NYGGF4-V5 were cotransfected into H4 neuroglioma cells, and immunoprecipitation of either protein by FLAG or V5 antibody successfully coprecipitated the other protein as detected by immunoblot (Fig. 3B). Furthermore, both proteins showed extensive colocalization, especially in the perinuclear region, when cotransfected into either H4 cells or Neuro 2A cells (Fig. 3C).
Characterization of the LRP1-Nyggf4 interaction
We next used the mammalian two-hybrid system to determine whether the LRP1-Nyggf4 interaction required the intact NPVY motif of the LRP1-C2 domain (Fig. 4). Nyggf4 interacted with wild-type LRP1 intracellular domain (LICD), but not with LICD where the NPVY motif in C2 domain was mutated to NAVA. In contrast, mutating the NPTY motif in C1 domain to NATA in the LRP1 domain had no effect on Nyggf4 binding. This indicated both that the binding of Nyggf4 involved a canonical NPXY motif and was specific for the motif in LRP1-C2.
Figure 4
Figure 4
Mammalian two-hybrid assays with wild-type and mutant LRP1. NPXY motifs of the cytoplasmic domain of LRP1 were mutated and the interaction of the cytoplasmic domain with Nyggf4 was assessed as described in Fig. 2. NATA represents the mutation of the NPXY motif of LRP1-C1 and NAVA represents the mutation of NPXY motif of LRP1-C2. Nyggf4 binds to wild-type LRP1 and to LRP1-NATA but not to LRP1-NAVA. *, P < 0.01; ***, P < 0.001.
Expression of NYGGF4 mRNA in Alzheimer's disease
Given the potential role for NYGGF4 as an LRP1-interacting protein and a role for LRP1 in AD, we then asked whether there was altered expression of mRNA for Nyggf4 and LRP1 in that disease (Fig. 5A). Expression of human NYGGF4 was significantly reduced in probable and definite AD as compared to age-matched controls (F1,88 = 15.419, p < 0.001). Interestingly, expression of NYGGF4 decreased over the progression of the disease, as assessed by either CDR scores (F6,90 = 3.917, p < 0.01; data not shown), Braak stage (F5,82 = 8.979, p < 0.001; data not shown), or increasing plaque density (F3,94 = 4.096, p < 0.01; Fig. 5B). The levels of NYGGF4 decreased with even the smallest increase in plaque densities. The associations between NYGGF4 levels and disease progression all demonstrated highly significant linear trends (F1,95 = 17.425, p < 0.01 for CDR score, F1,85 = 25.053, p < 0.001 for Braak stage, and F1,96 = 13.102, p < 0.001 for plaque density).
Figure 5
Figure 5
Expresssion of LRP1 and NYGGF4 in Alzheimer disease. A. Expression of LRP1 and NYGGF4 in entorhinal cortex (BA28/36), comparing controls and subjects with AD. ***, p < 0.001 B. Expression of LRP1 and NYGGF4 as a function of neuritic plaque density. Plaque density scores are derived from counts across five cortical regions: 0, no neuritic plaques; 1, 1-6 plaques per mm2; 2, 7-12 plaques per mm2; and, 3, >12 neuritic plaques per mm2. ***, p < 0.001 for negative linear trend.
LRP1 was also significantly reduced (39% reduction) in probable and definite AD, as compared to age-matched controls (F1,88 = 15.877, p < 0.001; Fig. 5A). LRP1 expression also showed decreased expression over the course of disease, as measured by CDR score, Braak stage, or plaque load (Fig. 5B, and data not shown). The decrease in LRP1 with increasing Braak stage was significant (F5,82 = 5.462, P < 0.001) and the linear trend was significant as well (F1,86 = 9.381, p < 0.01). Although the decrease of LRP1 with increasing CDR score was not significant (F6,90 = 1.65, p = 0.143), the linear trend was significant (F1,95 = 4.832, p < 0.05). Finally, LRP1 expression was significantly reduced (30% for group 1, 37% for group 2, and 54% for group 3, all compared to group 0) with increasing neuritic plaque load (F3,94 = 7.650, p < 0.001; Fig. 5B) with a strong negative linear trend (F1,96 = 22.215, p < 0.001).
Expression of Nyggf4 mRNA in mouse models for Alzheimer's disease
Subsequently, we asked whether there was altered expression of mRNA for Nyggf4 and Lrp1 in mice with different human APOE isoforms, as LRP1 is a major receptor for APOE and APOE is a major AD risk factor (Fig. 6). Interestingly, expression of Nyggf4 was significantly upregulated in mice carrying human APOE ε4 gene compared to mice carrying human APOE ε2 and human APOE ε3 gene (F1, 17 = 5.992, p < 0.001 and F1,17, = 0.008, p < 0.01, respectively). Furthermore, expression of Lrp1 was significantly decreased in these mice (F1, 17 = 0.312, p < 0.001 for APOE ε2 and F1,17, = 16.463, p < 0.01, for APOE ε3 respectively). For comparison, Bace1 levels were unchanged in the mice while another Lrp1-binding protein, Lrpap showed increased expression in the ApoE4 mice, similar to Nyggf4 (F1, 17 = 2.695, p < 0.05 for APOE ε2 and F1,17, = 1.012, p = 0.079, for APOE ε3 respectively).
Figure 6
Figure 6
Expression of Lrp1, Nyggf4, Bace1, and Lrpap in a mouse model of Alzheimer's disease. Relative mRNA expression levels of Bace1, Lrp1, Lrpap, and Nyggf4 from whole brain tissue of mice expressing either the ApoE2, ApoE3, or ApoE4 isoform. All values are normalized to three ubiquitously expressed housekeeping genes (Actb, Gapdh, and Rpl13a using qBase. *, p < 0.05, **, p < 0.01, and ***, p < 0.001.
Discussion
In the current study, we screened for novel interactors of the LRP1 intracellular domain using both conventional and split-ubiquitin screens (see Fig. 1). Two separate baits, each encompassing one of the two NPXY motifs of the LRP1 intracellular domain (Figure 1), were used in the conventional screens (Table 1). For the split-ubiquitin screen, mLRP4, which consisted of domain IV, transmembrane and cytoplasmic tail of LRP1 (Figure 1) was used, after validating the approach with full-length APP (Table 2). NYGGF4 was identified as an LRP1 interactor using both LRP1-C2 in the conventional screen as well as in the slit-ubiquitin screen (Tables 1 and 2). This interaction was validated as specific in yeast, as well as in mammalian two-hybrid screens and in colocalization and coprecipitation experiments. We observed that the interaction of NYGGF4 with LRP1 is mediated by the NPVY sequence in LRP1. Interestingly, unlike other LRP1-binding proteins, which can also interact with APP, NYGGF4 was shown to bind LRP1 but not APP, indicating that the NYGGF4-LRP1 interaction shows specificity not seen with some other interactors.
NYGGF4 is a 250 amino acid cytoplasmic protein that is largely defined by single PTB domain. Amongst the clones identified in this study, all contained the PTB domain with flanking sequence supporting a role for this PTB domain in the interaction with LRP1. This conclusion is supported by a recent study that used numerous PTB domains to screen for interacting proteins [36]. In that study, the PTB domain of NYGGF4 (there identified as Q7Z2X4), was shown to pull down a complex of LRP1 and cubulin, the latter previously associated with megalin, which is another member of the LDLR family.
Altogether, NYGGF4 remains a poorly characterized gene that was first identified as a gene showing increased expression in obese subjects [37]. Those studies demonstrated high expression of NYGGF4 in adipose tissue, heart and skeletal muscle and showed that NYGGF4 increased proliferation of 3T3-L1 preadipocytes. Later studies by the same group showed a role for NYGGF4 in glucose homeostasis in mature adipocytes, with increased expression of NYGGF4 leading to reduced insulin-stimulated glucose uptake and impaired insulin-stimulated GLUT4 translocation [38]. When fed with a high fat, high sucrose (diabetogenic) diet to induce obesity, ApoE deficient mice showed no differences in plasma lipid levels, lipoprotein profiles or atherosclerotic lesion areas [39] and are hence resistant to many of the effects of the diabetogenic diet. In a similar vein, disruption of LRP1 in adipocytes led to a delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, and improved glucose tolerance, while showing resistance to dietary fat-induced obesity and glucose intolerance [40]. These results, when taken together with our studies, lead us to hypothesize that the LRP1-NYGGF4 interaction may mediate critical effects of LRP1 on diet-induced obesity, glucose tolerance, and cardiovascular risk factors. In support of this, review of SNPs in NYGGF4 analyzed in a large study [41] indicate that two (rs2215598 and rs6739369) show nominal association with hypertension (P = 0.00021 and P = 0.00008, respectively).
The very strong association of ApoE with AD also raises the question as to the role of ApoE receptors such as LRP1, and the molecules associated with them, in AD. It was interesting to observe that expression of NYGGF4 is decreased in AD (Fig. 5). Moreover the levels of NYGGF4, as well as LRP1, decreased as a function of disease progression, particularly as defined by increasing neuritic pathology. Further studies would need to address the mechanisms of altered expression of these genes in AD progression, which might include loss of neurons as well as additional mechanisms. Interestingly, the functional linkage between ApoE, LRP1, and NYGGF4 receives support from our observations in ApoE-transgenic mice, where ApoE genotype modulates expression of Lrp1 mRNA and expression of Nyggf4 mRNA in opposite directions. The mechanism for this would require further experimentation, however it appears that levels of this ApoE binding protein and its associated adaptor are regulated by ApoE isoforms in such a way that would likely lead to alterations in downstream signaling. How this might modulate cardiovascular risk or cognitive function is of course a very interesting question for future studies.
Conclusions
Extensive proteomic analyses, including yeast-two hybrid screening, mammalian two-hybrid screening, copreciptation, and colocalization, identify NYGGF4 as an LRP1-binding protein. NYGGF4 is not well studied but appears well situated to mediate the effects of LRP1 on aspects of obesity, glucose tolerance, and cardiovascular risk factors. Moreover, the relationship between ApoE genotype and NYGGF4 expression supports an important relationship between these two proteins in AD risk. Further study of NYGGF4 in the CNS and the periphery will clarify the role of the protein in physiological processes and in disease.
Methods
Two-hybrid screening
All yeast two-hybrid screening was carried out together with Dualsystems Biotech (Zurich). For conventional yeast two-hybrid screening, baits flanking either the first (LRP1-C1, 4445KRRVQGAKGFQHQRMTNGAMNVEIGNPTYKMY4476) or second (LRP1-C2, 4497KPTNFTNPVYATLYMGGHGSRHSLASTDEKRELLGR4533) NPXY motifs of LRP1 (shown above in bold lettering) were cloned into the DUALhybrid bait vector in frame with the LexA DNA-binding domain, and the resultant construct confirmed by sequencing. After validating that baits, by themselves, did not activate reporter gene expression, an adult mouse brain cDNA library was screened (Clontech, Mountain View, CA). Bait dependency of each putative clone was confirmed by retransforming into strains carrying either the relevant LRP1 construct or a control vector. All remaining baits were then sequenced.
Split-ubiquitin yeast two-hybrid screening, which has the advantage that it allows for screening with membrane-inserted transmembrane proteins, was carried out as previously described [33]. To first validate the method, we used full-length amyloid precursor protein (APP) as bait, onto which we fused (at the COOH-terminal) the COOH-terminal portion of ubiquitin ("Cub", see [33]) and an artifical transcription factor (LexA-VP16). A mouse brain cDNA library with a mutated version of the amino-terminal portion of ubiquitin ("NubG", see [33]), fused to the amino-terminal of prey sequences was used to screen for potential positive interactors. Specific clones remaining after false positives were eliminated by the use of irrelevant baits (p53 and lamin A/C) were sequenced.
Since LRP1 is a large protein not readily expressed in heterologous systems, minireceptors that include ligand-binding domains of LRP1 have been generated [42]. The minireceptor mLRP4 consists of the signal peptide, a FLAG tag, and the entire sequence from ligand binding domain IV through the COOH-terminal of the native receptor. As with APP, Cub and an artificial transcription factor (LexA-VP16) were fused to the COOH-terminal of mLRP4 (a gift of Dr. Guojun Bu) and screening was carried out as described above.
GST pulldown experiments
GST pulldowns were carried out as previously described [43]. Briefly, COS-7 cells were transfected with control vector or with NYGGF4-V5 using Lipofectamin 2000 (Invitrogen), according to the manufacturer's instructions, and lysed after 24-48 hrs. Subsequently, purified GST or GST fused to the cytoplasmic domain of LRP1 (beginning at the KRR membrane anchor) previously incubated with glutathione beads were incubated with 100 μg of cell lysate. After washing three times with wash buffer, beads were boiled in SDS sample buffer and run on 10% SDS-PAGE gel. Proteins were analyzed by immunoblotting and ECL detection.
Mammalian two-hybrid assays
To confirm interactions in mammalian cells, the Checkmate mammalian two-hybrid system (Promega) was used according to manufacturer's instructions. H4 neuroglioma cells were transfected with various combinations of vectors expressing the following proteins: a naked GAL4 DNA binding domain (pBIND); a GAL4 DNA binding domain fused to the intracellular domain of LRP1 (pBIND-LRP1; again beginning at the KRR membrane anchor) or APP (pBIND-APP); a naked VP16 transactivation moiety activation domain (pACT); a VP16 transactivation moiety fused to JIP1b (pACT-JIP1b), EB-1 (pACT-EB-1) or Nyggf4 (pACT-Nyggf4) (the lower case font for Nyggf4 here and elsewhere in the manuscript is to indicate that the murine sequence was used). A reporter construct with a GAL4 consensus binding sequence upstream of firefly luciferase coding sequence was also cotransfected in all conditions. Interactions were monitored by transactivation of luciferase expression. Both firefly luciferase (reflecting gene activation) and Renilla luciferase (reflecting transfection efficiency) were measured in the same sample at the same time, leading to much reduced noise. Data were obtained from three or more independent experiments and expressed as a ratio of firefly luciferase to Renilla luciferase expression (Firelfy/Renilla).
Coimmunoprecipitation experiments
H4 neuroglioma cells were cotransfected with FLAG-mLRP4 and NYGGF4-V5 plasmids for 24 hours using Fugene6. Cells were lysed in lysis buffer containing 1% Triton X100 and protease inhibitor cocktail in 1× phosphate buffer saline (PBS). 100 μg of lysates were dissolved in 500 μl of lysis buffer and incubated with 5 μg of antibody or control IgG for 2 hours, then with additional Protein-G agarose beads for 1 hour at 4°C. Beads were washed with wash buffer containing 0.5% Triton X100 in PBS three times and then boiled in SDS loading buffer. Immunoblotting was performed as described in GST pulldown.
Colocalization experiments
H4 or Neuro-2A cells were cotransfected with FLAG-mLRP4 and NYGGF4-V5 using Fugene6 (Roche) for 24 hours and immunostained with rabbit 1704 anti-LRP1 and mouse anti-V5 antibodies, then subsequently with AlexaFluor 488 anti-rabbit IgG and AlexaFluor 594 anti-mouse IgG (Invitrogen) antibodies. The 1704 anti-LRP1 antibody was kindly provided by Dr. Edward Koo.
Gene expression in postmortem brains
All assessments and post-mortem procedures were approved by the Institutional Review Boards of Pilgrim Psychiatric Center, Mount Sinai School of Medicine, and the James J. Peters VA Medical Center. Subject selection, cognitive assessment and neuropathological assessment were carried out as previously described [44]. Briefly, frozen post-mortem brain tissue from the entorhinal cortex (Brodmann area 28/36) of subjects diagnosed with or without AD (normal neuropathology, N = 33; definite AD, N = 52; probable AD, N = 9; possible AD, N = 8) were obtained from the Mount Sinai/Bronx Veterans Administration (VA) Medical Center Department of Psychiatry Brain Bank. Normal controls had no history of any psychiatric or neurological disorders and no discernible neuropathological lesions. Neuritic plaque density was quantified in 5 cortical regions [Brodmann area 9 (BA9; middle frontal gyrus), Brodmann area 45/47 (BA45/47; orbital frontal gyrus), Brodmann area 21/22 (BA21/22; superior temporal gyrus), Brodmann area 39 (BA39; inferior parietal cortex), and Brodmann area 17 (BA17; calcarine cortex)], as previously described [45]. The results from these analyses were then used to bin the samples into gour groups: Samples with a score of 0, corresponded to those with no plaques observed in the 5 cortical regions; a score of 1 was used for samples with only 1-6 neuritic plaques per mm2; and a score of 2 and 3 were used for samples with 7-12 and >12 neuritic plaques per mm2, respectively.
Total RNA extraction and reverse transcriptase (RT) reactions were performed after DNAse treatment and template RNA quality, including degradation and DNA contamination, were controlled. Taqman® probes for endogenous control gene (RPLP0, Hs99999902_m1; GUSB, Hs99999908_m1; B2M, Hs99999907_m1) and experimental probes (LRP1, Hs01059330_m1; NYGGF4, Hs00952182_m1) were purchased from Applied Biosystems Inc. and the reactions were carried out with TaqMan® Universal PCR Master Mix (430437, Roche) using ABI Prism 7900HT at Mount Sinai Quantitative PCR Shared Research Facility. Expression levels of each sample were normalized to the geometric mean of GUSB, B2M, and RPLP0 expression levels.
Gene expression in mouse models for Alzheimer's disease
Male APOE knock-in (KI) mice, homozygous for human APOE *2, *3 and *4 were originally obtained from Taconic (Germantown, NY, USA) and a colony maintained at the Animal Resources Centre (ARC, Perth, Western Australia). These mice have been previously described [4650]. RNA was extracted from whole brain of male C57BL mice expressing either the apolipoprotein ε2 (ApoE2) (n = 10), ApoE3 (n = 10), or ApoE4 (n = 9) isoform using an RNeasy Mini-Prep Kit (Qiagen). The quality of all RNA samples was measured using an RNA 6000 Nano Kit (Agilent Technologies) and each sample used for subsequent cDNA synthesis possessed an RNA Integrity Number (RIN) of 0.9 or higher. cDNA was generated from total RNA extracts using a High Capacity cDNA Archive Kit (Applied Biosystems) as per manufacturer instruction. mRNA levels of Bace1, Lrp1, Lrpap, and Nyggf4 were determined via qPCR using the appropriate TaqMan UPL probe and primer sets (Applied Biosystems). Four ubiquitously expressed housekeeping genes (Actb, Gapdh, 18s, and Rpl13a) were used as references and all data was normalized using qBase [51]. qBase selected three of the housekeeping genes (Actb, Gapdh, and Rpl13a) as endogenous references based on their geometric mean expression.
Statistical analyses
Statistical analyses were performed using SPSS 11.0 software. For mammalian two- hybrid data, a t-test was used to compare effects of either LRP1 or APP on Firefly/Renilla ratio with each of the interactors or to vector alone. For expression data, an ANCOVA was carried out with LRP1 and NYGGF4 as dependent variables and either case status, CDR score, Braak Stage, or neurtic pathology scores as independent variables. Since data for NYGGF4 expression were not normally distributed, NYGGF4 data was log transformed. In each analysis, we used post-mortem interval, sex, sample pH, or ApoE4 allele as covariates if they were associated with the dependent variable. Sex showed no associations in LRP1 expression versus CDR score and Braak stage and was therefore omitted from the analysis. We also assessed the linear relationship by linear regression analysis controlling for covariates. All data are presented as means ± SEM and significant findings were noted when p < 0.05.
Notes
Declarations
Acknowledgements
A part of this work was carried out at the Marine Biological Laboratory, Woods Hole, MA. We thank Dr. Guojun Bu for the mLRP4 construct, Dr. Eddie Koo for anti-LRP1, and Rebecca Vitale for her help with this study. This work was supported by grants from the National Institute of Aging of the National Institutes of Health [AG010491 (SEG, PI; JDB, PL), AG005138 (Mary Sano, PI; JDB, PL), AG002219 (VH, PI; JDB, PL), and AG21792 (JDB, PI)]. JDB is the G. Harold and Leila Y. Mathers Professor of Geriatrics and Adult Development.
Authors’ Affiliations
(1)
Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
(2)
Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY, 10029, USA
(3)
Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
(4)
Centre of Excellence for Alzheimer's Disease Research & Care, School of Exercise Biomedical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia
(5)
Sir James McCusker Alzheimer's Disease Research Unit (Hollywood Private Hospital), Perth, Western Australia, Australia
(6)
James J Peters Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA
(7)
Department of Neurology, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
(8)
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
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@article {Dewhurst416, author = {Dewhurst, S and McIntyre, K and Schnabel, K and Hall, C B}, title = {Human herpesvirus 6 (HHV-6) variant B accounts for the majority of symptomatic primary HHV-6 infections in a population of U.S. infants.}, volume = {31}, number = {2}, pages = {416--418}, year = {1993}, publisher = {American Society for Microbiology Journals}, abstract = {Two variants of human herpesvirus 6 were identified. To assess their epidemiology and disease association, we analyzed viral isolates and/or uncultured peripheral blood mononuclear cells from 76 infants with symptomatic primary infection. In 97\% of cases, human herpesvirus 6 variant B was detected, but variant A was not.}, issn = {0095-1137}, URL = {https://jcm.asm.org/content/31/2/416}, eprint = {https://jcm.asm.org/content/31/2/416.full.pdf}, journal = {Journal of Clinical Microbiology} }
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How much does the Arbonne detox cost?
How much does the Arbonne detox cost?
Arbonne 30 Days to Healthy Living cost? The full Arbonne cleanse, 30 Days to Healthy Living Program costs $444 retail price. Most people who decide to do the program don’t actually pay this much.
Does the Arbonne 30 day cleanse work?
My skin looks so much better than it did before. I’m also using Arbonne skin care products, and I think coupled with the 30 Days, I have almost cured my rosacea. One of the best things about this was that it made my menstrual cramps go away. I have struggled with debilitating cramps since I was 10.
Can you lose weight with Arbonne?
Does it work for weight loss? Arbonne specifically states that the 30 Days to Healthy Living program is not a weight loss program, though you will likely lose weight on the diet.
How do you use Arbonne detox?
Arbonne 7 Day Detox Instructions
1. Order the Arbonne 7 Day Body Cleanse from an Arbonne consultant.
2. Take one vial of the supplement and blend it well with 32 ounces of cold water.
3. Repeat usage for seven consecutive days.
4. Follow a diet made up of mostly fruits and vegetables.
5. Exercise a minimum of 30 minutes per day.
How do you do the Arbonne 30 day cleanse?
58 second clip suggested5:25What A Sample Day Looks Like in Arbonne’s 30 Days To Healthy …YouTubeStart of suggested clipEnd of suggested clipYou can also put it into your morning smoothie. But that’s the very first step. Next you’ll haveMoreYou can also put it into your morning smoothie. But that’s the very first step. Next you’ll have your morning fistic. And detox tea so the fist sticks are loaded with vitamins B and b12.
What can you not eat on Arbonne 30 day cleanse?
Avoid the following as these are foods that generally not beneficial for overall wellbeing:
• Artificial sweeteners (e.g. sucralose, aspartame)
• Alcohol.
• Coffee.
• Dairy.
• Wheat and gluten-containing foods.
• Soy (however, fermented soy such as organic, non GMO tempeh is an acceptable vegan protein option)
How much weight do you lose on Arbonne 30 day cleanse?
The Arbonne detox is really about getting healthy and to continue to live a healthy lifestyle, most people experience weight loss and a loss in inches. Some people in my group lost 15 – 20 pounds because of the drastic change in their diet but most importantly, learned to eat and live healthier!
Does Arbonne detox tea help you lose weight?
Recently, I began using Arbonne’s detox tea in the morning and evening, and after only about 2 days, I had lost almost an inch around my waist. (The weight loss was from water retention and bloating, not from fat loss.)
Can you drink Arbonne cleanse all at once?
To use the 7-day body cleanse, mix 1 packet of the cleanse with 32 ounces of water. Sip it throughout the day, and go about your normal healthy living, clean eating diet throughout the day. Do this for 7 days straight.
How to use Arbonne 7 day detox cleanse?
Those who are taking the detox thinking that an Arbonne 7 Day Cleanse is a weight loss program are only deceiving themselves. Add one serving (1fl oz) of the 7-day Body Cleanse concentrate to 32oz of water. Shake well to mix and drink throughout the day.
Is Arbonne a good nutrition line?
It is not known as a strong nutrition line but by its beauty supply. Arbonne International began operation in 1980. It produces the Arbonne 7 Day Body Cleanse and the Arbonne Weight Loss Program. These products are sold through its website, company consultants, and Amazon.
Can you take Arbonne detox while pregnant or nursing?
Pregnant women or nursing mothers must seek their doctor’s advice before taking any detox because of the harmful effect it has on them. According to BusinessforHome.org, In December 2015, an individual sued Arbonne claiming a product from its line caused her liver damage.
Can you improve digestive health in one week with Arbonne?
Can you improve digestive health in one week? Based on the Arbonne 7 Day Cleanse ingredients and customer testimonials, yes. Some customers mentioned not losing weight, but we noted that it’s not a weight-loss supplement. The goal of the 7 Day Cleanse is to improve digestive health while supporting antioxidant activity.
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A study published in October 2010 in the Annals of Internal Medicine compared two groups of middle-aged people trying to lose weight and their sleep patterns. For four days, one group slept four-and-a-half hours per night, and the second slept eight-and-a-half hours per night. The members in the first group lost 60 percent more muscle and burned 55 percent less fat over the course of the study, demonstrating how sensitive the metabolism is to a lack of adequate sleep — even over a short period of time.
Exposure to the type of blue light emitted by smartphones, computers, and tablets immediately before and after dinner increased hunger and impacted glucose metabolism in people who participated in a small Northwestern University study. The study authors aren't sure of the reasons for the link, and say more research is needed -- but even if the link between blue light and appetite doesn't hold up in later studies, other research shows that limiting mealtime distractions helps control portions. Weight Loss Tips for Women Over 40
High Intensity Interval Training (HIIT) is where you exert maximum effort through quick, intense bursts of exercise followed by short recovery periods, and it’s a great way to amp up your weight loss. If you’re currently only using doing steady state cardio workouts like jogging or elliptical weight loss exercises, for example, you could benefit from incorporating HIIT workouts to your regimen. Because the intervals get your heart rate more elevated, they help you work harder, not longer. Studies show that HIIT also burns more fat than other workouts. If you’re looking to try HIIT for the first time, check out these HIIT workouts on Get Healthy U TV!
Christine Taylor is probably better known as Marcia Brady. That’s right; your 90s teen crush is now 46. But with her bouncy blonde hair and blue eyes, she is still as stunning as she ever was. The mother of two and ex-wife of Ben Stiller starred in Zoolander, The Wedding Singer and Dodgeball. She also appeared on Saved By The Bell and Arrested Development.
losing fat at 40
According to research in the American Journal of Clinical Nutrition, getting just three daily servings of whole grains reduced the risk of developing dangerous levels of blood pressure. Better yet, slating whole grains into your diet is effortless. Swap white rice for brown rice, white bread for seven-grain, and semolina pasta for the whole wheat stuff.
most effective weight loss for women over 40
If you're scratching your head wondering why your husband can lose 25 pounds in two months by making some simple lifestyle changes, here's why. “Women naturally have a higher percentage of body fat and lower muscle mass than men do,” explains Gillian Mueller Goddard, M.D., endocrinologist at Park Avenue Endocrinology & Nutrition PLLC in New York City. “Muscle is more metabolically active than fat is, it utilizes more energy in the form of calories. The average man is also just larger than the average woman, so it takes more calories to maintain a larger body mass. Between these two differences, men can consume more calories to maintain or lose weight than women can.” How I lost 50 lbs at 47 years old | My Weight Loss Journey
Spreading your meals throughout the day might keep you from getting too hungry and overeating. If so, it is a good idea. Athletes perform better when they eat more often in smaller amounts. If you are someone who has a hard time stopping once you start eating, 3 meals a day may make it easier for you to stick to an appropriate intake than lots of little snacks. Weight Loss Diet Plan for Women Over 35 (Daily Meal Plan)
Gluten-free breads and other products are fooling you with their healthy-looking labels. Studies show that gluten-free replacements of foods that normally contain the protein are not healthier than the real thing — and they’re more expensive. Often, these breads have significantly less fiber than bread made with real whole wheat. As you get older, fiber is one of the nutrients you need the most. It keeps you full and ensures that your digestion keeps moving regularly.
Sound a bit extreme? That's because it is extreme. The Master Cleanse is really more of a fast than a diet. Most people, if they stick to the plan, will lose a bit of weight, largely due to the fact that they are taking in exponentially fewer calories on this diet than they would if they were eating normally. Also probably because mixing all of those things into the same glass is more than a little disgusting. What's more? Once a dieter who has done the Master Cleanse goes back to a normal eating pattern, he or she is likely going to gain the weight right back again.
Load up on low-fat dairy: Women who consumed milk, yogurt, and cheese three to four times a day lost 70 percent more body fat than women who didn't eat dairy in a study published in the January 2003 American Society for Nutritional Sciences Journal of Nutrition. The reason: Calcium, along with other substances in dairy, actually revs up your metabolism, telling your body to burn excess fat faster, according to study author Michael Zemel, Ph.D., director of the Nutrition Institute at the University of Tennessee in Knoxville. And no, fortified o.j. won't do the trick. The best results come from dairy products instead of from other calcium-rich foods (like broccoli), calcium-fortified products (such as orange juice) or supplements. Women reap the largest fat-burning benefit when they consume three servings of dairy and 1,200 milligrams of calcium a day, Zemel's research shows.
Eating an apple each day can help prevent metabolic syndrome, a disorder associated with abdominal fat, cardiovascular disease, and diabetes. They’ll keep the doctor away and your muffin tops at bay because apples are a low-calorie, nutrient dense source of fiber, which studies have proven to be integral to reducing visceral fat. A recent study at Wake Forest Baptist Medical Center found that for every 10-gram increase in soluble fiber eaten per day, visceral fat was reduced by 3.7 percent over five years! That’s just one reason why apples are one of the Best Fruits for Fat Loss!
losing weight in your 40s and 50s
You deserve that glass of Scotch or wine, we know. But the unfortunate truth is that your body doesn’t metabolize alcohol as efficiently as you age. So, not only are you going to add on (or not be able to lose) weight because of alcohol, you also wind up looking older and sleeping worse. “[As you age] it will be increasingly difficult to get a good night’s rest with alcohol in your system and sleepless nights lead to carb and sugar cravings the next day,” says registered dietitian Martha McKittrick in 30 Foods You Should Never Eat After Age 30. Meanwhile, alcohol zaps moisture from your skin making fine lines more noticeable and speeding up your skin’s loss of elasticity.
When you’re looking to give your body a boost, you know turning to a solid weightlifting session, afternoon bike ride, even a a quick 30-minute HIIT session will get your metabolism cranked up. Metabolism is simple. It’s a series of chemical processes by which your cells produce the energy needed to sustain life—and the higher it revs, the more energy your body burns.
hard to lose weight after 50
Eat clean. Our metabolism gets damaged by the chemicals and preservatives in our foods. Things like pesticides, growth hormones, trans fats, HFCS, etc. have all been linked to obesity and have even been labeled "obesogens" within the health and wellness community. Consume your foods in their most natural form as often as possible and this will have a huge impact on your metabolism overall.
Wondering how Kim Kardashian shed her post-baby weight so quickly? Calling it the "greatest challenge" of her life, Kim lost around 25 kilos in 11 months leading up to her wedding. Featuring a diet that mainly consists of protein rich foods high in healthy fats like avocado and nuts, as well as eggs, fresh fruit and vegetables, and cheese, while eliminating the intake of carbs.
weight loss foods
Dried goji berries might be a staple of every health food store, but it’s worth looking for them a couple aisles over in the tea section. Lycium barbarum, the plant from which goji berries are harvested, is a traditional Asian therapy for diabetes and other diseases, but it also boasts a slimming effect. In a study published in the Journal of the American College of Nutrition, participants were either given a single dose of L. barbarum or a placebo after a meal. The researchers found that one hour after the dose, the goji group was burning calories at a rate 10 percent higher than the placebo group, and the effects lasted up to four hours. Bonus: Most goji teas are mixed with green tea, further boosting your calorie burn.
Back in January, Posh tweeted a picture of the cookbook Eating the Alkaline Way. "Love this healthy eating cook book!!" she enthused. Clearly, it loves her back; Beckham has maintained her signature svelte frame with a diet rich in fruits and vegetables that curtails consumption of acid-forming foods like dairy, pasta, meat and fish. The goal? To keep the body's pH balance between 7.35 and 7.45. Other famous fans of the diet book, penned by Natasha Corrett, the stepsister of Sienna Miller, include Jennifer Aniston, Kirsten Dunst and Gwyneth Paltrow.
weight gain at age 40
A circuit is when you move from one exercise to another with no break in between. Try mixing cardio into your circuit to help with weight loss. A sample circuit could be: upper body exercise, jumping jacks, lower body exercise, running in place. Try two to three circuits and hit all of your muscle groups, resting for two to three minutes before starting a new circuit. MEN OVER 40 How To Increase Testosterone And Get Rid Of Belly Fat
If there’s any kind of fat to avoid, it’s trans fats. These fatty acids have been shown to raise your bad cholesterol and lower your good cholesterol — that’s the opposite of what you want your dietary fats to do for your body. Butter and oil, on the other hand, can help reduce your cholesterol and encourage the absorption of fat-soluble nutrients.
best way to lose stomach fat woman
I’m 45 years old, I’m st my highest weight ever and extremely frustrated. I have fybormyalga and recently had brain surgery so my exercise lever is low. But I’ve been doing the slimfast shakes for the last two months, I cut my calorie intake down but I’ve only lost 6 lbs. Is slimfast even a good way to go or should I try something else. Please help I need to lose 30 lbs. Smart Cardio For Men Over 40 -- Functional Cardio Day
Guadagnino came back into the spotlight in 2018 with the reboot of MTV’s hit reality TV show Jersey Shore, called Jersey Shore Family Reunion. In the six years since the MTV show last aired, PopSugar reported in May 2018 that Guadagnino has adopted the keto diet and launched a dedicated Instagram account where he goes by @ketoguido. He recommends eating eggs, bacon, butter, steak, fatty fish, plants, and exercising a few times each week. According to a March 8, 2018, Instagram post, Guadagnino says his old way of eating had him 50 lbs heavier and looking 10 years older.
Keeping your carbs in check—especially the refined kind—can help combat age-related insulin resistance and promote steady blood sugar levels, Cederquist says. Adding more protein to your diet can also help. Not only does the nutrient help stave off age-related muscle loss, but it also helps keep your metabolism revved, because the body has to work harder to digest it than, say, a bagel, Cederquist says. How much of each nutrient you consume each time you eat matters, too. In a perfect world each meal and snack should have:
Want to see those numbers on the scale get smaller? Try adding some fish to your meal plan. Research published in Obesity reveals that adding some omega-3s to subjects’ diet helped them lose more weight, keep it off longer, and limit those nagging hunger pangs. For women over 40, omega-3-rich fish, like salmon and tuna, are a particularly good choice; studies suggest that adding them to your diet may reduce your risk of hot flashes, too. Zumba Dance - Lose Belly Fat Fast - Best Exercises For Losing Weight - Lose Weight Fast And Safe
Although it’s true that egg whites are low in calories, fat-free, and contain most of the protein found in an egg, eating the entire egg is beneficial to your metabolism. The yolk contains many metabolism-stoking nutrients, including fat-soluble vitamins, essential fatty acids and—most significantly—choline, a powerful compound that attacks the gene mechanism that triggers your body to store fat around your liver. Worried about cholesterol? New studies have found that moderate consumption of two whole eggs per day has no negative effect on a person’s lipid (fat) profile and may actually improve it.
The movie “Tully” aims to be an honest depiction of life balancing the demands of a newborn with two other children, in all of its spit-up filled, sleep deprived, utterly exhausted glory. It’s about a mom called Marlo (played by Charlize Theron) who just had her third child and is on the precipice of postpartum depression, until her brother sends a night nanny (Tully) to her rescue. 6 Muscle Gaining Mistakes (SLOW OR NO GROWTH!!)
Women in their 40s should be picky about their haircuts with due regard to the face shapes – otherwise, they may miss a nice chance to balance facial features and to get the desired rejuvenating effect. "A lot of women get hung up on long hair making their face look slimmer but a lot of the time that's not the case," says Jen Atkin. Indeed, while round face shapes do strive for slimming, narrow faces will hardly benefit from it.
I was the type of person who up until my late 30s could eat whatever I wanted and never work out and rarely gained a pound. If I wanted to “loose” weight meaning the five pounds of holiday weight I had put on all I had to do was start exercising doing some cardio and it fell off. Then all the sudden that stopped and now I am 20 pounds over weight and almost 41 years old and the only way for me to loose weight is to starve. I have been tested for medical conditions, I do not take any medications. I have been to a nutritionist, several actually. I have revamped my diet, I have done weight watchers, I hired a trainer and I work out 6 days a week. I have been told work out less you will be less hungry, did that nada. Cut carbs, cut diary, tried that too. The conclusion I have come to is that due to my small frame (I am only 5’1) I have to work out daily and not eat more than 1200 calories a day if I want to lose weight. I cannot do that, it makes me utterly miserable and angry. I had my metabolism tested via one of those breathing machines and it was so slow. Doctors will never admit that anyone should eat less than 1200 but my doctor looked at me and basically said 1200 is the maximum you can eat. I have never yo yo dieted, in fact I was never on a diet until I was 38, never needed to be. My Mom had the same exact thing happen to her. At this point I have two choices, be miserable and hungry all of the time, or be 20 pounds over weight and be happy, I chose the latter. Trying to live and eat 1200 calories a day every single day, is not reasonable and is a recipe for failure. I compare this to men who don’t want to admit that as they age they need Viagra. All of them say oh no I have sex like a 20 year old, no you don’t. And they don’t talk about their struggles with each other they just boast. For women I think we may just need to accept that extra 20 pounds that comes along with age, rather than fighting a loosing battle and being miserable.
I am 70 and I am trying to learn as much as possible about diet. Right now I am sort of Paleo, sort of Bulletproof and sort of Nutritional Ketosis. Actually I am reading Jimmy’s book “Keto Clarity,” but as of now I think it is too much fuss (checking blood sugar all the time) to get fat adapted. I eat turkey every day because I can buy gluten free slices (.30 pound slices) cooked and can just wrap them up and pack them for lunch. Do you have any substitute for that for variety that is just as fast? Something precooked. The other question has to do with 16-18 hour fasts. I usually do them for a couple days every other week and typically lose a pound a day. Do you really think someone can get into Ketosis that fast and I imagine that after I eat my turkey I am right out of it.?
It’s like butter that grows on trees. But instead of the cholesterol, trans fats, and saturated fats in real butter, avocado contains metabolism-enhancing monounsaturated fat. And that’s not all. Each creamy fruit is also packed with fiber and free-radical-killing antioxidants. Free radicals are destructive rogue oxygen molecules—natural byproducts of metabolism—that trigger various chain reactions in the body that destroy cells and DNA, causing all kinds of health problems. Antioxidants in fresh fruits and vegetables can help neutralize some free radicals, but they can’t reach the mitochondria—the base camp for the free radical army—and that’s a problem. When your mitochondria aren’t working properly, your metabolism runs less efficiently. Enter: Avocado. New research conducted in Mexico found that monounsaturated-rich oil pressed from the fruit can help mitochondria become more resilient. Researchers say the results jive with low-disease rates in Mediterranean countries where olive oil—nutritionally similar to the avocado—is a diet staple. How To Boost Your Metabolism And Burn More Fat | 3 Simple Tips
Want to tell your boss and office cubicle to shove it, but don’t know how and what to do next? Listen to this weekly podcast all about reinventing, redefining and rebranding yourself at a time in your life when you’re finally ready to — midlife! Experts share their insights on taking that first leap out of your comfort zone, and finding what you’re truly meant to be doing.
Wondering why the same tried-and-true tricks you used to lose weight back in your teens and twenties no longer work after 40? From a biological point of view, the answer is pretty simple: If we maintain the same diet and exercise habits we began in our twenties, most of us will inevitably put on some weight — and the process of losing weight becomes much more difficult in middle age. Why is this? Our body composition, dietary needs, and hormones all shift, beginning for some as early as the mid-thirties. In order to maintain a healthy weight, certain lifestyle habits must be developed to counteract those changes. Here are five things you need to know about losing weight after 40:
There appears to be a connection between estrogen and body weight regulation. With lower estrogen levels, lab animals tend to eat more and be less physically active. Levels that are too high or too low appear to lead to fat storage. And, lower estrogen levels may also slow down your metabolic rate (the speed at your body converts stored energy into working energy).
Christy Brissette, MS, RD is one of North America's top dietitians and a leading nutrition and food communications expert. She is the President of 80 Twenty Nutrition, a nutrition and food media company. Her mission is to end food confusion and dieting once and for all. Christy appears on national TV and is interviewed for international magazines, radio and websites. She empowers her clients to look and feel their best with the healing power of healthy, delicious food. She helps clients achieve results through cutting-edge, creative and fun meal plans and recipes. You can still enjoy your favourite foods and have the body of your dreams!
Research has found that people burn fewer calories when they sleep during the day and log their waking hours after the sun’s gone down. To come to this finding, researchers at the University of Colorado at Boulder studied 14 healthy adults for six days. For two days, study participants slept at night and stayed awake during the day, then they reversed their routines to mimic the schedules of night owls. When participants slept during the day, researchers found that they burned 52 to 59 fewer calories than they did while catching their Zzzs in the evening—likely because the schedule messed with their circadian rhythm, the body’s internal clock that plays a major role in metabolism function. If you have no choice but to sleep during the day, aim to cut 50-60 calories from your daily diet.
Somebody in a position of power needs to find the courage to state these things are not happening by chance, they are part of the plan to totally change the makeup of the European population. The European of the future will be a 'negroid-euro-asian' resembling North africans'.This is 'their' plan. Will we just sit and watch as our history, culture and race are eliminated?
VB6, the term popularized by food luminary Mark Bittman, encourages eating only vegan foods and meals until 6 p.m. This translates to a higher intake of fiber-rich, plant-based foods throughout the day. (Think walnut-topped oatmeal for breakfast rather than eggs and bacon.) Considering that the average American consumes only half of the daily recommended intake of fiber, that’s a win!
building muscle in your 40s
If you want to weigh less, you’ve got to eat less, right? Well, if you take in too few calories, it can cause your body to lose muscle mass, which will decrease the rate of your metabolism. Plus, when you skimp on calories, your body slows the rate at which is burns calories to conserve the fuel it’s got. “Under-fueling is just as risky as over-fueling,” explains Carolyn Brown, MS RD at Foodtrainers in Manhattan. Lisa Moskovitz, RD, CDN agrees: “In an attempt for quick, noticeable weight loss, many people wrongfully believe that eating as few calories as possible is the best solution. Not only can this lead to numerous nutritional deficiencies as the body is getting less food overall, it can actually have the opposite effect on weight loss.” Instead of cutting calories like crazy, use the simple diet and exercise hacks below that can help you slim down quickly and safely without screwing up your metabolism.
Being over 40 doesn't automatically mean that you now have to cut out certain foods to get (or stay) slim—unless you know deep down that a food is truly getting in the way of your goals. "If having a square of chocolate leads to eating an entire bag of chocolate, having a square of chocolate does not work for you," Cederquist says. (Regain control with these 6 tips to stop overeating.) How to Lose Stubborn Belly Fat After 40
When you're tossing fruit, ice and other smoothie mix-ins into your blender, take an extra second to add one more metabolism-boosting ingredient -- whey protein powder. "Whey protein increases calorie burn and fat utilization, helps the body maintain muscle, and triggers the brain to feel full," says Paul Arciero, a professor in the Health and Exercise Sciences department at Skidmore College who has studied whey's effects on the body. All types of protein rev up your metabolism -- protein has a thermogenic effect, meaning it makes your body produce more heat and, in turn, burn more calories -- but whey may be the most effective non-meat protein. A study published in the American Journal of Clinical Nutrition revealed that fat oxidation and the thermic effect was greater with whey than with soy or casein.
The movie “Tully” aims to be an honest depiction of life balancing the demands of a newborn with two other children, in all of its spit-up filled, sleep deprived, utterly exhausted glory. It’s about a mom called Marlo (played by Charlize Theron) who just had her third child and is on the precipice of postpartum depression, until her brother sends a night nanny (Tully) to her rescue. 6 Muscle Gaining Mistakes (SLOW OR NO GROWTH!!)
Remember when you were little and would try to write with different hands? Eventually, a long time ago, you probably gave up on that. But personal trainer to the stars Jay Cardiello says it can be a great weight loss trick. “It takes 15 minutes for your brain to realize that you’re full,” he explains. “To give your mind time to catch up to your mouth, simply switch your fork to non-dominate hand. It may be frustrating, but it’s a simple and unnoticeable way to curb overeating and lose weight.” Find out more of Cardiello’s and other experts’ tips with these 25 Easy (and Cheap!) Ways to Lose 5 Pounds. Quick Sweat Cardio Workout to Lose Weight & Burn Belly Fat Fast
Breakfast is the most important meal of the day, especially when you opt for eggs. Research published in the International Journal of Obesity reveals that study subjects who ate eggs for breakfast had a 61 percent greater drop in their BMI and a 34 percent greater waist measurement reduction than those who ate a similar number of calories, but from carb-rich sources. And for more great ways to look your very best, here are the 15 Men’s Haircuts That Will Make You Look Instantly Younger. How to go from “sugar burner” to “fat burner” in less than 1 week with strategic carb manipulation…
Crash diets -- those involving eating fewer than 1,200 (if you're a woman) or 1,800 (if you're a man) calories a day -- are bad for anyone hoping to quicken their metabolism. Although these diets may help you drop pounds, that comes at the expense of good nutrition. Plus, it backfires, since you can lose muscle, which in turn slows your metabolism. The final result is your body burns fewer calories and gains weight faster than before the diet. Most Effective Cardio Exercises for Women Over 40
The 36-year-old model's body is so incredible, she's logged camera time for Victoria's Secret and Sport's Illustrated Swim. And her tip for keeping her diet in check is kind of genius: She keeps her bod on display at all times. "Eating smart is all about having an awareness of your body," she explained to Women's Health in 2012. "The most obvious way to do that is by seeing it. So when you're trying to lose weight, spend more time wearing less. I don't think I could eat a plate of nachos naked—could you?"
Want to maximize your fat-burning potential after 40? Start by making sure you’re getting plenty of calcium in your diet. The results of a study conducted at the University of Tennessee, Knoxville reveal that obese women who consumed more calcium lost 11 pounds of body fat in over a 12-month period. Even better, increasing your calcium intake can help increase the strength of your bones, reducing your risk of a fall or fracture.
how to burn fat after 40
It is the intent of AMB WELLNESS PARTNERS LLC (“Sponsor") to operate products through this Website consistent with the work of Dr. Anthony Balduzzi, NMD. However, Sponsor is not a healthcare practitioner or provider. To the extent that any information is provided through this Website, it is for general informational purposes only and is not intended to constitute or substitute for (i) medical advice or counseling, (ii) the practice of medicine including but not limited to psychiatry, psychology, psychotherapy or the provision of health care diagnosis or treatment, (iii) the creation of a physician-patient or clinical relationship, or (iv) an endorsement, a recommendation or a sponsorship of any third party, product or service by the Sponsor or any of the Sponsor's related companies, agents, employees, consultants or service providers. If you have or suspect that you have a medical problem, contact your health care provider. Information and statements regarding dietary supplements available on this Website have not been evaluated by the Food and Drug Administration and are not intended to diagnose, treat, cure, or prevent any disease. FTC LEGAL DISCLAIMER: Results are atypical, and your results may vary. Testimonials are not purported to be typical results, and your weight loss, if any, may vary. Please see our full FTC Legal Disclaimer for a comprehensive disclaimer of risks of use, typical results, testimonials, & other legal items. READ FULL DISCLAIMER & TERMS. 3 Simple Steps That Shrink & Incinerate "Over 40" Belly Fat
Whether due to the night-waking of young children or hot flashes from the onset of perimenopause, middle-age is when sleep quality goes downhill for many women. Lack of sleep has long been linked to an increased risk of obesity and diabetes, because it’s harder for the body to regulate glucose leading to something called insulin resistance, which can cause weight gain. Building Muscle After 40 While Burning Fat (Dumbbell Workout)
“It’s easy to kick back at the end of a long day and open up a bottle of wine,” says Amy Shapiro, MS, RD, CDN, founder of Real Nutrition NYC. “Before you know it, you’ve had two or three glasses each night!” Wine contains 120 calories per 5 oz pour, and it’s easy to overlook those calories. That means that after a few hefty pours you’ve consumed over 400 calories — and that doesn’t include dinner. “Cut back to one 5 oz pour a day, or scale back your drinking overall by 25% and you’ll see a few pounds come off,” she says. And to blast even more fat, don’t miss these 50 Best-Ever Weight-Loss Secrets From Skinny People!
Trading in your usual snack for some almonds can help you shed weight and improve your health. Loaded with fiber and protein, almonds can help keep you feeling full for longer, and may even help you slash the stress that can lead to weight gain. Research published in Current Medical Research and Opinion also reveals that adding magnesium-rich foods, like almonds, to your diet can help reduce anxiety, lowering cortisol levels and decreasing your body’s tendency to store belly fat. Every Women Over 40 Should Do These 8 Exercises | Women Over 40 Should Do These 8 Exercise
"At age 40 to maintain your weight, that is to not gain weight, you're going to have to eat 100 calories less a day, and that has nothing to do with anything other than the natural course of aging. That means your resting metabolic rate," Madelyn Fernstrom, PhD, director of the University of Pittsburgh Medical Center Weight Management Center and associate director of the UPMC Nutrition Center in Pittsburgh, tells WebMD.
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This high-protein, very-low-carb diet created by French doctor Pierre Dukan became popular after it was reported that British royal Kate Middleton was a fan. It’s really Atkins repackaged, though. You start off by limiting yourself to meats, eggs, and nonfat dairy. You’ll lose water weight, yes, but you miss out on fiber-rich foods like beans, legumes, and whole grains.
It’s no surprise that as we age, our metabolism slows down, says Leah Kaufman, MS, RD, CDN, founder of Just for Today. Exercising in a different way or at a higher intensity may help get your metabolism back to where it once was. “Changing up your routine can increase the speed at which your body is burning calories,” she says. Try one of these Best Workouts for Weight Loss!
By the time you hit 40, you’re a veritable font of wisdom on topics as diverse as how to get over a lost love to what truly determines happiness. Ahead, we’ve gathered the top pieces of knowledge experts say women over 40 possess from a mix of lifestyle gurus and, of course, women over 40 themselves. And for more advice on aging gracefully, check out 40 Ways to Conquer Your 40s.
stomach weight loss
Getting your gut health in order is a good idea no matter what your age, but after 40, it’s essential. Improving your digestive regularity with prebiotic fiber-rich foods, like asparagus and leafy greens, may help reduce your risk of colon cancer, and can even help regulate the hormonal challenges that come along with menopause. Researchers at Tufts University School of Medicine have also found fiber effective at reducing estrogen concentrations in the bloodstream, helping you avoid the hot flashes and mood swings that can hit around mid-life.
how to build muscle in your 40s
Conclusion: I wouldn’t recommend exclusively eating smoked salmon and capers any longer than one day, as scurvy is a very real and serious affliction (you know, among other things). But if you love smoked salmon and capers and want to get your lifetime supply of Omega-3s in one fell swoop, this diet plan is for you. Just make sure you don’t have any plans to socialize during the day because it’s sort of awkward to bring a pack of smoked salmon along on, say, a date. Awkward, yes … but not unheard of. Another story for another time.
This is less of a diet and more of a lifestyle, which makes it one of the more sustainable options for long-term benefits. In essence, a plant-based diet means your meals are primarily composed of fruits, veggies, nuts, whole grains, and seeds. You can still eat meat when you’re plant-based, but it should be viewed as more of a side dish rather than the main component of your meals. My Diet and Exercise Routine! After 40!
As you age, your risk for heart diseases increases. And while spreading a teaspoon of salted butter on whole-grain toast every once in a blue isn’t detrimental to your health, loading your chicken recipes with butter and buttering your pans on the daily can. Butter contains seven grams of saturated fat per tablespoon, and using just two spoonfuls can put you over your daily limit of the fat.
Don’t have a dinner companion? Try eating in front of a mirror instead. According to a study published in the Journal of the Association for Consumer Research, people who ate in front of a mirror were more acutely aware of their poor food choices, finding them less pleasurable. And for more clever hacks, check out these 50 Genius Weight-Loss Motivation Tricks. 12 Minute Exercise "Shortcut" For Men and Women Over 40
How intense does the strength training need to be? Are push ups and squats and using hand weights during your HIIT training enough or should it be a more classic free weight workout where you do 3 reps of 12? I eat well and work out 6 days per week (get healthy u TV, running, etc) for 30-60 minutes each day. Nothing is helping my weight loss and I'm so frustrated!
how to lose weight after 55
Interval training—alternating between high-intensity bursts of movement and a moderate pace—has been shown to amp up metabolism for up to 24 hours postworkout. "You don't have to do a lot to see the benefits," says Wayne Westcott, PhD. "Aim for 15 to 25 minutes of interval training 3 or 4 days per week." If you're just getting started or have a lot of weight to lose, do walking or stationary cycling intervals, which are easier on the joints. If you want to challenge yourself, lace up your sneaks and jump rope or go for a run.
Government diet experts recommend that adults consume 45-65 percent of their calories from carbohydrates, 20-35 percent from fat, and 10-35 percent from protein. As you age, we recommend focusing on boosting protein towards the higher end of that range, and keeping carbohydrates and fat at the lower end. Shifting your macronutrients towards more protein and fiber and less carbohydrates and fat can help you control calories and stay lean. How To Lose Belly Fat | Is Menopause Really to Blame Over 50?
Christy is a spokesperson, nutrition and food writer and blogger for Huffington Post and others, a recipe developer and YouTube video producer. She is regularly interviewed by CTV National News, CBC, The Globe and Mail and many more on nutrition and health. She has her finger on the pulse of the latest nutrition and food science and trends, and synthesizes and prioritizes it just for you.
High amounts of sodium can lead to belly bloating and there’s a good chance you are already getting more sodium than you need. (Psst! Get rid of bloating, fast, with these 24 Ways to Shrink Your Belly in 24 Hours.) To cut back on salt intake, Alexandra Miller, RDN, LDN, Corporate Dietitian at Medifast says to eat fewer processed foods like bread, pizza, and condiments. “Read the Nutrition Facts label to find how much sodium is in each serving,” she says. “Very Low Sodium is 35 milligrams or less per serving; Low-Sodium is 140 milligrams or less per serving; Reduced (or less) sodium is at least 25 percent less sodium per serving than the usual sodium level.” How to Lose Weight for Men over Forty - It's 80% this...
A weight-loss diet plan when you're over 40 looks like any healthy plan, but with moderate portions that fit your calorie needs. No one diet is best; instead, certain habits help you succeed. Avoid sugary sweets, especially soda and baked treats, as well as refined grains found in white bread, pasta and rice. Your intake of alcohol, even that supposedly healthy glass of red wine, should also be limited.
Keeping a regular eating schedule could be the key to ditching those extra pounds after 40. Researchers at Hebrew University found that feeding mice high-fat foods on a regular schedule kept them leaner than when they were fed the same foods on a sporadic basis. Sticking to a consistent eating schedule can also help you fend off the hunger pangs that can prompt cravings for high-fat or sugary foods, which often get worse around menopause.
If you have one soda a day, studies show that you’re accumulating fat around your organs (visceral fat) and likely giving yourself a “soda belly”—a protruding, beer belly-like gut that’s the result of about 1.8 pounds of fat pushing out your belly. And that’s in addition to all the other harmful things we know about soda. (Diet doesn’t do you any favors.) Soda is such a concern that we’ve compiled an exclusive report that ranks every popular regular and diet soda!
stubborn weight loss after 40
That mom of three who also teaches spin class and always looks fanfreakintastic? Awesome. But that’s not attainable for everyone, which can leave you feeling frustrated that you can’t be a workout god or goddess, too. The good news: You only need 2 ½ minutes to boost your metabolism and start burning calories, too. Research printed in the journal Physiological Reports showed that people who did five 30-second bursts of max-effort cycling, followed by 4 minutes of rest, burned 200 extra calories that day and boosted their metabolism for the next 24-48 hours. It’s highly unlikely you have a stationary bike handy at your place of work, but a similar result could be achieved by running up the stairs and doing jumping jacks. And while we’re talking work, check out these 21 Ways Your Job Is Making You Fat.
best diet for 45 year old woman
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measurements of Extenze
measurements of Extenze
measurements of Extenzemeasurements of Extenze
This can cause hypersensitive responses or even unintentional impacts on your physical body. measurements of Extenze. ExtenZe declares to decrease the signs of erectile disorder as well as improve your sex-related functionality as the substances create their means via your body system. However no proof exists in favor of its own functionality. Quite the opposite is actually true. Right here’s what a few of one of the most dependable research points out regarding ExtenZe: A found that uncontrolled overuse of sildenafil, a typical component in ExtenZe in addition to prescribed ED medicines like Viagra, can easily lead to signs like seizures, amnesia, low blood sugar level, and loss of nerves function.
A 2019 research discovered that active ingredients and also hormonal agents typically located in ExtenZe could improve your risk of building gynecomastia (additionally referred to as “male boobs”) (measurements of Extenze). Several of the active ingredients in ExtenZe have actually undoubtedly been utilized as organic treatments to manage ED for centuries. Some have analysis to support them up.
Still others might even possess excess or risky negative effects if you take a lot of. Here’s a list of elements commonly located in ExtenZe as well as what they’re supposed to accomplish: Yohimbe, or even yohimbine, is actually a natural supplement made from the skin of the Pausinystalia johimbe tree and popular in traditional West African medicine for to manage male the inability to conceive. It’s presumed to be actually reliable in handling ED considering that it that commonly as well as aid create nitric oxide, which strengthen blood flow to the penis. measurements of Extenze.
measurements of Extenzemeasurements of Extenze
It can easily create unsafe side impacts if taken with Viagra. Horny goat weed has an element knowned as icariin. This blocks a chemical called protein phosphodiesterase kind 5 (PDE5) that can easily cease canals in your penis from expanding, which is actually necessary for adequate blood stream to circulate in and also produce you set up. A found some remodeling in ED along with sexy goat weed, as well as an additional research study revealed that icariin can shut out PDE5.Zinc is actually a mineral that is necessary to your diet regimen.
measurements of Extenze
measurements of Extenzemeasurements of Extenze
However located this to be correct just if you’re certainly not already obtaining enough zinc, so taking extra zinc will not have any sort of effects on your ED.Pregnenolone is a naturally occurring hormone that aids your body system bring in testosterone and a lot of various other hormonal agents – measurements of Extenze. However there’s no proof that taking supplements possesses any sort of impact on ED or even sexual function.
It is actually shown some encouraging outcomes in for managing ED – measurements of Extenze. Yet your body system will not create any additional DHEA if you take it in a supplement, as well as DHEA supplements can easily possess risky interactions with specific drugs. Biotab Nutraceuticals, which makes ExtenZe, has been actually captured up in several lawsuits related to bring in false insurance claims about what it may do.
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Asperger syndrome
(redirected from Asbergers)
Also found in: Dictionary.
Related to Asbergers: autism
Asperger syndrome
(ăs′pər-gər) or
Asperger's syndrome
(-gərz)
n.
A form of autism spectrum disorder that is less severe than other forms, characterized by difficulty with social interaction and communication and by repetitive behavior or restricted interests. No longer in clinical usage.
Asperger syndrome
Children who have autistic behavior but no problems with language.
Mentioned in: Autism
Asperger,
Hans, Austrian physician, 1844-1954.
Asperger syndrome - personality disorder characterized by insensitivity to others and speaking in a manner which is one-sided. Synonym(s): autistic psychopathy
Patient discussion about Asperger syndrome
Q. My brother has Asperger Syndrome, what should we do? Thank you for your attention! My brother has Asperger Syndrome, which is also known as very high function autism. As he has grown, he has become intelligent, and he is a fully functional boy. He plays his video games, does his homework, very social, and he is a normal boy. Yeah, he may seem a bit weird (like he may talk to himself, and be loud) but he’s fully functional. He is in the 8th grade, today my mother went to an interview for his high school future. The lady wants to put him with the autistic children!?! I want him to go to basic a class that’s the lowest and easiest level, but my mom is upset, and we are worried they won't let him....what should we do?
A. it is an uneasy problem. i understand your point of view- putting him in a regular classroom can boost his development and putting him in a special classroom can cause a retardation in development. but i also understand your mother, children can be very cruel. he can get harassed and bullied and that will cause a problem too. but you can avoid that by confronting the class before he enters it and explain the situation.
Q. What is asperger`s syndrome? what is asperger`s syndrome and how is it linked to Autistic spectrum disorder (ASD) or pervasive developmental disorder (PDD)?
A. Let me make it clear that PDD and ASD are same and autism is one of its types. Other types of PDD or ASD are asperger`s syndrome, Childhood disintegrative disorder, Rett's syndrome, Pervasive development disorder not otherwise specified (PDDNOS). They all have almost similar symptoms with some major differences so they are named differently. Like in asperger`s syndrome, it’s a milder form of autism. Here a child gets obsessive for one thing and excels in it to a good level as they don’t have delay in language and cognitive development. They do face problems in social interaction.
Q. What is the difference between Asperger's Syndrome and Autism? My 3 year old nephew has been diagnosed with Asperger's Syndrome. Is this the same as Autism?
A. Here is a video which explains about Asperger's Syndrome, which might help you understand the difference between that and autism:
http://www.5min.com/Video/What-is-Asperger-Syndrome-6213
More discussions about Asperger syndrome
References in periodicals archive ?
Asbergers doesn't disappear as you grow up, but adults can usually adapt and have fewer problems.
He suffers from a condition called Asberger's Syndrome, or AS.
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Tuberculosis: The Long Pandemic
In late 2012, a Nepalese man began a three month-journey, on foot, by car and boat, and in an airplane, through South Asia, Brazil and Mexico, and into Texas. He brought with him an infection called XDR-TB, short for extensively drug resistant tuberculosis, a disease still relatively rare in the US, but one that public health officials fear because it is spreading across the world. We have become complacent about TB because it has been successfully treated with antibiotics since the 1950s and because most tuberculosis cases occur in underdeveloped countries where malnourished and sick people with weakened immune systems live in crowded and unsanitary conditions. But with easy global travel and spreading antibiotic resistance, especially on the Eastern border of Europe and in Africa, China and India, more awareness of this ancient disease is needed again in areas of the world where improved living conditions have made TB uncommon and unknown.
A long history
Three-thousand-year-old writings from China and India, passages in the Old Testament, and the writings of Hippocrates all describe the affliction we call tuberculosis. The disease became a scourge as more and more people crowded into urban centers in northern climates in the middle ages. Between the 1500s and 1800s, hundreds of millions of people in Western Europe, England and the eastern US died of TB, then called consumption and attributed either to a “malignant miasma” in the air or to hereditary constitutional weakness. Squalid living conditions, poor indoor ventilation and malnutrition common during the early industrial revolution facilitated the spread of the disease, which in 1882 was finally proven to be caused by a bacterium, Mycobacterium tuberculosis. When living conditions began to improve in the early 1800s the death rate began to decline, but a cure awaited the development of antibiotics in the mid-twentieth century. The goal of eradicating TB, however, has not been achieved.
Latent vs active infections? The immune system decides.
Anyone can be infected with the TB bacteria, acquired by inhaling the respiratory droplets of someone who has an active infection in their lungs. Inhaled TB bacteria are captured by cells that scour the airways for invaders. The bacteria reproduce themselves inside those cells, eventually killing them and exciting an immune response that in 90% of people will clean up the infected area, called a “tubercle,” in a process called caseating necrosis because the dead tissue resembles crumbled cheese. The tubercles may leave small scars in the lung, visible on chest X-ray, without ever having caused any symptoms of illness. Infection in these immuno-competent people, the vast majority, is called latent TB, a condition that affects almost a third of the world’s population, including 13 million people in the US.
In 10 % of people who get infected with the TB bacteria, the immune response is insufficient. Active tuberculosis is the result. Caseating tubercles may grow to large size and collapse producing cavities in the lung. Tubercles that erupt into the airways allow surviving bacteria to spread to other people in sputum and respiratory droplets. In addition, bacteria may travel to other parts of the body via the lymphatic system, setting up infectious nodes in almost any tissue. Typical symptoms of active tuberculosis develop over weeks to months and include chronic cough, night sweats and fever, weight loss, weakness, fatigue, and skin pallor. Tubercles in various organs and lymph nodes give rise to local symptoms from swelling and inflammation.
Latent infections come alive
Latent TB can reactivate and become active TB if the carrier’s immune system weakens – a result of other disease such as HIV, drug treatment that suppresses the immune system, or just deterioration of health that accompanies drug use or poor living conditions. Ten million cases of active infection occur each worldwide year.
Before antibiotics: high altitude and collapsing lungs
In the 1840s a botany student who suffered from TB traveled to the Himalaya mountains and came home to report his cure, setting in motion the sanatorium treatment for which high altitude locations such as Davos Switzerland and Denver, Colorado became renowned. Much later, scientific work showed that the mycobacterium tuberculosis grows poorly at low oxygen pressures, a fact that may well have added to the other health and nutritional benefits of sanatorium life. Attempts to put infected parts of lungs “to rest” by collapsing them with injections of nitrogen into the chest began in the 1880s. German Author Thomas Mann memorialized this procedure, called an artificial pneumothorax, in his novel The Magic Mountain. The treatment method continued well into the 1940s, when the development of antibiotics finally offered a cure for TB.
Not the usual antibiotic treatment
Antibiotic treatment of TB is not easy. Patients must take two to four drugs on a strict schedule for 6-9 months and tolerate some unpleasant side effects like nausea. Until their sputum is free of TB bacteria – which can take several weeks – they must be strictly isolated. Caretakers benefit from proper mask wearing because the tuberculosis bacteria is larger than N95 mask pores. Because drug resistance has been a result of poor compliance with the drug regimens, strict monitoring and observation of patients is necessary. Often drugs must be taken under direct observation. Once drug resistant disease occurs, treatment becomes more complicated and prolonged, requiring trials of different antibiotics, with even more need for isolation of infectious patients and close supervision throughout the entire course of treatment.
Testing and vaccines
A tuberculin skin test, when positive, indicates prior infection with tuberculosis bacteria, and therefore latent disease in someone who has no symptoms. Chest X-ray and chest CT, as well as collection of sputum for microscopic analysis and culture are the mainstays of diagnosis in active disease or if someone with a positive skin test has any suspicious symptoms.
The only vaccine for TB, used since 1921, is made from a weakened bacterium similar to the TB bacterium. Its acronym BCG is short for the virus name (Bacille Calmette Guerin). BCG reliably prevents neonatal disseminated forms of TB such as meningitis, but is much less effective in preventing the adult respiratory form of TB, which is the usual version beyond childhood. It has not been regularly administered in the US because most people handle primary infections easily. However the spread of drug resistant forms of TB may change that recommendation, especially for people regularly exposed to patients. In the meantime, work on new vaccines employing new technologies continues.
Drug resistance is spreading
TB was on the decline in the US until the 1980s, when HIV disease appeared, devastating the immune systems of its sufferers and making them susceptible to active TB. With better treatment of HIV, TB is on the decline again, but popping up increasingly in the homeless population, particularly where they congregate indoors in crowded shelters. Recently, cases of drug resistant TB have occurred in people who had never been treated, meaning that the drug resistant bacteria are spreading, not just evolving in treated patients. In eastern Europe 30% of new TB cases are now resistant to many of the TB drugs. The traveler who appeared in Texas with XDR-TB was a warning. We need robust public health measures to monitor infectious diseases, improve sanitation and living conditions as much as we need development of new antibiotics.
Respond to Tuberculosis: The Long Pandemic
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Idiopathisches multiples Pigmentsarkom der Haut
@article{Kaposi2005IdiopathischesMP,
title={Idiopathisches multiples Pigmentsarkom der Haut},
author={Kaposi},
journal={Archiv f{\"u}r Dermatologie und Syphilis},
year={2005},
volume={4},
pages={265-273}
}
• Kaposi
• Published 1 June 1872
• Medicine
• Archiv für Dermatologie und Syphilis
Humanized Mice as a Model to Study Human Viral Pathogenesis and Novel Antiviral Drugs
TLDR
It is shown that these mice sustain long term engraftment and systemic expansion of human cells, including the major targets of Kaposi’s sarcoma Herpesvirus (KSHV) and Human immunodeficiency virus type 1 (HIV-1), in peripheral blood and different lymphoid organs.
Utilising omics approaches to understand Kaposi's sarcoma-associated herpesvirus
TLDR
Light is shed on previously unidentified mechanisms employed by KSHV to hijack the host cell, and may aid in the development of novel therapeutics against this important pathogen.
Characterisation of the interactions between the KSHV ORF57 protein and the human TREX complex
TLDR
A series of compounds are presented that are able to prevent both KSHV and HSV-1 lytic replication, and a hit compound identified was shown to disrupt formation of the vRNP, lytic protein expression and infectious virions, while allowing endogenous hTREX formation within a therapeutic window, where no cytotoxicity was observed.
Identification of novel tumor predisposition families and underlying genetic defects
TLDR
A registry based familial clustering of cancers in Finland based on STAT4 as a candidate susceptibility gene for Kaposi sarcoma and the results show that STAT4 activation is not affected by p.Thr446Ile mutation.
KSHV: pathways to tumorigenesis and persistent infection.
Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma
Whole-exome sequencing reveals a homozygous splice-site mutation in the gene encoding STIM1 in a child with classic Kaposi sarcoma.
Case Report: Successful Treatment of Kaposi’s Sarcoma With Anlotinib in an HIV-Negative Patient After the Treatment of Drug Reaction With Eosinophilia and Systemic Symptoms Accessory Tragus
TLDR
This case indicates that anlotinib may be a potential treatment option for Kaposi’s Sarcoma, a neoplasm derived from endothelial cells and associated with human herpesvirus-8 (HHV-8) infection, in an 84-year-old man with a history of psoriasis.
Molecular Mechanisms of Kaposi Sarcoma Development
TLDR
Kaposi’s sarcoma-associated herpes virus (KSHV) is the underlying cause of this disease and impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines.
Vascular Tumors
...
...
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Entity
Time filter
Source Type
San Fedele Superiore, Italy
Testa U.,Oncology and Molecular Medicine
Journal of Cellular Biochemistry
Defects in apoptosis are observed in many cancer cell types and contribute in a relevant way to tumorigenesis. Apoptosis is a complex and well-regulated cell death program that plays a key role in the control of cell homeostasis, particularly at the level of the hematopoietic system. Apoptosis can be initiated through two different mechanisms involving either activation of the death receptors (extrinsic pathway) or activation of a mitochondrial apoptotic process (intrinsic pathway). Among the various death receptors a peculiar role is played by TNF-related apoptosis-inducing ligand (TRAIL)-receptors (TRAIL-Rs) and their ligand TRAIL. TRAIL recently received considerable interest for its potent anti-tumor killing activity, sparing normal cells. Here, we will review the expression and the abnormalities of TRAIL/TRAIL-R system in hematologic malignancies. The large majority of primary hematologic tumors are resistant to TRAIL-mediated apoptosis, basically due to the activation of anti-apoptotic signaling pathway (such as NF-kB), overexpression of anti-apoptotic proteins (such as FLIP, Bcl-2, XIAP) or expression of TRAIL decoy receptors or reduced TRAIL-R1/-R2 expression. Strategies have been developed to bypass this TRAIL resistance and are based on the combination of TRAIL with chemotherapy or radiotherapy, or with proteasome or histone deacetylase or NF-κB inhibitors. The agents used in combination with TRAIL either enhance TRAIL-R1/-R2 expression or decrease expression of anti-apoptotic proteins (c-FLIP, XIAP, Bcl-2). Many of these combinatorial therapies hold promise for future developments in treatment of hematologic malignancies. © 2010 Wiley-Liss, Inc. Source
Zeuner A.,Oncology and Molecular Medicine
Cell Death and Differentiation
Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.Cell Death and Differentiation advance online publication, 18 July 2014; doi:10.1038/cdd.2014.105. Source
Bonci D.,Oncology and Molecular Medicine
Recent Patents on Cardiovascular Drug Discovery
MicroRNAs (miRNAs) are a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of miRNAs has been described in various disease states including cancer and cardiac disease. A particular miRNA that was consistently reported to be upregulated in both cancer and various forms of cardiovascular diseases is miR-21. MiR-21 exerts oncogenic activity and therefore is considered as an oncomir. In the cardiovascular system miR-21 is enriched in fibroblasts and contributes to the development of fibrosis and heart failure. MiR-21 therefore emerges as an interesting candidate for the development of therapeutic strategies against many forms of cancer as well as heart diseases. Indeed, treatment with anti-miR-21 oligonucleotides reduced breast cancer growth. Inhibition of miR-21 by synthetic miRNA antagonists (antagomirs) improved heart function in a cardiac disease model. The same beneficial effects were observed in miR-21 knockout mice subjected to pressure-overload of the left ventricle underlining the key role of miR-21 as a therapeutic target. We here overview the current patent situation about the therapeutic use of miR-21 modulation in cancer and cardiovascular disease. © 2010 Bentham Science Publishers Ltd. Source
Among strategies aimed at developing new nanoparticle-based vaccines, exosomes hold much promise. They are nanovesicles released by basically all eukaryotic cell types originating from intraluminal vesicles which accumulate in multivesicular bodies. Exosomes have immunogenic properties whose strength correlates with the amounts of associated antigens. Engineering antigens to target them in exosomes represents the last frontier in terms of nanoparticle-based vaccines. Here we report a new method to incorporate protein antigens in exosomes relying on the unique properties of a mutant of the HIV-1 Nef protein, Nefmut. This is a biologically inactive mutant we found incorporating into exosomes at high levels also when fused at its C-terminus with foreign proteins. We compared both biochemical and antigenic properties of Nefmut exosomes with those of previously characterized Nefmut -based lentiviral virus-like particles (VLPs). We found that exosomes incorporate Nefmut and fusion protein derivatives with similar efficiency of VLPs. When an envelope fusion protein was associated with both exosomes and VLPs to favor cross-presentation of associated antigens, Nefmut and its derivatives incorporated in exosomes were cross-presented at levels at least similar to what observed when the antigens were delivered by engineered VLPs. This occurred despite exosomes entered target cells with an apparent lower efficiency than VLPs. The unique properties of HIV-1 Nefmut in terms of exosome incorporation efficiency, carrier of foreign antigens, and lack of anti-cellular effects open the way toward the development of a flexible, safe, cost-effective exosome-based CD8+ T cell vaccine platform. © 2012 Elsevier Ltd. Source
Testa U.,Oncology and Molecular Medicine
Annals of Hematology
Leukemia-initiating cells (LICs) or leukemia stem cells (LSCs) are defined by their ability to form tumors after xenotransplantation in immunodeficient mice and appear to be rare in most human leukemias. In various leukemias, only small subpopulations of cells can transfer disease upon transplantation into immunocompromised NOD/SCID mice, and markers that distinguish the leukemogenic cancer cells from the bulk populations of non-leukemogenic cells have been identified. However, the phenotype of LICs is heterogeneous: it is variable for the different types of acute myeloid leukemias; cells with different membrane phenotype can act as LICs in each B-acute lymphoid leukemia; LICs change during the evolution of chronic myeloid leukemia from the chronic to the acute phase. There is a general consensus that the identification and characterization of leukemic stem cells might lead to the identification of new therapeutic targets and, through this way, to more effective treatments by focusing therapy on the most malignant cells. © Springer-Verlag 2010. Source
Discover hidden collaborations
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[Skip to Content]
Children's Health System - Alabama (iFrame)
Children's of Alabama
Healthcare as amazing as their potential
www.childrensal.org
1600 7th Avenue South
Birmingham, AL 35233
(205) 638 - 9100
Kidney Stones
What Are Kidney Stones?
Kidney stones happen when minerals form crystals inside the kidneys. Then they get bigger and become kidney stones. Kidney stones can move into the urinary tract. There, they can cause problems like pain and blood in the urine (pee). Some stones also can block the flow of pee.
Most kidney stones pass out of the body without causing any damage. Pain medicine and plenty of fluids help most kids with kidney stones get better.
What Are the Signs & Symptoms of Kidney Stones?
Usually, kidney stones don't cause symptoms until they move around in the kidney or pass into the ureter (the muscular tube that connects the kidney to the bladder). Small stones can pass out of the body with little or no pain.
Larger stones in the urinary system may get stuck and cause symptoms like:
• pain, which usually:
• starts in the side or back
• spreads to the lower belly and groin as the stones move through the urinary tract
• comes and goes in waves
• blood in the pee (hematuria)
• nausea and vomiting
• needing to pee often or urgently
• fever or chills (signs of a possible infection)
Sometimes, a stone that's too big to move can create a backup of pee. This can make one or both kidneys swell, causing pain in the side and back. If it's not treated, it may cause long-term kidney damage.
What Causes Kidney Stones?
Most kids who get kidney stones have a health condition that increases their risk for them. These include:
• some medicines
• special diets, like a ketogenic diet that is sometimes used to prevent seizures
• diabetes
• obesity
• problems with how the urinary tract is formed
• metabolic disorders (problems with how the body breaks down and uses food)
• gout (a type of arthritis)
• other kidney conditions
• conditions that affect the thyroid or parathyroid gland
• some urinary tract infections (UTIs)
Other things that can make a kidney stone more likely are:
• not drinking enough water
• eating too much salt
• not having enough citric acid (the acid in citrus fruits such as oranges) in the urine
• having too much calcium in the urine
Kidney stones mostly affect adults. But kids and teens can get them.
Some types of kidney stones run in families, so having a relative with kidney stones can make a person more likely to get them. Kids who have had kidney stones before are more likely to get them again.
How Are Kidney Stones Diagnosed?
The doctor will ask about:
• the symptoms and how long they've been going on
• your child's diet
• whether your child could be dehydrated
• whether there's a family history of kidney stones, or urinary or kidney problems
The doctor will do an exam and probably order:
• blood tests
• urine tests
• kidney function tests
• imaging tests, such as ultrasounds, X-rays, or CT scans. These can show a stone's exact size and location. This helps doctors decide on the best treatment.
How Are Kidney Stones Treated?
Treatment depends on the type of kidney stone and its size. Some kids only need to drink a lot of water and take pain medicines to pass a kidney stone. Those with larger stones may need surgery or other treatments to help remove the stones.
There are different types of stones. A stone that passes in pee and is caught in a strainer can be tested to see what type it is. Knowing that can help doctors find the cause and offer advice how to treat it and prevent other stones.
Home Treatment
To help pass a small stone, give your child plenty of water to drink and medicine to ease the pain. Often, over-the-counter medicines such as ibuprofen and acetaminophen are enough. But sometimes, doctors prescribe pain medicine.
The doctor might ask you to strain your child's pee for a few days to collect the kidney stones. Examining them can help the doctor decide if your child needs more treatment.
Hospital Treatment
Kids whose kidney stones block the urinary tract or cause severe pain or dehydration may need care in a hospital. They might get intravenous (IV) fluids and pain medicine to help the stones pass and treat dehydration.
Large stones rarely pass on their own. To get rid of large stones and stones that are damaging the kidneys, doctors can do a procedure to break up the stone. This lets the smaller pieces pass on their own or be removed with a scope or surgery.
Can Kidney Stones Be Prevented?
It's not always possible to prevent some types of kidney stones.
But all kids who've had kidney stones should:
• Drink a lot of liquids (water is best) throughout the day. Avoid dark sodas, soft drinks, and sports drinks. If their pee is almost clear, that's a sign they're drinking enough. Ask your doctor how much your child should drink.
• Limit the salt and protein in their diet.
If dietary changes don't prevent kidney stones, medicines can help. Depending on the type of kidney stone your child had, the doctor can prescribe treatments or medicines to lower the levels of crystal-forming substances in the pee.
Doctors will keep an eye on kids who have had kidney stones and try to prevent new ones. The doctor might have your child use a 24-hour urine collection test. This measures the volume of pee within a 24-hour period and checks what's in it.
Reviewed by: Robert S. Mathias, MD
Date reviewed: November 2019
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W8MD Diet | COVID-19 portal | Vitamin D | Vaccine | Keto
WikiMD is the world's largest medical encyclopedia with
13,998 pages, 4,159,038 edits & 43,363,369 views.
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ATC code N04
From WikiMD's free health, diet & wellness encyclopedia
Jump to navigation Jump to search
ATC codes
N Nervous system
N01 Anesthetics
N02 Analgesics
N03 Antiepileptics
N04 Anti-parkinson drugs
N05 Psycholeptics
N06 Psychoanaleptics
N07 Other nervous system drugs
ATCvet only
QN51 Products for animal euthanasia
A B C D G H QI J L M N P R S V
(Hover over links to see titles)
ATC code N04 Anti-parkinson drugs is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products.[1][2] Subgroup N04 is part of the anatomical group N Nervous system.[3]
Codes for veterinary use (ATCvet codes) can be created by placing the letter Q in front of the human ATC code: for example, QN04.[4]
National issues of the ATC classification may include additional codes not present in this list, which follows the WHO version.
N04A Anticholinergic agents
N04AA Tertiary amines
N04AA01 Trihexyphenidyl
N04AA02 Biperiden
N04AA03 Metixene
N04AA04 Procyclidine
N04AA05 Profenamine
N04AA08 Dexetimide
N04AA09 Phenglutarimide
N04AA10 Mazaticol
N04AA11 Bornaprine
N04AA12 Tropatepine
N04AB Ethers chemically close to antihistamines
N04AB01 Etanautine
N04AB02 Orphenadrine (chloride)
N04AC Ethers of tropine or tropine derivatives
N04AC01 Benzatropine
N04AC30 Etybenzatropine
N04B Dopaminergic agents
N04BA Dopa and dopa derivatives
N04BA01 Levodopa
N04BA02 Levodopa and decarboxylase inhibitor
N04BA03 Levodopa, decarboxylase inhibitor and COMT inhibitor
N04BA04 Melevodopa
N04BA05 Melevodopa and decarboxylase inhibitor
N04BA06 Etilevodopa and decarboxylase inhibitor
N04BB Adamantane derivatives
N04BB01 Amantadine
N04BC Dopamine agonists
N04BC01 Bromocriptine
N04BC02 Pergolide
N04BC03 Dihydroergocryptine mesylate
N04BC04 Ropinirole
N04BC05 Pramipexole
N04BC06 Cabergoline
N04BC07 Apomorphine
N04BC08 Piribedil
N04BC09 Rotigotine
N04BD Monoamine oxidase B inhibitors
N04BD01 Selegiline
N04BD02 Rasagiline
N04BD03 Safinamide
N04BX Other dopaminergic agents
N04BX01 Tolcapone
N04BX02 Entacapone
N04BX03 Budipine
N04BX04 Opicapone
References
ATC code N04 is part of WikiMD's free ^articles!
^ATC code N04 (article) is provided for informational purposes only. No expressed or implied warranties as to the validity of content.
WikiMD is not a substitute for professional advice. By accessing and using WikiMD you agree to the terms of use.
Templates etc. when imported from Wikipedia, are licensed under CC BY-SA 3.0. See full disclaimers.
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What is it?
Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare conditions that impair the body’s metabolism from breaking down certain fats from food into energy.
What causes it?
The body typically uses glucose (sugar) for energy, but also gets energy from fat when it uses up available glucose. People with fatty acid oxidation disorders (FAOD) cannot efficiently use fat for energy.
What are some of the common symptoms?
• Muscle cell rupture
• Low blood sugar
• Muscle weakness
• Decreased muscle tone
• Disease of the heart muscle
How many people have it?
It is estimated that 2,000 to 3,500 people are living with LC-FAOD in the U.S.1
Most common types of long-chain FAOD
• Carnitine Palmitoyltransferase (CPT I or CPT II) Deficiency
• Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency
• Long-chain 3-hydroxy-acyl-CoA Dehydrogenase (LCHAD) Deficiency
• Trifunctional Protein (TFP) Deficiency
1Ultragenyx Pharmaceutical Inc. Data on file. 2019.
*These organizations are an incomplete listing of rare disease support organizations and are not controlled by, endorsed by, or affiliated with Ultragenyx Pharmaceutical Inc. The list is meant for informational purposes only and is not intended to replace your healthcare professional’s medical advice. Ask your doctor or nurse any questions you may have about your disease or treatment plan. If you would like to have your group added to the list, please contact [email protected].
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5eff3d1f6f98e57329caed0ceb9053d3
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7,024,508,534,679,022,000
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Rss
The Ultimate Guide To Bring Back Balance In To Your Life
As we are growing up, all we want to be is happy because we would not have had many responsibilities as a child. But once we have already grown up and reached adulthood, we know that life is just not easy to combat. Problems might come your way all the time, you may have to go to work every single day, you have to balance personal and social lives and all the while, you also have to make time for yourself as well. This is almost impossible to do and it can make the balance we once had, get out of our grasp. The minute we lose the balance that kept us going, it becomes a little harder to function. We would suffer from stress, from physical problems like pains and aches and we would not even be happy anymore. This is why you have to try and gain that balance back because it is what helps you stay healthy and happy for the rest of your life.
What is right for you?
The main thing you have to remember is that there is no right thing that you can do. Each human being is different and special, so you have to try and find what is best for you. While some people might find their balance through activities like yoga, others might lean more towards something more different like a good remedial massage Preston. Naturopathy, yoga, osteopathy and more are all different ways to help your body, mind and soul so it is up to you to find what is most appropriate.
Professional help would be necessary
Something that many people fail to realize is how valuable professional help is. We live in the world of technology and the internet, which means we can find anything we want at the click of a button. However, even though it is easy to begin something like yoga on our own, we are not going to get any better without help. For treatments like naturopathy, only a trained specialist is going to know exactly what your body is in need of. So you can look for naturopathy Preston and make sure that you find the best professional health clinic to help you.
Do some research
A lot of the time we have a tendency to believe that we cannot do something without knowing all the details. If you are someone who is pregnant and wants to try out alternate treatment methods, you can do so and to start, you would need to do some research first! A little research can be a massive help.
Comments are closed.
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5eff3d1f6f98e57329caed0ceb9053d3
|
-4,061,856,693,123,325,000
|
Contact The Staff
By Phone
The fastest and easiest way to schedule your appointment for Functional Medicine or Chiropractic with the doctor is to contact our Boulder, Colorado office at (303) 447-2225.
Our staff will promptly schedule you with a convenient time to see the doctor. Please don't delay as the majority of health conditions tend to worsen or recur without the appropriate care.
Online
Booking online is easy. Just choose your preferred date and time. If it's available, we'll send you a confirmation! If your preferred time is already booked, we'll send you our next closest availability to see if it works for you.
Sincerely,
Wolfe Chiropractic and Functional Medicine
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|
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5eff3d1f6f98e57329caed0ceb9053d3
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-4,353,024,472,692,433,000
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19 Jan
Is it possible to whiten your teeth with a tooth paste?
There is a wide variety of tooth pastes nowadays that promise miracles. But is that something you can rely on? The fact is that you cannot get that same effect as the teeth whitening procedure but there are some tooth pastes that can help you remove coffee and smoking stains. If you use it regularly you may achieve some effect, but that won’t be enough – that is a fact. So, if you are interested in whitening your teeth there is no better at this than Dr. Waldman Dentistry Toronto. There are hundreds of different dentist but you need to choose the one that corresponds with your financial situation. Before you hire someone make sure you ask about the price.
The whitening tooth pastes that we use contain chemicals that polish and clean the teeth from stains. These pastes are good for your oral health but they won’t give you the effect that you desire. The best effect can be achieved only by vising a dentist.
There are certain tooth pastes that have the so called blue pigment that fights against yellow teeth. These chemicals will make the teeth visually whiter but that is not a permanent solution. They may cause an illusion that the teeth are white, but they are not.
The treatments with these tooth pastes should be used at least twice a day. But be careful not to use it more than two times because these pastes are not like the regular paste we use. It is not recommended to use it more than two times. So make sure you follow all the instructions given by the dentist and to now wait to have an immediate effect. This takes time, it all takes time.
Not that it is a dangerous product, in fact it is a safe product to us. The real fact here is that if you don’t take a good care of your teeth no one else will. You will end up having so many problems that you will become disappointed.
If you already used a whitening paste before, you will notice that it cannot change the original, real color of your teeth. These are some of the things you need to know about tooth paste. If you are determined to buy this kind of paste, make sure you are careful with it and follow all the instructions. If you are not very satisfied with the effects of this usage, you can always ask your dentist for a recommendation. If you want to achieve perfectly white teeth, then you must perform this procedure for a few times. There are some brands that claim that their formula will give you white teeth immediately. These are just some empty promises that no one else will take them seriously. You need to understand when you want to achieve something so badly, you need to follow the instruction and you will see the positive results very soon.
|
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5eff3d1f6f98e57329caed0ceb9053d3
|
563,949,163,391,771,700
|
Is RBM20 a Promising Target for HFpEF Therapy?
2019-03-03T18:12:05Z (GMT) by Wei Guo Andrea R Sanchez Walk
Heart Failure (HF) is a major public health issue with an estimated prevalence of over 37.7 million individuals worldwide [1], and remains the leading cause of morbidity, mortality, and hospitalization among adults and elderly [2,3]. In the USA, the total medical costs for patients with HF are expected to rise from US$20.9 billion in 2012 to $53.1 billion by 2030 [1]. About half of the patients with heart failure display preserved ejection fraction in contrast to the other half that present contractile dysfunction and a dilated heart (HF with reduced ejection fraction, HFrEF) [4,5]. Prototypical manifestations of heart failure with preserved ejection fraction (HFpEF), previously known as diastolic dysfunction, include increase in passive stiffness, insufficient recoil, and decrease in full relaxation [6]. Anaggregation of severalcontributors such as hypertension, metabolic syndrome, obesity and diabetes mellitus have been associated with the development of HFpEF [6]. Despite significant therapeutic improvements in the treatment of virtually all cardiac disorders, HF is an exception, in that its prevalence is rising, and its morbidity and mortality remain unacceptably high [7,8]. Currently, no effective therapies are available for HFpEF, at least with regard to major clinical events. Therefore, novel insights into pathophysiology and molecular mechanisms of HFpEF progression are required to develop novel therapeutic approaches.
|
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5eff3d1f6f98e57329caed0ceb9053d3
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2,027,676,525,142,784,800
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Yum Korea In Florida
keto
The Reality About Low Carbohydrate Diets
Low carbohydrate diets are extremely effective in attaining weight reduction when followed. However the keyword there is that they should be followed. Nevertheless, there are debates about their healthiness. Absolutely, individuals enter into these diet plans to reduce weight. However what every person entering this is not only the aspect of losing weight however likewise as always, keeping the weight off. It goes beyond that. It also involves being and remaining healthy and practical in whatever we do daily. A slim individual is certainly not appealing if she or he is weak from absence of nutrients and energy due to these low carb diet plans. The body uses up carbs first as a source of energy. If there are more carbs taken in, the body stores the surplus as fat. If there are fewer carbs taken it, the body is forced to use the stored fat for its energy requirement. The concept of these low carb diets is to take in food low in carbs so that the body is required to utilize its saved fat. By drastically decreasing carbs to a small fraction of an individual's diet plan, the body enters into ketosis. The body burns its own fat to convert into energy A person in ketosis is getting energy from ketones. Ketones are little carbon fragments that are created by the breakdown of saved fat. One feels less starving when his or her body remains in ketosis. Completion result is that he or she is most likely to consume less even if allowed to do so. In effect, the body is changed from a carbohydrate-burning machine into a fat-burning one, therefore making fat the primary energy source. This brings us to the most basic truth of dieting: the less fat you have, the lighter you weigh. The end result is the desired weight-loss. There are diets like Atkins that seem to be a dream become a reality. It originates from its style that a person might consume as much as she or he wants from a variety of food that other diet plans guide far from. Steaks, meat, crab, eggs, all types of protein based food are permitted considering that the body will burn carbohydrates initially and not protein or fats. Essentially, it follows the same low carb principle of decreasing carb intake and requiring the body to utilize fat towards weight loss. However professionals are worried about the long term security of the diet. By modern medical requirements, the threat of heart problem, stroke, cancer, liver and kidney issues are really incredibly high. These threats have been pointed out repeated by a variety of health researches on high fat diet plans. Other low carb diet plans are cleansing in nature such as the detox diet plan. It assists in the health reassessment of one's way of life, consuming patterns and focus on foods. Here, one becomes more knowledgeable about one's food consumption. However, there are individuals, such as diabetics, people with low blood sugar or consuming disorders have to stay clear of it. They will find themselves more in trouble than they are currently. Low carb diet plans serve their purpose. There is no replacement for the conventional, proven healthy lifestyle of a balance diet of the standard food groups in the nutritionists' pyramid order integrated with the appropriate exercise. Must an individual still go through with these diets for whatever reason, he or she should be geared up with understanding of not just the advantages but many especially the dangers. Everybody desires that slim, healthy appearance. Everybody needs to likewise go for health in a sustainable way.
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5eff3d1f6f98e57329caed0ceb9053d3
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3,576,224,920,760,877,600
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The inventor of the microscope, Anton van Leeuwenhoek, reported in 1694 that mites live in dust. Now, more than 300 years later, it is an established fact that dust mites can be found in house dust all over the world. Dust mites are not insects but are more closely related to spiders and ticks. There are two common dust mites, the American house dust mite (Dermatophagoides farinae) and the European house dust mite (D. pteronyssinus). Due to their very small size, thesdust mitee dust mites are not visible to the naked eye. They live in bedding, couches, carpet, stuffed toys and old clothing. Dust mites feed on the dead skin that falls off the bodies of humans and animals and on other organic material found where they live.
Though these mites live in many homes, only people who are allergic to them know they are there. Dust mites are second only to pollen in causing allergic reactions. When dust mites grow, they shed their skin. The shed skin and feces are what cause allergic reactions in people. Allergic reactions range from itchy noses and eyes to severe asthma attacks.
Habits and Habitats
Dust mites do not live in air ducts in homes. Many people spend much time and money cleaning the air ducts to reduce dust mites. There are a number of good reasons to keep ducts clean, but this is not one of them because dust mites need about 70 percent relative humidity or higher to live, and they need food. Areas where people spend much time, like a bed or a favorite plush chair, are prime sites for dust mites. The top part of mattresses containing fibrous material is a favorite place for dust mites during warm and humid times. The deeper parts of mattresses may provide protected areas for the dust mites during unfavorable conditions. Clothing is used by dust mites as a means of transportation from room to room or even from house to house.
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5eff3d1f6f98e57329caed0ceb9053d3
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9,054,171,047,506,782,000
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22 May
Hay fever - Causes, Symptoms , Treatments
Contents:
1. Pollinoz children
2. pollen allergens during hay fever
3. treatment of hay fever
Hay fever is a seasonal allergic disease, which manifests itself inwind-pollinated flowering plants.Often, it is worsening in the warm season, during the flowering shrubs, trees and plants, which is due to hit in the air a huge number of pollen.When inhaled, it enters the mucous human and can cause severe reactions in people prone to allergies.
Hay fever allergies manifested by symptoms:
• bad cold and the difficulty of nasal breathing during certain flowering plants;
• frequent sneezing;
• itching and burning sensation in the nose;
• tearing and swelling of the eyes;
• itching, feeling cramps and a feeling of "grains of sand" in the eyes;
• shortness of breath, cough;
• swelling of the nasal mucosa;
• itching and skin rashes;
• asthma attacks in some cases.
Symptoms usually repeated over a long period in the same time of year, and may last from two weeks to five months.Self-healing does not hap
pen often, and marked only a partial reduction of allergy cases without conducting therapy.
With bouts of the disease each year are becoming longer and more severe.Danger pollinosis as allergies is that without proper treatment, it may develop into bronchial asthma.
Thus, hay fever may manifest as allergic rhinitis, conjunctivitis, atopic dermatitis, and have serious consequences for the patient in the form of asthma.In addition, the hallmark of hay fever is consistently recurring seasonal displays, which coincides with the dusting the plants on which man reacts to pollen.
Pollinoz children
Clinical hay fever symptoms can occur at any age, but most often it appears in children from 3 to 10 years.Quite often, the symptoms of hay fever in children are observed in cases of genetic predisposition, when the parents also suffer from this disease (atopy phenomenon).In addition, boys suffer more girls.
common symptoms of hay fever in children are:
• alllergichesky rhinitis;
• allergic conjunctivitis;
• rinokonyunktivalny syndrome.
Allergic rhinitis is manifested frequent sneezing, itching, profuse nasal discharge and congestion.These symptoms may vary in severity.
Allergic conjunctivitis is characterized by itching and burning in the eyes, redness of the eyelids and lacrimation, photophobia, pain in the brow.In severe cases there may be blepharospasm, keratitis, erosion along the limb.
Rinokonyunktivalny syndrome includes symptoms of both diseases, and may be accompanied by loss of appetite, fatigue, sweating, insomnia, tearfulness.In severe cases of hay fever in children can develop asthma, which is characterized by attacks of breathlessness, cough, labored wheezing, feeling of pressure in the chest.
The disease in children can also occur in the form of urticaria and angioedema.And in severe hay fever in children and the massive concentration of pollen in the air, observed:
• cardiovascular changes (tachycardia, hypertension);
• irregularities in the digestive system (nausea, epigastric pain, unstable chair);
• changes in the nervous system (headache, fatigue, sleep disturbance, increased body temperature).
pollen allergens during hay fever
seasonal exacerbation of hay fever due to certain life cycle of flowering plants.Therefore, if every year, at one and the same time, the patient develops symptoms of hay fever (eg, runny nose, itchy eyes, sneezing, watery eyes), then the most likely reason - it is pollen, blooming at this time.
On Earth, there are several thousand species of plants, but only fifty cause pollinosis.Each climatic region is characterized by the predominance of its plant species are able to cause allergic reactions.In our band of the most common allergens are:
• weed pollens (ragweed, wormwood);
• tree pollen (birch, alder, poplar);
• pollen (chamomile, dandelion, sunflower);
• some pollen grains (rye, bluegrass, ryegrass).
Most patients with hay fever allergy occurs only on certain types of plants and trees pollen.Therefore pollinosis accounted only for the duration of flowering, and the symptoms depend on the individual sensitivity, as well as on the amount of pollen in the air.
When an allergic reaction to one of the plants there is a high probability that the same reaction occurs and at other plants of the same family.Some patients are allergic to 2-3 formed a group of plants.If hay fever is an actual problem of cross-reactivity of patients to other allergens that are found in foods of plant origin.For example, a person who is allergic to birch pollen may observe similar manifestations in the use of hazelnut, potatoes, pears, peaches, celery, and other foods.
If an allergic reaction to pollen, you must be wary of herbal medicine, as well as the breeding of indoor plants.Moreover, each year, the number of significant increases allergens and allergies to them - are amplified.Therefore, the earlier a patient to see a specialist, the better the chance to stop and to facilitate the development of the disease.
treatment of hay fever
hay fever diagnosis based on the presence of typical manifestations of allergic rhinitis, eye lesions, skin changes in the spring and summer season, asthma attacks, as well as their seasonal repetition.
During exacerbation in the peripheral blood, mucus cytogram nose, and sputum bronchial asthma manifests eosinophilia, indicating the presence of an allergy.And in the period of remission of hay fever are the main method of diagnosis allergological skin samples.
treatment of hay fever involves:
• an elimination event;
• diet therapy;
• drug therapy;
• specific immunotherapy.
an elimination event signify the termination or reduction of exposure to allergens that cause hay fever began.
Diet therapy involves exclusion from the diet of honey and a number of products (cross-reactive foods).
Drug treatment of hay fever include basic anti-inflammatory drugs, antagonists of H1 histamine receptors, and symptomatic agents.
Specific immunotherapy is conducting vaccinations against allergies.This method of treatment is carried out in the autumn-winter period and assumes a gradual "habituation" of the body to allergens by introducing them in small doses.Treatment pollinosis manner achieves and maintain a positive result for several years.
addition to the treatment of hay fever, allocate more physiotherapy treatment, as well as extracorporeal blood purification technique, which allows you to clean up the internal environment of substances that are involved and support the pathological processes in the body.
Attention!
This article is available exclusively in the educational purposes and is not research material or professional medical advice.
make an appointment to see a doctor
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5eff3d1f6f98e57329caed0ceb9053d3
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2,306,171,858,973,524,000
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Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders
NADPH-cytochrome P450 reductase
POR gene encodes a co-enzyme od steroidogenesis. It helps the endoplasmatic enzymes CYP21A2 and CYP17A1. Mutations cause autosomal recessive Antley-Bixler syndrome with genital anomalies.
Genetests:
Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA
Research Method Genomic sequencing of the entire coding region
Turnaround 25 days
Specimen type genomic DNA
Research Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 25 days
Specimen type genomic DNA
Related Diseases:
Antley-Bixler syndrome 1
POR
Disordered steroidogenesis due to POR deficiency
POR
References:
1.
Hershkovitz E et al. (2008) Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency.
[^]
2.
Biason-Lauber A et al. (1997) A single amino acid substitution in the putative redox partner-binding site of P450c17 as cause of isolated 17,20-lyase deficiency.
[^]
3.
Reardon W et al. (2000) Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?
[^]
4.
Shen AL et al. (2002) Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase.
[^]
5.
Kelley RI et al. (2002) Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia.
[^]
6.
Otto DM et al. (2003) Identification of novel roles of the cytochrome p450 system in early embryogenesis: effects on vasculogenesis and retinoic Acid homeostasis.
[^]
7.
Hurley ME et al. (2004) Antley-Bixler syndrome with radioulnar synostosis.
[^]
8.
Flück CE et al. (2004) Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.
[^]
9.
Huang N et al. (2005) Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
[^]
10.
Peterson RE et al. (1985) Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia.
[^]
11.
Arlt W et al. (2004) Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study.
[^]
12.
Shephard EA et al. (1989) Isolation of a human cytochrome P-450 reductase cDNA clone and localization of the corresponding gene to chromosome 7q11.2.
[^]
13.
None (1986) Congenital adrenal hyperplasia.
[^]
14.
Fukami M et al. (2005) Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients.
[^]
15.
Adachi M et al. (2006) POR R457H is a global founder mutation causing Antley-Bixler syndrome with autosomal recessive trait.
[^]
16.
NCBI article
NCBI 5447 [^]
17.
OMIM.ORG article
Omim 124015 [^]
18.
Orphanet article
Orphanet ID 117944 [^]
19.
Wikipedia article
Wikipedia EN (Cytochrome_P450_reductase) [^]
Update: April 29, 2019
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• GENERAL RESEARCH
The Heart-Brain Connection
Your heart and brain are more than just hard-working, neighboring organs. These two arms of the body have a close connection that directly influences one another – and studies show that what’s good for your heart, is good for your brain too (and vice versa!).
skin cells and mitochondria
The connection between the heart and the brain is more than just physical, it's essential for our overall well-being.
• The heart pumps oxygen-rich blood to the brain, providing it with the nutrients it needs to function optimally. This steady flow is crucial for clear thinking and emotional stability.
• The autonomic nervous system regulates both your heart rate and cognitive function. There are two branches of the ANS – the sympathetic nervous system, which alarms the body’s ‘fight-or-flight' state, and the parasympathetic nervous system, which helps us relax and recover. These two systems of the ANS work together, influencing both the heart and the brain and impacting your overall health.
• Your emotions can influence your heart rate and therefore your heart rate variability (HRV), and changes in HRV can reflect shifts in cognitive states.
• Your emotions can influence a physiological reaction, such as heart palpitations or sweating in response to what’s happening in your external environment. In reverse, any changes in HRV can indicate changes in cognitive function and long-term emotional regulation.
The intricate interplay between these two arms of the body can give us crucial insights into our health and longevity.
Factors to Watch
When it comes to heart health and cognitive function, there's an overlap in the factors that can impact our well-being.
• Hypertension, or high blood pressure, puts a strain on the cardiovascular system and interferes with the blood flow to the brain.
• High cholesterol can also restrict the flow of blood to the brain and impair cognitive function as a result.
• Oxidative stress is another important factor that can impact the function of the blood vessels and brain if left unchecked.
Lifestyle Strategies for Heart and Brain Health
Follow a Mediterranean style diet
Rich in fruits, vegetables, nuts, seeds, and healthy fats like liver oil – the Mediterranean diet has become one of the most widely studied diets to support cardiovascular health and cognitive function. Promoting an abundance of antioxidants and anti-inflammatory compounds from whole food sources, the Mediterranean diet has been shown to protect both the heart and brain from oxidative stress. Fatty fish is also a staple in the diet, providing plenty of omega-3 fatty acids to support the brain and cardiovascular system.
By reducing processed foods and adding more whole foods and healthy fats to your plate, you’ll be on your way to providing your cardiovascular system and your brain with the building blocks required to function optimally.
Address stress
Unwanted stress can have a profound effect on both the heart and the brain. When the body is under stress, it releases hormones like cortisol and adrenaline, which increase both heart rate and blood pressure. Over time, these physiological changes can contribute to the development of cardiovascular complications.
In the brain, ongoing elevated stress can shrink the hippocampus – a part of the brain involved in memory and learning, while simultaneously contributing a hyperactive amygdala – a part of the brain that responds to fear and stress. This may contribute to impaired cognitive function, poor memory, concentration and decision-making.
Managing stress is an effective tool to maintain the health of both the brain and the heart to support your overall well-being. From introducing relaxation practices like deep breathing or meditation, to engaging in regular exercise and setting lifestyle boundaries to promote a sense of work-life balance. Self-care tools that support your mental and emotional well-being will ultimately help to improve the way your body functions at a physiological level.
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Sleep Quality
Getting enough quality sleep is essential for heart health and cognitive function. The body undergoes crucial processes during sleep, including the repair of tissues, regulation of hormones and so much more. Research shows that disrupted sleep may lead to heart health complications, and that poor sleep may increase the risk of cardiovascular complications including high blood pressure – which has been shown to contribute to cognitive decline.
Creating a consistent sleep schedule and unwinding with a relaxing bedtime routine can help signal to your body that it’s time to turn in. Some easy ways to influence your circadian rhythm and help your body adjust to a new bedtime routine is to exposure yourself to sunlight when you first wake up in the morning and avoid screen time thirty minutes to an hour before bed. Try to wait at least one hour after waking before having your first cup of coffee. This will make sure the caffeine doesn’t interfere with your cortisol signaling and you get the biggest bang for your buck energy-wise. Sleep expert from UC Berkeley Dr. Matthew Walker recommends avoiding caffeine 12-14 hours before sleep, but everybody is different. Having your last cup of coffee for the day around 8-10 hours before you plan on sleeping sounds like a reasonable compromise for the average adult.
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Candidates for Scleral and Semi-Scleral Lenses
People with irregular cornea have trouble getting regular lenses. This is because most contact lenses only cover the eye’s pupil. Scleral lenses are designed to fit over the entire cornea. They provide a smooth surface over the corneal irregularity. This helps to improve the function of the cornea. Scleral contact lenses are gas permeable. They offer better comfort and function than normal lenses. The size of the lenses is determined by the complexity of the eye condition. Here are some of the people that can be helped to see better by using scleral lenses.
Patients With an Irregular Shaped Cornea
A normal cornea is shaped like a tiny dome. Some patients have a cornea that is more of a cone than a dome. Others have groves and irregular depressions on their cornea. Such people have a difficult time fitting into regular lenses. Scleral lenses have a design that vaults over the cornea and land on to the sclera.
Patients With Dry Eye
Dry eye disease is becoming very common. Changes in the weather, as well as lifestyle, are causing many people to have dry eyes. Dry eye affects the eye’s tear film. If the tear-field dries too fast, the eye lacks enough lubrication. GP lenses do not rehydrate the eye. Regular GP contact lenses irritate the eye and make dry eye even more severe over time. Scleral lenses have a gap between the eye and the lens that facilitates enough lubrication for the eye.
Patients Suffering From Ocular Conditions
Systemic ocular conditions can make it hard for patients to use regular lenses. Scleral lenses protect the ocular surface. Inflammation and problems caused by ocular disease make the eye sensitive. Scleral lenses protect the ocular surface from exposure to the elements. They create a liquid layer that acts as a cushion for the pupils.
Patients With Refractive Error
Patients with refractive error conditions benefit from scleral lenses. GP lenses provide a sharp vision, which is good for patients with refractive errors. If the shape of the retina is compromised, scleral lenses can fix the quality of vision for the patient.
Patients With Astigmatism
Patients with astigmatism have a hard time fitting into regular lenses. If your cornea is misshapen, then normal lenses are not for you. If your retina is misshapen, then you may not be a good candidate for normal soft lenses. Soft lenses are unstable for astigmatism patients. They cause unstable fluctuations that worsen the patient’s vision. Patients with lenticular astigmatism especially cannot use soft contact lenses. The scleral GP lenses trap a liquid underneath the lens. This is good for astigmatic patients.
Does Insurance Pay for Scleral Lenses?
Medical insurance is very tricky when it comes to eye care. Most of them are very restrictive on how they cover eye care services. A good vision insurance cover should pay for all the expenses. Some pay for the initial installation, but not for the follow-up and aftercare. It is good to consult with your health care insurance provider before making an appointment.
For more information on scleral lenses, visit Centennial Family Eyecare at our offices in Las Vegas, Nevada. You can also call (702) 941-7800 to book an appointment.
Best
Optometrists
in Las Vegas
2016
admin 9650 Skye Canyon Drive, Ste 140
Las Vegas, NV 89166 7028032020
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Relief From Sciatica
Sciatica Pain Relief
Relief From Sciatica - Sciatica Pain Relief
The term "sciatica" refers to pain along a specific nerve - frog sciatic nerve, which runs from your lower back down through each leg. It usually caused by a wayward vertebral disc, more commonly referred to as a pinched nerve or a herniated, ruptured, or slipped disc that has shifted from it's normal position in the vertebral column and is putting pressure on the radicular nerve (nerve root), which connects to the sciatic nerve diagram club.
At-home remedies such as heat and ice packs davenport university alleviate pain and reduce inflammation. They should be used in twenty minute intervals every couple of hours for optimum effect. Over-the-counter or prescription medications such as acetaminophen (Tylenol) may also bring sciatica pain relief. Non-steroidal anti-inflammatory drugs (NSAIDs) can be particularly helpful in reducing inflammation, but can have painful side effects.
If pain persists for two to three months and the aforementioned treatments have not worked, surgery may be the most effective solution. Sufferers and their doctors must choose between two surgical procedures performed to relieved treatment of sciatica. These surgeries are elective and effective, relieving 75% to 95% of patients' pain.
Sciatica treatment chiropractic care ease the painful information on sciatica pain causes work as correctives to prevent future recurrences of the condition by helping to strengthen and tone the lower back. We have taken the privilege of proclaiming this article to be a very informative and interesting article on Sciatica. We now give you the liberty to proclaim it too.
The intensity and duration of the pain varies with each person, and ranges from an infrequent and slightly irritating sensation to a constant, debilitating pain. It normally affects the lower back and one leg only, but pain may also extend to the feet and toes. Typical "flare-ups" last two weeks to a few months. During these episodes, sufferers have several options for sciatica leg pain exercises. Ischias: sciatic nerve or sciatica was written with the intention of making it very memorable to its reader. Only then is an article considered to have reached it's objective.
If pain is severe, a patient may receive an epidural steroid injection. Steroids are injected directly into the painful area around the nerve and greatly reduce inflammation and pain. These injections are temporary and provide sciatic nerve cushion anywhere from one week to a year. It is not necessary that only the learned can write about Sciatica. As long as one ahs a flair for writing, and an interest for gaining information on Sciatica, anyone can write about it.
I wanted to talk to you about sciatic nerve cushion support relieve back pain. Most people would say that back pain is probably about the worst pain that you could ever experience. It's not like a paper cut that effects a tiny fraction of your body. Back pain is an electrical storm of pain that travels across your back. It's crippling in a way because any little movement could lead to it. You could be reaching into your refrigerator and you feel the sharp pains spread throughout the back. It's a rough time and being able to get easy relief is important. This is why I wanted to share with you sciatica how can magnetic therapy relieve sciatica? pain.
The sciatica exercises that relieve back pain are really easy. The first one involves you laying on your back and pulling your knees up to your chest, giving them a hug. The idea here is to stretch out the lower back, which rarely ever gets a stretch. The other exercise is grabbing onto something above you and allowing it to stretch out your upper body. It's sort of like hanging on the monkey bars. We wish to stress on the importance and a guide to exercises forum sciatica through this article. This is because we see the need of propagating its necessity and importance!
Essentially what is happening is that there is some nerve or nerves are getting irritated. A common reason is due to your spinal discs. They're supposed to hold onto liquid and slowly compress throughout the day. If you have a burst disc or one that is too low, your vertebrae will actually grind together and most likely on a nerve. You can also experience the pain of sciatica when a tight muscle compresses on a nerve. The idea of the exercises is to help get the stress off the nerves and get rid of the pain.
Sadly one of the most common sciatic neuralgia symptoms experienced by an estimated 8 out of 10 people, chronic low back pain may be caused by a range of diseases (inc. obesity) and disorders affecting the lumbar spine. Low back pain is often accompanied by sciatica, a disabling pain from an entangled sciatic nerve, which is typically felt in the thighs as well as lower back and buttocks.
Persons self image and their self-esteem depends almost entirely on how other people perceive them, or perhaps how other people perceive them. It is very hard to totally ignore the criticism and not care about the opinions of others. With excess weight, of course, the more you weight the harder it will get. People will stare at you no matter where you go, not to mention that snickering and jokes are a real way of helping to lower your self-esteem.
In some obese patients, the spine can become tilted and suffer additional stress. Over time, this can deprive the back of proper support and an unnatural curvature of the spine may develop. Ignorance is bliss they say. However, do you find this practical when you read so much about Sciatica?
Unfortunately this can often led to a self destructive circle leading people to become depressed and complacent with their weight which can lead to more weight gain. Obese people may stop going out doors, therefore they receive less exercise, which leads to weight gain, which lead to less exercise and so forth. This low self-esteem has the ability to manifest itself in a way that makes it increasingly difficult for a person to motivate himself or herself in order to make an improvement in their life. Make the best use of life by learning and reading as much as possible. read about things unknown, and more about things known, like about Sciatica.
Relationships can be very difficult for obese people to enjoy when they are overweight. Sex can be become awkward with couples becoming self-conscious about their bodies. The extra weight in the bedroom can make performing very difficult and excessive sweating is probably not the sexiest thing either. If they don't already have a partner it can be difficult for obese people to find a lover. The fact that they do not go out to social events as often as they should coupled with their low self esteem often results in many people giving up. life is short. Use it to its maximum by utilizing whatever knowledge it offers for knowledge is important for all walks of life. Even the crooks have to be intelligent!
Becoming obese is the easiest part but now you have to lose those pounds and this is the hard part. It will be a struggle at first, but you need to stay strong, the health, social and emotional benefits of the new you will be unbelievable. A life of less food and more exercise sounds scary to a lot of people but it doesn't have to be, if you make sure you have good support it will be easier to achieve this goal. Just think how good you will feel when you look into the mirror and walk down the street with your new body and new confidence.
Food addiction can be a very difficult thing to overcome; when someone who eats a lot first cuts back the body can have withdrawal symptoms from sugars and fats, often leading to depression. The extra support around for this week or two can make a world of difference. Whenever one reads any reading matter, it is vital that the person enjoys reading it. One should grasp the meaning of the matter, only then can it be considered that the reading is complete.
If you want to deal with your obesity problem you need to motivate yourself. But even then motivation may not be enough, outside support is mandatory. Other people helping you can make the difference between succeeding and failing; these people also often stop you from eating that extra food you should be avoiding. Thinking of life how to treat sciatica nerve pain to be impossible to imagine. Sciatica treatment cause of sciatica can be applied in all situations of life.
People, who are overweight, or worse obese, face many consequences, which have the ability to become a daily nightmare. For some it is their lifestyle choices, which has led them to become obese, others perhaps have gathered the extra weight through no fault of their own. Just as a book shouldn't be judged by its cover, we wish you read this entire article on Sciatica pain relief ? natural lower back pain relief burning limbs: the truth about sciatica.
To live this overweight and obese life can be difficult, people have to face every new day with the fear of prejudice from others making it hard to live in the world which demands perfection and looks down upon them. It's a sad reality that many people have to face, a reality, which comes at a great personal cost. We have tried to place the best definition about Sciatic pain relief article. This has taken a lot of time, but we only wish that the definition we gave suits your needs.
Recent studies by (Fishman L., Ardman C. Back Pain: How to Relieve Low Back pain relief using the drx9000) explains how obese patients may incur sciatica medicine back pain from a herniated or "slipped" disc. Art institute of houston pain in the lumbo-sacral spine occurs when discs and other spinal structures are damaged from having to adjust to the pressure of extra weight on the back. In addition, when excessive weight is pushed into spaces between bones in the low back area, the patient can experience compressed nerves and even piriformis syndrome. (Deep Pain in Your Buttocks) Whenever one reads any reading matter likeSciatica, it is vital that the person enjoys reading it. One should grasp the meaning of the matter, only then can it be considered that its reading is complete.
At least 80% of us will experience some form of Back Pain in our lives and more than 1 in 4 people will become clinically obese in their lifetime, don't let it be you! Sciatica proved to be the foundation for the writing of this page. We have used all facts and definitions of Sciatica to produce worthwhile reading material for you.
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I was reading that when you are pregnant, the cervix softens up and if it gets bumped, say from sex, it can bleed a little pinkish blood.
2015-07-15 21:08:45
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Related Questions
Could you be pregnant if after your period you started to experience brownish pink discharge?
A brownish pinkish discharge is not a normal indication of pregnancy.
Could you be pregnant if you are 10 days late for your period but have had pinkish spotting for four days?
pink spotting is a pregnancy sign you could be well pregnant its called Implantation bleeding
Could you be pregnant if you have been feeling tired bloated getting headaches and just started pinkish spotting but period is not due for 2 weeks?
Possibly. Take a pregnancy test if you miss your period
If a home pregnancy test is positive but you started could it be wrong?
It depends on the blood if it was a heavy long period then you probably arent, but if it was a light brown/pinkish blood then it might be implantation blood meaning you are pregnant
Could you be pregnant if it has been 38 days since the first day of your last period and you have pinkish brown spotting but no other symptoms or could you have an infection?
It could be pregnancy if your period is late. Do a test.
Is it normal to spot pinkish red blood and mucus at 6 weeks?
If you are spotting pinkish red blood and mucus at 6 weeks pregnant, this could be normal. However, you will want to see a doctor to ensure that the pregnancy is still viable.
Are you pregnant if you had 3 positive pregnancy tests and started bleeding and then had one negative test?
It could have been a chemical pregnancy, when your body thinks it is pregnant but the embryo did not fully implant.
What does it mean when you get pinkish brown spotting and does it mean you could be pregnant?
Yes it means you could be pregnant if sexually active or you have a water infection.
Could you be pregnant if you started your period before sex?
You can get pregnant anytime you have sex. Sex during a period makes pregnancy very unlikely.
Could you be pregnant if you're spotting pinkish stuff and have missed your period?
Yes you could. Take a test.
Could you still be pregnant if you had your last period?
If you've had a regular period, you are not pregnant. Don't confuse this with spotting which is a pinkish fluid that lightly "spots" in a pantyliner throughout the day. Spotting could possibly mean a pregnancy, or it just might mean your period is coming. To know for sure, have a pregnancy test done either with a home version or from the doctor.
You started your period five days early could you be pregnant?
If you are having a period, you are not pregnant. However many women confuse their periods with vaginal bleeding and vaginal bleeding can be a sign of pregnancy particularly in early pregnancy.
If you have taken two pregnancy tests and both said you were not pregnant but you still havent started your period could you be pregnant?
Yes. You might require an actual blood test to see if you are pregnant.
If you are spotting and its pinkish is that a bad sign?
It could be a sign of pregnancy, or another issue. Best to consult with your physician.
Have had pinkish discharge for 3 days passed one red blood clot have had negative pregnancy test results could this be an early sign of implantation bleeding and of pregnancy?
That is either a menstrual cycle or a miscarraige. You are definitely not pregnant and if so, something isn't right.
You have all the pregnancy symptoms and no period but the home pregnancy test was negative Could I be pregnant?
Well, since you have had ALL the pregnancy symptoms and no period, you could be pregnant! But since your home pregnancy test was negative you couldn't be pregnant. You may want to go to your doctor and ask him if you are pregnant.
You missed your period last month but started this month could you still be pregnant?
Typically, if you have your period, you are not pregnant. To be sure, buy a home pregnancy test from your local pharmacy.
Period late tummy sore breasts sore could you be pregnant?
You very well could be pregnant. Get a pregnancy test if your suspect pregnancy.
Could you be pregnant if there was pinkish spotting on the day your period is due On the next day pinkish red spotting but not enough for a pad no cramping but sore breast and headaches?
That sound like your pregnant I had that same sign take a test
If you took a pregnancy test and it was positive and then a week later a pregnancy test was negative could you have been pregnant and had a miscarriage?
If you started to bleed soon after, then there is a possibility that you could of had a miscarriage. Pregnancy tests are not always acurrate though and that could of been the problem. If it was a miscarriage then I would go and see the docter, because you should get cleaned out nad the docter will tell you if you really were pregnant or not.
What are the chances of you being pregnant if you have had no symptoms of pregnancy but has not started period?
If you have had sex you could be pregnant, but this is not the place to find out so go seek professional help, or get a proper pregnany test.
You had your period but you have pregnancy symptoms are you pregnant?
you could be. get a pregnancy test and check it out for sure.
You have taken two negative pregnancy tests and your period started but was 2 weeks late but could you still be pregnant?
With two negative pregnancy test and a period that'd be extremely unlikely.
Could you be pregnant if you got your period two weeks early and now having pregnancy symptoms and cramping?
Hiya! Yes you could be pregnant. Do a pregnancy test.
I have pregnancy symptoms like tender breast exhaustion frequent urination and nausea but I got a light period when i was supposed to and the pregnancy test was negative could i be pregnant?
It is possible that you could be pregnant. The "light period" could have been implantation bleeding, which occurs when the fertilized egg implants on the wall of the uterus. Implantation bleeding is usually brown or pinkish in color, and it is often like a very light period. The best thing to do would be to take another pregnancy test in a few days.
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Like most things in life (OK, like all things in life), the flu shot is not a silver bullet. Although the vaccine protects against the flu strains you’re most likely to get exposed to, it’s still possible to get sick—especially within the first two weeks after getting the shot. Your body needs time to build up the antibodies required to fight off infection, so the sooner you get the shot, the better. In the meantime, take care to avoid exposure to the flu as much as you can by steering clear of sick friends and washing your hands regularly.
MORE: Can You Get Sick After a Flu Shot?
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Ask a doctor
Veneers to Fix Teeth or Braces? (photo)
Can Veenering Fix my Outwards and Rotated Lateral Incisor?I Consulted Few Doctors,some Say It Can N Other Recommend Braces.Help!
Doctor Answers 5
Veneers or Braces
Based on the photo, I would absolutely recommend moving the teeth over cutting them down to place veneers. You would have to remove alot of tooth structure to correct the smile with veneers and will likely need root canal treatment on one or two teeth.
Ontario Cosmetic Dentist
Veneers for rotated teeth
In the situation like yours the best approach will be orthodontic treatment. It will give aesthetic, stable, long-term results, protecting the gums and teeth.
Olga Kharevich, DMD, PhD (in memoriam)
Miami Cosmetic Dentist
5.0 out of 5 stars 30 reviews
Veneers to Fix Teeth or Braces?
Doing braces will be the best more conservative approach for you. If you want a smile makeover with Veneers there are chances of other procedures needed. I know you are thinking, braces will take a long time and its uncomfortable, but you will surprise with the latest technology available now a days, orthodontist have great tools and techniques. Also they do not have to look ugly, they have porcelain brackets that makes you feel confident about yor smile. Remember, most of orthodontist consultation are free and they will go over all your options, cost and lenght of treatment.
Pamela Marzban, DDS
Fairfax Cosmetic Dentist
You might also like...
Braces are always best long term
With braces you can keep your teeth more intact. After braces you may not need anything or you may need minor bonding or worst case scenario, conservative venneers.
If you do not get braces (or Invisalign), then the teeth would require agressive grinding to correct the rotation and misalignment. This may require the need to do a root canal. The teeth will be weaker and this is irreversible. When they need to be redone, you may end up with crowns and eventually you may run out of tooth structure.
Doing braces will also level out any other teeth and give you a more stable bite that will reduce tooth wear, chipping, etc. And everything will look better, including the laterals than if you only did venneers.
Good luck
Dr. T
Mauricio C. Tijerino, DMD
Miami Beach Cosmetic Dentist
Veneer or Orthodontics to Solve Protruding Incisor
The tooth certainly could be restored. The downside of doing a veneer is that significant tooth structure would have to be removed to get it back into alignment and could possibly damage the nerve. Orthodontics could also resolve the problem. If you have other concerns with your smile or bite, having those corrected along with the one tooth would be an additional benefit. If its just the one tooth you are concerned about and do not want to go through the process and time orthodontics would involve, then do the veneeer.
Donald L. Wilcox, DDS
Glendale Cosmetic Dentist
5.0 out of 5 stars 5 reviews
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.
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Video_3_The Use of Live Cell Imaging and Automated Image Analysis to Assist With Determining Optimal Parameters for Angiogenic Assay in vitro.MP4 (706.9 kB)
Video_3_The Use of Live Cell Imaging and Automated Image Analysis to Assist With Determining Optimal Parameters for Angiogenic Assay in vitro.MP4
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posted on 10.04.2019, 04:30 by Brooke M. Huuskes, Ryan J. DeBuque, Peter G. Kerr, Chrishan S. Samuel, Sharon D. Ricardo
Testing angiogenic potential and function of cells in culture is important for the understanding of the mechanisms that can modulate angiogenesis, especially when discovering novel anti- or pro-angiogenic therapeutics. Commonly used angiogenic assays include tube formation, proliferation, migration, and wound healing, and although well-characterized, it is important that methodology is standardized and reproducible. Human endothelial progenitor cells (EPCs) are critical for post-natal vascular homeostasis and can be isolated from human peripheral blood. Endothelial colony forming cells (ECFCs) are a subset of EPCs and are of interest as a possible therapeutic target for hypoxic diseases such as kidney disease, as they have a high angiogenic potential. However, once ECFCs are identified in culture, the exact timing of passaging has not been well-described and the optimal conditions to perform angiogenic assays such as seeding density, growth media (GM) concentrations and end-points of these assays is widely varied in the literature. Here, we describe the process of isolating, culturing and passaging ECFCs from patients with end-stage renal disease (ESRD), aided by image analysis. We further describe optimal conditions, for human bladder endothelial cells (hBECs), challenged in angiogenic assays and confirm that cell density is a limiting factor in accurately detecting angiogenic parameters. Furthermore, we show that GM along is enough to alter the angiogenic potential of cells, seeded at the same density. Lastly, we report on the success of human ECFCs in angiogenic assays and describe the benefits of live-cell imaging combined with time-lapse microscopy for this type of investigation.
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Quick Answer: What Is Special About Blood Type O Positive?
Which blood group is best for human?
Type O negative red blood cells are considered the safest to give to anyone in a life-threatening emergency or when there’s a limited supply of the exact matching blood type.
That’s because type O negative blood cells don’t have antibodies to A, B or Rh antigens..
Can your blood type change?
Usually, you will have the same blood type all of your life. However, in some cases, the blood types have changed. This has been due to unusual circumstances, such as having a bone marrow transplant or getting certain types of cancers or infections. Not all of the changes in blood type are permanent.
Is coffee bad for O blood type?
Beverages. People with type O blood should avoid drinking the following, according to the diet plan: beer. coffee.
Is it hard to get pregnant with O positive blood?
Women with blood type O may struggle to conceive, they said, due to a lower egg count and poorer egg quality, according to a study. Women with blood group A seem to be better protected against falling egg counts. The finding could prompt experts to look more closely at a woman’s blood group when charting her fertility.
What is the best blood type to have?
According to Northwestern Medicine, studies show that: People with type O blood have the lowest risk of heart disease while people with B and AB have the highest.
What foods should O positive blood types avoid?
Those with type O blood should choose high-protein foods and eat lots of meat, vegetables, fish, and fruit but limit grains, beans, and legumes. To lose weight, seafood, kelp, red meat, broccoli, spinach, and olive oil are best; wheat, corn, and dairy are to be avoided.
Can O+ and O have a baby?
That means each child of these parents has a 1 in 8 chance to have a baby with an O- blood type. Each of their kids will also have a 3 in 8 chance of having A+, a 3 in 8 chance of being O+, and a 1 in 8 chance for being A-. An A+ parent and an O+ parent can definitely have an O- child.
How do you get O blood type?
Everyone has an ABO blood type (A, B, AB, or O) and an Rh factor (positive or negative). Just like eye or hair color, our blood type is inherited from our parents. Each biological parent donates one of two ABO genes to their child. The A and B genes are dominant and the O gene is recessive.
What is RZRZ blood type?
Alice’s blood type is O positive, but that’s just part of her blood’s story. Red blood cells carry markers on their surface called antigens. These antigens are what determine a donor’s blood type.
Which blood group should not marry?
People with Rh compound are termed as Rh positive and people without the Rh compound are known as Rh negative. According to Dr Gita Prakash, it is very important that couples get their Rh checked before getting married or having a child, as it can raise complications in the baby.
What blood type can Rejects pregnancy?
Blood types are categorized by A, B, and O, and given an Rh factor of positive or negative. A-B-0 and Rh incompatibility happens when a mother’s blood type conflicts with that of her newborn child. It is possible for a mother’s red blood cells to cross into the placenta or fetus during pregnancy.
What makes blood type O special?
Type O is routinely in short supply and in high demand by hospitals – both because it is the most common blood type and because type O negative blood is the universal blood type needed for emergency transfusions and for immune deficient infants.
What blood type are most black people?
OIncreasing African-American donations is vital because blood types O and B, the blood types of about 70 percent of African-Americans, are also the blood types most in demand.
Which blood type lives the longest?
In a survey of German doctors aged >75 years, group O appeared to be associated with longer life expectancy9. Findings of two studies performed on centenarians were contradictory. Blood type B was observed more frequently in 269 Japanese centenarians (29.4%) than in controls (21.9%)10.
Are eggs good for blood type O?
Type O should include lean beef meat, lamb, turkey and chicken in their diet. Especially, more intakes of seafood, kelp and iodized salt will increase hormone production. They should also eat egg, nuts and seeds in moderation. It is also advisable for blood type O to eat their food when seated.
Which blood group is most powerful?
Of the eight main blood types, people with type O have the lowest risk for heart disease. People with types AB and B are at the greatest risk, which could be a result of higher rates of inflammation for these blood types. A heart-healthy lifestyle is particularly important for people with types AB and B blood.
What is special about O positive?
Type O positive blood is given to patients more than any other blood type, which is why it’s considered the most needed blood type. 38% of the population has O positive blood, making it the most common blood type. … Those with O positive blood can only receive transfusions from O positive or O negative blood types.
Is Chicken Good for O positive blood type?
Type O blood: A high-protein diet heavy on lean meat, poultry, fish, and vegetables, and light on grains, beans, and dairy. D’Adamo also recommends various supplements to help with tummy troubles and other issues he says people with type O tend to have.
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5eff3d1f6f98e57329caed0ceb9053d3
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6,213,748,984,817,206,000
|
Modern surgical approaches to female reproductive tract
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منابع مشابه
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ژورنال
عنوان ژورنال: Human Reproduction Update
سال: 1996
ISSN: 1355-4786,1460-2369
DOI: 10.1093/humupd/2.5.419
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Learn The Five Components Of Physical Fitness
• Posted on February 27, 2017 at 10:16 am
Fitness components are:
* Cardiorespiratory (CR) resistance – the efficiency with which the body carries oxygen and nutrients needed for strong activity and transports waste products from cells.
* Muscle strength – the greatest amount of muscle strength or muscle group can exert in a single effort.
* Muscle endurance – the ability of the muscle or muscle group to perform repeated movements with sub-maximal force for a long time.
* Flexibility – the ability to move a joint or group of joints through a full and normal range of motion.
* Board composition – body fat percentage compared to total body mass.
Improving the first three components of fitness listed above will have positive effects on body composition and result in less fat.
Excessive body fat will reduce other fitness components, reduces performance, detracts from appearance, and negatively affect their health.
Factors such as speed, agility, muscle strength, eye-hand coordination and eye-foot coordination are classified as part of fitness “bike”.
The factors that most affect your athletic ability. appropriate training can improve these factors within the limits of their potential.
A reasonable weight loss and fitness program aimed at improving or maintaining all components of physical and motor fitness through sound, progressive training, special mission physical.
Principles of exercise
Adherence to some basic principles that exercise is important to develop effective programs. The same principles of exercise apply to everyone at all fitness levels, from level equalizer Olympia for the weekend. The basic principles of exercise should be followed.
Always
To achieve the training effect, you must exercise regularly. You should take each of the first four fitness components at least three times a
week. rarely exercise can do more harm than good. Setting is also important to rest, sleep, and follow a balanced diet.
Continuity
The intensity (strength) and / or duration (how long) of exercise must gradually increase to improve the level of fitness.
Balance
To be effective, programs must include activities that address all components of fitness, since overemphasizing any one of them could harm other people.
Variation
Provide a variety of activities reduces boredom and increases motivation and progress.
Specificity
Training should focus on specific objectives. For example, people become better runners if their training emphasizes running. Although swimming is great exercise, no time better than 2 kilometers to function both as a running program.
Recovery
A day training hard for certain components of fitness should be followed by a training day or rest day easier for parts and / or muscle group (s) to help permit recovery.
Another way to allow recovery is to alternate muscle groups are held every day, especially when training for strength and / or muscle endurance.
Overload
Workload of each exercise session must exceed the normal demands placed on the body to achieve the training effect.
Top
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5eff3d1f6f98e57329caed0ceb9053d3
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2,322,408,266,894,899,700
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Skip to main content
Retinal image quality with multifocal, EDoF, and accommodative intraocular lenses as studied by pyramidal aberrometry
This article has been updated
Abstract
Background
To study and compare the clinical optical image quality following implantation with different premium IOLs by analysing the point spread function (PSF) Strehl ratio using a pyramidal wavefront sensor (PWS)-based aberrometer.
Methods
This study included 194 eyes implanted with: (a) 19 AcrySof SA60AT (control group); (b) 19 Miniwell; (c) 24 LENTIS Mplus LS-313 MF30; d) 33 LENTIS Mplus LS-313 MF15; (e) 17 AkkoLens Lumina; (f) 31 AT LISA Tri 839MP; (g) 20 Precizon Presbyopic; (h) 20 AcrySof IQ PanOptix; (i) 11 Tecnis Eyhance. Main outcome measures were PSF Strehl ratio, PSF Strehl ratio excluding second-order aberrations (PSFw2), total root mean square (RMS), low-order aberration (LOA) and high-order aberration (HOA) RMS measured by PWS aberrometer.
Results
AT LISA Tri had the highest PSFw2 Strehl ratio at both 3.0- and 4.0-mm pupil size (0.52 ± 0.14 and 0.31 ± 0.10; P < 0.05), followed by SA60AT (0.41 ± 0.11 and 0.28 ± 0.07) and PanOptix (0.4 ± 0.07 and 0.26 ± 0.04). AT LISA Tri was found to provide a significantly better retinal image quality than PanOptix at both 3.0 mm (P < 0.0001) and 4.0 mm (P = 0.004). Mplus MF15 was found to be significantly better than Mplus MF30 at both 3.0 mm (P < 0.0001) and 4.0 mm (P = 0.002). Total RMS, LOA RMS, HOA RMS, PSF Strehl ratio and PSFw2 varied significantly between the studied groups (P < 0.001).
Conclusions
Far distance clinical image quality parameters measured by PWS aberrometer differed significantly according to the technology of the implanted lens. AT LISA Tri, SA60AT and PanOptix showed the highest values of far distance retinal image quality, while the lowest PSFw2 Strehl ratios were displayed by Miniwell, Mplus MF30 and Precizon Presbyopic.
Background
Cataract surgery can be considered not only as a therapeutic but also as a refractive procedure, by the replacement of the natural opacified crystalline lens by an intraocular lens (IOL). On the other hand, an eventual degradation of the retinal image after cataract surgery, excluding corneal irregularity or loss of transparency, could be attributed not only to the IOL optical properties, but also to an imbalance of the compensatory effect between the positive spherical aberration of the cornea and the negative spherical aberration of the crystalline lens, which might be relevant when young patients are operated [1, 2].
The "ex vivo" optical bench through-focus image quality analysis and the clinical visual performance in real patients by study of the defocus curves after different types of IOL implantation has been investigated by Plaza-Puche et al., and it was found to be significantly correlated [3]. This correlation makes it necessary to study the quality of IOL both in vitro and in vivo for different models, and at different pupillary diameters [3, 4].
The selection of the IOL according to its optical and aberrometric characteristics, especially when considering the use of multifocal or extended depth of focus (EDoF) implants, is a relevant concept. Any IOL should ideally minimize ocular wavefront aberrations and optimize the retinal image quality [5], to prevent the impact that a low retinal image can have in visual quality and contrast sensitivity: this aspect can influence patient’s satisfaction after cataract surgery and interfere with the entire neuroadaptation process [6].
Wavefront aberrometry describes the individual optical characteristics of low- and high-order aberrations (LOA and HOA, respectively) in Zernike polynomials. The point spread function (PSF) and the Strehl ratio provide information on the overall optical performance of the human eye: PSF is the irradiance distribution of light from a point source projected onto the retina and it indicates the extent of blurring of the retinal image; the Strehl ratio is the ratio of the peak height of the PSF and to the maximum attainable intensity using an ideal diffraction limited optical system [7].
However, the interpretation of the aberrometric metrics in pseudophakic patients has been different in many cases and different models of aberrometers, with different working principles such as the most commonly used Hartmann–Shack method, Tscherning principle, or Ray-tracing, which have been used to measure wavefront aberration profiles; [7,8,9,10,11] however, these aberrometers present several limitations after multifocal IOL implant [12]. A new pyramidal wavefront sensor (PWS) has been developed and validated and it helps improve the aberration compensation efficiency by sensing aberrations [13,14,15].
The big advantage of a PWS is that the wavefront is sampled at the very last measuring stage, and this allows for a much higher resolution. For instance, a Hartmann–Shack sensor discretizes the wavefront at the lenslet stage and the number of lens on the lenslet determines the number of measured samples: for Hartmann–Shack, we usually have 1000–2000 lenses with a resolution of 250–1250 µm. Osiris, on the contrary has a resolution of 41 µm (45,000 samples at maximum pupil size). Consequently, Osiris can measure sharp edges (like the ones on a diffractive lens) and evaluate their effect on the PSF. These optical advantages have relevant clinical implications in the performance of this new type of aberrometry on clinical basis in refractive and lens surgery.
The present study aimed to evaluate the clinical optical quality of the eye with different types of IOLs in vivo: monofocal spherical, multifocal, EDoF or accommodative IOLs implantation, by studying the PSF Strehl ratio in the far distance image with a model of PWS-based aberrometer.
Methods
Study design
This is a prospective, consecutive, comparative, case series study. Inclusion criteria were uncomplicated cataract or refractive lens exchange surgery and the absence of any comorbidity or anatomical feature such as keratoconus and corneal scars that could limit the visual potential and the light transmission in the study eye. Exclusion criteria included amblyopia, axial length over 25.0 mm, any type of corneal opacity, previous ocular surgery including corneal or refractive surgery, chronic or recurrent uveitis, acute ocular disease or external/internal infection, diabetes mellitus with retinal changes. Cases with confirmed or suspicion of optic nerve damage due to glaucoma were excluded. Eyes should have postoperative corrected distance visual acuity (CDVA) of 0.1 logMAR or better and excellent foveal fixation, normal pseudophakia, total absence of posterior capsule opacification or have already performed Nd:YAG capsulotomy prior to the instrumental optical quality evaluation. Only eyes with mean preoperative keratometry between 42.5 and 45 D, spherical aberration within ± 0.25 μm, corneal HOA < 0.5 µm and angle kappa < 0.4 mm were included in the study. Cases with intraocular complications that could affect IOL performance or IOL stability were excluded, as well as any capsular changes that would increase the risk of decentration or tilt of the IOL, such as zonular weakness or pseudoexfoliation syndrome. All procedures adhered to the tenets of Helsinki Declaration of the World Medical Association. Institutional research ethical board commettee approval was obtained from our institution for the purpose of this clinical investigation.
Clinical evaluation and optical quality
Assessment after 3 months using the same photopic conditions for all the studied IOLs included: uncorrected distance visual acuity (UDVA) and CDVA in logMAR, uncorrected near visual acuity (UNVA) and corrected near visual acuity (CNVA) at 40 cm in logMAR, and manifest refraction. In case of neuroadaptation failure, defined as a subjective reduction in this quality of vision, generally owing to perception of blurred vision, dysphotopsia or photic phenomena, explantation was decided when symptoms were unacceptable and were creating disability for the normal performance of the patient’s life. Explantation was decided between the third and sixth postoperative month. In such cases, the clinical and optical quality evaluation of those patients was assessed immediately prior to the IOL exchange. No corneal refractive surgical procedures of any type were performed either during the cataract surgery or along the follow-up of the patients included in this investigation until the end of the study protocol, at the end of the third month.
All patients had an evaluation of the optical quality of the far distance image using the PWS-based aberrometer Osiris (Costruzione Strumenti Oftalmici [CSO], Firenze, Italy). To perform measurements with Osiris, pupils were dilated using 0.5% tropicamide. In all cases, three consecutive acquisitions were obtained and the following aberrometric parameters were analysed: total root mean square (RMS), LOA RMS, HOA RMS and PSF Strehl ratio. For the purpose of the measurement of the far distance retinal image quality based on PSF Strehl ratio, the second-order aberrations were eventually excluded in the analysis of the PSF Strehl ratio (PSFw2) to avoid any bias induced by residual ametropia and delete its effect on the PSF as it is not related itself with the optical performance of the IOL, and the calculation of this parameter was based only in the magnitude of HOA present in each eye. For a given pupil radius, the second-order aberration removal is performed by decomposing the wavefront in terms of Zernike. The wavefront can thus be expressed as:
$$WF\left(\rho ,\theta \right)=\left(\sum {c}_{n}^{m}{Z}_{n}^{m}\left(\rho ,\theta \right)\right)+R\left(\rho ,\theta \right)$$
where \({Z}_{n}^{m}\left(\rho ,\theta \right)\) is the Zernike polynomial with order (n, m), \({c}_{n}^{m}\) is the coefficient resulting in the fitting and \(R\left(\rho ,\theta \right)\) is the residual. The removal of the second-order can simply be performed by setting \({c}_{2}^{-2}= {c}_{2}^{0}= {c}_{2}^{+2}=0\) or in the previous formula or by subtracting \({c}_{2}^{-2}{Z}_{2}^{-2}\left(\rho ,\theta \right)+{c}_{2}^{0}{Z}_{2}^{0}\left(\rho ,\theta \right)+{c}_{2}^{+2}{Z}_{2}^{+2}\left(\rho ,\theta \right)\) from the overall wavefront.
All aberrometric parameters mentioned above were calculated for the far distance image for two different pupil diameters of 3.0 and 4.0 mm.
The osiris pyramidal aberrometry system
The Osiris aberrometer bases its working principle on a high-resolution four-faced PWS. By comparing the light intensity among four images of the entrance pupil of the patient (known as sub-pupils), we are able to obtain measurements of the wavefront and refractive error. The wavefront error as well as the refractive error is sampled with 45,000 points at maximum pupil, which corresponds to a resolution of 41 µm. The device uses an extended light-emitting diode source emitting at 850 nm as a measurement on visible light would have dramatically reduced the pupil size. The results are then converted to the 585 nm wavelength correcting the effect of longitudinal chromatic aberration. The software shows the direct outcome of the device and due to its dense resolution, does not need Zernike polynomial based modal reconstruction to retrieve the ocular wavefront shape.
A PWS-based aberrometer measures the slopes of a wavefront focusing the foveal source image on the top of a pyramidal prism with a large apex angle. The prism acts to split the beam into 4 parts creating “sub-pupils”. The “sub-pupils” will be identical in case of aberration free wavefront and in the presence of optical aberrations, the intensity distribution among the pupils will be a function of the first derivative of the wavefront along x- and y-axis. It has been demonstrated that for each point, the derivative along the x-axis is proportional to the difference between the left and right sub-pupils, and the one along the y-axis is proportional to the difference between the top and bottom sub-pupils. The wavefront error matrix is finally calculated with a numerical integration method starting from the directional derivatives. Nevertheless, a Zernike fitting is available during the analysis process for back-compatibility with previous devices and to split the overall wavefront error in Zernike main components [13]. The Osiris aberrometer provides accurate and repeatable measures of LOAs and HOAs, even in the challenging cases of peripheral retina and multifocal optics [15].
IOLs studied
All patients underwent microincisional cataract surgery as described in a previous study by our group [4]. Each patient received one out of nine different IOL implants (Table 1): monofocal spherical AcrySof SA60AT as control group (Alcon, Inc., group A); EDoF Miniwell (SIFI, group B); multifocal refractive LENTIS Mplus LS-313 MF30 (Oculentis GmbH, group C); multifocal refractive LENTIS Mplus LS-313 MF15 (Oculentis GmbH, group D); AkkoLens Lumina accommodative intraocular lens (AkkoLens Clinical B.V., Breda, The Netherlands, group E); multifocal diffractive AT LISA Tri 839 MP (Carl Zeiss Meditec, group F); multifocal refractive Precizon Presbyopic (Ophtec BV, group G); multifocal diffractive AcrySof IQ PanOptix Trifocal (Alcon, Inc., group H); new aspheric monofocal Tecnic Eyhance (Johnson & Johnson Vision, Inc., group I). For all participants, the IOL types implanted were selected based on the patient’s lifestyle and surgeon’s advice as well as patient’s need and preferences to decide if they may benefit more from near vision than from good intermediate vision. The IOL power selected was targeted to emmetropia. The Lumina AkkoLens accommodative IOL was implanted in the context of an independent clinical trial (P16-006-V1) [16, 17].
Table 1 Summary of studied groups
Statistical analysis
Absolute and relative frequencies were calculated to describe the qualitative variables, whereas means and standard deviations were used for quantitative ones. For non-time-dependent variables, the Chi-squared test (Pearson or Fisher) and ANOVA were estimated to determine differences between groups. However, for time-dependent variables, paired t-tests and mixed linear models were used. The type I error was fixed at 5%. To detect a significant difference in the postoperative values of PSFw2 (the main outcome) with 80%, 90% and 95% power, 11, 14 and 16 eyes per group would have been necessary, respectively [18]. All calculations were made using IBM SPSS Statistics v. 25 and R v. 3.5.1.
Results
Demographics characteristics and clinical data
A total of 194 eyes of 120 cataract patients aged between 40 and 84 years (63.5 ± 9.7 years) were included in this study. They were grouped according to the type of pseudophakic IOL implanted, in nine different groups (Table 1). There were no intraoperative complications such as posterior capsule rupture or any postoperative complications such as IOL tilt or decentration in any of these patients included in the study. Table 2 showed the patient's demographics characteristics and clinical variables of the analysed groups. These groups were well matched at baseline in terms of sex and IOL power (P > 0.05), but not for age (P = 0.013) and laterality (P < 0.001). Miniwell (group B) had the highest rate of IOL substitution due to patient dissatisfaction related to neuroadaptation failure (6 eyes of 3 patients, 31.6%, P = 0.002).
Table 2 Non-time-dependent clinical variables of the analysed intervention groups
Table 3 showed the visual acuity and manifest refraction at both near and far distances. All treated groups had an improvement in UDVA, but it was not statistically significant in AkkoLens (group E, P = 0.068). Regarding CDVA, even if all treated groups reached a mean visual acuity between 0.86–1.03 logMAR, a postoperative improvement was only observed in SA60AT (group A, P < 0.001), Mplus MF15 (group D, P = 0.016) and PanOptix (group H, P = 0.019); nevertheless, the wide range of preoperative CDVA makes statistical implication about postoperative improvement less meaningful, as both patients undergoing cataract surgery and refractive lens exchange surgery have been included. All groups with the exception of group A (SA60AT) and group D (Mplus MF15) had an improvement in UNVA: postoperative data of UNVA of group D might result from the hyperopic refractive error and higher standard deviation of the spherical component in that group.
Table 3 Time-dependent variables of the analysed intervention groups
AT LISA Tri (group E, P = 0.027) and Eyhance (group I, P = 0.015) had a significant improvement in CNVA; Mplus MF15 had a significant reduction in CNVA (group D, P = 0.019).
Postoperative aberrations
Wavefront aberrations in the far distance image were compared for each of the nine lens types at two different pupil sizes (3.0 and 4.0 mm). Total RMS, LOA RMS, HOA RMS, PSF Strehl ratio, PSFw2 Strehl ratio were recorded and analysed. Overall, the grouping outcomes of postoperative aberrations of the far distance image with 3.0 mm and 4.0 mm pupil diameters are presented in Table 4. In terms of postoperative aberrations in the study groups, a between-group ANOVA reveal a statistically significant difference for all the values at both 3.0 and 4.0 mm pupil diameters (all P < 0.001). In addition, all the studied aberrations varied significantly as pupil diameter increase (P < 0.05). When looking to the PSFw2 Strehl ratio, AT LISA Tri (group F) had the highest significant PSFw2 Strehl ratio at both 3.0 and 4.0 mm pupil sizes (0.52 ± 0.14 and 0.31 ± 0.1), followed by SA60AT (group A, 0.41 ± 0.11 and 0.28 ± 0.07) and PanOptix (group H, 0.4 ± 0.07 and 0.26 ± 0.04). Figure 1 shows the values of PSF Strehl ratio with and without LOA, obtained at 3.0 mm, and the significance compared to the monofocal control group A. AT LISA Tri (group F) had a significant higher value of PSFw2 than the monofocal control group A (P < 0.0001), PanOptix (group H) was not significantly different (P = 0.345), while all the other groups have a significant lower PSFw2 than group A (P < 0.0001).
Table 4 Postoperative values of wavefront aberrations of the analysed intervention groups at two pupil sizes obtained at 3 months
Fig. 1
figure 1
PSF Strehl ratio with and without low-order aberration for each group, obtained with a pyramidal wavefront sensor-based aberrometer, and level of significance compared to the monofocal spherical control group. *P < 0.05, **P < 0.001
Discussion
Recently, the impact of IOLs’ optic aberrations on retinal image quality is gaining increasing attention [3, 19, 20]. Significant correlations were found between visual acuity and ex vivo image quality metric for multifocal and monofocal IOLs, giving surgeons the opportunity to predict visual outcomes [3]. The far distance retinal image quality is of primary importance when considering neuroadaptation, as a decreased quality of image with blurred vision limits the neuroadaptation process. Neuroadaptation failure is mainly characterized by decreased quality of vision, sometimes with no correlation with the objective parameters of optical quality and no solid underlying reason such as posterior capsule opacification, dry eye, or retinal disease. The reduction in this far distance quality of vision is generally due to sensations of blurred vision, dysphotopsia or photic phenomena. Therefore, it is of primary concern how our brain reacts to a new input, such as what follows after implanting multifocal or EDoF lenses, and it is in good part related to the far distance retinal image quality, as a bad retinal image quality is inevitably a compromise and a limitation for the neuroadaptation process; however, other factors such as photic phenomena or the type of defocus curve are also considered to play a role in the tolerance to such atypical optics [6].
The most commonly used aberrometers are based on the Hartmann–Shack sensor: aberrometers based on this kind of working principle usually provide reproducible measurements in normal eyes but presents several limitations due to overlapping of the spots, especially in eyes with high levels of aberrations or after multifocal IOL implant: in the case of diffractive IOL, indeed, different replicas of the wavefront might be confusing [12]. The reconstructed wavefront and associated metrics are incorrect as all the information with regard to the add power of the diffractive lens are ignored [21]. The PWS-based aberrometer represents an important and novel tool that offers advantages for the purpose of these measurements [13]. To the best of our knowledge, the extensive evaluation of postoperative optical effect based on the study of the far distance PSF Strehl ratio obtained with a PWS-based aberrometer in pseudophakic eyes implanted with different IOLs has not been reported in peer-reviewed literature for all these studied lenses together and never explored before.
In this investigation, we evaluated the retinal image quality for the distance focus of a monofocal spherical IOL commonly used in clinical practice (AcrySof SA60AT), an EDoF (Miniwell), 3 multifocal refractive IOLs (LENTIS Mplus 15, LENTIS Mplus 30, Precizon Presbyopic), 2 multifocal diffractive IOLs (AT LISA Tri, AcrySof IQ Panoptix), an accommodative IOL (AkkoLens Lumina) and a new monofocal aspheric IOL (Tecnis Eyhance). The study obtained ocular aberrations using a new PWS-based aberrometer (Osiris) in all eyes at a pupillary diameter of 3.0 and 4.0 mm.
When considering the impact of IOLs on optical aberrations, one must consider how much light energy is intentionally and unintentionally directed off axis, especially when considering EDoF or multifocal—both diffractive and refractive—IOLs. In a monofocal IOL, the goal is to focus all light energy on axis in the plane of the retina. Therefore, in our control group implanted with a monofocal spherical IOL, we had a good retinal image quality (PSFw2 Strehl ratio 0.41 ± 0.11 and 0.28 ± 0.07 at 3.0 and 4.0 mm, respectively).
In the case of those aspheric multifocal lenses that increase depth of focus through spherical aberration, retinal optical quality in the far focus will inevitably be compromised, since the goal is to achieve a beneficial compromise between the gain in depth of focus and the loss in image quality [19, 22]. In fact, we found a drastic significant reduction in PSFw2 Strehl ratio values in the Miniwell group (0.28 ± 0.07 and 0.21 ± 0.06 at 3.0 and 4.0 mm, respectively; P < 0.0001): this data may partly explain the higher IOL exchange rate obtained in this group (31.6%).
In case of a rotationally asymmetric refractive multifocal lens, its vertical asymmetric optical geometry provides two distant foci for far and near vision by the presence of a calculated magnitude intraocular primary coma [23, 24]. Although some amounts of vertical coma have a positive effect on near visual acuity because of the enhanced depth of focus, high values of this aberration could limit the eye’s optical quality [25]. As expected, we found a trend toward a larger magnitude of HOA RMS in the far distance image in those eyes implanted with a 3.00 D posterior sector-shaped near-vision zone (Mplus MF30, group C: 0.30 ± 0.15 µm at 3.0 mm and 0.50 ± 0.12 µm at 4.0 mm). These findings suggest that the use of a larger add for the rotationally asymmetric IOL limits optical quality, with a relative effect on retinal image quality, as expressed by a significant lower value of PSFw2 Strehl ratio at both pupil diameters (0.23 ± 0.07 at 3.0 mm and 0.16 ± 0.05 at 4.0 mm; P < 0.0001).
Precizon Presbyopic is a continuous transitional focus IOL that obtains a smoother transition between distance and near vision by combining different sectors in the optical zone of the IOL [26, 27]. In our study, those eyes (group G) presented significant lower levels of retinal image quality (0.27 ± 0.07 and 0.17 ± 0.04 at 3.0and 4.00 mm, respectively; P < 0.0001) than the monofocal spherical group (SA60AT).
Another approach to correct near and far vision is (1) diffractive structure covering the entire anterior optical surface as in the AT LISA Tri 839 MP or (2) diffractive structure in the central 4.5 mm portion (15 diffractive zones) as in the AcrySof IQ PanOptix Trifocal, [28] to create three wavefronts of different curvatures emerging from the IOL: a regular flat wavefront for distance correction and two additional converging spherical wavefronts produced by the diffractive rings for near and intermediate vision [29]. These designs offer two of the highest mean postoperative value of retinal image quality in both groups, significantly higher than the control group for AT LISA Tri (Group F, P < 0.0001: 0.52 ± 0.14 and 0.31 ± 0.1 at 3.0 and 4.0 mm, respectively) but not significantly different than the monofocal control group for PanOptix (group H, P = 0.345: 0.4 ± 0.07 and 0.26 ± 0.04 at 3.0 and 4.0 mm, respectively).
The AkkoLens Lumina consists of two optical elements, which move one over the other in a plane perpendicular to the optical axis, aiming to produce a continuous variable-focus lens and change the dioptric power of the system while they change their position [16, 17]. We found a good level of PSFw2 Strehl ratio, even though significantly lower when compared to the monofocal spherical group (0.32 ± 0.11 and 0.23 ± 0.16 at 3.0 and 4.0 mm, respectively; P < 0.0001).
Finally, we also report herein for the first time the far distance retinal image quality in patients implanted with a Tecnis Eyhance. It is a new aspheric monofocal IOL that aims to enhance the image quality at intermediate distances without compromising distance vision, based on a continuous refractive optical surface design [30]. These patients had a relatively good retinal image quality (0.36 ± 0.11 and 0.21 ± 0.06 at 3.0 and 4.0 mm, respectively), but significantly lower than the monofocal spherical control group (P < 0.0001).
Finally, we compared those groups implanted with IOLs based on a similar basis for the far distance image. When comparing the values of PSFw2 between the diffractive IOLs, AT LISA Tri was found to provide a significantly better retinal image quality than PanOptix at both 3.0 mm (P < 0.0001) and 4.0 mm (P = 0.004), probably due to the aspheric design of the AT LISA Tri. Among the rotational asymmetric refractive IOLs, LENTIS Mplus MF15 was found to be significantly better than LENTIS Mplus MF30 at both 3.0 mm (P < 0.0001) and at 4.0 mm (P = 0.002). There were highly significant differences (P < 0.0001) among all groups regarding almost all postoperative ocular aberration components. This suggests that ocular aberration in pseudophakic patients were mainly caused by the optic of the implanted IOL. Consequently, studying ocular aberrations using a PWS-based aberrometer makes it possible to directly study the retinal image quality and thus guide the physician in IOL selection and in the future development of their patients’ optics.
The PWS-based aberrometer is a potentially good tool to evaluate the clinical quality of IOL performance when implanted in the human eye, evaluating the wavefront of the patient when looking at the infinity. Those lenses that are affected by the best optical outcome in the far distance focus with pyramidal aberrometry should also perform better in general.
A limitation of this study is that the post-hoc analysis could not be performed since we have several groups, which would make the results of such comparisons underpowered. Furthermore, one should consider that we cannot fully remove the influence of residual ametropia by removing the second-order aberrations, as there might be some interplay between the different Zernike modes. Finally, the Osiris – even if it has a higher resolution than previous aberrometers – is only able to simulate the main PSF of a diffractive lens, but not the others. Resolution considers the refractive quality of the diffraction pattern, but not the diffraction effect. In this study, measured wavefront error is the one of a patient looking at the infinity and its related PSF represent vision of a point for the far distance focus; in case of diffractive lenses, it is compressive all the aberrations eventually induced by the splitting system, but it does not comprehend the loss of contrast due to replicas. We focused our attention of the PSF of the main replica by evaluating if the splitting mechanism could affect the quality of the main focus. This might partly explain the high value of PSFw2 obtained with these two types of IOLs, that it was found to be comparable and/or higher than one of the monofocal IOLs.
Conclusions
The diffractive multifocal AT LISA Tri showed the best far distance retinal image quality, significantly higher than the control group, followed by a not statistically significant near tie between the Alcon SA60AT monofocal spheric IOL and the Alcon Panoptix multifocal diffractive IOL. On the other hand, EDoF Miniwell, LENTIS Mplus MF30 and Precizon Presbyopic showed the significantly poorest retinal image qualities. When comparing IOLs whose optics had a similar design, AT LISA Tri had a significantly better far distance retinal image quality than PanOptix, and LENTIS Mplus MF15 had a significantly better retinal image quality than LENTIS Mplus MF30.
The explanation why lenses with diffractive optics, such as the diffractive IOLs included in this investigation, give higher values of far distance retinal image quality is out of the scope of this study. Learning how the different IOL optics influence the quality of retinal image by the study of induced aberrations with the novel PWS-based aberrometer, may be considered as a new clinical tool for IOL selection. It could influence IOL selection for the correction of pseudophakic presbyopia and guide surgeons in the evaluation and selection of the IOL to be implanted. Preoperative measurement of corneal HOA may be also important in sphericity inducing IOL to avoid explantation of these IOLs. Future prospective studies on this topic are warranted to correlate the findings of this report and to elucidate the relationship between far distance retinal image quality (assessed by the study of the PSF Strehl ratio), quality of vision perceived by the patient and the success of the neuroadaptation process that follow the implantation of lenses with multifocal or EDoF, in order to increase the optical quality of future lenses depending on their potential to create an adequate quality of retinal image and preventing the risk of neuroadaptation failure related to poor retinal image quality.
Availability of data and materials
All data analysed during this study are included in this published article and its supplementary information files.
Change history
• 24 January 2022
The family name, middle name and first name of the last author are tagged incorrectly in article xml. The article has been updated to rectify the errors.
Abbreviations
CDVA:
Corrected distance visual acuity
CNVA:
Corrected near visual acuity
IOL:
Intraocular lens
EDoF:
Extended depth of focus
LOA:
Low-order aberrations
HOA:
High-order aberrations
PSF:
Point spread function
PWS:
Pyramidal wavefront sensor
UDVA:
Uncorrected distance visual acuity
UNVA:
Uncorrected near visual acuity
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Acknowledgements
Not applicable.
Funding
This study has been financed in part by the Network for Cooperative Research in Health “OFTARED”—Reference: RD16/0008/0012. Funded by Instituto de Salud Carlos III and co-funded by European Regional Development Fund (ERDF), Project “A way to make Europe".
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JLA and JLAB conceived the study and its design and participated in data collection as well as manuscript revision. FD participated in the study design and data collection, drafted and revised the manuscript. FT and JB participated in data collection as well as revised the manuscript. AP performed the statistical analysis and revised the manuscript. All authors read and approved the final manuscript.
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Correspondence to Jorge L. Alio.
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This study adhered to the tenets of the Declaration of Helsinki for research on human subjects. Informed consent was obtained from all participants. Institutional clinical research ethical board commettee approbal from Vissum Instituto Oftalmologico de Alicante was obtained for the purpose of this investigation.
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Competing interests
Author Jorge L. Alio is a member of the Editorial Board for Eye and Vision. The other authors declare that they have no competing interests.
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Alio, J.L., D’Oria, F., Toto, F. et al. Retinal image quality with multifocal, EDoF, and accommodative intraocular lenses as studied by pyramidal aberrometry. Eye and Vis 8, 37 (2021). https://doi.org/10.1186/s40662-021-00258-y
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Pragmatic application of a clinical prediction rule in primary care to identify patients with low back pain with a good prognosis following a brief spinal manipulation intervention
Abstract
Background
Patients with low back pain are frequently encountered in primary care. Although a specific diagnosis cannot be made for most patients, it is likely that sub-groups exist within the larger entity of nonspecific low back pain. One sub-group that has been identified is patients who respond rapidly to spinal manipulation. The purpose of this study was to examine the association between two factors (duration and distribution of symptoms) and prognosis following a spinal manipulation intervention.
Methods
Data were taken from two previously published studies. Patients with low back pain underwent a standardized examination, including assessment of duration of the current symptoms in days, and the distal-most distribution of symptoms. Based on prior research, patients with symptoms of <16 days duration and no symptoms distal to the knee were considered to have a good prognosis following manipulation. All patients underwent up to two sessions of spinal manipulation treatment and a range of motion exercise. Oswestry disability scores were recorded before and after treatment. If ≥ 50% improvement on the Oswestry was achieved, the intervention was considered a success. Sensitivity, specificity, and positive likelihood ratio were calculated for the association of the two criteria with the outcome of the treatment.
Results
141 patients (49% female, mean age = 35.5 (± 11.1) years) participated. Mean pre- and post-treatment Oswestry scores were 41.9 (± 10.9) and 24.1 (± 14.2) respectively. Sixty-three subjects (45%) had successful treatment outcomes. The sensitivity of the two criteria was 0.56 (95% CI: 0.43, 0.67), specificity was 0.92 (95% CI: 0.84, 0.96), and the positive likelihood ratio was 7.2 (95% CI: 3.2, 16.1).
Conclusion
The results of this study demonstrate that two factors; symptom duration of less than 16 days, and no symptoms extending distal to the knee, were associated with a good outcome with spinal manipulation.
Peer Review reports
Background
Low back pain (LBP) is a common and costly condition in primary care practices[1]. Managing patients with LBP is complicated by many factors, including the inability to identify a pathological cause for the majority of patients[2, 3]. The fact that a specific diagnosis based on pathoanatomy can be made in only 10–20% of LBP sufferers seen in primary care leaves a large group of patients often given a nominal diagnosis such as "non-specific", or "mechanical" LBP.
Many experts agree that sub-groups exist within the large category of patients diagnosed with "non-specific" LBP[4, 5]. The difficulty in identifying pathoanatomical causes in most patients combined with the high false positive rates of imaging studies[6] have led many to further conclude that meaningful sub-groups should be based on a patient's symptoms and clinical presentation [79]. The identification of sub-groups could improve the outcomes of clinical care by establishing more accurate prognoses, efficiently directing patients to therapies most likely to benefit their particular sub-group [1012].
One proposed sub-group among patients with otherwise non-specific LBP consists of those who are likely to respond to spinal manipulation[13] There is evidence supporting the effectiveness of manipulation for patients with LBP,[14] however common sense, as well as research evidence,[15, 16] recognizes that not all patients with LBP should be expected to respond to a manipulation intervention. The efficiency of primary care management of patients with LBP could be improved if a pragmatic tool existed to identify those patients with LBP who are likely to respond to this approach.
Flynn et al[16] examined factors from the clinical presentation of patients with LBP that predicted a successful response to two sessions of a manipulation intervention delivered by a physical therapist. Five clinical factors were identified as forming the most parsimonious set of predictors for identifying patients who achieved at least a 50% improvement in disability within one week with a maximum of two manipulation interventions (Table 1)[16]. The positive likelihood ratio for patients with at least 4 of these 5 criteria present was 24.4, which corresponded to a 95% likelihood of success with spinal manipulation among this sub-group of patients. Childs et al[17] sought to validate the effectiveness of these criteria for predicting a successful outcome from manipulation by randomizing patients to either a manipulation or strengthening/stabilization exercise intervention and examining outcomes based on the previously established criteria. The study found that patients with at least 4 out of 5 criteria present who received the manipulation intervention had better short-term (one- and four-week) and long-term (six-month) outcomes then patients receiving the manipulation who did not have at least 4 of 5 criteria. Furthermore, patients with at least 4 out of 5 criteria receiving manipulation had better short- and long-term outcomes than patients with 4 of 5 criteria who were randomized to receive the exercise intervention[17].
Table 1 Original criteria for predicting success with a manipulation intervention.17
The results of these studies support the validity of these five criteria for identifying patients with LBP likely to benefit both immediately and in the long-term, from spinal manipulation. The pragmatism of applying these criteria for routine use in primary care, however, may be compromised by the requirements that the patient complete a questionnaire (the Fear Avoidance Beliefs Questionnaire[18]), and the clinician perform an examination of hip range of motion and spinal mobility. Therefore, the purpose of this report was to use data collected from previously published studies to examine the association between two pragmatic criteria (duration of symptoms and distribution of symptoms) and response to a manipulation intervention performed by a physical therapist.
Methods
Subjects
Subjects for this analysis were 141 patients with LBP who were participants in one of two previous studies. Seventy-one subjects were participants in the study used to develop the criteria for predicting success with manipulation,[16] and 70 subjects randomized to receive the manipulation intervention were taken from the study that validated the criteria[17]. These subjects underwent the same inclusion criteria, examination procedures, and treatment protocol and therefore were used to examine the validity of two criteria (duration of symptoms and distribution of symptoms) for predicting success with manipulation. Each study protocol was approved by the participating institutions and subjects all provided informed consent for participation.
Subjects were between 18–60 years of age with a primary complaint of LBP with or without referral into the lower extremity, and an Oswestry disability score of at least 30%. Patients with "red flags" for a serious spinal condition (e.g., tumor, compression fracture, infection, etc.), signs consistent with nerve root compression (i.e., positive straight leg raise <45°, or diminished reflexes, sensation, or lower extremity strength), current pregnancy, or prior surgery to the lumbar spine or buttock were excluded.
Baseline examination
All subjects completed a series of self-report questionnaires and underwent a standardized physical examination prior to treatment. Subjects were asked to identify the date of onset of their LBP. Subjects also completed a body diagram to indicate the anatomical distribution of symptoms,[19] a numeric pain rating to indicate the current intensity of pain on a scale from 0–10[20], and the Fear Avoidance Beliefs Questionnaire to indicate the subject's fear of pain and beliefs about avoiding activity[18]. The modified Oswestry questionnaire (OSW)[21] was completed by each subject to quantify the level of disability related to LBP. The OSW is a well-validated tool for measuring disability in patients with LBP[22, 23]. The version used in this study has been shown to possess high levels of reliability and responsiveness[24]. The OSW was completed at baseline, and again after one week of treatment.
Treatment
After completing the baseline examination, all subjects received the same manipulation intervention protocol. Subjects were sent to physical therapy and received 1–2 treatment sessions within one week before re-examination. Subjects received the manipulation intervention at each treatment session. The same manipulation technique was used for all subjects. The subject was supine. The physical therapist positioned the subject into side-bending, and then rotated the subject in the opposite direction. A quick thrust to the pelvis was delivered by the therapist in a posterior and inferior direction (Figure 1). If a cavitation (i.e. a "pop") occurred, the physical therapist proceeded to instruct the patient in the range of motion (ROM) exercise. If no cavitation was produced, the manipulation was attempted again. A maximum of two attempts per side was permitted. The ROM exercise was performed supine by rocking the pelvis back and forth. Subjects were instructed to perform 10 repetitions of the ROM exercise in the clinic and 10 repetitions 3–4 times daily on the days they did not attend physical therapy.
Figure 1
figure1
Manipulation technique.
Data analysis
All subjects were categorized on two criteria from the baseline examination. The body diagram was used to determine if the subject's symptoms extended distal to the knee or not. The categorization of symptom distribution using body diagrams has been found to be highly reliable[25]. The subject's report was used to determine if the symptom duration was less than 16 days. Subjects with both criteria present (i.e., no symptoms distal to the knee and symptom duration less than 16 days) were categorized as likely to have a good prognosis following the manipulation intervention. Subjects with 1 or 0 criteria present were categorized as likely to have a poor prognosis.
We first examined the relationship between the two criteria rule and the original five-criteria rule for predicting success. Subjects with at least 4 out of 5 of the original criteria present were categorized as having a good prognosis with manipulation, while those with three or fewer were categorized as having a poor prognosis. Using the five-criteria rule as the reference standard, we calculated the accuracy of the two criteria as the percentage of times the two-criteria categorization agreed with the five-criteria categorization. We also calculated the sensitivity, specificity, and likelihood ratios with associated 95% confidence interval (CI).
The outcome of the manipulation intervention was determined from the change on the OSW occurring between the baseline and post-treatment examinations. The percent improvement on the OSW was calculated as (Initial OSW - Final OSW) /Initial OSW* 100%. If the percent improvement was ≥ 50%, the intervention was considered a success.
The association between the two criteria and manipulation outcome was examined by calculating the sensitivity, specificity, and positive likelihood ratio statistics with corresponding 95% CI. The sensitivity was calculated as the percentage of subjects with a successful outcome who had a good prognosis based on the presence of both criteria (i.e., the true positive rate). Specificity was calculated as the percentage of subjects with a non-successful outcome who were categorized with a poor prognosis based on the presence of only 1 or 0 criterion (i.e., the true negative rate). The positive likelihood ratio was calculated as (sensitivity / (1-specificity)) and represents the increase in odds favoring a successful outcome when both criteria are present[26].
Results
The baseline characteristics of the 141 subjects are listed in table 2. At baseline, 105 subjects (74%) did not have symptoms distal to the knee, and 50 (36%) had a duration of symptoms < 16 days. Overall, 41 subjects (29%) had both criteria present and were categorized as having a good prognosis. One hundred subjects (71%) were categorized as having a poor prognosis; 73 had one, and 27 had zero criterion present. Characteristics of subjects with or without both criteria present are presented in table 3. Patients with both criteria present had higher baseline OSW scores (mean difference 5.6 points, 95% CI: 1.7, 9.5). The accuracy of the two criteria rule as compared with the original five criteria rule was high, with a percent agreement of 83.7%. The sensitivity and specificity were 0.67 and 0.93 respectively, resulting in a positive likelihood ratio of 8.9 and negative likelihood ratio of 0.36 (table 4).
Table 2 Baseline subject characteristics (n = 141).
Table 3 Baseline characteristics of subjects with or without both criteria for success with manipulation present
Table 4 Accuracy of two criteria rule relative to the five criteria rule for predicting response to manipulation
The mean baseline and one-week OSW scores were 41.9 (± 10.9) and 24.1 (± 14.2) respectively. The mean percent change on the OSW was 41.2% (± 33.9%). Sixty-three subjects (45%) experienced 50% or greater improvement on the OSW and were categorized as successful with the treatment (mean change 73.8% (± 15.4%)), and 55% were categorized as unsuccessful (mean change 14.8% (± 17.9%)). Subjects with both criteria present experienced significantly greater change on the OSW, and were more likely to be categorized as a successful manipulation outcome than subjects with one or zero criteria present (Table 5).
Table 5 Manipulation outcomes based on the number of criteria present
The distribution of outcome with the manipulation intervention based on the presence of both criteria is displayed in table 6. The sensitivity associated with the presence of both criteria was 0.56 (95% CI: 0.43, 0.67), and the specificity was 0.93 (95% CI: 0.84, 0.96), with a positive likelihood ratio of 7.2 (95% CI: 3.2, 16.1).
Table 6 Accuracy of two criteria rule for success with manipulation for predicting clinical outcome
Discussion
The results of this study demonstrate a strong association between the two pragmatic criteria and response to a manipulation intervention delivered by a physical therapist. These two criteria (duration of symptoms less than 16 days and no symptoms extending distal to the knee) can be easily assessed in a primary care setting. The two pragmatic criteria also showed a high level of accuracy in relation to judgments based on the original five criteria (84% agreement, 67% sensitivity, 93% specificity). Judgments from the two criteria showed a strong predictive relationship with the clinical outcome. Although the two criteria rule did sacrifice some accuracy related to the original five criteria rule, it appears that sufficient accuracy is maintained with a substantial increase in ease of use. The original five criteria rule has been validated in a randomized clinical trial[17]. This two criteria rule will also require further validation through randomized trials to confirm that patients with both factors respond best to an intervention involving manipulation versus an alternative intervention, or no intervention at all.
Current clinical practice guidelines and expert recommendations generally support a "stepped care" approach for management of patients with LBP[27] in which treatment is initially limited to providing positive information and advice based on the understanding that the majority of patients will recover within 4–6 weeks. Referral to physical therapy may therefore not be initiated (ie, "stepped up") until patients fail to demonstrate the anticipated recovery. However, the results of this analysis, .along with our previous analyses,[16, 17] suggest that patients with LBP seen in primary care whose duration of symptoms is less than 16 days without any symptoms extending distal to the knee, may benefit from an immediate referral to physical therapy for a couple of sessions of a manipulation intervention along with range of motion exercise. This analysis only examined results immediately after one week of treatment (up to 2 sessions), however the randomized trial by Childs et al[17] show that the benefit of early manipulation with range of motion exercise in patients fitting the criteria for success persisted up to six months after the treatment period. In addition, several studies have demonstrated that patients with LBP whose disability persists beyond 4–6 weeks are at significantly increased risk of developing chronic disability, persistent work restrictions, and increased health care utilization [2831].
In this study, 29% of subjects fit the two criteria and were designated as having a good prognosis with manipulation, suggesting this sub-group of patients may not be inconsequential. The high specificity (0.92) and positive likelihood ratio (7.2) indicate that patients with both criteria present should be referred for a manipulation intervention based on the high likelihood of rapid success. The sensitivity (0.56) and negative likelihood ratio (0.48) associated with this two-criteria rule were only moderate, indicating a relatively high potential for false negative results (i.e., subjects designated as likely non-responders who ultimately experienced success with manipulation). Given the safety of manipulation in the lumbar spine[32], this finding suggests that referral of patients who do not have both criteria present may be appropriate in some cases. The criteria for treatment outcome with manipulation was determined after 1–2 treatment sessions, suggesting that the effectiveness of this treatment can be determined quickly in referred patients. Those patients who do not respond quickly may then be rapidly directed towards an alternative treatment approach. There is preliminary evidence to suggest that the addition of a strength and stabilization program after the manipulation intervention may help to reduce the likelihood of recurrence,[33] however more research is needed.
The exclusion criteria used in this study should be taken into account when considering the clinical implications of the results. In particular it is important to note that patients with signs of nerve root compression, low levels of disability, or prior surgery to the low back were excluded. The likely response of these patients to a manipulation intervention cannot be determined from these results. This study used one manipulation technique. It cannot be ascertained if the same criteria would apply to a different technique, however the lack of specificity associated with manipulation techniques[34, 35] suggests that the choice of a particular technique may not be as important as the choice of the patient on whom spinal manipulation is to be used.
Conclusion
Individuals with "non-specific" LBP are not a homogenous group, and different sub-groups of patients are likely to preferentially respond to different therapeutic management strategies. One sub-group consists of those patients with a good prognosis following spinal manipulation intervention. The results of this study demonstrate an association between two factors; symptom duration of less than 16 days, and no symptoms extending distal to the knee, and outcome of a manipulation intervention.
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Pre-publication history
1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/6/29/prepub
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Acknowledgements
Supported in part by a grant from the Foundation for Physical Therapy and the Wilford Hall Medical Center Commander's Intramural Research Program.
The opinions and assertions contained herein are the private views of the author (JDC) and are not to be construed as official or as reflecting the views of the Department of the Air Force or the Department of Defense.
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Correspondence to Julie M Fritz.
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The author(s) declare that they have no competing interests.
Authors' contributions
JMF participated in the design and statistical analysis of this study. JDC participated in the design and performance of this study. TWF participated in the conceptual development and performance of this study.
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Fritz, J.M., Childs, J.D. & Flynn, T.W. Pragmatic application of a clinical prediction rule in primary care to identify patients with low back pain with a good prognosis following a brief spinal manipulation intervention. BMC Fam Pract 6, 29 (2005). https://doi.org/10.1186/1471-2296-6-29
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Keywords
• Physical Therapist
• Negative Likelihood Ratio
• Positive Likelihood Ratio
• Spinal Manipulation
• Nerve Root Compression
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Chemical Burns
Continuing Education Activity
Healthcare professionals should be knowledgeable about chemical burns from exposure to acids (pH less than 7), alkalis (pH greater than 7), and irritants to recognize, manage and care for these common types of injury. Chemical burns are the result of exposures to a variety of substances commonly found in the home, workplace, and surrounding environment. The burn may be obvious, for example, from a direct spill or other exposure, or more covert, especially in children. Chemical burns can cause short-term, long-term, and lifelong health problems, especially if undertreated. Occasionally, they can result in premature death, especially if ingested in an attempt to self-harm. This activity reviews the pathophysiology and presentation of chemical burns and highlights the role of the interprofessional team in its management.
Objectives:
• Summarize the various possible causes of chemical burns.
• Describe the physical exam and evaluation process of a patient with a suspected chemical burn
• Reviewe the treatment and management options available for patients presenting with chemical burns.
• Explain the importance of interprofessional team strategies for improving care coordination and communication to aid in prompt diagnosis of chemical burns and improving outcomes in patients diagnosed with the condition.
Introduction
Healthcare professionals should understand chemical burns from exposure to acids (pH less than 7), alkalis (pH greater than 7), and irritants to recognize, manage and care for these common types of injury.[1][2][3]
Etiology
Chemical burns are the result of exposures to a variety of substances commonly found in the home, workplace, and surrounding environment. The burn may be obvious, for example, from a direct spill or other exposure, or more covert, especially in children. Chemical burns can cause short-term, long-term, and lifelong health problems, especially if undertreated. Occasionally, they can result in premature death, especially if ingested in an attempt to self-harm.[4][5]
Common causes of chemical burns include the following:
• Acids: Sulfuric, nitric, hydrofluoric, hydrochloric, acetic acid, formic, phosphoric, phenols, and chloroacetic acid
• Bases: Sodium and potassium hydroxide, calcium hydroxide, sodium and calcium hypochlorite, ammonia, phosphates, silicated, sodium carbonate, lithium hydride
• Oxidants: Bleaches like chlorites used in the home, peroxides, chromates, magnates
• Miscellaneous: White phosphorus, metals, hair coloring agents, airbag injuries
• Vesicants like mustard gas
Epidemiology
Chemical burns occur commonly in children who explore at their "cruiser" level. Many households keep toxic chemicals under the sink or in other low-lying locations where a child may access them. Additionally, in the workplace or home environment, an individual may contact one or more chemicals that have the potential to cause external or internal injury, either because of unawareness of exposure or casual contact. [6][7]
In the last few years in the United Kingdom, there have been many caustic chemical assaults on women.
Children tend to suffer chemical injuries in the home; whereas, adults suffer chemical injuries in the workplace.
Pathophysiology
Chemical burns cause damage as a result of irritant properties, acidity/alkalinity, concentration, form, amount of contact, the length of exposure, and location of contact. For example, contact with a mucosal surface such as the eye is likely to cause earlier and more extensive damage than contact with intact skin where there may be some barrier protection. After inadvertent or intentional ingestion, there will be prompt contact with the mucosal surface and both direct and absorptive toxicity.
Toxicokinetics
After exposure to an alkaline agent, the -OH moiety causes injury due to liquefaction necrosis (mnemonic tip: alkaline has an "L"), which leads to often irreversible changes in the protein matrix. Additionally, there is vascular damage that can create a local or systemic effect.
Acidic agents cause coagulation necrosis (mnemonic tip: acidic has a "C"), which leads to cytotoxicity. Additionally, there are mucosal or skin changes which may prevent further toxicity and limit absorption.
Overall, alkaline agents are more toxic than acidic agents, due to the irreversible changes in protein and tissue damage.
History and Physical
The most common findings represent structural changes to the tissue directly affected, for example, the eye, oral mucosa, skin, esophagus, and lower intestinal system, especially the stomach and pylorus, respiratory system, among others. In children, ingestion is generally the most worrisome event, because of changes, both short-term and long-term, often leading to extensive tissue death. Eye exposure, either acid or alkali, represents a significant acute injury. Copious irrigation is necessary, and measuring pH is appropriate, although rarely informative.
Evaluation
Direct examination of external exposure sites is mandatory, and if there is ingestion, endoscopic evaluation is necessary. In the instance of Hydrofluoric (HF) acid exposure (see treatment below), monitoring of serum calcium and magnesium levels is critical to prevent chelation with the fluoride ion and cytotoxicity. With most other topical exposures, observation and serial monitoring of changes are sufficient.[8][9]
Any gastrointestinal (GI) exposure must be seen by an experienced endoscopist who may need to perform serial evaluations to document healing. Likewise, eye injuries must be examined by an experienced ophthalmologist who will follow-up with the patient sequentially and guide additional therapy.
With ingestions, especially when concerned about systemic absorption, laboratory evaluation (complete blood count [CBC], platelets, electrolytes, calcium, magnesium, arterial/venous blood gas, liver and kidney studies, lactic acid level, and, occasionally, coagulation studies) may be indicated. Radiographic studies, especially including an upright chest film, may help to determine if there is the presence of free air, which is suggestive of a perforation. Non-contrast CT may be used if there is concern about mediastinal free air, resulting from a perforation after exposure. Previously, a radio-opaque contrast was used, but this should be avoided in suspected perforation.
Treatment / Management
Copious irrigation of affected external areas is mandated. Endoscopic examination best explores internal injuries after ingestion. If there is concern about ingestion of disc or other flat batteries, radiographic assessment is mandated. It would be unusual that CT scanning would be needed, and MRI studies are interdicted. Ultrasonography in experienced hands may provide answers as to location as well. [10][4][11]
It is not appropriate to introduce emetic agents or "neutralizing" agents into the treatment regimen after ingestion. There is high concern about aspiration, increased tissue damage with retching, and a strong possibility of exacerbating a bad situation. There is no current recommendation of systemic medications such as steroids, antibiotics, or prophylactic renal/hepatic therapies.
HF acid, among all the exposures mentioned above, can be treated with copious irrigation and application of a paste (commercially available and often supplied in an industrial setting where HF may be used commonly or made in the emergency department with powdered calcium gluconate and surgical lubricants). Some have recommended benzalkonium chloride solution. When applied, the treating clinician should use barrier protection. In some circumstances, intradermal or intraarterial injections of calcium (gluconate strongly preferred) have been used. Relief of pain is a good marker of efficacy of treatment. Monitoring of calcium and magnesium levels is important. Oral ingestion, often in the context of suicidal behavior, is likely to be fatal and may be treated with lavage. Monitoring of heart rhythms and electrolytes, including calcium and magnesium, is necessary. Lavage may be helpful, especially if calcium salts are used.
Disc batteries have the potential to leak alkali and cause local, generally esophageal, burns. This is typically seen in children and will require endoscopic management and radiographic tracking of location. Early removal is strongly recommended. If the battery has passed the pylorus, watchful waiting, and inspection of stool for passage is appropriate.
Differential Diagnosis
• CBRNE- Chemical decontamination
• CBRNE- Chemical warfare agents
• CBRNE- Vesicants, Mustard-Hd, Hn1-3
• Caustic ingestions
• Hazmat
• Magnesium and thermite poisoning
• Ocular burns and chemical injuries
Prognosis
The prognosis depends on the type of chemical and extent of the injury. Most small lesions heal well, but larger wounds often do not heal and can develop into scars. Hydrofluoric acid burns have typically been associated with loss of digits.
Chemical injuries to the eye are the most serious, resulting in severe scarring and permanent loss of vision.
Complications
The most common complications are pain and scarring.
Vision loss occurs when the eye is injured.
Most patients require multiple doctor visits, and many patients require skin grafts to alleviate the scars.
Postoperative and Rehabilitation Care
Except for first degree burns, all other burns require some type of followup. Skin burns need to be evaluated every 2-4 days until there are signs of healing. Patients with eye burns need to be seen in 24 hours.
For those who suffer a burn to the esophagus, endoscopy has to be repeated in 14-21 days to ensure that there is no stricture formation.
Consultations
Besides a general surgeon or a burn specialist, other consultants involved in the care of these patients include an ophthalmologist, ENT surgeon, Gastroenterologist and a pediatrician.
Deterrence and Patient Education
To avoid chemical injury in children, parents should keep all dangerous chemicals out of reach of the children.
Individuals who have attempted suicide with chemicals need a psychiatric referral.
Pearls and Other Issues
Chemical burns have the potential to impair short and long-term health and, especially when the eye or esophagus are involved, severely alter the individual's well-being. The clinician must be vigilant to monitor even minor appearing burns, especially with HF acid, as what initially appears to be minor may have serious side effects.
Enhancing Healthcare Team Outcomes
Because burns can occur on almost any part of the body, specific guidelines in the management of each organ system are lacking. However, there is expert evidence on managing the patient as a whole. However, there still remain several gaps in the early management of chemical burns. What solution to rinse the skin or the eye and when to debride are two issues that continue to be debated. But there is no debate that the eye should be rinsed thoroughly, and the patient must be seen by the ophthalmologist. Because burns can affect all organ systems an interprofessional approach with interaction is necessary to avoid the high morbidity of the disorder.
Since most burn patients are managed in a burn unit, the role of the nurse is vital. Often these professionals are the first to identify burn-related complications like infections, melena, difficulty swallowing, eschar formation and declining urine output. The pharmacist should be closely involved when burns are caused by medications like podophyllotoxin, formic acid or topical salicylic acid. Knowledge in managing topical burns, especially in children can help prevent disability. [12] [13] (level III)
Outcomes
The outcomes following a chemical burn depend on the chemical, extent of burn, comorbidity of the patient and time to intervention. Some chemicals are more harmful than others, but chemical burns to the eye are always serious. Because chemical burns can cause poor cosmesis and functional disability, a team approach to management is vital.[14][15] (Level V)
(Click Image to Enlarge)
Severe alkali burn to the right eye. Being lipophilic, alkali solutions penetrate the eye more rapidly and have the potential to penetrate ocular tissues. Acids, on the other hand, cause precipitation of proteins which creates a barrier and prevents further damage in most cases. There is destruction of the limbal stem cells causing limbal stem cell deficiency and opacification and neovasculatization of the cornea. There is symblepharon formation where by there are adhesions between the tarsal and bulbar conjunctiva with loss of the normal fornix. Other complications that can arise are increased intraocular pressure from inflammatory changes and direct damage to the trabecular meshwork. Loss of goblet cells and scarring of the lacrimal ductules exacerbates dryness.
Severe alkali burn to the right eye. Being lipophilic, alkali solutions penetrate the eye more rapidly and have the potential to penetrate ocular tissues. Acids, on the other hand, cause precipitation of proteins which creates a barrier and prevents further damage in most cases. There is destruction of the limbal stem cells causing limbal stem cell deficiency and opacification and neovasculatization of the cornea. There is symblepharon formation where by there are adhesions between the tarsal and bulbar conjunctiva with loss of the normal fornix. Other complications that can arise are increased intraocular pressure from inflammatory changes and direct damage to the trabecular meshwork. Loss of goblet cells and scarring of the lacrimal ductules exacerbates dryness.
Contributed by Prof. Bhupendra C.K. Patel MD, FRCS
Article Details
Article Author
Tess VanHoy
Article Author
Heidi Metheny
Article Editor:
Bhupendra Patel
Updated:
2/25/2021 4:31:56 PM
PubMed Link:
Chemical Burns
References
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Oseni OG,Olamoyegun KD,Olaitan PB, Paediatric burn epidemiology as a basis for developing a burn prevention program. Annals of burns and fire disasters. 2017 Dec 31 [PubMed PMID: 29983674]
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Rochlin DH,Rajasingh CM,Karanas YL,Davis DJ, Full-Thickness Chemical Burn From Trifluoroacetic Acid: A Case Report and Review of the Literature. Annals of plastic surgery. 2018 Jul 27 [PubMed PMID: 30059387]
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Stone Ii R,Natesan S,Kowalczewski CJ,Mangum LH,Clay NE,Clohessy RM,Carlsson AH,Tassin DH,Chan RK,Rizzo JA,Christy RJ, Advancements in Regenerative Strategies Through the Continuum of Burn Care. Frontiers in pharmacology. 2018 [PubMed PMID: 30038569]
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Malisiewicz B,Meissner M,Kaufmann R,Valesky E, [Physical and chemical emergencies in dermatology]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2018 May [PubMed PMID: 29500476]
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Baradaran-Rafii A,Eslani M,Haq Z,Shirzadeh E,Huvard MJ,Djalilian AR, Current and Upcoming Therapies for Ocular Surface Chemical Injuries. The ocular surface. 2017 Jan [PubMed PMID: 27650263]
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Huang YF,Wang LL, [How to improve the prevention and treatment of ocular chemical burns in China: important elements]. [Zhonghua yan ke za zhi] Chinese journal of ophthalmology. 2018 Jun 11 [PubMed PMID: 29895113]
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Ferreira AL,Ferreira JM,da Silva PM,Constancio DF, Genitalia burn: accident or violence? Concerns that transcend injury treatment. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2014 Jun [PubMed PMID: 25119763]
[14]
Lobeck I,Dupree P,Stoops M,de Alarcon A,Rutter M,von Allmen D, Interdisciplinary approach to esophageal replacement and major airway reconstruction. Journal of pediatric surgery. 2016 Jul [PubMed PMID: 26995523]
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Sudden Infant Death Syndrome (SIDS)
Topic Overview
What is sudden infant death syndrome (SIDS)?
Sometimes a baby who seems healthy dies during sleep. This is called sudden infant death syndrome or SIDS.
In most cases, a parent or caregiver places the baby down to sleep and returns later to find the baby has died. It's no one's fault. SIDS can happen even when you do everything right.
Although SIDS is rare, it is one of the most common causes of death in babies between 1 and 12 months of age. Most babies who die of SIDS are between the ages of 2 and 4 months.
What causes SIDS?
Doctors don't know what causes SIDS. It seems to happen more often in premature and low-birth-weight babies. It also is seen more often in babies whose mothers didn't get medical care during the pregnancy and in babies whose mothers smoke. SIDS may also be more likely in babies who were part of a multiple pregnancy (for example, twins or triplets) or whose mothers are younger than 20.
When babies sleep on their bellies, they may not breathe well. Not too long ago, side sleeping was said to be okay. But babies placed on their sides can easily roll onto their bellies and could have trouble breathing.
Researchers are studying the possibility that SIDS may be caused by problems with how well the brain controls breathing, heart rate and rhythm, and temperature during the first few months of life. More research on this is needed.
What are the symptoms?
SIDS has no symptoms or warning signs. Babies who die of SIDS seem healthy before being put to bed. They show no signs of struggle and are often found in the same position as when they were placed in the bed.
How is SIDS diagnosed?
SIDS is named the cause of death only when no other cause is found. To find out why a baby died, medical experts review the baby's and parents' medical histories, study the area where the baby died, and do an autopsy.
What can you do to reduce the risk of SIDS?
Doing certain things may help protect a baby from SIDS and/or other deaths related to sleep:footnote 1, footnote 2
• The most important thing you can do is to always place your baby to sleep on his or her back rather than on the stomach or side.
• Don't smoke while you are pregnant. And don't expose your baby to second-hand smoke smoke after your baby is born.
• For the first 6 months, have your baby sleep in a crib, cradle, or bassinet in the same room where you sleep. It is a safer sleeping arrangement than sharing a bed. Many families choose to bedshare, or find that they end up bedsharing even if they did not plan to do so. Bedsharing should be discussed with your health care provider.
• Stop or reduce your use of alcohol and other drugs. If you smoke or have used alcohol, illegal drugs, or medicine that makes you sleep very soundly (sedatives), bedsharing is especially risky and should be avoided.
• Never sleep with a baby on a couch or armchair. And it is not safe to place your baby on a couch to sleep. The safest place for a baby is in a crib, cradle, or bassinet that meets safety standards.
• Some babies fall asleep while travelling in a car seat. Keep an eye on a baby sleeping in the car and take your baby out of the car seat once you have reached your destination. Babies should not be left to sleep in a car seat, a stroller, baby swing, sling, or bouncer seat because their airway may become restricted.
• Keep soft items and loose bedding out of the crib. Items such as blankets, stuffed animals, toys, and pillows could suffocate or trap your baby. Dress your baby in sleepers instead of using blankets.
• Make sure that your baby's crib has a firm mattress (with a fitted sheet) or a firm surface. Don't use bumper pads or other products that attach to crib slats or sides. They could suffocate or trap your baby.
• Keep the room at a comfortable temperature so that your baby can sleep in lightweight clothes without a blanket. Usually, the temperature is about right if an adult can wear a long-sleeved T-shirt and pants without feeling cold. Make sure that your baby doesn't get too warm. Your baby is likely too warm if he or she sweats or tosses and turns a lot.
• Breastfeed your baby.
• Consider giving your baby a pacifier at nap time and bedtime. This may help prevent SIDS, though experts don't know why. If you breastfeed, wait until breastfeeding is well established before you start giving him or her a pacifier.
There is no sure way to prevent SIDS, and no examination or test can predict whether a baby is likely to die of SIDS. Don't rely on breathing (apnea) monitors, special mattresses, or other devices marketed as a way to reduce your baby's risk of SIDS. None of these items have been proved to lower the risk of SIDS. The Public Health Agency of Canada and other experts do not advise their use.
Remember, SIDS is rare. Be as safe as you can, but don't let fear keep you from enjoying your baby. Tell your baby's caregivers what you expect them to do. Don't assume that they know what to do to help keep your infant safe during sleep.
How can a family cope after losing a baby to SIDS?
Each member of your family may respond to the loss of the baby in a different way. These different ways of coping with the baby's death can strain a marriage and a family. Along with feeling grief, family members may be struggling with feelings of guilt. Support from family, friends, your doctor, and possibly other health professionals is very important for everyone. You might find it helpful to:
• Join a grief support group. Ask your doctor if one for parents who have lost babies to SIDS is available in your area.
• Get help from a counsellor, a psychologist, or a psychiatrist. Many families benefit from group counselling to help them deal with the tensions that arise after the loss of a baby.
• Talk with a close family member, a friend, or a spiritual adviser.
References
Citations
1. Public Health Agency of Canada, et al. (2011). Joint Statement on Safe Sleep: Preventing Sudden Infant Deaths in Canada. Available online: http://www.phac-aspc.gc.ca/hp-ps/dca-dea/stages-etapes/childhood-enfance_0-2/sids/pdf/jsss-ecss2011-eng.pdf.
2. Health Canada, Consumer Product Safety (2012). Is your child safe? Sleep time. Health Canada. http://www.hc-sc.gc.ca/cps-spc/pubs/cons/child-enfant/sleep-coucher-eng.php. Accessed October 14, 2015.
Credits
Adaptation Date: 11/5/2019
Adapted By: HealthLink BC
Adaptation Reviewed By: HealthLink BC
Is it an emergency?
If you or someone in your care has chest pains, difficulty breathing, or severe bleeding, it could be a life-threatening emergency. Call 9-1-1 or the local emergency number immediately.
If you are concerned about a possible poisoning or exposure to a toxic substance, call Poison Control now at 1-800-567-8911.
Thanks to our partners and endorsers:
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The woman is a new mom.
Postpartum Anxiety: How To Deal With It?
April 5, 2021 admin 0
What is the other baby blues you need to know about? Well, it is not actually a baby blues syndrome nor postpartum depression. So, what is it? In case you have an overly worried sensation after giving birth to your baby, you may suffer from a postpartum anxiety disorder. This condition can occur alongside depression. If you are experiencing a long-term symptom of anxiety, book a visit at Omnicare Medical in Southbank.
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Secondhand Smoke and Children Fact Sheet
Secondhand smoke is a mixture of the smoke given off by the burning end of a cigarette, pipe or cigar and the smoke exhaled from the lungs of smokers. Secondhand smoke is estimated to cause 3,000 lung cancer deaths annually and 35,000 heart disease deaths in non-smokers each year.
Children are especially susceptible: their lungs are still developing and childhood exposure to secondhand smoke results in decreased lung function. Children who breathe secondhand smoke are more likely to develop asthma, the leading serious chronic childhood disease in the US .
• In the U.S. , 43 percent of children are exposed to second-hand smoke in their own homes and 85 percent of children have detectable levels of cotinine in their blood.
• Exposure to secondhand smoke increases the severity and frequency of asthma episodes; 200,000 to 1,000,000 asthmatic children with asthma have experienced aggravated symptoms.
• Exposure to secondhand smoke causes 150,000 to 300,000 lower respiratory tract infections (pneumonia and bronchitis) annually in children 18 months and younger; these infections result in 7,500 to 15,000 hospitalizations each year.
• Secondhand smoke exposure causes buildup of fluid in the middle ear, resulting in 700,000 to 1.6 million physician office visits. Middle ear infections are the most common cause of childhood operations and of childhood hearing loss.
• A California EPA study estimated 1,900 to 2,700 sudden infant death syndrome (SIDS) deaths annually associated with secondhand smoke exposure.
This article was published by Lung.org, copyright 2013. It can be accessed online at the following link.
Tobacco Smoke
Secondhand Smoke Fact Sheet
Secondhand Smoke and Children Fact Sheet
What's Secondhand Smoke
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