diff --git "a/test_predictions.txt" "b/test_predictions.txt" new file mode 100644--- /dev/null +++ "b/test_predictions.txt" @@ -0,0 +1,32304 @@ +A O +novel O +SCN5A O +mutation O +manifests O +as O +a O +malignant O +form O +of O +long O +QT O +syndrome O +with O +perinatal O +onset O +of O +tachycardia O +/ O +bradycardia O +. O + +OBJECTIVE O +: O +Congenital O +long O +QT O +syndrome O +( O +LQTS O +) O +with O +in O +utero O +onset O +of O +the O +rhythm O +disturbances O +is O +associated O +with O +a O +poor O +prognosis O +. O + +In O +this O +study O +we O +investigated O +a O +newborn O +patient O +with O +fetal O +bradycardia O +, O +2 O +: O +1 O +atrioventricular O +block O +and O +ventricular O +tachycardia O +soon O +after O +birth O +. O + +METHODS O +: O +Mutational O +analysis O +and O +DNA O +sequencing O +were O +conducted O +in O +a O +newborn O +. O + +The O +2 O +: O +1 O +atrioventricular O +block O +improved O +to O +1 O +: O +1 O +conduction O +only O +after O +intravenous O +lidocaine B +infusion O +or O +a O +high O +dose O +of O +mexiletine B +, O +which O +also O +controlled O +the O +ventricular O +tachycardia O +. O + +RESULTS O +: O +A O +novel O +, O +spontaneous O +LQTS O +- O +3 O +mutation O +was O +identified O +in O +the O +transmembrane O +segment O +6 O +of O +domain O +IV O +of O +the O +Na O +( O +v O +) O +1 O +. O +5 O +cardiac O +sodium O +channel O +, O +with O +a O +G O +--> O +A O +substitution O +at O +codon O +1763 O +, O +which O +changed O +a O +valine O +( O +GTG B +) O +to O +a O +methionine O +( O +ATG O +). O + +The O +proband O +was O +heterozygous O +but O +the O +mutation O +was O +absent O +in O +the O +parents O +and O +the O +sister O +. O + +Expression O +of O +this O +mutant O +channel O +in O +tsA201 O +mammalian O +cells O +by O +site O +- O +directed O +mutagenesis O +revealed O +a O +persistent O +tetrodotoxin B +- O +sensitive O +but O +lidocaine B +- O +resistant O +current O +that O +was O +associated O +with O +a O +positive O +shift O +of O +the O +steady O +- O +state O +inactivation O +curve O +, O +steeper O +activation O +curve O +and O +faster O +recovery O +from O +inactivation O +. O + +We O +also O +found O +a O +similar O +electrophysiological O +profile O +for O +the O +neighboring O +V1764M O +mutant O +. O + +But O +, O +the O +other O +neighboring O +I1762A O +mutant O +had O +no O +persistent O +current O +and O +was O +still O +associated O +with O +a O +positive O +shift O +of O +inactivation O +. O + +CONCLUSIONS O +: O +These O +findings O +suggest O +that O +the O +Na O +( O +v O +) O +1 O +. O +5 O +/ O +V1763M O +channel O +dysfunction O +and O +possible O +neighboring O +mutants O +contribute O +to O +a O +persistent O +inward O +current O +due O +to O +altered O +inactivation O +kinetics O +and O +clinically O +congenital O +LQTS O +with O +perinatal O +onset O +of O +arrhythmias O +that O +responded O +to O +lidocaine B +and O +mexiletine B +. O + + +Allelic O +expression O +imbalance O +of O +human O +mu O +opioid O +receptor O +( O +OPRM1 O +) O +caused O +by O +variant O +A118G O +. O + +As O +a O +primary O +target O +for O +opioid B +drugs I +and O +peptides O +, O +the O +mu O +opioid O +receptor O +( O +OPRM1 O +) O +plays O +a O +key O +role O +in O +pain O +perception O +and O +addiction O +. O + +Genetic O +variants O +of O +OPRM1 O +have O +been O +implicated O +in O +predisposition O +to O +drug O +addiction O +, O +in O +particular O +the O +single O +nucleotide O +polymorphism O +A118G O +, O +leading O +to O +an O +N40D O +substitution O +, O +with O +an O +allele O +frequency O +of O +10 O +- O +32 O +%, O +and O +uncertain O +functions O +. O + +We O +have O +measured O +allele O +- O +specific O +mRNA O +expression O +of O +OPRM1 O +in O +human O +autopsy O +brain O +tissues O +, O +using O +A118G O +as O +a O +marker O +. O + +In O +8 O +heterozygous O +samples O +measured O +, O +the O +A118 O +mRNA O +allele O +was O +1 O +. O +5 O +- O +2 O +. O +5 O +- O +fold O +more O +abundant O +than O +the O +G118 O +allele O +. O + +Transfection O +into O +Chinese O +hamster O +ovary O +cells O +of O +a O +cDNA O +representing O +only O +the O +coding O +region O +of O +OPRM1 O +, O +carrying O +adenosine I +, O +guanosine O +, O +cytidine O +, O +and O +thymidine O +in O +position O +118 O +, O +resulted O +in O +1 O +. O +5 O +- O +fold O +lower O +mRNA O +levels O +only O +for O +OPRM1 O +- O +G118 O +, O +and O +more O +than O +10 O +- O +fold O +lower O +OPRM1 O +protein O +levels O +, O +measured O +by O +Western O +blotting O +and O +receptor O +binding O +assay O +. O + +After O +transfection O +and O +inhibition O +of O +transcription O +with O +actinomycin O +D O +, O +analysis O +of O +mRNA O +turnover O +failed O +to O +reveal O +differences O +in O +mRNA O +stability O +between O +A118 O +and O +G118 O +alleles O +, O +indicating O +a O +defect O +in O +transcription O +or O +mRNA O +maturation O +. O + +These O +results O +indicate O +that O +OPRM1 O +- O +G118 O +is O +a O +functional O +variant O +with O +deleterious O +effects O +on O +both O +mRNA O +and O +protein O +yield O +. O + +Clarifying O +the O +functional O +relevance O +of O +polymorphisms O +associated O +with O +susceptibility O +to O +a O +complex O +disorder O +such O +as O +drug O +addiction O +provides O +a O +foundation O +for O +clinical O +association O +studies O +. O + + +Genetic O +polymorphisms O +in O +the O +carbonyl O +reductase O +3 O +gene O +CBR3 O +and O +the O +NAD O +( O +P O +) O +H O +: O +quinone O +oxidoreductase O +1 O +gene O +NQO1 O +in O +patients O +who O +developed O +anthracycline O +- O +related O +congestive O +heart O +failure O +after O +childhood O +cancer O +. O + +BACKGROUND O +: O +Exposure O +to O +anthracyclines B +as O +part O +of O +cancer O +therapy O +has O +been O +associated O +with O +the O +development O +of O +congestive O +heart O +failure O +( O +CHF O +). O + +The O +potential O +role O +of O +genetic O +risk O +factors O +in O +anthracycline B +- O +related O +CHF O +remains O +to O +be O +defined O +. O + +Thus O +, O +in O +this O +study O +, O +the O +authors O +examined O +whether O +common O +polymorphisms O +in O +candidate O +genes O +involved O +in O +the O +pharmacodynamics O +of O +anthracyclines B +( O +in O +particular O +, O +the O +nicotinamide O +adenine O +dinucleotide O +phosphate O +: O +quinone O +oxidoreductase O +1 O +gene O +NQO1 O +and O +the O +carbonyl O +reductase O +3 O +gene O +CBR3 O +) O +had O +an O +impact O +on O +the O +risk O +of O +anthracycline O +- O +related O +CHF O +. O + +METHODS O +: O +A O +nested O +case O +- O +control O +study O +was O +conducted O +within O +a O +cohort O +of O +1979 O +patients O +enrolled O +in O +the O +Childhood O +Cancer O +Survivor O +Study O +who O +received O +treatment O +with O +anthracyclines B +and O +had O +available O +DNA O +. O + +Thirty O +patients O +with O +CHF O +( O +cases O +) O +and O +115 O +matched O +controls O +were O +genotyped O +for O +polymorphisms O +in O +NQO1 O +( O +NQO1 O +* O +2 O +) O +and O +CBR3 O +( O +the O +CBR3 O +valine O +[ O +V O +] O +to O +methionine O +[ O +M O +] O +substitution O +at O +position O +244 O +[ O +V244M O +]). O + +Enzyme O +activity O +assays O +with O +recombinant O +CBR3 O +isoforms O +( O +CBR3 O +V244 O +and O +CBR3 O +M244 O +) O +and O +the O +anthracycline B +substrate O +doxorubicin B +were O +used O +to O +investigate O +the O +functional O +impact O +of O +the O +CBR3 O +V244M O +polymorphism O +. O + +RESULTS O +: O +Multivariate O +analyses O +adjusted O +for O +sex O +and O +primary O +disease O +recurrence O +were O +used O +to O +test O +for O +associations O +between O +the O +candidate O +genetic O +polymorphisms O +( O +NQO1 O +* O +2 O +and O +CBR3 O +V244M O +) O +and O +the O +risk O +of O +CHF O +. O + +Analyses O +indicated O +no O +association O +between O +the O +NQO1 O +* O +2 O +polymorphism O +and O +the O +risk O +of O +anthracycline B +- O +related O +CHF O +( O +odds O +ratio O +[ O +OR O +], O +1 O +. O +4 O +; O +P O +=. O +97 O +). O + +There O +was O +a O +trend O +toward O +an O +association O +between O +the O +CBR3 O +V244M O +polymorphism O +and O +the O +risk O +of O +CHF O +( O +OR O +, O +8 O +. O +16 O +; O +P O +=. O +56 O +for O +G O +/ O +G O +vs O +A O +/ O +A O +; O +OR O +, O +5 O +. O +44 O +; O +P O +=. O +92 O +for O +G O +/ O +A O +vs O +A O +/ O +A O +). O + +In O +line O +, O +recombinant O +CBR3 O +V244 O +( O +G O +allele O +) O +synthesized O +2 O +. O +6 O +- O +fold O +more O +cardiotoxic O +doxorubicinol B +per O +unit O +of O +time O +than O +CBR3 O +M244 O +( O +A O +allele O +; O +CBR3 O +V244 O +[ O +8 O +. O +26 O ++/- O +3 O +. O +57 O +nmol O +/ O +hour O +. O +mg O +] O +vs O +CBR3 O +M244 O +[ O +3 O +. O +22 O ++/- O +0 O +. O +67 O +nmol O +/ O +hour O +. O +mg O +]; O +P O +=. O +1 O +). O + +CONCLUSIONS O +: O +The O +functional O +CBR3 O +V244M O +polymorphism O +may O +have O +an O +impact O +on O +the O +risk O +of O +anthracycline B +- O +related O +CHF O +among O +childhood O +cancer O +survivors O +by O +modulating O +the O +intracardiac O +formation O +of O +cardiotoxic O +anthracycline I +alcohol B +metabolites O +. O + +Larger O +confirmatory O +case O +- O +control O +studies O +are O +warranted O +. O + + +Debrisoquine B +phenotype O +and O +the O +pharmacokinetics O +and O +beta O +- O +2 O +receptor O +pharmacodynamics O +of O +metoprolol B +and O +its O +enantiomers O +. O + +The O +metabolism O +of O +the O +cardioselective O +beta O +- O +blocker O +metoprolol B +is O +under O +genetic O +control O +of O +the O +debrisoquine O +/ O +sparteine O +type O +. O + +The O +two O +metabolic O +phenotypes O +, O +extensive O +( O +EM O +) O +and O +poor O +metabolizers O +( O +PM O +), O +show O +different O +stereoselective O +metabolism O +, O +resulting O +in O +apparently O +higher O +beta O +- O +1 O +adrenoceptor O +antagonistic O +potency O +of O +racemic O +metoprolol B +in O +EMs O +. O + +We O +investigated O +if O +the O +latter O +also O +applies O +to O +the O +beta O +- O +2 O +adrenoceptor O +antagonism O +by O +metoprolol B +. O + +The O +drug O +effect O +studied O +was O +the O +antagonism O +by O +metoprolol B +of O +terbutaline B +- O +induced O +hypokalemia O +. O + +By O +using O +pharmacokinetic O +pharmacodynamic O +modeling O +the O +pharmacodynamics O +of O +racemic O +metoprolol B +and O +the O +active O +S B +- I +isomer I +, O +were O +quantitated O +in O +EMs O +and O +PMs O +in O +terms O +of O +IC50 O +values O +, O +representing O +metoprolol B +plasma O +concentrations O +resulting O +in O +half O +- O +maximum O +receptor O +occupancy O +. O + +Six O +EMs O +received O +0 O +. O +5 O +mg O +of O +terbutaline B +s O +. O +c O +. O + +on O +two O +different O +occasions O +: O +1 O +) O +1 O +hr O +after O +administration O +of O +a O +placebo O +and O +2 O +) O +1 O +hr O +after O +150 O +mg O +of O +metoprolol B +p O +. O +o O +. O + +Five O +PMs O +were O +studied O +according O +to O +the O +same O +protocol O +, O +except O +for O +a O +higher O +terbutaline O +dose O +( O +0 O +. O +75 O +mg O +) O +on O +day O +2 O +. O + +Blood O +samples O +for O +the O +analysis O +of O +plasma O +potassium B +, O +terbutaline B +, O +metoprolol B +( O +racemic O +, O +R I +- I +and O +S B +- I +isomer I +), O +and O +alpha B +- I +hydroxymetoprolol I +concentrations O +were O +taken O +at O +regular O +time O +intervals O +, O +during O +8 O +hr O +after O +metoprolol B +. O + +In O +PMs O +, O +metoprolol B +increased O +the O +terbutaline B +area O +under O +the O +plasma O +concentration O +vs O +. O + +time O +curve O +(+ O +67 O +%). O + +Higher O +metoprolol B +/ O +alpha B +- I +hydroxymetoprolol I +ratios O +in O +PMs O +were O +predictive O +for O +higher O +R O +-/ O +S B +- I +isomer I +ratios O +of O +unchanged O +drug O +. O + +There O +was O +a O +difference O +in O +metoprolol B +potency O +with O +higher O +racemic O +metoprolol B +IC50 O +values O +in O +PMs O +( O +72 O ++/- O +7 O +ng O +. O +ml O +- O +1 O +) O +than O +EMs O +( O +42 O ++/- O +8 O +ng O +. O +ml O +- O +1 O +, O +P O +less O +than O +. O +1 O +). O + +( O +ABSTRACT O +TRUNCATED O +AT O +250 O +WORDS O +) O + + +The O +first O +founder O +DGUOK O +mutation O +associated O +with O +hepatocerebral O +mitochondrial O +DNA O +depletion O +syndrome O +. O + +Deoxyguanosine B +kinase O +( O +dGK O +) O +deficiency O +is O +a O +frequent O +cause O +of O +mitochondrial O +DNA O +depletion O +associated O +with O +a O +hepatocerebral O +phenotype O +. O + +In O +this O +study O +, O +we O +describe O +a O +new O +splice O +site O +mutation O +in O +the O +DGUOK O +gene O +and O +the O +clinical O +, O +radiologic O +, O +and O +genetic O +features O +of O +these O +DGUOK O +patients O +. O + +This O +new O +DGUOK O +homozygous O +mutation O +( O +c O +. O +444 O +- O +62C O +> O +A O +) O +was O +identified O +in O +three O +patients O +from O +two O +North O +- O +African O +consanguineous O +families O +with O +combined O +respiratory O +chain O +deficiencies O +and O +mitochondrial O +DNA O +depletion O +in O +the O +liver O +. O + +Brain O +MRIs O +are O +normal O +in O +DGUOK O +patients O +in O +the O +literature O +. O + +Interestingly O +, O +we O +found O +subtentorial O +abnormal O +myelination O +and O +moderate O +hyperintensity O +in O +the O +bilateral O +pallidi O +in O +our O +patients O +. O + +This O +new O +mutation O +creates O +a O +cryptic O +splice O +site O +in O +intron O +3 O +( O +in O +position O +- O +62 O +) O +and O +is O +predicted O +to O +result O +in O +a O +larger O +protein O +with O +an O +in O +- O +frame O +insertion O +of O +20 O +amino O +acids O +. O + +In O +silico O +analysis O +of O +the O +putative O +impact O +of O +the O +insertion O +shows O +serious O +clashes O +in O +protein O +conformation O +: O +this O +insertion O +disrupts O +the O +alpha5 O +helix O +of O +the O +dGK O +kinase O +domain O +, O +rendering O +the O +protein O +unable O +to O +bind O +purine O +deoxyribonucleosides O +. O + +In O +addition O +, O +a O +common O +haplotype O +that O +segregated O +with O +the O +disease O +in O +both O +families O +was O +detected O +by O +haplotype O +reconstruction O +with O +10 O +markers O +( O +microsatellites O +and O +SNPs O +), O +which O +span O +4 O +. O +6 O +Mb O +of O +DNA O +covering O +the O +DGUOK O +locus O +. O + +In O +conclusion O +, O +we O +report O +a O +new O +DGUOK O +splice O +site O +mutation O +that O +provide O +insight O +into O +a O +critical O +protein O +domain O +( O +dGK O +kinase O +domain O +) O +and O +the O +first O +founder O +mutation O +in O +a O +North O +- O +African O +population O +. O + + +Adenosine O +A O +( O +2A O +) O +receptor O +gene O +( O +ADORA2A O +) O +variants O +may O +increase O +autistic O +symptoms O +and O +anxiety O +in O +autism O +spectrum O +disorder O +. O + +Autism O +spectrum O +disorders O +( O +ASDs O +) O +are O +heterogeneous O +disorders O +presenting O +with O +increased O +rates O +of O +anxiety O +. O + +The O +adenosine O +A O +( O +2A O +) O +receptor O +gene O +( O +ADORA2A O +) O +is O +associated O +with O +panic O +disorder O +and O +is O +located O +on O +chromosome O +22q11 O +. O +23 O +. O + +Its O +gene O +product O +, O +the O +adenosine O +A O +( O +2A O +) O +receptor O +, O +is O +strongly O +expressed O +in O +the O +caudate O +nucleus O +, O +which O +also O +is O +involved O +in O +ASD O +. O + +As O +autistic O +symptoms O +are O +increased O +in O +individuals O +with O +22q11 O +. O +2 O +deletion O +syndrome O +, O +and O +large O +22q11 O +. O +2 O +deletions O +and O +duplications O +have O +been O +observed O +in O +ASD O +individuals O +, O +in O +this O +study O +, O +98 O +individuals O +with O +ASD O +and O +234 O +control O +individuals O +were O +genotyped O +for O +eight O +single O +- O +nucleotide O +polymorphisms O +in O +ADORA2A O +. O + +Nominal O +association O +with O +the O +disorder O +was O +observed O +for O +rs2236624 O +- O +CC O +, O +and O +phenotypic O +variability O +in O +ASD O +symptoms O +was O +influenced O +by O +rs3761422 O +, O +rs5751876 O +and O +rs35320474 O +. O + +In O +addition O +, O +association O +of O +ADORA2A O +variants O +with O +anxiety O +was O +replicated O +for O +individuals O +with O +ASD O +. O + +Findings O +point O +toward O +a O +possible O +mediating O +role O +of O +ADORA2A O +variants O +on O +phenotypic O +expression O +in O +ASD O +that O +need O +to O +be O +replicated O +in O +a O +larger O +sample O +. O + + +High O +frequency O +of O +lamivudine B +resistance O +mutations O +in O +Brazilian O +patients O +co O +- O +infected O +with O +HIV O +and O +hepatitis O +B O +. O + +This O +study O +analyzed O +the O +genotype O +distribution O +and O +frequency O +of O +lamivudine B +( O +LAM B +) O +and O +tenofovir B +( O +TDF O +) O +resistance O +mutations O +in O +a O +group O +of O +patients O +co O +- O +infected O +with O +HIV O +and O +hepatitis O +B O +virus O +( O +HBV O +). O + +A O +cross O +- O +sectional O +study O +of O +847 O +patients O +with O +HIV O +was O +conducted O +. O + +Patients O +provided O +blood O +samples O +for O +HBsAg O +detection O +. O + +The O +load O +of O +HBV O +was O +determined O +using O +an O +in O +- O +house O +real O +- O +time O +polymerase O +chain O +reaction O +. O + +HBV O +genotypes O +/ O +subgenotypes O +, O +antiviral O +resistance O +, O +basal O +core O +promoter O +( O +BCP O +), O +and O +precore O +mutations O +were O +detected O +by O +DNA O +sequencing O +. O + +Twenty O +- O +eight O +patients O +with O +co O +- O +infection O +were O +identified O +. O + +The O +distribution O +of O +HBV O +genotypes O +among O +these O +patients O +was O +A O +( O +n O += O +9 O +; O +50 O +%), O +D O +( O +n O += O +4 O +; O +22 O +. O +2 O +%), O +G O +( O +n O += O +3 O +; O +16 O +. O +7 O +%), O +and O +F O +( O +n O += O +2 O +; O +11 O +. O +1 O +%). O + +Eighteen O +patients O +were O +treated O +with O +LAM B +and O +six O +patients O +were O +treated O +with O +LAM B +plus O +TDF O +. O + +The O +length O +of O +exposure O +to O +LAM B +and O +TDF O +varied O +from O +4 O +to O +216 O +months O +. O + +LAM B +resistance O +substitutions O +( O +rtL180M O ++ O +rtM204V O +) O +were O +detected O +in O +10 O +( O +50 O +%) O +of O +the O +20 O +patients O +with O +viremia O +. O + +This O +pattern O +and O +an O +accompanying O +rtV173L O +mutation O +was O +found O +in O +four O +patients O +. O + +Three O +patients O +with O +the O +triple O +polymerase O +substitution O +pattern O +( O +rtV173L O ++ O +rtL180M O ++ O +rtM204V O +) O +had O +associated O +changes O +in O +the O +envelope O +gene O +( O +sE164D O ++ O +sI195M O +). O + +Mutations O +in O +the O +BCP O +region O +( O +A1762T O +, O +G1764A O +) O +and O +in O +the O +precore O +region O +( O +G1896A O +, O +G1899A O +) O +were O +also O +found O +. O + +No O +putative O +TDF O +resistance O +substitution O +was O +detected O +. O + +The O +data O +suggest O +that O +prolonged O +LAM B +use O +is O +associated O +with O +the O +emergence O +of O +particular O +changes O +in O +the O +HBV O +genome O +, O +including O +substitutions O +that O +may O +elicit O +a O +vaccine O +escape O +phenotype O +. O + +No O +putative O +TDF O +resistance O +change O +was O +detected O +after O +prolonged O +use O +of O +TDF O +. O + + +Identification O +of O +a O +novel O +FBN1 O +gene O +mutation O +in O +a O +Chinese O +family O +with O +Marfan O +syndrome O +. O + +PURPOSE O +: O +To O +identify O +the O +mutation O +in O +the O +fibrillin O +- O +1 O +gene O +( O +FBN1 O +) O +in O +a O +Chinese O +family O +with O +Marfan O +syndrome O +( O +MFS O +). O + +METHODS O +: O +Patients O +and O +family O +members O +were O +given O +complete O +physical O +, O +ophthalmic O +, O +and O +cardiovascular O +examinations O +. O + +Genomic O +DNA O +was O +extracted O +from O +leukocytes O +of O +venous O +blood O +of O +six O +individuals O +in O +the O +family O +and O +170 O +healthy O +Chinese O +individuals O +. O + +All O +of O +the O +65 O +coding O +exons O +and O +their O +flanking O +intronic O +boundaries O +of O +FBN1 O +were O +amplified O +in O +the O +proband O +by O +polymerase O +chain O +reaction O +and O +followed O +by O +direct O +sequencing O +. O + +The O +mutation O +identified O +in O +the O +proband O +was O +screened O +in O +the O +other O +family O +members O +and O +the O +170 O +healthy O +Chinese O +individuals O +by O +direct O +sequencing O +. O + +Protein O +conservation O +analysis O +was O +performed O +in O +six O +species O +using O +an O +online O +ClustalW O +tool O +. O + +Protein O +structure O +was O +modeled O +based O +on O +the O +Protein O +data O +bank O +and O +mutated O +in O +DeepView O +v4 O +. O +0 O +. O +1 O +to O +predict O +the O +functional O +consequences O +of O +the O +mutation O +. O + +RESULTS O +: O +A O +novel O +heterozygous O +c O +. O +3703T O +> O +C O +change O +in O +exon O +29 O +of O +FBN1 O +was O +detected O +in O +the O +proband O +, O +which O +resulted O +in O +the O +substitution O +of O +serine O +by O +proline O +at O +codon O +1235 O +( O +p O +. O +S1235P O +). O + +This O +mutation O +was O +also O +present O +in O +two O +family O +members O +but O +absent O +in O +the O +other O +, O +unaffected O +family O +members O +and O +the O +170 O +healthy O +Chinese O +individuals O +. O + +The O +mutant O +residue O +located O +in O +the O +calcium B +binding O +epidermal O +growth O +factor O +- O +like O +# O +15 O +domain O +is O +highly O +conserved O +among O +mammalian O +species O +and O +could O +probably O +induce O +conformation O +change O +of O +the O +domain O +. O + +CONCLUSIONS O +: O +We O +indentified O +a O +novel O +p O +. O +S1235P O +mutation O +in O +FBN1 O +, O +which O +is O +the O +causative O +mutation O +for O +MFS O +in O +this O +family O +. O + +Our O +result O +expands O +the O +mutation O +spectrum O +of O +FBN1 O +and O +contributes O +to O +the O +study O +of O +the O +molecular O +pathogenesis O +of O +Marfan O +syndrome O +. O + + +Molecular O +and O +phenotypic O +analysis O +of O +patients O +with O +deletions O +within O +the O +deletion O +- O +rich O +region O +of O +the O +Duchenne O +muscular O +dystrophy O +( O +DMD O +) O +gene O +. O + +Eighty O +unrelated O +individuals O +with O +Duchenne O +muscular O +dystrophy O +( O +DMD O +) O +or O +Becker O +muscular O +dystrophy O +( O +BMD O +) O +were O +found O +to O +have O +deletions O +in O +the O +major O +deletion O +- O +rich O +region O +of O +the O +DMD O +locus O +. O + +This O +region O +includes O +the O +last O +five O +exons O +detected O +by O +cDNA5b O +- O +7 O +, O +all O +exons O +detected O +by O +cDNA8 O +, O +and O +the O +first O +two O +exons O +detected O +by O +cDNA9 O +. O + +These O +80 O +individuals O +account O +for O +approximately O +75 O +% O +of O +109 O +deletions O +of O +the O +gene O +, O +detected O +among O +181 O +patients O +analyzed O +with O +the O +entire O +dystrophin O +cDNA O +. O + +Endpoints O +for O +many O +of O +these O +deletions O +were O +further O +characterized O +using O +two O +genomic O +probes O +, O +p20 O +( O +DXS269 O +; O +Wapenaar O +et O +al O +.) O + +and O +GMGX11 O +( O +DXS239 O +; O +present O +paper O +). O + +Clinical O +findings O +are O +presented O +for O +all O +80 O +patients O +allowing O +a O +correlation O +of O +phenotypic O +severity O +with O +the O +genotype O +. O + +Thirty O +- O +eight O +independent O +patients O +were O +old O +enough O +to O +be O +classified O +as O +DMD O +, O +BMD O +, O +or O +intermediate O +phenotype O +and O +had O +deletions O +of O +exons O +with O +sequenced O +intron O +/ O +exon O +boundaries O +. O + +Of O +these O +, O +eight O +BMD O +patients O +and O +one O +intermediate O +patient O +had O +gene O +deletions O +predicted O +to O +leave O +the O +reading O +frame O +intact O +, O +while O +21 O +DMD O +patients O +, O +7 O +intermediate O +patients O +, O +and O +1 O +BMD O +patient O +had O +gene O +deletions O +predicted O +to O +disrupt O +the O +reading O +frame O +. O + +Thus O +, O +with O +two O +exceptions O +, O +frameshift O +deletions O +of O +the O +gene O +resulted O +in O +more O +severe O +phenotype O +than O +did O +in O +- O +frame O +deletions O +. O + +This O +is O +in O +agreement O +with O +recent O +findings O +by O +Baumbach O +et O +al O +. O + +and O +Koenig O +et O +al O +. O + +but O +is O +in O +contrast O +to O +findings O +, O +by O +Malhotra O +et O +al O +. O + +at O +the O +5 O +' O +end O +of O +the O +gene O +. O + + +Absence O +of O +PKC O +- O +alpha O +attenuates O +lithium B +- O +induced O +nephrogenic O +diabetes O +insipidus O +. O + +Lithium B +, O +an O +effective O +antipsychotic B +, O +induces O +nephrogenic O +diabetes O +insipidus O +( O +NDI O +) O +in O +40 O +% O +of O +patients O +. O + +The O +decreased O +capacity O +to O +concentrate O +urine O +is O +likely O +due O +to O +lithium B +acutely O +disrupting O +the O +cAMP O +pathway O +and O +chronically O +reducing O +urea O +transporter O +( O +UT O +- O +A1 O +) O +and O +water O +channel O +( O +AQP2 O +) O +expression O +in O +the O +inner O +medulla O +. O + +Targeting O +an O +alternative O +signaling O +pathway O +, O +such O +as O +PKC O +- O +mediated O +signaling O +, O +may O +be O +an O +effective O +method O +of O +treating O +lithium B +- O +induced O +polyuria O +. O + +PKC O +- O +alpha O +null O +mice O +( O +PKCa O +KO O +) O +and O +strain O +- O +matched O +wild O +type O +( O +WT O +) O +controls O +were O +treated O +with O +lithium B +for O +0 O +, O +3 O +or O +5 O +days O +. O + +WT B +mice O +had O +increased O +urine O +output O +and O +lowered O +urine O +osmolality O +after O +3 O +and O +5 O +days O +of O +treatment O +whereas O +PKCa O +KO O +mice O +had O +no O +change O +in O +urine O +output O +or O +concentration O +. O + +Western O +blot O +analysis O +revealed O +that O +AQP2 O +expression O +in O +medullary O +tissues O +was O +lowered O +after O +3 O +and O +5 O +days O +in O +WT O +mice O +; O +however O +, O +AQP2 O +was O +unchanged O +in O +PKCa O +KO O +. O + +Similar O +results O +were O +observed O +with O +UT O +- O +A1 O +expression O +. O + +Animals O +were O +also O +treated O +with O +lithium B +for O +6 O +weeks O +. O + +Lithium B +- O +treated O +WT O +mice O +had O +19 O +- O +fold O +increased O +urine O +output O +whereas O +treated O +PKCa O +KO O +animals O +had O +a O +4 O +- O +fold O +increase O +in O +output O +. O + +AQP2 O +and O +UT O +- O +A1 O +expression O +was O +lowered O +in O +6 O +week O +lithium B +- O +treated O +WT O +animals O +whereas O +in O +treated O +PKCa O +KO O +mice O +, O +AQP2 O +was O +only O +reduced O +by O +2 O +- O +fold O +and O +UT O +- O +A1 O +expression O +was O +unaffected O +. O + +Urinary O +sodium B +, O +potassium B +and O +calcium B +were O +elevated O +in O +lithium B +- O +fed O +WT O +but O +not O +in O +lithium B +- O +fed O +PKCa O +KO O +mice O +. O + +Our O +data O +show O +that O +ablation O +of O +PKCa O +preserves O +AQP2 O +and O +UT O +- O +A1 O +protein O +expression O +and O +localization O +in O +lithium B +- O +induced O +NDI O +, O +and O +prevents O +the O +development O +of O +the O +severe O +polyuria O +associated O +with O +lithium B +therapy O +. O + + +Decreased O +Whole O +- O +Body O +Fat O +Mass O +Produced O +by O +Chronic O +Alcohol B +Consumption O +is O +Associated O +with O +Activation O +of O +S6K1 O +- O +Mediated O +Protein O +Synthesis O +and O +Increased O +Autophagy O +in O +Epididymal O +White O +Adipose O +Tissue O +. O + +BACKGROUND O +: O +Chronic O +alcohol B +consumption O +leads O +to O +a O +loss O +of O +white O +adipose O +tissue O +( O +WAT O +) O +but O +the O +underlying O +mechanisms O +for O +this O +lipodystrophy O +are O +not O +fully O +elucidated O +. O + +This O +study O +tested O +the O +hypothesis O +that O +the O +reduction O +in O +WAT O +mass O +in O +chronic O +alcohol B +- O +fed O +mice O +is O +associated O +with O +a O +decreased O +protein O +synthesis O +specifically O +related O +to O +impaired O +function O +of O +mammalian O +target O +of O +rapamycin O +( O +mTOR O +). O + +METHODS O +: O +Adult O +male O +mice O +were O +provided O +an O +alcohol B +- O +containing O +liquid O +diet O +for O +24 O +weeks O +or O +an O +isonitrogenous O +isocaloric O +control O +diet O +. O + +In O +vivo O +protein O +synthesis O +was O +determined O +at O +this O +time O +and O +thereafter O +epididymal O +WAT O +( O +eWAT O +) O +was O +excised O +for O +analysis O +of O +signal O +transduction O +pathways O +central O +to O +controling O +protein O +synthesis O +and O +degradation O +. O + +RESULTS O +: O +While O +chronic O +alcohol B +feeding O +decreased O +whole O +- O +body O +and O +eWAT O +mass O +, O +this O +was O +associated O +with O +a O +discordant O +increase O +in O +protein O +synthesis O +in O +eWAT O +. O + +This O +increase O +was O +not O +associated O +with O +a O +change O +in O +mTOR O +, O +4E O +- O +BP1 O +, O +Akt O +, O +or O +PRAS40 O +phosphorylation O +. O + +Instead O +, O +a O +selective O +increase O +in O +phosphorylation O +of O +S6K1 O +and O +its O +downstream O +substrates O +, O +S6 O +and O +eIF4B O +was O +detected O +in O +alcohol B +- O +fed O +mice O +. O + +Alcohol B +also O +increased O +eEF2K O +phosphorylation O +and O +decreased O +eEF2 O +phosphorylation O +consistent O +with O +increased O +translation O +elongation O +. O + +Alcohol B +increased O +Atg12 O +- O +5 O +, O +LC3B O +- O +I O +and O +- O +II O +, O +and O +ULK1 O +S555 O +phosphorylation O +, O +suggesting O +increased O +autophagy O +, O +while O +markers O +of O +apoptosis O +( O +cleaved O +caspase O +- O +3 O +and O +- O +9 O +, O +and O +PARP O +) O +were O +unchanged O +. O + +Lipolytic O +enzymes O +( O +ATGL O +and O +HSL O +phosphorylation O +) O +were O +increased O +and O +lipogenic O +regulators O +( O +PPARgamma O +and O +C O +/ O +EBPalpha O +) O +were O +decreased O +in O +eWAT O +by O +alcohol B +. O + +Although O +alcohol B +increased O +TNF O +- O +alpha O +, O +IL O +- O +6 O +, O +and O +IL O +- O +1beta O +mRNA O +, O +no O +change O +in O +key O +components O +of O +the O +NLRP3 O +inflammasome O +( O +NLRP3 O +, O +ACS O +, O +and O +cleaved B +caspase O +- O +1 O +) O +was O +detected O +suggesting O +alcohol B +did O +not O +increase O +pyroptosis O +. O + +Plasma O +insulin O +did O +not O +differ O +between O +groups O +. O + +CONCLUSIONS O +: O +These O +results O +demonstrate O +that O +the O +alcohol B +- O +induced O +decrease O +in O +whole O +- O +body O +fat O +mass O +resulted O +in O +part O +from O +activation O +of O +autophagy O +in O +eWAT O +as O +protein O +synthesis O +was O +increased O +and O +mediated O +by O +the O +specific O +increase O +in O +the O +activity O +of O +S6K1 O +. O + + +Nefiracetam O +( O +DM O +- O +9384 O +) O +reverses O +apomorphine B +- O +induced O +amnesia O +of O +a O +passive O +avoidance O +response O +: O +delayed O +emergence O +of O +the O +memory O +retention O +effects O +. O + +Nefiracetam O +is O +a O +novel O +pyrrolidone O +derivative O +which O +attenuates O +scopolamine B +- O +induced O +learning O +and O +post O +- O +training O +consolidation O +deficits O +. O + +Given O +that O +apomorphine B +inhibits O +passive O +avoidance O +retention O +when O +given O +during O +training O +or O +in O +a O +defined O +10 O +- O +12h O +post O +- O +training O +period O +, O +we O +evaluated O +the O +ability O +of O +nefiracetam O +to O +attenuate O +amnesia O +induced O +by O +dopaminergic B +agonism I +. O + +A O +step O +- O +down O +passive O +avoidance O +paradigm O +was O +employed O +and O +nefiracetam O +( O +3 O +mg O +/ O +kg O +) O +and O +apomorphine B +( O +0 O +. O +5 O +mg O +/ O +kg O +) O +were O +given O +alone O +or O +in O +combination O +during O +training O +and O +at O +the O +10 O +- O +12h O +post O +- O +training O +period O +of O +consolidation O +. O + +Co O +- O +administration O +of O +nefiracetam O +and O +apomorphine B +during O +training O +or O +10h O +thereafter O +produced O +no O +significant O +anti O +- O +amnesic O +effect O +. O + +However O +, O +administration O +of O +nefiracetam O +during O +training O +completely O +reversed O +the O +amnesia O +induced O +by O +apomorphine B +at O +the O +10h O +post O +- O +training O +time O +and O +the O +converse O +was O +also O +TRUE O +. O + +These O +effects O +were O +not O +mediated O +by O +a O +dopaminergic B +mechanism O +as O +nefiracetam O +, O +at O +millimolar O +concentrations O +, O +failed O +to O +displace O +either O +[ O +3H O +] O +SCH O +23390 O +or O +[ O +3H O +] O +spiperone O +binding O +from O +D1 O +or O +D2 O +dopamine O +receptor O +subtypes O +, O +respectively O +. O + +It O +is O +suggested O +that O +nefiracetam O +augments O +molecular O +processes O +in O +the O +early O +stages O +of O +events O +which O +ultimately O +lead O +to O +consolidation O +of O +memory O +. O + + +Pethidine O +- O +associated O +seizure O +in O +a O +healthy O +adolescent O +receiving O +pethidine O +for O +postoperative O +pain O +control O +. O + +A O +healthy O +17 O +- O +year O +- O +old O +male O +received O +standard O +intermittent O +doses O +of O +pethidine O +via O +a O +patient O +- O +controlled O +analgesia O +( O +PCA O +) O +pump O +for O +management O +of O +postoperative O +pain O +control O +. O + +Twenty O +- O +three O +h O +postoperatively O +he O +developed O +a O +brief O +self O +- O +limited O +seizure O +. O + +Both O +plasma O +pethidine B +and O +norpethidine B +were O +elevated O +in O +the O +range O +associated O +with O +clinical O +manifestations O +of O +central O +nervous O +system O +excitation O +. O + +No O +other O +risk O +factors O +for O +CNS O +toxicity O +were O +identified O +. O + +This O +method O +allowed O +frequent O +self O +- O +dosing O +of O +pethidine B +at O +short O +time O +intervals O +and O +rapid O +accumulation O +of O +pethidine O +and O +norpethidine B +. O + +The O +routine O +use O +of O +pethidine O +via O +PCA O +even O +for O +a O +brief O +postoperative O +analgesia O +should O +be O +reconsidered O +. O + + +Recovery O +of O +tacrolimus B +- O +associated O +brachial O +neuritis O +after O +conversion O +to O +everolimus B +in O +a O +pediatric O +renal O +transplant O +recipient O +-- O +case O +report O +and O +review O +of O +the O +literature O +. O + +TAC O +has O +been O +shown O +to O +be O +a O +potent O +immunosuppressive O +agent O +for O +solid O +organ O +transplantation O +in O +pediatrics O +. O + +Neurotoxicity O +is O +a O +potentially O +serious O +toxic O +effect O +. O + +It O +is O +characterized O +by O +encephalopathy O +, O +headaches O +, O +seizures O +, O +or O +neurological O +deficits O +. O + +Here O +, O +we O +describe O +an O +eight O +- O +and O +- O +a O +- O +half O +- O +yr O +- O +old O +male O +renal O +transplant O +recipient O +with O +right O +BN O +. O + +MRI O +demonstrated O +hyperintense O +T2 O +signals O +in O +the O +cervical O +cord O +and O +right O +brachial O +plexus O +roots O +indicative O +of O +both O +myelitis O +and O +right O +brachial O +plexitis O +. O + +Symptoms O +persisted O +for O +three O +months O +despite O +TAC O +dose O +reduction O +, O +administration O +of O +IVIG O +and O +four O +doses O +of O +methylprednisolone B +pulse O +therapy O +. O + +Improvement O +and O +eventually O +full O +recovery O +only O +occurred O +after O +TAC O +was O +completely O +discontinued O +and O +successfully O +replaced O +by O +everolimus B +. O + + +MOL1 O +is O +required O +for O +cambium O +homeostasis O +in O +Arabidopsis O +. O + +Plants O +maintain O +pools O +of O +pluripotent O +stem O +cells O +which O +allow O +them O +to O +constantly O +produce O +new O +tissues O +and O +organs O +. O + +Stem O +cell O +homeostasis O +in O +shoot O +and O +root O +tips O +depends O +on O +negative O +regulation O +by O +ligand O +- O +receptor O +pairs O +of O +the O +CLE O +peptide O +and O +leucine O +- O +rich O +repeat O +receptor O +- O +like O +kinase O +( O +LRR O +- O +RLK O +) O +families O +. O + +However O +, O +regulation O +of O +the O +cambium O +, O +the O +stem O +cell O +niche O +required O +for O +lateral O +growth O +of O +shoots O +and O +roots O +, O +is O +poorly O +characterized O +. O + +Here O +we O +show O +that O +the O +LRR O +- O +RLK O +MOL1 O +is O +necessary O +for O +cambium O +homeostasis O +in O +Arabidopsis O +thaliana O +. O + +By O +employing O +promoter O +reporter O +lines O +, O +we O +reveal O +that O +MOL1 O +is O +active O +in O +a O +domain O +that O +is O +distinct O +from O +the O +domain O +of O +the O +positively O +acting O +CLE41 O +/ O +PXY O +signaling O +module O +. O + +In O +particular O +, O +we O +show O +that O +MOL1 O +acts O +in O +an O +opposing O +manner O +to O +the O +CLE41 O +/ O +PXY O +module O +and O +that O +changing O +the O +domain O +or O +level O +of O +MOL1 O +expression O +both O +result O +in O +disturbed O +cambium O +organization O +. O + +Underlining O +discrete O +roles O +of O +MOL1 O +and O +PXY O +, O +both O +LRR O +- O +RLKs O +are O +not O +able O +to O +replace O +each O +other O +when O +their O +expression O +domains O +are O +interchanged O +. O + +Furthermore O +, O +MOL1 O +but O +not O +PXY O +is O +able O +to O +rescue O +CLV1 O +deficiency O +in O +the O +shoot O +apical O +meristem O +. O + +By O +identifying O +genes O +mis O +- O +expressed O +in O +mol1 O +mutants O +, O +we O +demonstrate O +that O +MOL1 O +represses O +genes O +associated O +with O +stress O +- O +related O +ethylene O +and O +jasmonic O +acid O +hormone O +signaling O +pathways O +which O +have O +known O +roles O +in O +coordinating O +lateral O +growth O +of O +the O +Arabidopsis O +stem O +. O + +Our O +findings O +provide O +evidence O +that O +common O +regulatory O +mechanisms O +in O +different O +plant O +stem O +cell O +niches O +are O +adapted O +to O +specific O +niche O +anatomies O +and O +emphasize O +the O +importance O +of O +a O +complex O +spatial O +organization O +of O +intercellular O +signaling O +cascades O +for O +a O +strictly O +bidirectional O +tissue O +production O +. O + + +In O +vivo O +evidences O +suggesting O +the O +role O +of O +oxidative O +stress O +in O +pathogenesis O +of O +vancomycin B +- O +induced O +nephrotoxicity O +: O +protection O +by O +erdosteine O +. O + +The O +aims O +of O +this O +study O +were O +to O +examine O +vancomycin B +( O +VCM O +)- O +induced O +oxidative O +stress O +that O +promotes O +production O +of O +reactive B +oxygen I +species I +( O +ROS B +) O +and O +to O +investigate O +the O +role O +of O +erdosteine O +, O +an O +expectorant O +agent O +, O +which O +has O +also O +antioxidant O +properties O +, O +on O +kidney O +tissue O +against O +the O +possible O +VCM O +- O +induced O +renal O +impairment O +in O +rats O +. O + +Rats O +were O +divided O +into O +three O +groups O +: O +sham O +, O +VCM O +and O +VCM O +plus O +erdosteine O +. O + +VCM O +was O +administrated O +intraperitoneally O +( O +i O +. O +p O +.) O + +with O +200mgkg O +(- O +1 O +) O +twice O +daily O +for O +7 O +days O +. O + +Erdosteine O +was O +administered O +orally O +. O + +VCM O +administration O +to O +control O +rats O +significantly O +increased O +renal O +malondialdehyde B +( O +MDA B +) O +and O +urinary O +N B +- I +acetyl O +- O +beta O +- I +d I +- I +glucosaminidase I +( O +NAG O +, O +a O +marker O +of O +renal O +tubular O +injury O +) O +excretion O +but O +decreased O +superoxide O +dismutase O +( O +SOD O +) O +and O +catalase O +( O +CAT O +) O +activities O +. O + +Erdosteine O +administration O +with O +VCM O +injections O +caused O +significantly O +decreased O +renal O +MDA B +and O +urinary O +NAG O +excretion O +, O +and O +increased O +SOD O +activity O +, O +but O +not O +CAT O +activity O +in O +renal O +tissue O +when O +compared O +with O +VCM O +alone O +. O + +Erdosteine O +showed O +histopathological O +protection O +against O +VCM O +- O +induced O +nephrotoxicity O +. O + +There O +were O +a O +significant O +dilatation O +of O +tubular O +lumens O +, O +extensive O +epithelial O +cell O +vacuolization O +, O +atrophy B +, O +desquamation O +, O +and O +necrosis O +in O +VCM O +- O +treated O +rats O +more O +than O +those O +of O +the O +control O +and O +the O +erdosteine O +groups O +. O + +Erdosteine O +caused O +a O +marked O +reduction O +in O +the O +extent O +of O +tubular O +damage O +. O + +It O +is O +concluded O +that O +oxidative O +tubular O +damage O +plays O +an O +important O +role O +in O +the O +VCM O +- O +induced O +nephrotoxicity O +and O +the O +modulation O +of O +oxidative O +stress O +with O +erdosteine O +reduces O +the O +VCM O +- O +induced O +kidney O +damage O +both O +at O +the O +biochemical O +and O +histological O +levels O +. O + + +Mutation O +screening O +of O +the O +GUCA1B O +gene O +in O +patients O +with O +autosomal O +dominant O +cone O +and O +cone O +rod O +dystrophy O +. O + +Background O +: O +Heterozygous O +mutations O +in O +GUCA1A O +( O +MIM O +# O +600364 O +) O +have O +been O +identified O +to O +cause O +autosomal O +dominantly O +inherited O +cone O +dystrophy O +, O +cone O +rod O +dystrophy O +and O +macular O +dystrophy O +. O + +However O +, O +the O +role O +of O +GUCA1B O +gene O +mutations O +in O +inherited O +retinal O +disease O +has O +been O +controversial O +. O + +We O +therefore O +performed O +a O +mutation O +analysis O +of O +the O +GUCA1B O +gene O +in O +a O +clinically O +well O +characterized O +group O +of O +patients O +of O +European O +and O +North O +- O +American O +geographical O +origin O +with O +autosomal O +dominantly O +inherited O +cone O +dystrophy O +and O +cone O +rod O +dystrophy O +. O + +Material O +and O +Methods O +: O +Twenty O +- O +four O +unrelated O +patients O +diagnosed O +with O +cone O +dystrophy O +or O +cone O +rod O +dystrophy O +according O +to O +standard O +diagnostic O +criteria O +and O +a O +family O +history O +consistent O +with O +an O +autosomal O +dominant O +mode O +of O +inheritance O +were O +included O +in O +the O +study O +. O + +Mutation O +analysis O +of O +all O +coding O +exons O +of O +the O +GUCA1B O +gene O +was O +performed O +by O +polymerase O +chain O +reaction O +amplification O +of O +genomic O +DNA O +and O +subsequent O +DNA O +sequencing O +. O + +Results O +: O +Three O +different O +sequence O +variants O +, O +c O +.- O +17T O +> O +C O +, O +c O +. O +171T O +> O +C O +, O +c O +. O +465G O +> O +T O +were O +identified O +. O + +The O +sequence O +variant O +c O +. O +465G O +> O +T O +encodes O +a O +conservative O +amino O +acid O +substitution O +, O +p O +. O +Glu155Asp O +, O +located O +in O +EF O +- O +hand O +4 O +, O +the O +calcium O +binding O +site O +of O +GCAP2 O +protein O +. O + +All O +sequence O +variants O +were O +previously O +reported O +in O +healthy O +subjects O +. O + +Conclusion O +: O +The O +absence O +of O +clearly O +pathogenic O +mutations O +in O +the O +selected O +patient O +group O +suggests O +that O +the O +GUCA1B O +gene O +is O +a O +minor O +cause O +for O +retinal O +degenerations O +in O +Europeans O +or O +North O +- O +Americans O +. O + + +Cardioprotective O +effect O +of O +tincture O +of O +Crataegus B +on O +isoproterenol B +- O +induced O +myocardial O +infarction O +in O +rats O +. O + +Tincture O +of O +Crataegus O +( O +TCR O +), O +an O +alcoholic O +extract O +of O +the O +berries O +of O +hawthorn O +( O +Crataegus O +oxycantha O +), O +is O +used O +in O +herbal O +and O +homeopathic O +medicine O +. O + +The O +present O +study O +was O +done O +to O +investigate O +the O +protective O +effect O +of O +TCR O +on O +experimentally O +induced O +myocardial O +infarction O +in O +rats O +. O + +Pretreatment O +of O +TCR O +, O +at O +a O +dose O +of O +0 O +. O +5 O +mL O +/ O +100 O +g O +bodyweight O +per O +day O +, O +orally O +for O +30 O +days O +, O +prevented O +the O +increase O +in O +lipid B +peroxidation O +and O +activity O +of O +marker O +enzymes O +observed O +in O +isoproterenol B +- O +induced O +rats O +( O +85 O +mg O +kg O +(- O +1 O +) O +s O +. O +c O +. O +for O +2 O +days O +at O +an O +interval O +of O +24 O +h O +). O + +TCR O +prevented O +the O +isoproterenol B +- O +induced O +decrease O +in O +antioxidant O +enzymes O +in O +the O +heart O +and O +increased O +the O +rate O +of O +ADP B +- O +stimulated O +oxygen B +uptake O +and O +respiratory O +coupling O +ratio O +. O + +TCR O +protected O +against O +pathological O +changes O +induced O +by O +isoproterenol B +in O +rat O +heart O +. O + +The O +results O +show O +that O +pretreatment O +with O +TCR O +may O +be O +useful O +in O +preventing O +the O +damage O +induced O +by O +isoproterenol B +in O +rat O +heart O +. O + + +A O +novel O +splicing O +mutation O +in O +SLC12A3 O +associated O +with O +Gitelman O +syndrome O +and O +idiopathic O +intracranial O +hypertension O +. O + +We O +report O +a O +case O +of O +Gitelman O +syndrome O +( O +GS O +) O +in O +a O +dizygotic O +twin O +who O +presented O +at O +12 O +years O +of O +age O +with O +growth O +delay O +, O +metabolic O +alkalosis O +, O +hypomagnesemia O +and O +hypokalemia O +with O +inappropriate O +kaliuresis O +, O +and O +idiopathic O +intracranial O +hypertension O +with O +bilateral O +papilledema O +( O +pseudotumor O +cerebri O +). O + +The O +patient O +, O +her O +twin O +sister O +, O +and O +her O +mother O +also O +presented O +with O +cerebral O +cavernous O +malformations O +. O + +Based O +on O +the O +early O +onset O +and O +normocalciuria O +, O +Bartter O +syndrome O +was O +diagnosed O +first O +. O + +However O +, O +mutation O +analysis O +showed O +that O +the O +proband O +is O +a O +compound O +heterozygote O +for O +2 O +mutations O +in O +SLC12A3 O +: O +a O +substitution O +of O +serine O +by O +leucine O +at O +amino O +acid O +position O +555 O +( O +p O +. O +Ser555Leu O +) O +and O +a O +novel O +guanine O +to O +cytosine O +transition O +at O +the O +5 O +' O +splice O +site O +of O +intron O +22 O +( O +c O +. O +2633 O ++ O +1G O +> O +C O +), O +providing O +the O +molecular O +diagnosis O +of O +GS O +. O + +These O +mutations O +were O +not O +detected O +in O +200 O +normal O +chromosomes O +and O +cosegregated O +within O +the O +family O +. O + +Analysis O +of O +complementary O +DNA O +showed O +that O +the O +heterozygous O +nucleotide O +change O +c O +. O +2633 O ++ O +1G O +> O +C O +caused O +the O +appearance O +of O +2 O +RNA O +molecules O +, O +1 O +normal O +transcript O +and O +1 O +skipping O +the O +entire O +exon O +22 O +( O +r O +. O +2521_2634del O +). O + +Supplementation O +with O +potassium B +and O +magnesium O +improved O +clinical O +symptoms O +and O +resulted O +in O +catch O +- O +up O +growth O +, O +but O +vision O +remained O +impaired O +. O + +Three O +similar O +associations O +of O +Bartter O +syndrome O +/ O +GS O +with O +pseudotumor O +cerebri O +were O +found O +in O +the O +literature O +, O +suggesting O +that O +electrolyte O +abnormalities O +and O +secondary O +aldosteronism B +may O +have O +a O +role O +in O +idiopathic O +intracranial O +hypertension O +. O + +This O +study O +provides O +further O +evidence O +for O +the O +phenotypical O +heterogeneity O +of O +GS O +and O +its O +association O +with O +severe O +manifestations O +in O +children O +. O + +It O +also O +shows O +the O +independent O +segregation O +of O +familial O +cavernomatosis O +and O +GS O +. O + + +Association O +between O +polymorphisms O +in O +SLC30A8 O +, O +HHEX O +, O +CDKN2A O +/ O +B O +, O +IGF2BP2 O +, O +FTO O +, O +WFS1 O +, O +CDKAL1 O +, O +KCNQ1 O +and O +type O +2 O +diabetes O +in O +the O +Korean O +population O +. O + +According O +to O +recent O +genome O +- O +wide O +association O +studies O +, O +a O +number O +of O +single O +nucleotide O +polymorphisms O +( O +SNPs O +) O +are O +reported O +to O +be O +associated O +with O +type O +2 O +diabetes O +mellitus O +( O +T2DM O +). O + +The O +aim O +of O +the O +present O +study O +was O +to O +investigate O +the O +association O +among O +the O +polymorphisms O +of O +SLC30A8 O +, O +HHEX O +, O +CDKN2A O +/ O +B O +, O +IGF2BP2 O +, O +FTO O +, O +WFS1 O +, O +CDKAL1 O +and O +KCNQ1 O +and O +the O +risk O +of O +T2DM O +in O +the O +Korean O +population O +. O + +This O +study O +was O +based O +on O +a O +multicenter O +case O +- O +control O +study O +, O +including O +908 O +patients O +with O +T2DM O +and O +502 O +non O +- O +diabetic O +controls O +. O + +We O +genotyped O +rs13266634 O +, O +rs1111875 O +, O +rs10811661 O +, O +rs4402960 O +, O +rs8050136 O +, O +rs734312 O +, O +rs7754840 O +and O +rs2237892 O +and O +measured O +the O +body O +weight O +, O +body O +mass O +index O +and O +fasting O +plasma O +glucose B +in O +all O +patients O +and O +controls O +. O + +The O +strongest O +association O +was O +found O +in O +a O +variant O +of O +CDKAL1 O +[ O +rs7754840 O +, O +odds O +ratio O +( O +OR O +) O += O +1 O +. O +77 O +, O +95 O +% O +CI O += O +1 O +. O +50 O +- O +2 O +. O +10 O +, O +p O += O +5 O +. O +0 O +x O +10 O +(- O +11 O +)]. O + +The O +G O +allele O +of O +rs1111875 O +( O +OR O += O +1 O +. O +43 O +, O +95 O +% O +CI O += O +1 O +. O +18 O +- O +1 O +. O +72 O +, O +p O += O +1 O +. O +8 O +x O +10 O +(- O +4 O +)) O +in O +HHEX O +), O +the O +T O +allele O +of O +rs10811661 O +( O +OR O += O +1 O +. O +47 O +, O +95 O +% O +CI O += O +1 O +. O +23 O +- O +1 O +. O +75 O +, O +p O += O +2 O +. O +1 O +x O +10 O +(- O +5 O +)) O +in O +CDKN2A O +/ O +B O +) O +and O +the O +C O +allele O +of O +rs2237892 O +( O +OR O += O +1 O +. O +31 O +, O +95 O +% O + +CI O += O +1 O +. O +10 O +- O +1 O +. O +56 O +, O +p O += O +0 O +. O +3 O +) O +in O +KCNQ1 O +showed O +significant O +associations O +with O +T2DM O +. O + +Rs13266634 O +( O +OR O += O +1 O +. O +19 O +, O +95 O +% O +CI O += O +1 O +. O +0 O +- O +1 O +. O +42 O +, O +p O += O +0 O +. O +45 O +) O +in O +SLC30A8 O +showed O +a O +nominal O +association O +with O +the O +risk O +of O +T2DM O +, O +whereas O +SNPs O +in O +IGF2BP2 O +, O +FTO O +and O +WFS1 O +were O +not O +associated O +. O + +In O +conclusion O +, O +we O +have O +shown O +that O +SNPs O +in O +HHEX O +, O +CDKN2A O +/ O +B O +, O +CDKAL1 O +, O +KCNQ1 O +and O +SLC30A8 O +confer O +a O +risk O +of O +T2DM O +in O +the O +Korean O +population O +. O + + +Serotonin O +6 O +receptor O +gene O +is O +associated O +with O +methamphetamine B +- O +induced O +psychosis O +in O +a O +Japanese O +population O +. O + +BACKGROUND O +: O +Altered O +serotonergic O +neural O +transmission O +is O +hypothesized O +to O +be O +a O +susceptibility O +factor O +for O +psychotic O +disorders O +such O +as O +schizophrenia O +. O + +The O +serotonin O +6 O +( O +5 O +- O +HT6 O +) O +receptor O +is O +therapeutically O +targeted O +by O +several O +second O +generation O +antipsychotics O +, O +such O +as O +clozapine B +and O +olanzapine B +, O +and O +d B +- I +amphetamine I +- O +induced O +hyperactivity O +in O +rats O +is O +corrected O +with O +the O +use O +of O +a O +selective O +5 O +- O +HT6 O +receptor O +antagonist O +. O + +In O +addition O +, O +the O +disrupted O +prepulse O +inhibition O +induced O +by O +d B +- I +amphetamine I +or O +phencyclidine B +was O +restored O +by O +5 B +- I +HT6 I +receptor I +antagonist I +in O +an O +animal O +study O +using O +rats O +. O + +These O +animal O +models O +were O +considered O +to O +reflect O +the O +positive O +symptoms O +of O +schizophrenia O +, O +and O +the O +above O +evidence O +suggests O +that O +altered O +5 O +- O +HT6 O +receptors O +are O +involved O +in O +the O +pathophysiology O +of O +psychotic O +disorders O +. O + +The O +symptoms O +of O +methamphetamine B +( O +METH B +)- O +induced O +psychosis O +are O +similar O +to O +those O +of O +paranoid O +type O +schizophrenia O +. O + +Therefore O +, O +we O +conducted O +an O +analysis O +of O +the O +association O +of O +the O +5 O +- O +HT6 O +gene O +( O +HTR6 O +) O +with O +METH B +- O +induced O +psychosis O +. O + +METHOD O +: O +Using O +five O +tagging O +SNPs O +( O +rs6693503 O +, O +rs1805054 O +, O +rs4912138 O +, O +rs3790757 O +and O +rs9659997 O +), O +we O +conducted O +a O +genetic O +association O +analysis O +of O +case O +- O +control O +samples O +( O +197 O +METH O +- O +induced O +psychosis O +patients O +and O +337 O +controls O +) O +in O +the O +Japanese O +population O +. O + +The O +age O +and O +sex O +of O +the O +control O +subjects O +did O +not O +differ O +from O +those O +of O +the O +methamphetamine B +dependence O +patients O +. O + +RESULTS O +: O +rs6693503 O +was O +associated O +with O +METH B +- O +induced O +psychosis O +patients O +in O +the O +allele O +/ O +genotype O +- O +wise O +analysis O +. O + +Moreover O +, O +this O +association O +remained O +significant O +after O +Bonferroni O +correction O +. O + +In O +the O +haplotype O +- O +wise O +analysis O +, O +we O +detected O +an O +association O +between O +two O +markers O +( O +rs6693503 O +and O +rs1805054 O +) O +and O +three O +markers O +( O +rs6693503 O +, O +rs1805054 O +and O +rs4912138 O +) O +in O +HTR6 O +and O +METH O +- O +induced O +psychosis O +patients O +, O +respectively O +. O + +CONCLUSION O +: O +HTR6 O +may O +play O +an O +important O +role O +in O +the O +pathophysiology O +of O +METH B +- O +induced O +psychosis O +in O +the O +Japanese O +population O +. O + + +Reciprocal O +effects O +of O +NNK O +and O +SLURP O +- O +1 O +on O +oncogene O +expression O +in O +target O +epithelial O +cells O +. O + +AIMS O +: O +To O +elucidate O +how O +the O +nicotinic O +acetylcholine O +receptors O +expressed O +on O +bronchial O +and O +oral O +epithelial O +cells O +targeted O +by O +the O +tobacco O +nitrosamine B +( O +4 B +-( I +methylnitrosamino I +)- O +1 I +-( O +3 O +- I +pyridyl I +)- O +1 I +- O +butanone O +) O +( O +NNK O +) O +facilitate O +carcinogenic O +transformation O +. O + +MAIN O +METHODS O +: O +Since O +NNK O +- O +dependent O +transformation O +can O +be O +abolished O +by O +the O +nicotinergic O +secreted O +mammalian O +Ly O +- O +6 O +/ O +urokinase O +plasminogen O +activator O +receptor O +related O +protein O +- O +1 O +( O +SLURP O +- O +1 O +), O +we O +compared O +effects O +of O +NNK O +and O +recombinant O +( O +r O +) O +SLURP O +- O +1 O +on O +the O +expression O +of O +genes O +related O +to O +tumorigenesis O +in O +human O +immortalized O +bronchial O +and O +oral O +epithelial O +cell O +lines O +BEP2D O +and O +Het O +- O +1A O +, O +respectively O +. O + +KEY O +FINDINGS O +: O +NNK O +stimulated O +expression O +of O +oncogenic O +genes O +, O +including O +MYB O +and O +PIK3CA O +in O +BEP2D O +, O +ETS1 O +, O +NRAS O +and O +SRC O +in O +Het O +- O +1A O +, O +and O +AKT1 O +, O +KIT O +and O +RB1 O +in O +both O +cell O +types O +, O +which O +could O +be O +abolished O +in O +the O +presence O +of O +rSLURP O +- O +1 O +. O + +Other O +cancer O +- O +related O +genes O +whose O +upregulation O +by O +NNK O +was O +abolishable O +by O +rSLURP O +- O +1 O +were O +the O +growth O +factors O +EGF O +in O +BEP2D O +cells O +and O +HGF O +in O +Het O +- O +1A O +cells O +, O +and O +the O +transcription O +factors O +CDKN2A O +and O +STAT3 O +( O +Het O +- O +1A O +only O +). O + +NNK O +also O +upregulated O +the O +anti O +- O +apoptotic O +BCL2 O +( O +Het O +- O +1A O +) O +and O +downregulated O +the O +pro O +- O +apoptotic O +TNF O +( O +Het O +- O +1A O +), O +BAX O +and O +CASP8 O +( O +BEP2D O +), O +all O +of O +which O +could O +be O +abolished O +, O +in O +part O +, O +by O +rSLURP O +- O +1 O +. O + +NNK O +decreased O +expression O +of O +the O +CTNNB1 O +gene O +encoding O +the O +intercellular O +adhesion O +molecule O +beta O +- O +catenin O +( O +BEP2D O +), O +as O +well O +as O +tumor O +suppressors O +CDKN3 O +and O +FOXD3 O +in O +BEP2D O +cells O +and O +SERPINB5 O +in O +Het O +- O +1A O +cells O +. O + +These O +pro O +- O +oncogenic O +effects O +of O +NNK O +were O +abolished O +by O +rSLURP O +- O +1 O +that O +also O +upregulated O +RUNX3 O +. O + +SIGNIFICANCE O +: O +The O +obtained O +results O +identified O +target O +genes O +for O +both O +NNK O +and O +SLURP O +- O +1 O +and O +shed O +light O +on O +the O +molecular O +mechanism O +of O +their O +reciprocal O +effects O +on O +tumorigenic O +transformation O +of O +bronchial O +and O +oral O +epithelial O +cells O +. O + + +Long O +- O +term O +exposure O +of O +MCF O +- O +7 O +breast O +cancer O +cells O +to O +ethanol O +stimulates O +oncogenic O +features O +. O + +Alcohol B +consumption O +is O +a O +risk O +factor O +for O +breast O +cancer O +. O + +Little O +is O +known O +regarding O +the O +mechanism O +, O +although O +it O +is O +assumed O +that O +acetaldehyde B +or O +estrogen B +mediated O +pathways O +play O +a O +role O +. O + +We O +previously O +showed O +that O +long O +- O +term O +exposure O +to O +2 O +. O +5 O +mM O +ethanol O +( O +blood O +alcohol B +~ O +0 O +. O +12 O +%) O +of O +MCF O +- O +12A O +, O +a O +human O +normal O +epithelial O +breast O +cell O +line O +, O +induced O +epithelial O +mesenchymal O +transition O +( O +EMT O +) O +and O +oncogenic O +transformation O +. O + +In O +this O +study O +, O +we O +investigated O +in O +the O +human O +breast O +cancer O +cell O +line O +MCF O +- O +7 O +, O +whether O +a O +similar O +exposure O +to O +ethanol O +at O +concentrations O +ranging O +up O +to O +peak O +blood O +levels O +in O +heavy O +drinkers O +would O +increase O +malignant O +progression O +. O + +Short O +- O +term O +( O +1 O +- O +week O +) O +incubation O +to O +ethanol O +at O +as O +low O +as O +1 O +- O +5 O +mM O +( O +corresponding O +to O +blood O +alcohol B +concentration O +of O +~ O +0 O +. O +48 O +- O +0 O +. O +24 O +%) O +upregulated O +the O +stem O +cell O +related O +proteins O +4-Oct O +and O +Nanog O +, O +but O +they O +were O +reduced O +after O +exposure O +at O +25 O +mM O +. O + +Long O +- O +term O +( O +4 O +- O +week O +) O +exposure O +to O +25 O +mM O +ethanol O +upregulated O +the O +4-Oct O +and O +Nanog O +proteins O +, O +as O +well O +as O +the O +malignancy O +marker O +Ceacam6 O +. O + +DNA O +microarray O +analysis O +in O +cells O +exposed O +for O +1 O +week O +showed O +upregulated O +expression O +of O +metallothionein O +genes O +, O +particularly O +MT1X O +. O + +Long O +- O +term O +exposure O +upregulated O +expression O +of O +some O +malignancy O +related O +genes O +( O +STEAP4 O +, O +SERPINA3 O +, O +SAMD9 O +, O +GDF15 O +, O +KRT15 O +, O +ITGB6 O +, O +TP63 O +, O +and O +PGR O +, O +as O +well O +as O +the O +CEACAM O +, O +interferon O +related O +, O +and O +HLA O +gene O +families O +). O + +Some O +of O +these O +findings O +were O +validated O +by O +RT O +- O +PCR O +. O + +A O +similar O +treatment O +also O +modulated O +numerous O +microRNAs O +( O +miRs O +) O +including O +one O +regulator O +of O +4-Oct O +as O +well O +as O +miRs O +involved O +in O +oncogenesis O +and O +/ O +or O +malignancy O +, O +with O +only O +a O +few O +estrogen B +- O +induced O +miRs O +. O + +Long O +- O +term O +25 O +mM O +ethanol O +also O +induced O +a O +5 O +. O +6 O +- O +fold O +upregulation O +of O +anchorage O +- O +independent O +growth O +, O +an O +indicator O +of O +malignant O +- O +like O +features O +. O + +Exposure O +to O +acetaldehyde B +resulted O +in O +little O +or O +no O +effect O +comparable O +to O +that O +of O +ethanol O +. O + +The O +previously O +shown O +alcohol B +induction O +of O +oncogenic O +transformation O +of O +normal O +breast O +cells O +is O +now O +complemented O +by O +the O +current O +results O +suggesting O +alcohol B +' O +s O +potential O +involvement O +in O +malignant O +progression O +of O +breast O +cancer O +. O + + +Large O +contiguous O +gene O +deletions O +in O +Sjogren O +- O +Larsson O +syndrome O +. O + +Sjogren O +- O +Larsson O +syndrome O +( O +SLS O +) O +is O +an O +autosomal O +recessive O +disorder O +characterized O +by O +ichthyosis O +, O +mental O +retardation O +, O +spasticity O +and O +mutations O +in O +the O +ALDH3A2 O +gene O +for O +fatty O +aldehyde O +dehydrogenase O +, O +an O +enzyme O +that O +catalyzes O +the O +oxidation O +of O +fatty O +aldehyde O +to O +fatty B +acid I +. O + +More O +than O +70 O +mutations O +have O +been O +identified O +in O +SLS O +patients O +, O +including O +small O +deletions O +or O +insertions O +, O +missense O +mutations O +, O +splicing O +defects O +and O +complex O +nucleotide O +changes O +. O + +We O +now O +describe O +2 O +SLS O +patients O +whose O +disease O +is O +caused O +by O +large O +contiguous O +gene O +deletions O +of O +the O +ALDH3A2 O +locus O +on O +17p11 O +. O +2 O +. O + +The O +deletions O +were O +defined O +using O +long O +distance O +inverse O +PCR O +and O +microarray O +- O +based O +comparative O +genomic O +hybridization O +. O + +A O +24 O +- O +year O +- O +old O +SLS O +female O +was O +homozygous O +for O +a O +352 O +- O +kb O +deletion O +involving O +ALDH3A2 O +and O +4 O +contiguous O +genes O +including O +ALDH3A1 O +, O +which O +codes O +for O +the O +major O +soluble O +protein O +in O +cornea O +. O + +Although O +lacking O +corneal O +disease O +, O +she O +showed O +severe O +symptoms O +of O +SLS O +with O +uncommon O +deterioration O +in O +oral O +motor O +function O +and O +loss O +of O +ambulation O +. O + +The O +other O +19 O +- O +month O +- O +old O +female O +patient O +was O +a O +compound O +heterozygote O +for O +a O +1 O +. O +44 O +- O +Mb O +contiguous O +gene O +deletion O +and O +a O +missense O +mutation O +( O +c O +. O +407C O +> O +T O +, O +P136L O +) O +in O +ALDH3A2 O +. O + +These O +studies O +suggest O +that O +large O +gene O +deletions O +may O +account O +for O +up O +to O +5 O +% O +of O +the O +mutant O +alleles O +in O +SLS O +. O + +Geneticists O +should O +consider O +the O +possibility O +of O +compound O +heterozygosity O +for O +large O +deletions O +in O +patients O +with O +SLS O +and O +other O +inborn O +errors O +of O +metabolism O +, O +which O +has O +implications O +for O +carrier O +testing O +and O +prenatal O +diagnosis O +. O + + +Serum O +Amyloid O +A O +Induces O +Inflammation O +, O +Proliferation O +and O +Cell O +Death O +in O +Activated O +Hepatic O +Stellate O +Cells O +. O + +Serum O +amyloid O +A O +( O +SAA O +) O +is O +an O +evolutionary O +highly O +conserved O +acute O +phase O +protein O +that O +is O +predominantly O +secreted O +by O +hepatocytes O +. O + +However O +, O +its O +role O +in O +liver O +injury O +and O +fibrogenesis O +has O +not O +been O +elucidated O +so O +far O +. O + +In O +this O +study O +, O +we O +determined O +the O +effects O +of O +SAA O +on O +hepatic O +stellate O +cells O +( O +HSCs O +), O +the O +main O +fibrogenic O +cell O +type O +of O +the O +liver O +. O + +Serum O +amyloid O +A O +potently O +activated O +IkappaB O +kinase O +, O +c O +- O +Jun O +N O +- O +terminal O +kinase O +( O +JNK O +), O +Erk O +and O +Akt O +and O +enhanced O +NF O +- O +kappaB O +- O +dependent O +luciferase O +activity O +in O +primary O +human O +and O +rat O +HSCs O +. O + +Serum O +amyloid O +A O +induced O +the O +transcription O +of O +MCP O +- O +1 O +, O +RANTES O +and O +MMP9 O +in O +an O +NF O +- O +kappaB O +- O +and O +JNK O +- O +dependent O +manner O +. O + +Blockade O +of O +NF O +- O +kappaB O +revealed O +cytotoxic O +effects O +of O +SAA O +in O +primary O +HSCs O +with O +signs O +of O +apoptosis O +such O +as O +caspase O +3 O +and O +PARP B +cleavage O +and O +Annexin O +V O +staining O +. O + +Serum O +amyloid O +A O +induced O +HSC O +proliferation O +, O +which O +depended O +on O +JNK O +, O +Erk O +and O +Akt O +activity O +. O + +In O +primary O +hepatocytes O +, O +SAA O +also O +activated O +MAP O +kinases O +, O +but O +did O +not O +induce O +relevant O +cell O +death O +after O +NF O +- O +kappaB O +inhibition O +. O + +In O +two O +models O +of O +hepatic O +fibrogenesis O +, O +CCl4 O +treatment O +and O +bile O +duct O +ligation O +, O +hepatic O +mRNA O +levels O +of O +SAA1 O +and O +SAA3 O +were O +strongly O +increased O +. O + +In O +conclusion O +, O +SAA O +may O +modulate O +fibrogenic O +responses O +in O +the O +liver O +in O +a O +positive O +and O +negative O +fashion O +by O +inducing O +inflammation O +, O +proliferation O +and O +cell O +death O +in O +HSCs O +. O + + +Influence O +of O +interleukin O +12B O +( O +IL12B O +) O +polymorphisms O +on O +spontaneous O +and O +treatment O +- O +induced O +recovery O +from O +hepatitis O +C O +virus O +infection O +. O + +BACKGROUND O +/ O +AIMS O +: O +Interleukin O +- O +12 O +( O +IL O +- O +12 O +) O +governs O +the O +Th1 O +- O +type O +immune O +response O +, O +affecting O +the O +spontaneous O +and O +treatment O +- O +induced O +recovery O +from O +HCV O +- O +infection O +. O + +We O +investigated O +whether O +the O +IL12B O +polymorphisms O +within O +the O +promoter O +region O +( O +4 O +bp O +insertion O +/ O +deletion O +) O +and O +the O +3 O +'- O +UTR O +( O +1188 O +- O +A O +/ O +C O +), O +which O +have O +been O +reported O +to O +influence O +IL O +- O +12 O +synthesis O +, O +are O +associated O +with O +the O +outcome O +of O +HCV O +infection O +. O + +METHODS O +: O +We O +analyzed O +186 O +individuals O +with O +spontaneous O +HCV O +clearance O +, O +501 O +chronically O +HCV O +infected O +patients O +, O +and O +217 O +healthy O +controls O +. O + +IL12B O +3 O +'- O +UTR O +and O +promoter O +genotyping O +was O +performed O +by O +Taqman O +- O +based O +assays O +with O +allele O +- O +specific O +oligonucleotide O +probes O +and O +PCR O +- O +based O +allele O +- O +specific O +DNA O +- O +amplification O +, O +respectively O +. O + +RESULTS O +: O +The O +proportion O +of O +IL12B O +promoter O +and O +3 O +'- O +UTR O +genotypes O +did O +not O +differ O +significantly O +between O +the O +different O +cohorts O +. O + +However O +, O +HCV O +genotype O +1 O +- O +infected O +patients O +with O +high O +baseline O +viremia O +carrying O +the O +IL12B O +3 O +'- O +UTR O +1188 O +- O +C O +- O +allele O +showed O +significantly O +higher O +sustained O +virologic O +response O +( O +SVR O +) O +rates O +( O +25 O +. O +3 O +% O +vs O +. O + +46 O +% O +vs O +. O + +54 O +. O +5 O +% O +for O +A O +/ O +A O +, O +A O +/ O +C O +and O +C O +/ O +C O +) O +due O +to O +reduced O +relapse O +rates O +( O +24 O +. O +2 O +% O +vs O +. O + +12 O +% O +vs O +. O + +zero O +% O +for O +A O +/ O +A O +, O +A O +/ O +C O +and O +C O +/ O +C O +). O + +CONCLUSIONS O +: O +IL12B O +3 O +'- O +UTR O +1188 O +- O +C O +- O +allele O +carriers O +appear O +to O +be O +capable O +of O +responding O +more O +efficiently O +to O +antiviral O +combination O +therapy O +as O +a O +consequence O +of O +a O +reduced O +relapse O +rate O +. O + +No O +association O +of O +IL12B O +polymorphisms O +and O +self O +- O +limited O +HCV O +infection O +could O +be O +demonstrated O +. O + + +No O +Evidence O +for O +BRAF O +as O +a O +melanoma O +/ O +nevus O +susceptibility O +gene O +. O + +Somatic O +mutations O +of O +BRAF O +have O +been O +identified O +in O +both O +melanoma O +tumors O +and O +benign O +nevi O +. O + +Germ O +line O +mutations O +in O +BRAF O +have O +not O +been O +identified O +as O +causal O +in O +families O +predisposed O +to O +melanoma O +. O + +However O +, O +a O +recent O +study O +suggested O +that O +a O +BRAF O +haplotype O +was O +associated O +with O +risk O +of O +sporadic O +melanoma O +in O +men O +. O + +Polymorphisms O +or O +other O +variants O +in O +the O +BRAF O +gene O +may O +therefore O +act O +as O +candidate O +low O +- O +penetrance O +genes O +for O +nevus O +/ O +melanoma O +susceptibility O +. O + +We O +hypothesized O +that O +promoter O +variants O +would O +be O +the O +most O +likely O +candidates O +for O +determinants O +of O +risk O +. O + +Using O +denaturing O +high O +- O +pressure O +liquid O +chromatography O +and O +sequencing O +, O +we O +screened O +peripheral O +blood O +DNA O +from O +184 O +familial O +melanoma O +cases O +for O +BRAF O +promoter O +variants O +. O + +We O +identified O +a O +promoter O +insertion O +/ O +deletion O +in O +linkage O +disequilibrium O +with O +the O +previously O +described O +BRAF O +polymorphism O +in O +intron O +11 O +( O +rs1639679 O +) O +reported O +to O +be O +associated O +with O +melanoma O +susceptibility O +in O +males O +. O + +We O +therefore O +investigated O +the O +contribution O +of O +this O +BRAF O +polymorphism O +to O +melanoma O +susceptibility O +in O +581 O +consecutively O +recruited O +incident O +cases O +, O +258 O +incident O +cases O +in O +a O +study O +of O +late O +relapse O +, O +673 O +female O +general O +practitioner O +controls O +, O +and O +the O +184 O +familial O +cases O +. O + +We O +found O +no O +statistically O +significant O +difference O +in O +either O +genotype O +or O +allele O +frequencies O +between O +cases O +and O +controls O +overall O +or O +between O +male O +and O +female O +cases O +for O +the O +BRAF O +polymorphism O +in O +the O +two O +incident O +case O +series O +. O + +Our O +results O +therefore O +suggest O +that O +the O +BRAF O +polymorphism O +is O +not O +significantly O +associated O +with O +melanoma O +and O +the O +promoter O +insertion O +/ O +deletion O +linked O +with O +the O +polymorphism O +is O +not O +a O +causal O +variant O +. O + +In O +addition O +, O +we O +found O +that O +there O +was O +no O +association O +between O +the O +BRAF O +genotype O +and O +mean O +total O +number O +of O +banal O +or O +atypical O +nevi O +in O +either O +the O +cases O +or O +controls O +. O + + +CFI O +- O +rs7356506 O +polymorphisms O +associated O +with O +Vogt O +- O +Koyanagi O +- O +Harada O +syndrome O +. O + +PURPOSE O +: O +Complement O +factor O +I O +( O +CFI O +) O +plays O +an O +important O +role O +in O +complement O +activation O +pathways O +and O +is O +known O +to O +affect O +the O +development O +of O +uveitis O +. O + +The O +present O +study O +was O +performed O +to O +investigate O +the O +existence O +of O +an O +association O +between O +CFI O +genetic O +polymorphisms O +and O +Vogt O +- O +Koyanagi O +- O +Harada O +( O +VKH O +) O +syndrome O +. O + +METHODS O +: O +A O +total O +of O +100 O +patients O +diagnosed O +with O +VKH O +syndrome O +and O +300 O +healthy O +controls O +were O +recruited O +for O +the O +study O +. O + +Two O +milliliters O +of O +peripheral O +blood O +were O +collected O +in O +a O +sterile O +anticoagulative O +tube O +. O + +CFI O +- O +rs7356506 O +polymorphisms O +were O +genotyped O +using O +Sequenom O +MassARRAY O +technology O +. O + +Allele O +and O +genotype O +frequencies O +were O +compared O +between O +patients O +and O +controls O +using O +a O +X O +( O +2 O +) O +test O +. O + +The O +analyses O +were O +stratified O +for O +recurrent O +status O +, O +complicated O +cataract O +status O +, O +and O +steroid O +- O +sensitive O +status O +. O + +RESULTS O +: O +No O +significant O +association O +was O +found O +between O +CFI O +- O +rs7356506 O +polymorphisms O +and O +VKH O +syndrome O +. O + +However O +, O +patients O +with O +recurrent O +VKH O +syndrome O +had O +lower O +frequencies O +of O +the O +G O +allele O +and O +GG O +homozygosity O +in O +CFI O +- O +rs7356506 O +when O +compared O +to O +the O +controls O +( O +p O += O +0 O +. O +16 O +, O +odds O +ratio O +[ O +OR O +]= O +0 O +. O +429 O +, O +95 O +% O +confidence O +interval O +[ O +CI O +]= O +0 O +. O +212 O +- O +0 O +. O +871 O +; O +p O += O +0 O +. O +14 O +, O +OR O += O +0 O +. O +364 O +, O +95 O +% O +CI O += O +0 O +. O +158 O +- O +0 O +. O +837 O +, O +respectively O +). O + +Furthermore O +, O +there O +were O +significant O +decreases O +in O +the O +frequencies O +of O +the O +G O +allele O +and O +GG O +homozygosity O +in O +CFI O +- O +rs7356506 O +in O +patients O +with O +VKH O +syndrome O +with O +complicated O +cataract O +compared O +to O +the O +controls O +( O +p O +< O +0 O +. O +1 O +, O +OR O += O +0 O +. O +357 O +, O +95 O +% O +CI O += O +0 O +. O +197 O +- O +0 O +. O +648 O +; O +p O +< O +0 O +. O +1 O +, O +OR O += O +0 O +. O +273 O +, O +95 O +% O +CI O += O +0 O +. O +135 O +- O +0 O +. O +551 O +, O +respectively O +). O + +Nevertheless O +, O +no O +significant O +association O +with O +patients O +with O +VKH O +syndrome O +in O +steroid O +- O +sensitive O +statuses O +was O +detected O +for O +CFI O +- O +rs7356506 O +polymorphisms O +. O + +CONCLUSIONS O +: O +Our O +results O +indicate O +that O +CFI O +polymorphisms O +are O +not O +significantly O +associated O +with O +VKH O +syndrome O +; O +nevertheless O +, O +we O +identified O +a O +trend O +for O +the O +association O +of O +CFI O +- O +7356506 O +with O +VKH O +syndrome O +that O +depends O +on O +the O +recurrent O +status O +and O +the O +complicated O +cataract O +status O +but O +not O +on O +the O +steroid O +- O +sensitive O +status O +. O + + +Two O +novel O +mutations O +in O +the O +MEN1 O +gene O +in O +subjects O +with O +multiple O +endocrine O +neoplasia O +- O +1 O +. O + +Multiple O +endocrine O +neoplasia O +type O +1 O +( O +MEN1 O +) O +is O +characterized O +by O +parathyroid O +, O +enteropancreatic O +endocrine O +and O +pituitary O +adenomas O +as O +well O +as O +germline O +mutation O +of O +the O +MEN1 O +gene O +. O + +We O +describe O +2 O +families O +with O +MEN1 O +with O +novel O +mutations O +in O +the O +MEN1 O +gene O +. O + +One O +family O +was O +of O +Turkish O +origin O +, O +and O +the O +index O +patient O +had O +primary O +hyperparathyroidism O +( O +PHPT O +) O +plus O +a O +prolactinoma O +; O +three O +relatives O +had O +PHPT O +only O +. O + +The O +index O +patient O +in O +the O +second O +family O +was O +a O +46 O +- O +yr O +- O +old O +woman O +of O +Chinese O +origin O +living O +in O +Taiwan O +. O + +This O +patient O +presented O +with O +a O +complaint O +of O +epigastric O +pain O +and O +watery O +diarrhea O +over O +the O +past O +3 O +months O +, O +and O +had O +undergone O +subtotal O +parathyroidectomy O +and O +enucleation O +of O +pancreatic O +islet O +cell O +tumor O +about O +10 O +yr O +before O +. O + +There O +was O +also O +a O +prolactinoma O +. O + +Sequence O +analysis O +of O +the O +MEN1 O +gene O +from O +leukocyte O +genomic O +DNA O +revealed O +heterozygous O +mutations O +in O +both O +probands O +. O + +The O +Turkish O +patient O +and O +her O +affected O +relatives O +all O +had O +a O +heterozygous O +A O +to O +G O +transition O +at O +codon O +557 O +( O +AAG O +--> O +GAG O +) O +of O +exon O +10 O +of O +MEN1 O +that O +results O +in O +a O +replacement O +of O +lysine O +by O +glutamic O +acid O +. O + +The O +Chinese O +index O +patient O +and O +one O +of O +her O +siblings O +had O +a O +heterozygous O +mutation O +at O +codon O +418 O +of O +exon O +9 O +( O +GAC O +--> O +TAT O +) O +that O +results O +in O +a O +substitution O +of O +aspartic O +acid O +by O +tyrosine O +. O + +In O +conclusion O +, O +we O +have O +identified O +2 O +novel O +missense O +mutations O +in O +the O +MEN1 O +gene O +. O + + +Common O +BRCA2 O +variants O +and O +modification O +of O +breast O +and O +ovarian O +cancer O +risk O +in O +BRCA1 O +mutation O +carriers O +. O + +The O +HH O +genotype O +of O +the O +nonconservative O +amino O +acid O +substitution O +polymorphism O +N372H O +in O +the O +BRCA2 O +gene O +was O +reported O +to O +be O +associated O +with O +a O +1 O +. O +3 O +- O +to O +1 O +. O +5 O +- O +fold O +increase O +in O +risk O +of O +both O +breast O +and O +ovarian O +cancer O +. O + +As O +these O +studies O +concerned O +sporadic O +cancer O +cases O +, O +we O +investigated O +whether O +N372H O +and O +another O +common O +variant O +located O +in O +the O +5 O +'- O +untranslated O +region O +( O +203G O +> O +A O +) O +of O +the O +BRCA2 O +gene O +modify O +breast O +or O +ovarian O +cancer O +risk O +in O +BRCA1 O +mutation O +carriers O +. O + +The O +study O +includes O +778 O +women O +carrying O +a O +BRCA1 O +germ O +- O +line O +mutation O +belonging O +to O +403 O +families O +. O + +The O +two O +BRCA2 O +variants O +were O +analyzed O +by O +the O +TaqMan O +allelic O +discrimination O +technique O +. O + +Genotypes O +were O +analyzed O +by O +disease O +- O +free O +survival O +analysis O +using O +a O +Cox O +proportional O +hazards O +model O +. O + +We O +found O +no O +evidence O +of O +a O +significant O +modification O +of O +breast O +cancer O +penetrance O +in O +BRCA1 O +mutation O +carriers O +by O +either O +polymorphism O +. O + +In O +respect O +of O +ovarian O +cancer O +risk O +, O +we O +also O +saw O +no O +effect O +with O +the O +N372H O +variant O +but O +we O +did O +observe O +a O +borderline O +association O +with O +the O +5 O +'- O +untranslated O +region O +203A O +allele O +( O +hazard O +ratio O +, O +1 O +. O +43 O +; O +CI O +, O +1 O +. O +1 O +- O +2 O +. O +0 O +). O + +In O +contrast O +to O +the O +result O +of O +Healey O +et O +al O +. O + +on O +newborn O +females O +and O +adult O +female O +controls O +, O +we O +found O +no O +departure O +from O +Hardy O +- O +Weinberg O +equilibrium O +in O +the O +distribution O +of O +N372H O +alleles O +for O +our O +female O +BRCA1 O +carriers O +. O + +We O +conclude O +that O +if O +these O +single O +- O +nucleotide O +polymorphisms O +do O +modify O +the O +risk O +of O +cancer O +in O +BRCA1 O +mutation O +carriers O +, O +their O +effects O +are O +not O +significantly O +larger O +than O +that O +of O +N372H O +previously O +observed O +in O +the O +general O +population O +. O + + +Transgelin O +increases O +metastatic O +potential O +of O +colorectal O +cancer O +cells O +in O +vivo O +and O +alters O +expression O +of O +genes O +involved O +in O +cell O +motility O +. O + +BACKGROUND O +: O +Transgelin O +is O +an O +actin O +- O +binding O +protein O +that O +promotes O +motility O +in O +normal O +cells O +. O + +Although O +the O +role O +of O +transgelin O +in O +cancer O +is O +controversial O +, O +a O +number O +of O +studies O +have O +shown O +that O +elevated O +levels O +correlate O +with O +aggressive O +tumor O +behavior O +, O +advanced O +stage O +, O +and O +poor O +prognosis O +. O + +Here O +we O +sought O +to O +determine O +the O +role O +of O +transgelin O +more O +directly O +by O +determining O +whether O +experimental O +manipulation O +of O +transgelin O +levels O +in O +colorectal O +cancer O +( O +CRC O +) O +cells O +led O +to O +changes O +in O +metastatic O +potential O +in O +vivo O +. O + +METHODS O +: O +Isogenic O +CRC O +cell O +lines O +that O +differ O +in O +transgelin O +expression O +were O +characterized O +using O +in O +vitro O +assays O +of O +growth O +and O +invasiveness O +and O +a O +mouse O +tail O +vein O +assay O +of O +experimental O +metastasis O +. O + +Downstream O +effects O +of O +transgelin O +overexpression O +were O +investigated O +by O +gene O +expression O +profiling O +and O +quantitative O +PCR O +. O + +RESULTS O +: O +Stable O +overexpression O +of O +transgelin O +in O +RKO O +cells O +, O +which O +have O +low O +endogenous O +levels O +, O +led O +to O +increased O +invasiveness O +, O +growth O +at O +low O +density O +, O +and O +growth O +in O +soft O +agar B +. O + +Overexpression O +also O +led O +to O +an O +increase O +in O +the O +number O +and O +size O +of O +lung O +metastases O +in O +the O +mouse O +tail O +vein O +injection O +model O +. O + +Similarly O +, O +attenuation O +of O +transgelin O +expression O +in O +HCT116 O +cells O +, O +which O +have O +high O +endogenous O +levels O +, O +decreased O +metastases O +in O +the O +same O +model O +. O + +Investigation O +of O +mRNA O +expression O +patterns O +showed O +that O +transgelin O +overexpression O +altered O +the O +levels O +of O +approximately O +250 O +other O +transcripts O +, O +with O +over O +- O +representation O +of O +genes O +that O +affect O +function O +of O +actin O +or O +other O +cytoskeletal O +proteins O +. O + +Changes O +included O +increases O +in O +HOOK1 O +, O +SDCCAG8 O +, O +ENAH O +/ O +Mena O +, O +and O +TNS1 O +and O +decreases O +in O +EMB O +, O +BCL11B O +, O +and O +PTPRD O +. O + +CONCLUSIONS O +: O +Increases O +or O +decreases O +in O +transgelin O +levels O +have O +reciprocal O +effects O +on O +tumor O +cell O +behavior O +, O +with O +higher O +expression O +promoting O +metastasis O +. O + +Chronic O +overexpression O +influences O +steady O +- O +state O +levels O +of O +mRNAs O +for O +metastasis O +- O +related O +genes O +. O + + +Association O +of O +sporadic O +chondrocalcinosis O +with O +a O +- O +4 O +- O +basepair O +G O +- O +to O +- O +A O +transition O +in O +the O +5 O +'- O +untranslated O +region O +of O +ANKH O +that O +promotes O +enhanced O +expression O +of O +ANKH O +protein O +and O +excess O +generation O +of O +extracellular O +inorganic O +pyrophosphate I +. O + +OBJECTIVE O +: O +Certain O +mutations O +in O +ANKH O +, O +which O +encodes O +a O +multiple O +- O +pass O +transmembrane O +protein O +that O +regulates O +inorganic O +pyrophosphate O +( O +PPi O +) O +transport O +, O +are O +linked O +to O +autosomal O +- O +dominant O +familial O +chondrocalcinosis O +. O + +This O +study O +investigated O +the O +potential O +for O +ANKH O +sequence O +variants O +to O +promote O +sporadic O +chondrocalcinosis O +. O + +METHODS O +: O +ANKH O +variants O +identified O +by O +genomic O +sequencing O +were O +screened O +for O +association O +with O +chondrocalcinosis O +in O +128 O +patients O +with O +severe O +sporadic O +chondrocalcinosis O +or O +pseudogout O +and O +in O +ethnically O +matched O +healthy O +controls O +. O + +The O +effects O +of O +specific O +variants O +on O +expression O +of O +common O +markers O +were O +evaluated O +by O +in O +vitro O +transcription O +/ O +translation O +. O + +The O +function O +of O +these O +variants O +was O +studied O +in O +transfected O +human O +immortalized O +CH O +- O +8 O +articular O +chondrocytes O +. O + +RESULTS O +: O +Sporadic O +chondrocalcinosis O +was O +associated O +with O +a O +G O +- O +to O +- O +A O +transition O +in O +the O +ANKH O +5 O +'- O +untranslated O +region O +( O +5 O +'- O +UTR O +) O +at O +4 O +bp O +upstream O +of O +the O +start O +codon O +( O +in O +homozygotes O +of O +the O +minor O +allele O +, O +genotype O +relative O +risk O +6 O +. O +0 O +, O +P O += O +0 O +. O +6 O +; O +overall O +genotype O +association O +P O += O +0 O +. O +2 O +). O + +This O +- O +4 O +- O +bp O +transition O +, O +as O +well O +as O +2 O +mutations O +previously O +linked O +with O +familial O +and O +sporadic O +chondrocalcinosis O +(+ O +14 O +bp O +C O +- O +to O +- O +T O +and O +C O +- O +terminal O +GAG O +deletion O +, O +respectively O +), O +but O +not O +the O +French O +familial O +chondrocalcinosis O +kindred O +143 O +- O +bp O +T O +- O +to O +- O +C O +mutation O +, O +increased O +reticulocyte O +ANKH O +transcription O +/ O +ANKH O +translation O +in O +vitro O +. O + +Transfection O +of O +complementary O +DNA O +for O +both O +the O +wild O +- O +type O +ANKH O +and O +the O +- O +4 O +- O +bp O +ANKH O +protein O +variant O +promoted O +increased O +extracellular O +PPi O +in O +CH O +- O +8 O +cells O +, O +but O +unexpectedly O +, O +these O +ANKH O +mutants O +had O +divergent O +effects O +on O +the O +expression O +of O +extracellular O +PPi O +and O +the O +chondrocyte O +hypertrophy O +marker O +, O +type O +X O +collagen O +. O + +CONCLUSION O +: O +A O +subset O +of O +sporadic O +chondrocalcinosis O +appears O +to O +be O +heritable O +via O +a O +- O +4 O +- O +bp O +G O +- O +to O +- O +A O +ANKH O +5 O +'- O +UTR O +transition O +that O +up O +- O +regulates O +expression O +of O +ANKH O +and O +extracellular O +PPi O +in O +chondrocyte O +cells O +. O + +Distinct O +ANKH O +mutations O +associated O +with O +heritable O +chondrocalcinosis O +may O +promote O +disease O +by O +divergent O +effects O +on O +extracellular O +PPi B +and O +chondrocyte O +hypertrophy O +, O +which O +is O +likely O +to O +mediate O +differences O +in O +the O +clinical O +phenotypes O +and O +severity O +of O +the O +disease O +. O + + +Contribution O +of O +STAT4 O +gene O +single O +- O +nucleotide O +polymorphism O +to O +systemic O +lupus O +erythematosus O +in O +the O +Polish O +population O +. O + +The O +STAT4 O +has O +been O +found O +to O +be O +a O +susceptible O +gene O +in O +the O +development O +of O +systemic O +lupus O +erythematosus O +( O +SLE O +) O +in O +various O +populations O +. O + +There O +are O +evident O +population O +differences O +in O +the O +context O +of O +clinical O +manifestations O +of O +SLE O +, O +therefore O +we O +investigated O +the O +prevalence O +of O +the O +STAT4 O +G O +> O +C O +( O +rs7582694 O +) O +polymorphism O +in O +patients O +with O +SLE O +( O +n O += O +253 O +) O +and O +controls O +( O +n O += O +521 O +) O +in O +a O +sample O +of O +the O +Polish O +population O +. O + +We O +found O +that O +patients O +with O +the O +STAT4 O +C O +/ O +G O +and O +CC O +genotypes O +exhibited O +a O +1 O +. O +583 O +- O +fold O +increased O +risk O +of O +SLE O +incidence O +( O +95 O +% O +CI O += O +1 O +. O +168 O +- O +2 O +. O +145 O +, O +p O += O +0 O +. O +3 O +), O +with O +OR O +for O +the O +C O +/ O +C O +versus O +C O +/ O +G O +and O +G O +/ O +G O +genotypes O +was O +1 O +. O +967 O +( O +95 O +% O +CI O += O +1 O +. O +152 O +- O +3 O +. O +358 O +, O +p O += O +0 O +. O +119 O +). O + +The O +OR O +for O +the O +STAT4 O +C O +allele O +frequency O +showed O +a O +1 O +. O +539 O +- O +fold O +increased O +risk O +of O +SLE O +( O +95 O +% O +CI O += O +1 O +. O +209 O +- O +1 O +. O +959 O +, O +p O += O +0 O +. O +4 O +). O + +We O +also O +observed O +an O +increased O +frequency O +of O +STAT4 O +C O +/ O +C O +and O +C O +/ O +G O +genotypes O +in O +SLE O +patients O +with O +renal O +symptoms O +OR O += O +2 O +. O +259 O +( O +1 O +. O +365 O +- O +3 O +. O +738 O +, O +p O += O +0 O +. O +14 O +), O +( O +p O +( O +corr O +) O += O +0 O +. O +238 O +) O +and O +in O +SLE O +patients O +with O +neurologic O +manifestations O +OR O += O +2 O +. O +867 O +( O +1 O +. O +467 O +- O +5 O +. O +604 O +, O +p O += O +0 O +. O +16 O +), O +( O +p O +( O +corr O +) O += O +0 O +. O +272 O +). O + +Moreover O +, O +we O +found O +a O +contribution O +of O +STAT4 O +C O +/ O +C O +and O +C O +/ O +G O +genotypes O +to O +the O +presence O +of O +the O +anti O +- O +snRNP O +Ab O +OR O += O +3 O +. O +237 O +( O +1 O +. O +667 O +- O +6 O +. O +288 O +, O +p O += O +0 O +. O +3 O +), O +( O +p O +( O +corr O +) O += O +0 O +. O +51 O +) O +and O +the O +presence O +of O +the O +anti O +- O +Scl O +- O +70 O +Ab O +OR O += O +2 O +. O +665 O +( O +1 O +. O +380 O +- O +5 O +. O +147 O +, O +p O += O +0 O +. O +28 O +), O +( O +p O +( O +corr O +) O += O +0 O +. O +476 O +). O + +Our O +studies O +confirmed O +an O +association O +of O +the O +STAT4 O +C O +( O +rs7582694 O +) O +variant O +with O +the O +development O +of O +SLE O +and O +occurrence O +of O +some O +clinical O +manifestations O +of O +the O +disease O +. O + + +Leukemia O +inhibitory O +factor O +protects O +the O +lung O +during O +respiratory O +syncytial O +viral O +infection O +. O + +BACKGROUND O +: O +Respiratory O +syncytial O +virus O +( O +RSV O +) O +infects O +the O +lung O +epithelium O +where O +it O +stimulates O +the O +production O +of O +numerous O +host O +cytokines O +that O +are O +associated O +with O +disease O +burden O +and O +acute O +lung O +injury O +. O + +Characterizing O +the O +host O +cytokine O +response O +to O +RSV O +infection O +, O +the O +regulation O +of O +host O +cytokines O +and O +the O +impact O +of O +neutralizing O +an O +RSV O +- O +inducible O +cytokine O +during O +infection O +were O +undertaken O +in O +this O +study O +. O + +METHODS O +: O +A549 O +, O +primary O +human O +small O +airway O +epithelial O +( O +SAE O +) O +cells O +and O +wild O +- O +type O +, O +TIR O +- O +domain O +- O +containing O +adapter O +- O +inducing O +interferon O +- O +b O +( O +Trif O +) O +and O +mitochondrial O +antiviral O +- O +signaling O +protein O +( O +Mavs O +) O +knockout O +( O +KO O +) O +mice O +were O +infected O +with O +RSV O +and O +cytokine O +responses O +were O +investigated O +by O +ELISA O +, O +multiplex O +analysis O +and O +qPCR O +. O + +Neutralizing O +anti O +- O +leukemia O +inhibitory O +factor O +( O +LIF O +) O +IgG O +or O +control O +IgG O +was O +administered O +to O +a O +group O +of O +wild O +- O +type O +animals O +prior O +to O +RSV O +infection O +. O + +RESULTS O +AND O +DISCUSSION O +: O +RSV O +- O +infected O +A549 O +and O +SAE O +cells O +release O +a O +network O +of O +cytokines O +, O +including O +newly O +identified O +RSV O +- O +inducible O +cytokines O +LIF O +, O +migration O +inhibitory O +factor O +( O +MIF O +), O +stem O +cell O +factor O +( O +SCF O +), O +CCL27 O +, O +CXCL12 O +and O +stem O +cell O +growth O +factor O +beta O +( O +SCGF O +- O +b O +). O + +These O +RSV O +- O +inducible O +cytokines O +were O +also O +observed O +in O +the O +airways O +of O +mice O +during O +an O +infection O +. O + +To O +identify O +the O +regulation O +of O +RSV O +inducible O +cytokines O +, O +Mavs O +and O +Trif O +deficient O +animals O +were O +infected O +with O +RSV O +. O + +In O +vivo O +induction O +of O +airway O +IL O +- O +1b O +, O +IL O +- O +4 O +, O +IL O +- O +5 O +, O +IL O +- O +6 O +, O +IL O +- O +12 O +( O +p40 O +), O +IFN O +- O +g O +, O +CCL2 O +, O +CCL5 O +, O +CCL3 O +, O +CXCL1 O +, O +IP O +- O +10 O +/ O +CXCL10 O +, O +IL O +- O +22 O +, O +MIG O +/ O +CXCL9 O +and O +MIF O +were O +dependent O +on O +Mavs O +expression O +in O +mice O +. O + +Loss O +of O +Trif O +expression O +in O +mice O +altered O +the O +RSV O +induction O +of O +IL O +- O +1b O +, O +IL O +- O +5 O +, O +CXCL12 O +, O +MIF O +, O +LIF O +, O +CXCL12 O +and O +IFN O +- O +g O +. O + +Silencing O +of O +retinoic O +acid O +- O +inducible O +gene O +- O +1 O +( O +RIG O +- O +I O +) O +expression O +in O +A549 O +cells O +had O +a O +greater O +impact O +on O +RSV O +- O +inducible O +cytokines O +than O +melanoma O +differentiation O +- O +associated O +protein O +5 O +( O +MDA5 O +) O +and O +laboratory O +of O +genetics O +and O +physiology O +2 O +( O +LGP2 O +), O +and O +Trif O +expression O +. O + +To O +evaluate O +the O +role O +of O +LIF O +in O +the O +airways O +during O +RSV O +infection O +, O +animals O +were O +treated O +with O +neutralizing O +anti O +- O +LIF O +IgG O +, O +which O +enhanced O +RSV O +pathology O +observed O +with O +increased O +airspace O +protein O +content O +, O +apoptosis O +and O +airway O +hyperresponsiveness O +compared O +to O +control O +IgG O +treatment O +. O + +CONCLUSIONS O +: O +RSV O +infection O +in O +the O +epithelium O +induces O +a O +network O +of O +immune O +factors O +to O +counter O +infection O +, O +primarily O +in O +a O +RIG O +- O +I O +dependent O +manner O +. O + +Expression O +of O +LIF O +protects O +the O +lung O +from O +lung O +injury O +and O +enhanced O +pathology O +during O +RSV O +infection O +. O + + +Urinary O +bladder O +cancer O +in O +Wegener O +' O +s O +granulomatosis O +: O +risks O +and O +relation O +to O +cyclophosphamide B +. O + +OBJECTIVE O +: O +To O +assess O +and O +characterise O +the O +risk O +of O +bladder O +cancer O +, O +and O +its O +relation O +to O +cyclophosphamide B +, O +in O +patients O +with O +Wegener O +' O +s O +granulomatosis O +. O + +METHODS O +: O +In O +the O +population O +based O +, O +nationwide O +Swedish O +Inpatient O +Register O +a O +cohort O +of O +1065 O +patients O +with O +Wegener O +' O +s O +granulomatosis O +, O +1969 O +- O +95 O +, O +was O +identified O +. O + +Through O +linkage O +with O +the O +Swedish O +Cancer O +Register O +, O +all O +subjects O +in O +this O +cohort O +diagnosed O +with O +bladder O +cancer O +were O +identified O +. O + +Nested O +within O +the O +cohort O +, O +a O +matched O +case O +- O +control O +study O +was O +performed O +to O +estimate O +the O +association O +between O +cyclophosphamide B +and O +bladder O +cancer O +using O +odds O +ratios O +( O +ORs O +) O +as O +relative O +risk O +. O + +In O +the O +cohort O +the O +cumulative O +risk O +of O +bladder O +cancer O +after O +Wegener O +' O +s O +granulomatosis O +, O +and O +the O +relative O +prevalence O +of O +a O +history O +of O +bladder O +cancer O +at O +the O +time O +of O +diagnosis O +of O +Wegener O +' O +s O +granulomatosis O +, O +were O +also O +estimated O +. O + +RESULTS O +: O +The O +median O +cumulative O +doses O +of O +cyclophosphamide B +among O +cases O +( O +n O += O +11 O +) O +and O +controls O +( O +n O += O +25 O +) O +were O +113 O +g O +and O +25 O +g O +, O +respectively O +. O + +The O +risk O +of O +bladder O +cancer O +doubled O +for O +every O +10 O +g O +increment O +in O +cyclophosphamide B +( O +OR O += O +2 O +. O +0 O +, O +95 O +% O +confidence O +interval O +( O +CI O +) O +0 O +. O +8 O +to O +4 O +. O +9 O +). O + +Treatment O +duration O +longer O +than O +1 O +year O +was O +associated O +with O +an O +eightfold O +increased O +risk O +( O +OR O += O +7 O +. O +7 O +, O +95 O +% O +CI O +0 O +. O +9 O +to O +69 O +). O + +The O +absolute O +risk O +for O +bladder O +cancer O +in O +the O +cohort O +reached O +10 O +% O +16 O +years O +after O +diagnosis O +of O +Wegener O +' O +s O +granulomatosis O +, O +and O +a O +history O +of O +bladder O +cancer O +was O +( O +non O +- O +significantly O +) O +twice O +as O +common O +as O +expected O +at O +the O +time O +of O +diagnosis O +of O +Wegener O +' O +s O +granulomatosis O +. O + +CONCLUSION O +: O +The O +results O +indicate O +a O +dose O +- O +response O +relationship O +between O +cyclophosphamide B +and O +the O +risk O +of O +bladder O +cancer O +, O +high O +cumulative O +risks O +in O +the O +entire O +cohort O +, O +and O +also O +the O +possibility O +of O +risk O +factors O +operating O +even O +before O +Wegener O +' O +s O +granulomatosis O +. O + + +Co O +- O +inheritance O +of O +a O +PKD1 O +mutation O +and O +homozygous O +PKD2 O +variant O +: O +a O +potential O +modifier O +in O +autosomal O +dominant O +polycystic O +kidney O +disease O +. O + +BACKGROUND O +: O +Autosomal O +dominant O +polycystic O +kidney O +disease O +( O +ADPKD O +), O +which O +is O +caused O +by O +mutations O +in O +polycystins O +1 O +( O +PC1 O +) O +and O +2 O +( O +PC2 O +), O +is O +one O +of O +the O +most O +commonly O +inherited O +renal O +diseases O +, O +affecting O +~ O +1 O +: O +1000 O +Caucasians O +. O + +MATERIALS O +AND O +METHODS O +: O +We O +screened O +Greek O +ADPKD O +patients O +with O +the O +denaturing O +gradient O +gel O +electrophoresis O +( O +DGGE O +) O +assay O +and O +direct O +sequencing O +. O + +RESULTS O +: O +We O +identified O +a O +patient O +homozygous O +for O +a O +nucleotide O +change O +c O +. O +1445T O +> O +G O +, O +resulting O +in O +a O +novel O +homozygous O +substitution O +of O +the O +non O +- O +polar O +hydrophobic O +phenylalanine O +to O +the O +polar O +hydrophilic O +cysteine O +in O +exon O +6 O +at O +codon O +482 O +( O +p O +. O +F482C O +) O +of O +the O +PKD2 O +gene O +and O +a O +de O +- O +novo O +PKD1 O +splice O +- O +site O +variant O +IVS21 O +- O +2delAG O +. O + +We O +did O +not O +find O +this O +PKD2 O +variant O +in O +a O +screen O +of O +280 O +chromosomes O +of O +healthy O +subjects O +, O +supporting O +its O +pathogenicity O +. O + +The O +proband O +' O +s O +parents O +did O +not O +have O +the O +PKD1 O +mutation O +. O + +Real O +- O +time O +PCR O +of O +the O +PKD2 O +transcript O +from O +a O +skin O +biopsy O +revealed O +20 O +- O +fold O +higher O +expression O +in O +the O +patient O +than O +in O +a O +healthy O +subject O +and O +was O +higher O +in O +the O +patient O +' O +s O +peripheral O +blood O +mononuclear O +cells O +( O +PBMCs O +) O +than O +in O +those O +of O +her O +heterozygote O +daughter O +and O +a O +healthy O +subject O +. O + +The O +greater O +gene O +expression O +was O +also O +supported O +by O +Western O +blotting O +. O + +Inner O +medullar O +collecting O +duct O +( O +IMCD O +) O +cells O +transfected O +with O +the O +mutant O +PKD2 O +mouse O +gene O +presented O +a O +perinuclear O +and O +diffuse O +cytoplasmic O +localization O +compared O +with O +the O +wild O +type O +ER O +localization O +. O + +Patch O +- O +clamping O +of O +PBMCs O +from O +the O +p O +. O +F482C O +homozygous O +and O +heterozygous O +subjects O +revealed O +lower O +polycystin O +- O +2 O +channel O +function O +than O +in O +controls O +. O + +CONCLUSIONS O +: O +We O +report O +for O +the O +first O +time O +a O +patient O +with O +ADPKD O +who O +is O +heterozygous O +for O +a O +de O +novo O +PKD1 O +variant O +and O +homozygous O +for O +a O +novel O +PKD2 O +mutation O +. O + + +Two O +novel O +mutations O +of O +the O +TSH O +- O +beta O +subunit O +gene O +underlying O +congenital O +central O +hypothyroidism O +undetectable O +in O +neonatal O +TSH O +screening O +. O + +CONTEXT O +: O +Patients O +with O +TSH O +- O +beta O +subunit O +defects O +and O +congenital O +hypothyroidism O +are O +missed O +by O +TSH O +- O +based O +neonatal O +screening O +. O + +OBJECTIVE O +: O +Our O +objective O +was O +to O +report O +the O +molecular O +consequences O +of O +a O +novel O +splice O +- O +junction O +mutation O +and O +a O +novel O +missense O +mutation O +in O +the O +TSH O +- O +beta O +subunit O +gene O +found O +in O +two O +patients O +with O +congenital O +central O +hypothyroidism O +and O +conventional O +treatment O +- O +resistant O +anemia O +. O + +RESULTS O +: O +Patient O +1 O +had O +a O +homozygous O +G O +to O +A O +nucleotide O +change O +at O +the O +5 O +' O +donor O +splice O +site O +of O +exon O +/ O +intron O +2 O +. O + +This O +resulted O +in O +a O +silent O +change O +at O +codon O +34 O +of O +the O +mature O +protein O +. O + +In O +vitro O +splicing O +assays O +showed O +that O +the O +mutant O +minigene O +dramatically O +affected O +pre O +- O +mRNA O +processing O +, O +causing O +exon O +2 O +to O +be O +completely O +skipped O +. O + +The O +putative O +product O +from O +a O +new O +out O +- O +of O +- O +frame O +translational O +start O +point O +in O +exon O +3 O +is O +expected O +to O +yield O +a O +nonsense O +25 O +- O +amino O +- O +acid O +peptide O +. O + +In O +patient O +2 O +, O +sequence O +analysis O +revealed O +a O +compound O +heterozygosis O +for O +the O +already O +reported O +313delT O +( O +C105Vfs114X O +) O +mutation O +and O +for O +a O +second O +novel O +mutation O +in O +exon O +3 O +, O +substituting O +G O +for O +A O +at O +cDNA O +nucleotide O +position O +323 O +, O +resulting O +in O +a O +C88Y O +change O +. O + +This O +cysteine O +residue O +is O +conserved O +among O +all O +dimeric O +pituitary O +and O +placental O +glycoprotein O +hormone O +- O +beta O +subunits O +. O + +Data O +from O +in O +silico O +analysis O +confirmed O +that O +the O +C88Y O +mutation O +would O +affect O +subunit O +conformation O +. O + +Indeed O +, O +two O +different O +bioinformatics O +approaches O +, O +PolyPhen O +and O +SIFT O +analysis O +, O +predicted O +C88Y O +to O +be O +a O +damaging O +substitution O +. O + +CONCLUSIONS O +: O +In O +isolated O +TSH O +deficiency O +, O +the O +exact O +molecular O +diagnosis O +is O +mandatory O +for O +diagnosis O +of O +isolated O +pituitary O +deficiency O +, O +delineation O +of O +prognosis O +, O +and O +genetic O +counseling O +. O + +Moreover O +, O +diagnosis O +of O +central O +hypothyroidism O +should O +be O +considered O +in O +the O +face O +of O +severe O +infant O +anemia O +of O +uncertain O +etiology O +. O + + +Mutations O +in O +the O +NDP O +gene O +: O +contribution O +to O +Norrie O +disease O +, O +familial O +exudative O +vitreoretinopathy O +and O +retinopathy O +of O +prematurity O +. O + +BACKGROUND O +: O +To O +examine O +the O +contribution O +of O +mutations O +within O +the O +Norrie O +disease O +( O +NDP O +) O +gene O +to O +the O +clinically O +similar O +retinal O +diseases O +Norrie O +disease O +, O +X O +- O +linked O +familial O +exudative O +vitreoretinopathy O +( O +FEVR O +), O +Coat O +' O +s O +disease O +and O +retinopathy O +of O +prematurity O +( O +ROP O +). O + +METHODS O +: O +A O +dataset O +comprising O +13 O +Norrie O +- O +FEVR O +, O +one O +Coat O +' O +s O +disease O +, O +31 O +ROP O +patients O +and O +90 O +ex O +- O +premature O +babies O +of O +< O +32 O +weeks O +' O +gestation O +underwent O +an O +ophthalmologic O +examination O +and O +were O +screened O +for O +mutations O +within O +the O +NDP O +gene O +by O +direct O +DNA O +sequencing O +, O +denaturing O +high O +- O +performance O +liquid O +chromatography O +or O +gel O +electrophoresis O +. O + +Controls O +were O +only O +screened O +using O +denaturing O +high O +- O +performance O +liquid O +chromatography O +and O +gel O +electrophoresis O +. O + +Confirmation O +of O +mutations O +identified O +was O +obtained O +by O +DNA O +sequencing O +. O + +RESULTS O +: O +Evidence O +for O +two O +novel O +mutations O +in O +the O +NDP O +gene O +was O +presented O +: O +Leu103Val O +in O +one O +FEVR O +patient O +and O +His43Arg O +in O +monozygotic O +twin O +Norrie O +disease O +patients O +. O + +Furthermore O +, O +a O +previously O +described O +14 O +- O +bp O +deletion O +located O +in O +the O +5 O +' O +unstranslated O +region O +of O +the O +NDP O +gene O +was O +detected O +in O +three O +cases O +of O +regressed O +ROP O +. O + +A O +second O +heterozygotic O +14 O +- O +bp O +deletion O +was O +detected O +in O +an O +unaffected O +ex O +- O +premature O +girl O +. O + +Only O +two O +of O +the O +13 O +Norrie O +- O +FEVR O +index O +cases O +had O +the O +full O +features O +of O +Norrie O +disease O +with O +deafness O +and O +mental O +retardation O +. O + +CONCLUSION O +: O +Two O +novel O +mutations O +within O +the O +coding O +region O +of O +the O +NDP O +gene O +were O +found O +, O +one O +associated O +with O +a O +severe O +disease O +phenotypes O +of O +Norrie O +disease O +and O +the O +other O +with O +FEVR O +. O + +A O +deletion O +within O +the O +non O +- O +coding O +region O +was O +associated O +with O +only O +mild O +- O +regressed O +ROP B +, O +despite O +the O +presence O +of O +low O +birthweight O +, O +prematurity O +and O +exposure O +to O +oxygen B +. O + +In O +full O +- O +term O +children O +with O +retinal O +detachment O +only O +15 O +% O +appear O +to O +have O +the O +full O +features O +of O +Norrie O +disease O +and O +this O +is O +important O +for O +counselling O +parents O +on O +the O +possible O +long O +- O +term O +outcome O +. O + + +Growth O +hormone O +dose O +in O +growth O +hormone O +- O +deficient O +adults O +is O +not O +associated O +with O +IGF O +- O +1 O +gene O +polymorphisms O +. O + +AIMS O +: O +Several O +SNPs O +and O +a O +microsatellite O +cytosine O +- O +adenine O +repeat O +promoter O +polymorphism O +of O +the O +IGF O +- O +1 O +gene O +have O +been O +reported O +to O +be O +associated O +with O +circulating O +IGF O +- O +1 O +serum O +concentrations O +. O + +Variance O +in O +IGF O +- O +1 O +concentrations O +due O +to O +genetic O +variations O +may O +affect O +different O +response O +to O +growth O +hormone O +( O +GH O +) O +treatment O +, O +resulting O +in O +different O +individually O +required O +GH O +- O +doses O +in O +GH O +- O +deficient O +patients O +. O + +The O +aim O +of O +this O +study O +was O +to O +test O +if O +the O +IGF O +- O +1 O +gene O +polymorphisms O +are O +associated O +with O +the O +GH O +- O +dose O +of O +GH O +- O +deficient O +adults O +. O + +MATERIALS O +& O +METHODS O +: O +A O +total O +of O +nine O +tagging O +SNPs O +, O +five O +additionally O +selected O +SNPs O +and O +a O +cytosine O +- O +adenine O +repeat O +polymorphism O +were O +determined O +in O +133 O +German O +adult O +patients O +( O +66 O +men O +, O +67 O +women O +; O +mean O +age O +45 O +. O +4 O +years O ++/- O +13 O +. O +1 O +standard O +deviation O +; O +majority O +Caucasian O +) O +with O +GH O +- O +deficiency O +( O +GHD O +) O +of O +different O +origin O +, O +derived O +from O +the O +prospective O +Pfizer O +International O +Metabolic O +Study O +( O +KIMS O +) O +Pharmacogenetics O +Study O +. O + +Patients O +received O +GH O +- O +treatment O +for O +12 O +months O +with O +finished O +dose O +- O +titration O +of O +GH O +and O +centralized O +IGF O +- O +1 O +measurements O +. O + +GH O +- O +dose O +after O +1 O +year O +of O +treatment O +, O +IGF O +- O +1 O +concentrations O +, O +IGF O +- O +1 O +- O +standard O +deviation O +score O +( O +SDS O +), O +the O +IGF O +- O +1 O +: O +GH O +ratio O +and O +anthropometric O +data O +were O +analyzed O +by O +genotype O +. O + +RESULTS O +: O +Except O +for O +rs1019731 O +, O +which O +showed O +a O +significant O +difference O +of O +IGF O +- O +1 O +- O +SDS O +by O +genotypes O +( O +p O += O +0 O +. O +2 O +), O +all O +polymorphisms O +showed O +no O +associations O +with O +the O +GH O +- O +doses O +, O +IGF O +- O +1 O +concentrations O +, O +IGF O +- O +1 O +- O +SDS O +and O +IGF O +- O +1 O +: O +GH O +ratio O +after O +adjusting O +for O +the O +confounding O +variables O +gender O +, O +age O +and O +BMI O +. O + +CONCLUSION O +: O +IGF O +- O +1 O +gene O +polymorphisms O +were O +not O +associated O +with O +the O +responsiveness O +to O +exogenous O +GH O +in O +GHD O +. O + +Therefore O +, O +genetic O +variations O +of O +the O +IGF O +- O +1 O +gene O +seem O +not O +to O +be O +major O +influencing O +factors O +of O +the O +GH O +- O +IGF O +- O +axis O +causing O +variable O +response O +to O +exogenous O +GH O +- O +treatment O +. O + + +Mutation O +analysis O +of O +FOXF2 O +in O +patients O +with O +disorders O +of O +sex O +development O +( O +DSD O +) O +in O +combination O +with O +cleft O +palate O +. O + +In O +contrast O +to O +disorders O +of O +sexual O +differentiation O +caused O +by O +lack O +of O +androgen B +production O +or O +inhibited O +androgen B +action O +, O +defects O +affecting O +development O +of O +the O +bipotent O +genital O +anlagen O +have O +rarely O +been O +investigated O +in O +humans O +. O + +We O +have O +previously O +documented O +that O +the O +transcription O +factor O +FOXF2 O +is O +highly O +expressed O +in O +human O +foreskin O +. O + +Moreover O +, O +Foxf2 O +knockout O +mice O +present O +with O +cleft O +palate O +in O +combination O +with O +hypoplasia O +of O +the O +genital O +tubercle O +. O + +We O +hypothesized O +that O +humans O +with O +disorders O +of O +sex O +development O +( O +DSD O +) O +in O +combination O +with O +cleft O +palate O +could O +have O +mutations O +in O +the O +FOXF2 O +gene O +. O + +Eighteen O +children O +with O +DSD O +and O +cleft O +palate O +were O +identified O +in O +the O +L O +beck O +DSD O +database O +( O +about O +1 O +, O +500 O +entries O +). O + +Genomic O +DNA O +sequence O +analysis O +of O +the O +FOXF2 O +gene O +was O +performed O +and O +compared O +with O +10 O +normal O +female O +and O +10 O +normal O +male O +controls O +, O +respectively O +. O + +Two O +heterozygous O +DNA O +sequence O +variations O +were O +solely O +present O +in O +one O +single O +patient O +each O +but O +in O +none O +of O +the O +20 O +normal O +controls O +: O +a O +duplication O +of O +GCC O +( O +c O +. O +97GCC O +[ O +9 O +]+[ O +10 O +]) O +resulting O +in O +an O +extra O +alanine O +within O +exon O +1 O +and O +a O +25 O +* O +G O +> O +A O +substitution O +in O +the O +3 O +'- O +untranslated O +region O +. O + +Two O +patients O +carried O +a O +c O +. O +262G O +> O +A O +sequence O +variation O +predicting O +for O +an O +Ala88Thr O +exchange O +which O +was O +also O +detected O +in O +2 O +normal O +controls O +. O + +Two O +silent O +mutations O +, O +c O +. O +1272C O +> O +T O +( O +Ser424Ser O +) O +and O +c O +. O +1284T O +> O +C O +( O +Tyr428Tyr O +), O +respectively O +, O +occurred O +in O +the O +coding O +region O +of O +exon O +2 O +, O +again O +in O +both O +patients O +and O +normal O +controls O +. O + +In O +conclusion O +, O +the O +majority O +of O +the O +detected O +sequence O +alterations O +were O +polymorphisms O +without O +obvious O +functional O +relevance O +. O + +However O +, O +it O +cannot O +be O +excluded O +that O +the O +2 O +unique O +DNA O +sequence O +alterations O +could O +have O +affected O +FOXF2 O +on O +the O +mRNA O +or O +protein O +level O +thus O +contributing O +to O +the O +observed O +disturbances O +in O +genital O +and O +palate O +development O +. O + + +A O +novel O +mutation O +screening O +system O +for O +Ehlers O +- O +Danlos O +Syndrome O +, O +vascular O +type O +by O +high O +- O +resolution O +melting O +curve O +analysis O +in O +combination O +with O +small O +amplicon O +genotyping O +using O +genomic O +DNA O +. O + +Ehlers O +- O +Danlos O +syndrome O +, O +vascular O +type O +( O +vEDS O +) O +( O +MIM O +# O +130050 O +) O +is O +an O +autosomal O +dominant O +disorder O +caused O +by O +type O +III O +procollagen O +gene O +( O +COL3A1 O +) O +mutations O +. O + +Most O +COL3A1 O +mutations O +are O +detected O +by O +using O +total O +RNA O +from O +patient O +- O +derived O +fibroblasts O +, O +which O +requires O +an O +invasive O +skin O +biopsy O +. O + +High O +- O +resolution O +melting O +curve O +analysis O +( O +hrMCA O +) O +has O +recently O +been O +developed O +as O +a O +post O +- O +PCR O +mutation O +scanning O +method O +which O +enables O +simple O +, O +rapid O +, O +cost O +- O +effective O +, O +and O +highly O +sensitive O +mutation O +screening O +of O +large O +genes O +. O + +We O +established O +a O +hrMCA O +method O +to O +screen O +for O +COL3A1 O +mutations O +using O +genomic O +DNA O +. O + +PCR O +primers O +pairs O +for O +COL3A1 O +( O +52 O +amplicons O +) O +were O +designed O +to O +cover O +all O +coding O +regions O +of O +the O +52 O +exons O +, O +including O +the O +splicing O +sites O +. O + +We O +used O +15 O +DNA O +samples O +( O +8 O +validation O +samples O +and O +7 O +samples O +of O +clinically O +suspected O +vEDS O +patients O +) O +in O +this O +study O +. O + +The O +eight O +known O +COL3A1 O +mutations O +in O +validation O +samples O +were O +all O +successfully O +detected O +by O +the O +hrMCA O +. O + +In O +addition O +, O +we O +identified O +five O +novel O +COL3A1 O +mutations O +, O +including O +one O +deletion O +( O +c O +. O +2187delA O +) O +and O +one O +nonsense O +mutation O +( O +c O +. O +2992C O +> O +T O +) O +that O +could O +not O +be O +determined O +by O +the O +conventional O +total O +RNA O +method O +. O + +Furthermore O +, O +we O +established O +a O +small O +amplicon O +genotyping O +( O +SAG O +) O +method O +for O +detecting O +three O +high O +frequency O +coding O +- O +region O +SNPs O +( O +rs1800255 O +: O +G O +> O +A O +, O +rs1801184 O +: O +T O +> O +C O +, O +and O +rs2271683 O +: O +A O +> O +G O +) O +in O +COL3A1 O +to O +differentiate O +mutations O +before O +sequencing O +. O + +The O +use O +of O +hrMCA O +in O +combination O +with O +SAG O +from O +genomic O +DNA O +enables O +rapid O +detection O +of O +COL3A1 O +mutations O +with O +high O +efficiency O +and O +specificity O +. O + +A O +better O +understanding O +of O +the O +genotype O +- O +phenotype O +correlation O +in O +COL3A1 O +using O +this O +method O +will O +lead O +to O +improve O +in O +diagnosis O +and O +treatment O +. O + + +Critical O +role O +of O +neuronal O +pentraxin O +1 O +in O +mitochondria O +- O +mediated O +hypoxic O +- O +ischemic O +neuronal O +injury O +. O + +Developing O +brain O +is O +highly O +susceptible O +to O +hypoxic O +- O +ischemic O +( O +HI O +) O +injury O +leading O +to O +severe O +neurological O +disabilities O +in O +surviving O +infants O +and O +children O +. O + +Previously O +, O +we O +have O +reported O +induction O +of O +neuronal O +pentraxin O +1 O +( O +NP1 O +), O +a O +novel O +neuronal O +protein O +of O +long O +- O +pentraxin O +family O +, O +following O +HI O +neuronal O +injury O +. O + +Here O +, O +we O +investigated O +how O +this O +specific O +signal O +is O +propagated O +to O +cause O +the O +HI O +neuronal O +death O +. O + +We O +used O +wild O +- O +type O +( O +WT O +) O +and O +NP1 O +knockout O +( O +NP1 O +- O +KO O +) O +mouse O +hippocampal O +cultures O +, O +modeled O +in O +vitro O +following O +exposure O +to O +oxygen B +glucose B +deprivation O +( O +OGD O +), O +and O +in O +vivo O +neonatal O +( O +P9 O +- O +10 O +) O +mouse O +model O +of O +HI O +brain O +injury O +. O + +Our O +results O +show O +induction O +of O +NP1 O +in O +primary O +hippocampal O +neurons O +following O +OGD O +exposure O +( O +4 B +- I +8 I +h I +) O +and O +in O +the O +ipsilateral O +hippocampal O +CA1 O +and O +CA3 O +regions O +at O +24 O +- O +48 O +h O +post O +- O +HI O +compared O +to O +the O +contralateral O +side O +. O + +We O +also O +found O +increased O +PTEN O +activity O +concurrent O +with O +OGD O +time O +- O +dependent O +( O +4 O +- O +8 O +h O +) O +dephosphorylation O +of O +Akt O +( O +Ser473 O +) O +and O +GSK O +- O +3b O +( O +Ser9 O +). O + +OGD O +also O +caused O +a O +time O +- O +dependent O +decrease O +in O +the O +phosphorylation O +of O +Bad O +( O +Ser136 O +), O +and O +Bax O +protein O +levels O +. O + +Immunofluorescence O +staining O +and O +subcellular O +fractionation O +analyses O +revealed O +increased O +mitochondrial O +translocation O +of O +Bad O +and O +Bax O +proteins O +from O +cytoplasm O +following O +OGD O +( O +4 O +h O +) O +and O +simultaneously O +increased O +release O +of O +Cyt O +C O +from O +mitochondria O +followed O +by O +activation O +of O +caspase O +- O +3 O +. O + +NP1 O +protein O +was O +immunoprecipitated O +with O +Bad O +and O +Bax O +proteins O +; O +OGD O +caused O +increased O +interactions O +of O +NP1 O +with O +Bad O +and O +Bax O +, O +thereby O +, O +facilitating O +their O +mitochondrial O +translocation O +and O +dissipation O +of O +mitochondrial O +membrane O +potential O +( O +D O +( O +m O +)). O + +This O +NP1 O +induction O +preceded O +the O +increased O +mitochondrial O +release O +of O +cytochrome O +C O +( O +Cyt O +C O +) O +into O +the O +cytosol O +, O +activation O +of O +caspase O +- O +3 O +and O +OGD O +time O +- O +dependent O +cell O +death O +in O +WT O +primary O +hippocampal O +neurons O +. O + +In O +contrast O +, O +in O +NP1 O +- O +KO O +neurons O +there O +was O +no O +translocation O +of O +Bad O +and O +Bax O +from O +cytosol O +to O +the O +mitochondria O +, O +and O +no O +evidence O +of O +D O +( O +m O +) O +loss O +, O +increased O +Cyt O +C O +release O +and O +caspase O +- O +3 O +activation O +following O +OGD O +; O +which O +resulted O +in O +significantly O +reduced O +neuronal O +death O +. O + +Our O +results O +indicate O +a O +regulatory O +role O +of O +NP1 O +in O +Bad O +/ O +Bax O +- O +dependent O +mitochondrial O +release O +of O +Cyt O +C O +and O +caspase O +- O +3 O +activation O +. O + +Together O +our O +findings O +demonstrate O +a O +novel O +mechanism O +by O +which O +NP1 O +regulates O +mitochondria O +- O +driven O +hippocampal O +cell O +death O +; O +suggesting O +NP1 O +as O +a O +potential O +therapeutic O +target O +against O +HI O +brain O +injury O +in O +neonates O +. O + + +Neuroprotective O +effect O +of O +neuroserpin O +in O +oxygen B +- O +glucose B +deprivation O +- O +and O +reoxygenation O +- O +treated O +rat O +astrocytes O +in O +vitro O +. O + +Neuroserpin O +( O +NSP O +) O +reportedly O +exerts O +neuroprotective O +effects O +in O +cerebral O +ischemic O +animal O +models O +and O +patients O +; O +however O +, O +the O +mechanism O +of O +protection O +is O +poorly O +understood O +. O + +We O +thus O +attempted O +to O +confirm O +neuroprotective O +effects O +of O +NSP O +on O +astrocytes O +in O +the O +ischemic O +state O +and O +then O +explored O +the O +relative O +mechanisms O +. O + +Astrocytes O +from O +neonatal O +rats O +were O +treated O +with O +oxygen B +- O +glucose B +deprivation O +( O +OGD O +) O +followed O +by O +reoxygenation O +( O +OGD O +/ O +R O +). O + +To O +confirm O +the O +neuroprotective O +effects O +of O +NSP O +, O +we O +measured O +the O +cell O +survival O +rate O +, O +relative O +lactate O +dehydrogenase O +( O +LDH O +) O +release O +; O +we O +also O +performed O +morphological O +methods O +, O +namely O +Hoechst O +33342 O +staining O +and O +Annexin O +V O +assay O +. O + +To O +explore O +the O +potential O +mechanisms O +of O +NSP O +, O +the O +release O +of O +nitric B +oxide I +( O +NO B +) O +and O +TNF O +- O +alpha O +related O +to O +NSP O +administration O +were O +measured O +by O +enzyme O +- O +linked O +immunosorbent O +assay O +. O + +The O +proteins O +related O +to O +the O +NF O +- O +kappaB O +, O +ERK1 O +/ O +2 O +, O +and O +PI3K O +/ O +Akt O +pathways O +were O +investigated O +by O +Western O +blotting O +. O + +To O +verify O +the O +cause O +- O +and O +- O +effect O +relationship O +between O +neuroprotection O +and O +the O +NF O +- O +kappaB O +pathway O +, O +a O +NF O +- O +kappaB O +pathway O +inhibitor O +sc3060 O +was O +employed O +to O +observe O +the O +effects O +of O +NSP O +- O +induced O +neuroprotection O +. O + +We O +found O +that O +NSP O +significantly O +increased O +the O +cell O +survival O +rate O +and O +reduced O +LDH O +release O +in O +OGD O +/ O +R O +- O +treated O +astrocytes O +. O + +It O +also O +reduced O +NO O +/ O +TNF O +- O +alpha O +release O +. O + +Western O +blotting O +showed O +that O +the O +protein O +levels O +of O +p O +- O +IKKBalpha O +/ O +beta O +and O +P65 O +were O +upregulated O +by O +the O +OGD O +/ O +R O +treatment O +and O +such O +effects O +were O +significantly O +inhibited O +by O +NSP O +administration O +. O + +The O +NSP O +- O +induced O +inhibition O +could O +be O +significantly O +reversed O +by O +administration O +of O +the O +NF O +- O +kappaB O +pathway O +inhibitor O +sc3060 O +, O +whereas O +, O +expressions O +of O +p O +- O +ERK1 O +, O +p O +- O +ERK2 O +, O +and O +p O +- O +AKT O +were O +upregulated O +by O +the O +OGD O +/ O +R O +treatment O +; O +however O +, O +their O +levels O +were O +unchanged O +by O +NSP O +administration O +. O + +Our O +results O +thus O +verified O +the O +neuroprotective O +effects O +of O +NSP O +in O +ischemic O +astrocytes O +. O + +The O +potential O +mechanisms O +include O +inhibition O +of O +the O +release O +of O +NO O +/ O +TNF O +- O +alpha O +and O +repression O +of O +the O +NF O +- O +kappaB O +signaling O +pathways O +. O + +Our O +data O +also O +indicated O +that O +NSP O +has O +little O +influence O +on O +the O +MAPK O +and O +PI3K O +/ O +Akt O +pathways O +. O + + +Interleukin O +6 O +( O +IL O +- O +6 O +) O +and O +Tumor O +Necrosis O +Factor O +alpha O +( O +TNF O +- O +alpha O +) O +Single O +Nucleotide O +Polymorphisms O +( O +SNPs O +), O +Inflammation O +and O +Metabolism O +in O +Gestational O +Diabetes O +Mellitus O +in O +Inner O +Mongolia O +. O + +BACKGROUND O +Gestational O +diabetes O +mellitus O +( O +GDM O +) O +is O +common O +all O +over O +the O +world O +. O + +GDM O +women O +are O +with O +inflammatory O +and O +metabolisms O +abnormalities O +. O + +However O +, O +few O +studies O +have O +focused O +on O +the O +association O +of O +IL O +- O +65 O +- O +72C O +/ O +G O +and O +TNF O +- O +alpha O +- O +857C O +/ O +T O +single O +nucleotide O +polymorphisms O +( O +SNPs O +), O +inflammatory O +biomarkers O +, O +and O +metabolic O +indexes O +in O +women O +with O +GDM O +, O +especially O +in O +the O +Inner O +Mongolia O +population O +. O + +The O +aim O +of O +this O +study O +was O +to O +investigate O +the O +associations O +of O +IL O +- O +65 O +- O +72C O +/ O +G O +and O +TNF O +- O +alpha O +- O +857C O +/ O +T O +SNPs O +, O +and O +inflammation O +and O +metabolic O +biomarkers O +in O +women O +with O +GDM O +pregnancies O +. O + +MATERIAL O +AND O +METHODS O +Blood O +samples O +and O +placentas O +from O +140 O +women O +with O +GDM O +and O +140 O +women O +with O +healthy O +pregnancies O +were O +collected O +. O + +Matrix O +- O +assisted O +laser O +desorption O +ionization O +time O +of O +flight O +mass O +spectrometry O +( O +MALDI O +- O +TOF O +- O +MS O +) O +and O +MassARRAY O +- O +IPLEX O +were O +performed O +to O +analyze O +IL O +- O +65 O +- O +72C O +/ O +G O +and O +TNF O +- O +alpha O +- O +857C O +/ O +T O +SNPs O +. O + +Enzyme O +linked O +immunosorbent O +assay O +( O +ELISA O +) O +was O +performed O +to O +analyze O +inflammatory O +biomarkers O +and O +adipokines O +. O + +RESULTS O +Distribution O +frequency O +of O +TNF O +- O +alpha O +- O +857CT O +( O +OR O += O +3 O +. O +316 O +, O +95 O +% O +CI O += O +1 O +. O +92 O +- O +8 O +. O +304 O +, O +p O += O +0 O +. O +25 O +) O +in O +women O +with O +GDM O +pregnancies O +were O +obviously O +higher O +than O +that O +in O +women O +with O +healthy O +pregnancies O +. O + +Women O +with O +GDM O +were O +of O +older O +maternal O +age O +, O +had O +higher O +BMI O +, O +were O +more O +nulliparous B +, O +and O +had O +T2DM O +and O +GDM O +history O +, O +compared O +to O +women O +with O +healthy O +pregnancies O +( O +p O +< O +0 O +. O +5 O +). O + +Inflammatory O +biomarkers O +in O +serum O +( O +hs O +- O +CRP O +, O +IL O +- O +6 O +, O +IL O +- O +8 O +, O +IL O +- O +6 O +/ O +IL O +- O +10 O +ratio O +) O +and O +placental O +( O +NF O +- O +kappaB O +, O +IL O +- O +6 O +, O +IL O +- O +8 O +, O +IL O +- O +6 O +/ O +IL O +- O +10 O +ratio O +, O +IL O +- O +1b O +, O +TNF O +- O +alpha O +) O +were O +significantly O +different O +( O +p O +< O +0 O +. O +5 O +) O +between O +women O +with O +GDM O +and O +women O +with O +healthy O +pregnancies O +. O + +Differences O +were O +found O +for O +serum O +FBG O +, O +FINS O +, O +HOMA O +- O +IR O +, O +and O +HOMA O +- O +beta O +, O +and O +placental O +IRS O +- O +1 O +, O +IRS O +- O +2 O +, O +leptin O +, O +adiponectin O +, O +visfatin O +, O +RBP O +- O +4 O +, O +chemerin O +, O +nesfatin O +- O +1 O +, O +FATP O +- O +4 O +, O +EL O +, O +LPL O +, O +FABP O +- O +1 O +, O +FABP O +- O +3 O +, O +FABP O +- O +4 O +, O +and O +FABP O +- O +5 O +. O + +CONCLUSIONS O +TNF O +- O +alpha O +- O +857C O +/ O +T O +SNP O +, O +hs O +- O +CRP O +, O +IL O +- O +6 O +, O +IL O +- O +8 O +, O +and O +IL O +- O +6 O +/ O +IL O +- O +10 O +were O +associated O +with O +GDM O +in O +women O +from O +Inner O +Mongolia O +, O +as O +was O +serious O +inflammation O +and O +disordered O +lipid B +and O +glucose B +metabolisms O +. O + + +Fine O +mapping O +and O +identification O +of O +a O +candidate O +gene O +SSH1 O +in O +disseminated O +superficial O +actinic O +porokeratosis O +. O + +Disseminated O +superficial O +actinic O +porokeratosis O +( O +DSAP O +) O +is O +an O +uncommon O +autosomal O +dominant O +chronic O +keratinization O +disorder O +, O +characterized O +by O +multiple O +superficial O +keratotic O +lesions O +surrounded O +by O +a O +slightly O +raised O +keratotic O +border O +. O + +Thus O +far O +, O +although O +two O +loci O +for O +DSAP O +have O +been O +identified O +, O +the O +genetic O +basis O +and O +pathogenesis O +of O +this O +disorder O +have O +not O +been O +elucidated O +yet O +. O + +In O +this O +study O +, O +we O +performed O +a O +genome O +- O +wide O +linkage O +analysis O +in O +three O +Chinese O +affected O +families O +and O +localized O +the O +gene O +in O +an O +8 O +. O +0 O +cM O +interval O +defined O +by O +D12S330 O +and O +D12S354 O +on O +chromosome O +12 O +. O + +Upon O +screening O +30 O +candidate O +genes O +, O +we O +identified O +a O +missense O +mutation O +, O +p O +. O +Ser63Asn O +in O +SSH1 O +in O +one O +family O +, O +a O +frameshift O +mutation O +, O +p O +. O +Ser19CysfsX24 O +in O +an O +alternative O +variant O +( O +isoform O +f O +) O +of O +SSH1 O +in O +another O +family O +, O +and O +a O +frameshift O +mutation O +, O +p O +. O +Pro27ProfsX54 O +in O +the O +same O +alternative O +variant O +in O +one O +non O +- O +familial O +case O +with O +DSAP O +. O + +SSH1 O +encodes O +a O +phosphatase O +that O +plays O +a O +pivotal O +role O +in O +actin O +dynamics O +. O + +Our O +data O +suggested O +that O +cytoskeleton O +disorganization O +in O +epidermal O +cells O +is O +likely O +associated O +with O +the O +pathogenesis O +of O +DSAP O +. O + + +Array O +- O +based O +comparative O +genomic O +hybridization O +analysis O +reveals O +recurrent O +chromosomal O +alterations O +and O +prognostic O +parameters O +in O +primary O +cutaneous O +large O +B O +- O +cell O +lymphoma O +. O + +PURPOSE O +: O +To O +evaluate O +the O +clinical O +relevance O +of O +genomic O +aberrations O +in O +primary O +cutaneous O +large O +B O +- O +cell O +lymphoma O +( O +PCLBCL O +). O + +PATIENTS O +AND O +METHODS O +: O +Skin O +biopsy O +samples O +of O +31 O +patients O +with O +a O +PCLBCL O +classified O +as O +either O +primary O +cutaneous O +follicle O +center O +lymphoma O +( O +PCFCL B +; O +n O += O +19 O +) O +or O +PCLBCL O +, O +leg O +type O +( O +n O += O +12 O +), O +according O +to O +the O +WHO O +- O +European O +Organisation O +for O +Research O +and O +Treatment O +of O +Cancer O +( O +EORTC O +) O +classification O +, O +were O +investigated O +using O +array O +- O +based O +comparative O +genomic O +hybridization O +, O +fluorescence O +in O +situ O +hybridization O +( O +FISH O +), O +and O +examination O +of O +promoter O +hypermethylation O +. O + +RESULTS O +: O +The O +most O +recurrent O +alterations O +in O +PCFCL B +were O +high O +- O +level O +DNA O +amplifications O +at O +2p16 O +. O +1 O +( O +63 O +%) O +and O +deletion O +of O +chromosome O +14q32 O +. O +33 O +( O +68 O +%). O + +FISH O +analysis O +confirmed O +c O +- O +REL O +amplification O +in O +patients O +with O +gains O +at O +2p16 O +. O +1 O +. O + +In O +PCLBCL O +, O +leg O +type O +, O +most O +prominent O +aberrations O +were O +a O +high O +- O +level O +DNA O +amplification O +of O +18q21 O +. O +31 O +- O +q21 O +. O +33 O +( O +67 O +%), O +including O +the O +BCL O +- O +2 O +and O +MALT1 O +genes O +as O +confirmed O +by O +FISH O +, O +and O +deletions O +of O +a O +small O +region O +within O +9p21 O +. O +3 O +containing O +the O +CDKN2A O +, O +CDKN2B O +, O +and O +NSG O +- O +x O +genes O +. O + +Homozygous O +deletion O +of O +9p21 O +. O +3 O +was O +detected O +in O +five O +of O +12 O +patients O +with O +PCLBCL O +, O +leg O +type O +, O +but O +in O +zero O +of O +19 O +patients O +with O +PCFCL B +. O + +Complete O +methylation O +of O +the O +promoter O +region O +of O +the O +CDKN2A O +gene O +was O +demonstrated O +in O +one O +PCLBCL O +, O +leg O +type O +, O +patient O +with O +hemizygous O +deletion O +, O +in O +one O +patient O +without O +deletion O +, O +but O +in O +zero O +of O +19 O +patients O +with O +PCFCL O +. O + +Seven O +of O +seven O +PCLBCL O +, O +leg O +type O +, O +patients O +with O +deletion O +of O +9p21 O +. O +3 O +and O +/ O +or O +complete O +methylation O +of O +CDKN2A O +died O +as O +a O +result O +of O +their O +lymphoma O +. O + +CONCLUSION O +: O +Our O +results O +demonstrate O +prominent O +differences O +in O +chromosomal O +alterations O +between O +PCFCL B +and O +PCLBCL O +, O +leg O +type O +, O +that O +support O +their O +classification O +as O +separate O +entities O +within O +the O +WHO O +- O +EORTC O +scheme O +. O + +Inactivation O +of O +CDKN2A O +by O +either O +deletion O +or O +methylation O +of O +its O +promoter O +could O +be O +an O +important O +prognostic O +parameter O +for O +the O +group O +of O +PCLBCL O +, O +leg O +type O +. O + + +Osteogenesis O +imperfecta O +type O +III O +with O +intracranial O +hemorrhage O +and O +brachydactyly O +associated O +with O +mutations O +in O +exon O +49 O +of O +COL1A2 O +. O + +Osteogenesis O +imperfecta O +( O +OI O +) O +is O +a O +heritable O +bone O +disorder O +characterized O +by O +fractures O +with O +minimal O +trauma O +. O + +Intracranial O +hemorrhage O +has O +been O +reported O +in O +a O +small O +number O +of O +OI O +patients O +. O + +Here O +we O +describe O +three O +patients O +, O +a O +boy O +( O +aged O +15 O +years O +) O +and O +two O +girls O +( O +aged O +17 O +and O +7 O +years O +) O +with O +OI O +type O +III O +who O +suffered O +intracranial O +hemorrhage O +and O +in O +addition O +had O +brachydactyly O +and O +nail O +hypoplasia O +. O + +In O +all O +of O +these O +patients O +, O +OI O +was O +caused O +by O +glycine O +mutations O +affecting O +exon O +49 O +of O +the O +COL1A2 O +gene O +, O +which O +codes O +for O +the O +most O +carboxy O +- O +terminal O +part O +of O +the O +triple O +- O +helical O +domain O +of O +the O +collagen O +type O +I O +alpha O +2 O +chain O +. O + +These O +observations O +suggest O +that O +mutations O +in O +this O +region O +of O +the O +collagen O +type O +I O +alpha O +2 O +chain O +carry O +a O +high O +risk O +of O +abnormal O +limb O +development O +and O +intracranial O +bleeding O +. O + + +Bilateral O +haemorrhagic O +infarction O +of O +the O +globus O +pallidus O +after O +cocaine B +and O +alcohol B +intoxication O +. O + +Cocaine B +is O +a O +risk O +factor O +for O +both O +ischemic O +and O +haemorrhagic O +stroke O +. O + +We O +present O +the O +case O +of O +a O +31 O +- O +year O +- O +old O +man O +with O +bilateral O +ischemia O +of O +the O +globus O +pallidus O +after O +excessive O +alcohol B +and O +intranasal O +cocaine B +use O +. O + +Drug O +- O +related O +globus O +pallidus O +infarctions O +are O +most O +often O +associated O +with O +heroin O +. O + +Bilateral O +basal O +ganglia O +infarcts O +after O +the O +use O +of O +cocaine B +, O +without O +concurrent O +heroin O +use O +, O +have O +never O +been O +reported O +. O + +In O +our O +patient O +, O +transient O +cardiac O +arrhythmia O +or O +respiratory O +dysfunction O +related O +to O +cocaine B +and O +/ O +or O +ethanol O +use O +were O +the O +most O +likely O +causes O +of O +cerebral O +hypoperfusion O +. O + + +The O +fibrinogen O +gamma O +10034C O +> O +T O +polymorphism O +is O +not O +associated O +with O +Peripheral O +Arterial O +Disease O +. O + +Conversion O +of O +fibrinogen O +to O +fibrin O +plays O +an O +essential O +role O +in O +hemostasis O +and O +results O +in O +stabilization O +of O +the O +fibrin O +clot O +. O + +Fibrinogen O +consists O +of O +three O +pairs O +of O +non O +- O +identical O +polypeptide O +chains O +, O +encoded O +by O +different O +genes O +( O +fibrinogen O +alpha O +[ O +FGA B +], O +fibrinogen O +beta O +[ O +FGB O +] O +and O +fibrinogen O +gamma O +[ O +FGG O +]). O + +A O +functional O +single O +nucleotide O +polymorphism O +( O +SNP O +) O +in O +the O +3 O +' O +untranslated O +region O +of O +the O +FGG O +gene O +( O +FGG O +10034C O +> O +T O +, O +rs2066865 O +) O +has O +been O +associated O +with O +deep O +venous O +thrombosis O +and O +myocardial O +infarction O +. O + +Aim O +of O +the O +present O +study O +was O +to O +analyze O +the O +role O +of O +this O +polymorphism O +in O +peripheral O +arterial O +disease O +( O +PAD O +). O + +The O +study O +was O +designed O +as O +case O +- O +control O +study O +including O +891 O +patients O +with O +documented O +PAD O +and O +777 O +control O +subjects O +. O + +FGG O +genotypes O +were O +determined O +by O +exonuclease O +( O +TaqMan O +) O +assays O +. O + +FGG O +genotype O +frequencies O +were O +not O +significantly O +different O +between O +PAD O +patients O +( O +CC O +: O +57 O +. O +3 O +%, O +CT O +: O +36 O +. O +7 O +%, O +TT O +: O +5 O +. O +8 O +%) O +and O +control O +subjects O +( O +CC O +: O +60 O +. O +9 O +%, O +CT O +: O +33 O +. O +5 O +%, O +TT O +5 O +. O +6 O +%; O +p O += O +0 O +. O +35 O +). O + +In O +a O +multivariate O +logistic O +regression O +analysis O +including O +age O +, O +sex O +, O +smoking O +, O +diabetes O +, O +arterial O +hypertension O +and O +hypercholesterolemia O +, O +the O +FGG O +10034 O +T O +variant O +was O +not O +significantly O +associated O +with O +the O +presence O +of O +PAD O +( O +Odds O +ratio O +1 O +. O +7 O +, O +95 O +% O +confidence O +interval O +0 O +. O +84 O +- O +1 O +. O +37 O +; O +p O += O +0 O +. O +60 O +). O + +The O +FGG O +10034C O +> O +T O +polymorphism O +was O +furthermore O +not O +associated O +with O +age O +at O +onset O +of O +PAD O +. O + +We O +conclude O +that O +the O +thrombophilic O +FGG O +10034 O +T O +gene O +variant O +does O +not O +contribute O +to O +the O +genetic O +susceptibility O +to O +PAD O +. O + + +Genotype O +rs8099917 O +near O +the O +IL28B O +gene O +and O +amino O +acid O +substitution O +at O +position O +70 O +in O +the O +core O +region O +of O +the O +hepatitis O +C O +virus O +are O +determinants O +of O +serum O +apolipoprotein O +B O +- O +100 O +concentration O +in O +chronic O +hepatitis O +C O +. O + +The O +life O +cycle O +of O +the O +hepatitis O +C O +virus O +( O +HCV O +) O +is O +closely O +related O +to O +host O +lipoprotein O +metabolism O +. O + +Serum O +levels O +of O +lipid B +are O +associated O +with O +the O +response O +to O +pegylated O +interferon O +plus O +ribavirin O +( O +PEG O +- O +IFN O +/ O +RBV O +) O +therapy O +, O +while O +single O +nucleotide O +polymorphisms O +( O +SNPs O +) O +around O +the O +human O +interleukin O +28B O +( O +IL28B O +) O +gene O +locus O +and O +amino O +acid O +substitutions O +in O +the O +core O +region O +of O +the O +HCV O +have O +been O +reported O +to O +affect O +the O +efficacy O +of O +PEG O +- O +IFN O +/ O +RBV O +therapy O +in O +chronic O +hepatitis O +with O +HCV O +genotype O +1b O +infection O +. O + +The O +aim O +of O +this O +study O +was O +to O +elucidate O +the O +relationship O +between O +serum O +lipid B +and O +factors O +that O +are O +able O +to O +predict O +the O +efficacy O +of O +PEG O +- O +IFN O +/ O +RB O +therapy O +, O +with O +specific O +focus O +on O +apolipoprotein O +B O +- O +100 O +( O +apoB O +- O +100 O +) O +in O +148 O +subjects O +with O +chronic O +HCV O +G1b O +infection O +. O + +Our O +results O +demonstrated O +that O +both O +the O +aa O +70 O +substitution O +in O +the O +core O +region O +of O +the O +HCV O +and O +the O +rs8099917 O +SNP O +located O +proximal O +to O +the O +IL28B O +were O +independent O +factors O +in O +determining O +serum O +apoB O +- O +100 O +and O +low O +- O +density O +lipoprotein O +( O +LDL O +) O +cholesterol B +levels O +. O + +A O +significant O +association O +was O +noted O +between O +higher O +levels O +of O +apoB O +- O +100 O +( O +P O += O +1 O +. O +1 O +10 O +(- O +3 O +)) O +and O +LDL B +cholesterol B +( O +P O += O +0 O +. O +2 O +) O +and O +the O +subjects O +having O +Arg70 O +. O + +A O +significant O +association O +was O +also O +observed O +between O +subjects O +carrying O +the O +rs8099917 O +TT O +responder O +genotype O +and O +higher O +levels O +of O +apoB O +- O +100 O +( O +P O += O +6 O +. O +4 O +10 O +(- O +3 O +)) O +and O +LDL O +cholesterol B +( O +P O += O +4 O +. O +2 O +10 O +(- O +3 O +)). O + +Our O +results O +suggest O +that O +apoB O +- O +100 O +and O +LDL O +cholesterol B +are O +markers O +of O +impaired O +cellular O +lipoprotein O +pathways O +and O +/ O +or O +host O +endogenous O +interferon O +response O +to O +HCV O +in O +chronic O +HCV O +infection O +. O + +In O +particular O +, O +serum O +apoB O +- O +100 O +concentration O +might O +be O +an O +informative O +marker O +for O +judging O +changes O +in O +HCV O +- O +associated O +intracellular O +lipoprotein O +metabolism O +in O +patients O +carrying O +the O +rs8099917 O +responder O +genotype O +. O + + +Phosphatidylinositol O +4 O +- O +kinase O +IIb O +negatively O +regulates O +invadopodia O +formation O +and O +suppresses O +an O +invasive O +cellular O +phenotype O +. O + +The O +type O +II O +phosphatidylinositol O +4 O +- O +kinase O +( O +PI4KII O +) O +enzymes O +synthesize O +the O +lipid B +phosphatidylinositol B +4 O +- I +phosphate I +( O +PI O +( O +4 O +) O +P O +), O +which O +has O +been O +detected O +at O +the O +Golgi O +complex O +and O +endosomal O +compartments O +and O +recruits O +clathrin B +adaptors O +. O + +Despite O +common O +mechanistic O +similarities O +between O +the O +isoforms O +, O +the O +extent O +of O +their O +redundancy O +is O +unclear O +. O + +We O +found O +that O +depletion O +of O +PI4KIIa O +and O +PI4KIIb O +using O +small O +interfering O +RNA O +led O +to O +actin O +remodeling O +. O + +Depletion O +of O +PI4KIIb O +also O +induced O +the O +formation O +of O +invadopodia O +containing O +membrane O +type O +I O +matrix O +metalloproteinase O +( O +MT1 O +- O +MMP O +). O + +Depletion O +of O +PI4KII O +isoforms O +also O +differentially O +affected O +trans O +- O +Golgi O +network O +( O +TGN O +) O +pools O +of O +PI O +( O +4 O +) O +P O +and O +post O +- O +TGN O +traffic O +. O + +PI4KIIb O +depletion O +caused O +increased O +MT1 O +- O +MMP O +trafficking O +to O +invasive O +structures O +at O +the O +plasma O +membrane O +and O +was O +accompanied O +by O +reduced O +colocalization O +of O +MT1 O +- O +MMP O +with O +membranes O +containing O +the O +endosomal O +markers O +Rab5 O +and O +Rab7 O +but O +increased O +localization O +with O +the O +exocytic O +Rab8 O +. O + +Depletion O +of O +PI4KIIb O +was O +sufficient O +to O +confer O +an O +aggressive O +invasive O +phenotype O +on O +minimally O +invasive O +HeLa O +and O +MCF O +- O +7 O +cell O +lines O +. O + +Mining O +oncogenomic O +databases O +revealed O +that O +loss O +of O +the O +PI4K2B O +allele O +and O +underexpression O +of O +PI4KIIb O +mRNA O +are O +associated O +with O +human O +cancers O +. O + +This O +finding O +supports O +the O +cell O +data O +and O +suggests O +that O +PI4KIIb O +may O +be O +a O +clinically O +significant O +suppressor O +of O +invasion O +. O + +We O +propose O +that O +PI4KIIb O +synthesizes O +a O +pool O +of O +PI O +( O +4 O +) O +P O +that O +maintains O +MT1 O +- O +MMP O +traffic O +in O +the O +degradative O +pathway O +and O +suppresses O +the O +formation O +of O +invadopodia O +. O + + +CenpH O +regulates O +meiotic O +G2 O +/ O +M O +transition O +by O +modulating O +the O +APC O +/ O +CCdh1 O +- O +cyclin O +B1 O +pathway O +in O +oocytes O +. O + +Meiotic O +resumption O +( O +G2 O +/ O +M O +transition O +) O +and O +progression O +through O +meiosis O +I O +( O +MI O +) O +are O +two O +key O +stages O +for O +producing O +fertilization O +- O +competent O +eggs O +. O + +Here O +, O +we O +report O +that O +CenpH O +, O +a O +component O +of O +the O +kinetochore O +inner O +plate O +, O +is O +responsible O +for O +G2 O +/ O +M O +transition O +in O +meiotic O +mouse O +oocytes O +. O + +Depletion O +of O +CenpH O +by O +morpholino B +injection O +decreased O +cyclin B +B1 O +levels O +, O +resulting O +in O +attenuation O +of O +maturation O +- O +promoting O +factor O +( O +MPF O +) O +activation O +, O +and O +severely O +compromised O +meiotic O +resumption O +. O + +CenpH O +protects O +cyclin O +B1 O +from O +destruction O +by O +competing O +with O +the O +action O +of O +APC O +/ O +C O +( O +Cdh1 O +) O +Impaired O +G2 O +/ O +M O +transition O +after O +CenpH O +depletion O +could O +be O +rescued O +by O +expression O +of O +exogenous O +cyclin O +B1 O +. O + +Unexpectedly O +, O +blocking O +CenpH O +did O +not O +affect O +spindle O +organization O +and O +meiotic O +cell O +cycle O +progression O +after O +germinal O +vesicle O +breakdown O +. O + +Our O +findings O +reveal O +a O +novel O +role O +of O +CenpH O +in O +regulating O +meiotic O +G2 O +/ O +M O +transition O +by O +acting O +via O +the O +APC O +/ O +C O +( O +Cdh1 O +)- O +cyclin O +B1 O +pathway O +. O + + +CRYBA3 O +/ O +A1 O +gene O +mutation O +associated O +with O +suture O +- O +sparing O +autosomal O +dominant O +congenital O +nuclear O +cataract O +: O +a O +novel O +phenotype O +. O + +PURPOSE O +: O +To O +identify O +the O +genetic O +defect O +leading O +to O +the O +congenital O +nuclear O +cataract O +affecting O +a O +large O +five O +- O +generation O +Swiss O +family O +. O + +METHODS O +: O +Family O +history O +and O +clinical O +data O +were O +recorded O +. O + +The O +phenotype O +was O +documented O +by O +both O +slit O +lamp O +and O +Scheimpflug O +photography O +. O + +One O +cortical O +lens O +was O +evaluated O +by O +electron O +microscopy O +after O +cataract O +extraction O +. O + +Lenticular O +phenotyping O +and O +genotyping O +were O +performed O +independently O +with O +short O +tandem O +repeat O +polymorphism O +. O + +Linkage O +analysis O +was O +performed O +, O +and O +candidate O +genes O +were O +PCR O +amplified O +and O +screened O +for O +mutations O +on O +both O +strands O +using O +direct O +sequencing O +. O + +RESULTS O +: O +Affected O +individuals O +had O +a O +congenital O +nuclear O +lactescent O +cataract O +in O +both O +eyes O +. O + +Linkage O +was O +observed O +on O +chromosome O +17 O +for O +DNA O +marker O +D17S1857 O +( O +lod O +score O +: O +3 O +. O +44 O +at O +theta O += O +0 O +). O + +Direct O +sequencing O +of O +CRYBA3 O +/ O +A1 O +, O +which O +maps O +to O +the O +vicinity O +, O +revealed O +an O +in O +- O +frame O +3 O +- O +bp O +deletion O +in O +exon O +4 O +( O +279delGAG O +). O + +This O +mutation O +involved O +a O +deletion O +of O +glycine O +- O +91 O +, O +cosegregated O +in O +all O +affected O +individuals O +, O +and O +was O +not O +observed O +in O +unaffected O +individuals O +or O +in O +250 O +normal O +control O +subjects O +from O +the O +same O +ethnic O +background O +. O + +Electron O +microscopy O +showed O +that O +cortical O +lens O +fiber O +morphology O +was O +normal O +. O + +CONCLUSIONS O +: O +The O +DeltaG91 O +mutation O +in O +CRYBA3 O +/ O +A1 O +is O +associated O +with O +an O +autosomal O +dominant O +congenital O +nuclear O +lactescent O +cataract O +. O + +A O +splice O +mutation O +( O +IVS3 O ++ O +1G O +/ O +A O +) O +in O +this O +gene O +has O +been O +reported O +in O +a O +zonular O +cataract O +with O +sutural O +opacities O +. O + +These O +results O +indicate O +phenotypic O +heterogeneity O +related O +to O +mutations O +in O +this O +gene O +. O + + +Vitamin B +D I +- O +binding O +protein O +gene O +polymorphism O +association O +with O +IA O +- O +2 O +autoantibodies O +in O +type O +1 O +diabetes O +. O + +BACKGROUND O +: O +Vitamin B +D I +- O +binding O +protein O +( O +DBP O +) O +is O +the O +main O +systemic O +transporter O +of O +1 O +. O +25 O +( O +OH O +) O +2D3 O +and O +is O +essential O +for O +its O +cellular O +endocytosis O +. O + +There O +are O +two O +known O +polymorphisms O +in O +exon O +11 O +of O +the O +DBP O +gene O +resulting O +in O +amino O +acid O +variants O +: O +GAT O +--> O +GAG O +substitution O +replaces O +aspartic O +acid O +by O +glutamic O +acid O +in O +codon O +416 O +; O +and O +ACG O +--> O +AAG O +substitution O +in O +codon O +420 O +leads O +to O +an O +exchange O +of O +threonine O +for O +lysine O +. O + +These O +DBP O +variants O +lead O +to O +differences O +in O +the O +affinity O +for O +1 O +. O +25 O +( O +OH O +) O +2D3 O +. O + +Correlations O +between O +DBP O +alleles O +and O +type O +1 O +diabetes O +have O +been O +described O +in O +different O +populations O +. O + +Therefore O +, O +we O +investigated O +the O +polymorphism O +in O +codon O +416 O +of O +the O +DBP O +gene O +for O +an O +association O +with O +autoimmune O +markers O +of O +type O +1 O +diabetes O +. O + +DESIGN O +AND O +METHODS O +: O +The O +present O +analysis O +was O +a O +case O +control O +study O +. O + +110 O +patients O +, O +68 O +controls O +, O +and O +115 O +first O +- O +degree O +relatives O +were O +genotyped O +for O +the O +DBP O +polymorphism O +in O +codon O +416 O +. O + +DNA O +typing O +of O +DBP O +locus O +was O +performed O +by O +the O +PCR O +- O +restriction O +fragment O +length O +polymorphism O +method O +( O +RFLP O +). O + +RESULTS O +: O +The O +frequencies O +of O +the O +Asp O +/ O +Glu O +and O +Glu O +/ O +Glu O +were O +significantly O +increased O +in O +diabetic O +subjects O +with O +detectable O +IA O +- O +2 O +antibodies O +( O +P O +< O +0 O +. O +1 O +). O + +On O +the O +contrary O +, O +the O +DBP O +Glu O +- O +containing O +genotype O +was O +not O +accompanied O +by O +differences O +in O +the O +prevalence O +of O +GAD65 O +antibodies O +. O + +These O +finding O +supports O +a O +role O +of O +the O +vitamin B +D I +endocrine O +system O +in O +the O +autoimmune O +process O +of O +type O +1 O +diabetes O +. O + + +Characterization O +of O +Bietti O +crystalline O +dystrophy O +patients O +with O +CYP4V2 O +mutations O +. O + +PURPOSE O +: O +Mutations O +of O +the O +CYP4V2 O +gene O +, O +a O +novel O +family O +member O +of O +the O +cytochrome O +P450 O +genes O +on O +chromosome O +4q35 O +, O +have O +recently O +been O +identified O +in O +patients O +with O +Bietti O +crystalline O +dystrophy O +( O +BCD O +). O + +The O +aim O +of O +this O +study O +was O +to O +investigate O +the O +spectrum O +of O +mutations O +in O +this O +gene O +in O +BCD O +patients O +from O +Singapore O +, O +and O +to O +characterize O +their O +phenotype O +. O + +METHODS O +: O +Nine O +patients O +with O +BCD O +from O +six O +families O +were O +recruited O +into O +the O +study O +. O + +The O +11 O +exons O +of O +the O +CYP4V2 O +gene O +were O +amplified O +from O +genomic O +DNA O +of O +patients O +by O +polymerase O +chain O +reaction O +and O +then O +sequenced O +. O + +Detailed O +characterization O +of O +the O +patients O +' O +phenotype O +was O +performed O +with O +fundal O +photography O +, O +visual O +field O +testing O +, O +fundal O +fluorescein B +angiography O +, O +and O +electroretinography O +( O +ERG O +). O + +RESULTS O +: O +Three O +pathogenic O +mutations O +were O +identified O +; O +two O +mutations O +, O +S482X O +and O +K386T O +, O +were O +novel O +and O +found O +in O +three O +patients O +. O + +The O +third O +mutation O +, O +a O +previously O +identified O +15 O +- O +bp O +deletion O +that O +included O +the O +3 O +' O +splice O +site O +for O +exon O +7 O +, O +was O +found O +in O +all O +nine O +patients O +, O +with O +six O +patients O +carrying O +the O +deletion O +in O +the O +homozygous O +state O +. O + +Haplotype O +analysis O +in O +patients O +and O +controls O +indicated O +a O +founder O +effect O +for O +this O +deletion O +mutation O +in O +exon O +7 O +. O + +Clinical O +heterogeneity O +was O +present O +in O +the O +patients O +. O + +Compound O +heterozygotes O +for O +the O +deletion O +in O +exon O +7 O +seemed O +to O +have O +more O +severe O +disease O +compared O +to O +patients O +homozygous O +for O +the O +deletion O +. O + +There O +was O +good O +correlation O +between O +clinical O +stage O +of O +disease O +and O +ERG O +changes O +, O +but O +age O +did O +not O +correlate O +with O +disease O +severity O +. O + +CONCLUSIONS O +: O +This O +study O +identified O +novel O +mutations O +in O +the O +CYP4V2 O +gene O +as O +a O +cause O +of O +BCD O +. O + +A O +high O +carrier O +frequency O +for O +the O +15 O +- O +bp O +deletion O +in O +exon O +7 O +may O +exist O +in O +the O +Singapore O +population O +. O + +Phenotype O +characterization O +showed O +clinical O +heterogeneity O +, O +and O +age O +did O +not O +correlate O +with O +disease O +severity O +. O + + +An O +extremely O +rare O +case O +of O +delusional O +parasitosis O +in O +a O +chronic O +hepatitis O +C O +patient O +during O +pegylated O +interferon O +alpha O +- I +2b I +and O +ribavirin B +treatment O +. O + +During O +treatment O +of O +chronic O +hepatitis O +C O +patients O +with O +interferon O +and O +ribavirin O +, O +a O +lot O +of O +side O +effects O +are O +described O +. O + +Twenty O +- O +three O +percent O +to O +44 O +% O +of O +patients O +develop O +depression O +. O + +A O +minority O +of O +patients O +evolve O +to O +psychosis O +. O + +To O +the O +best O +of O +our O +knowledge O +, O +no O +cases O +of O +psychogenic O +parasitosis O +occurring O +during O +interferon O +therapy O +have O +been O +described O +in O +the O +literature O +. O + +We O +present O +a O +49 O +- O +year O +- O +old O +woman O +who O +developed O +a O +delusional O +parasitosis O +during O +treatment O +with O +pegylated O +interferon I +alpha O +- O +2b O +weekly O +and O +ribavirin B +. O + +She O +complained O +of O +seeing O +parasites O +and O +the O +larvae O +of O +fleas O +in O +her O +stools O +. O + +This O +could O +not O +be O +confirmed O +by O +any O +technical O +examination O +. O + +All O +the O +complaints O +disappeared O +after O +stopping O +pegylated O +interferon O +alpha O +- O +2b O +and O +reappeared O +after O +restarting O +it O +. O + +She O +had O +a O +complete O +sustained O +viral O +response O +. O + + +Protein O +- O +Trap O +Insertional O +Mutagenesis O +Uncovers O +New O +Genes O +Involved O +in O +Zebrafish O +Skin O +Development O +, O +Including O +a O +Neuregulin O +2a O +- O +Based O +ErbB O +Signaling O +Pathway O +Required O +during O +Median O +Fin O +Fold O +Morphogenesis O +. O + +Skin O +disorders O +are O +widespread O +, O +but O +available O +treatments O +are O +limited O +. O + +A O +more O +comprehensive O +understanding O +of O +skin O +development O +mechanisms O +will O +drive O +identification O +of O +new O +treatment O +targets O +and O +modalities O +. O + +Here O +we O +report O +the O +Zebrafish O +Integument O +Project O +( O +ZIP O +), O +an O +expression O +- O +driven O +platform O +for O +identifying O +new O +skin O +genes O +and O +phenotypes O +in O +the O +vertebrate O +model O +Danio O +rerio O +( O +zebrafish O +). O + +In O +vivo O +selection O +for O +skin O +- O +specific O +expression O +of O +gene O +- O +break O +transposon O +( O +GBT O +) O +mutant O +lines O +identified O +eleven O +new O +, O +revertible O +GBT O +alleles O +of O +genes O +involved O +in O +skin O +development O +. O + +Eight O +genes O +-- O +fras1 O +, O +grip1 O +, O +hmcn1 O +, O +msxc O +, O +col4a4 O +, O +ahnak O +, O +capn12 O +, O +and O +nrg2a O +-- O +had O +been O +described O +in O +an O +integumentary O +context O +to O +varying O +degrees O +, O +while O +arhgef25b O +, O +fkbp10b O +, O +and O +megf6a O +emerged O +as O +novel O +skin O +genes O +. O + +Embryos O +homozygous O +for O +a O +GBT O +insertion O +within O +neuregulin O +2a O +( O +nrg2a O +) O +revealed O +a O +novel O +requirement O +for O +a O +Neuregulin O +2a O +( O +Nrg2a O +)- O +ErbB2 O +/ O +3 O +- O +AKT O +signaling O +pathway O +governing O +the O +apicobasal O +organization O +of O +a O +subset O +of O +epidermal O +cells O +during O +median O +fin O +fold O +( O +MFF O +) O +morphogenesis O +. O + +In O +nrg2a O +mutant O +larvae O +, O +the O +basal O +keratinocytes O +within O +the O +apical O +MFF O +, O +known O +as O +ridge O +cells O +, O +displayed O +reduced O +pAKT O +levels O +as O +well O +as O +reduced O +apical O +domains O +and O +exaggerated O +basolateral O +domains O +. O + +Those O +defects O +compromised O +proper O +ridge O +cell O +elongation O +into O +a O +flattened O +epithelial O +morphology O +, O +resulting O +in O +thickened O +MFF O +edges O +. O + +Pharmacological O +inhibition O +verified O +that O +Nrg2a O +signals O +through O +the O +ErbB O +receptor O +tyrosine O +kinase O +network O +. O + +Moreover O +, O +knockdown O +of O +the O +epithelial O +polarity O +regulator O +and O +tumor O +suppressor O +lgl2 O +ameliorated O +the O +nrg2a O +mutant O +phenotype O +. O + +Identifying O +Lgl2 O +as O +an O +antagonist O +of O +Nrg2a O +- O +ErbB O +signaling O +revealed O +a O +significantly O +earlier O +role O +for O +Lgl2 O +during O +epidermal O +morphogenesis O +than O +has O +been O +described O +to O +date O +. O + +Furthermore O +, O +our O +findings O +demonstrated O +that O +successive O +, O +coordinated O +ridge O +cell O +shape O +changes O +drive O +apical O +MFF O +development O +, O +making O +MFF O +ridge O +cells O +a O +valuable O +model O +for O +investigating O +how O +the O +coordinated O +regulation O +of O +cell O +polarity O +and O +cell O +shape O +changes O +serves O +as O +a O +crucial O +mechanism O +of O +epithelial O +morphogenesis O +. O + + +Mutation O +analysis O +of O +CHRNA1 O +, O +CHRNB1 O +, O +CHRND O +, O +and O +RAPSN O +genes O +in O +multiple O +pterygium O +syndrome O +/ O +fetal O +akinesia O +patients O +. O + +Multiple O +pterygium O +syndromes O +( O +MPS O +) O +comprise O +a O +group O +of O +multiple O +congenital O +anomaly O +disorders O +characterized O +by O +webbing O +( O +pterygia O +) O +of O +the O +neck O +, O +elbows O +, O +and O +/ O +or O +knees O +and O +joint O +contractures O +( O +arthrogryposis O +). O + +MPS O +are O +phenotypically O +and O +genetically O +heterogeneous O +but O +are O +traditionally O +divided O +into O +prenatally O +lethal O +and O +nonlethal O +( O +Escobar O +) O +types O +. O + +Previously O +, O +we O +and O +others O +reported O +that O +recessive O +mutations O +in O +the O +embryonal O +acetylcholine O +receptor O +g O +subunit O +( O +CHRNG O +) O +can O +cause O +both O +lethal O +and O +nonlethal O +MPS O +, O +thus O +demonstrating O +that O +pterygia O +resulted O +from O +fetal O +akinesia O +. O + +We O +hypothesized O +that O +mutations O +in O +acetylcholine O +receptor O +- O +related O +genes O +might O +also O +result O +in O +a O +MPS O +/ O +fetal O +akinesia O +phenotype O +and O +so O +we O +analyzed O +15 O +cases O +of O +lethal O +MPS O +/ O +fetal O +akinesia O +without O +CHRNG O +mutations O +for O +mutations O +in O +the O +CHRNA1 O +, O +CHRNB1 O +, O +CHRND O +, O +and O +rapsyn O +( O +RAPSN O +) O +genes O +. O + +No O +CHRNA1 O +, O +CHRNB1 O +, O +or O +CHRND O +mutations O +were O +detected O +, O +but O +a O +homozygous O +RAPSN O +frameshift O +mutation O +, O +c O +. O +1177 O +- O +1178delAA O +, O +was O +identified O +in O +a O +family O +with O +three O +children O +affected O +with O +lethal O +fetal O +akinesia O +sequence O +. O + +Previously O +, O +RAPSN O +mutations O +have O +been O +reported O +in O +congenital O +myasthenia O +. O + +Functional O +studies O +were O +consistent O +with O +the O +hypothesis O +that O +whereas O +incomplete O +loss O +of O +rapsyn O +function O +may O +cause O +congenital O +myasthenia O +, O +more O +severe O +loss O +of O +function O +can O +result O +in O +a O +lethal O +fetal O +akinesia O +phenotype O +. O + + +Pure O +monosomy O +and O +pure O +trisomy O +of O +13q21 O +. O +2 O +- O +31 O +. O +1 O +consequent O +to O +a O +familial O +insertional O +translocation O +: O +exclusion O +of O +PCDH9 O +as O +the O +responsible O +gene O +for O +autosomal O +dominant O +auditory O +neuropathy O +( O +AUNA1 O +). O + +Insertional O +translocations O +( O +IT O +) O +are O +rare O +structural O +rearrangements O +. O + +Offspring O +of O +IT O +balanced O +carriers O +are O +at O +high O +risk O +to O +have O +either O +pure O +partial O +trisomy O +or O +monosomy O +for O +the O +inserted O +segment O +as O +manifested O +by O +pure O +phenotypes O +. O + +We O +describe O +an O +IT O +between O +chromosomes O +3 O +and O +13 O +segregating O +in O +a O +three O +- O +generation O +pedigree O +. O + +Short O +tandem O +repeat O +( O +STR O +) O +segregation O +analysis O +and O +array O +- O +comparative O +genomic O +hybridization O +were O +used O +to O +define O +the O +IT O +as O +a O +25 O +. O +1 O +Mb O +segment O +spanning O +13q21 O +. O +2 O +- O +q31 O +. O +1 O +. O + +The O +phenotype O +of O +pure O +monosomy O +included O +deafness O +, O +duodenal O +stenosis O +, O +developmental O +and O +growth O +delay O +, O +vertebral O +anomalies O +, O +and O +facial O +dysmorphisms O +; O +the O +trisomy O +was O +manifested O +by O +only O +minor O +dysmorphisms O +. O + +As O +the O +AUNA1 O +deafness O +locus O +on O +13q14 O +- O +21 O +overlaps O +the O +IT O +in O +the O +PCDH9 O +( O +protocadherin O +- O +9 O +) O +gene O +region O +, O +PCDH9 O +was O +investigated O +as O +a O +candidate O +gene O +for O +deafness O +in O +both O +families O +. O + +Genotyping O +of O +STRs O +and O +single O +nucleotide O +polymorphisms O +defined O +the O +AUNA1 O +breakpoint O +as O +35 O +kb O +5 O +' O +to O +PCDH9 O +, O +with O +a O +2 O +. O +4 O +Mb O +area O +of O +overlap O +with O +the O +IT O +. O + +DNA O +sequencing O +of O +coding O +regions O +in O +the O +AUNA1 O +family O +and O +in O +the O +retained O +homologue O +chromosome O +in O +the O +monosomic O +patient O +revealed O +no O +mutations O +. O + +We O +conclude O +that O +AUNA1 O +deafness O +does O +not O +share O +a O +common O +etiology O +with O +deafness O +associated O +with O +monosomy O +13q21 O +. O +2 O +- O +q31 O +. O +3 O +; O +deafness O +may O +result O +from O +monosomy O +of O +PCHD9 O +or O +another O +gene O +in O +the O +IT O +, O +as O +has O +been O +demonstrated O +in O +contiguous O +gene O +deletion O +syndromes O +. O + +Precise O +characterization O +of O +the O +breakpoints O +of O +the O +translocated O +region O +is O +useful O +to O +identify O +which O +genes O +may O +be O +contributing O +to O +the O +phenotype O +, O +either O +through O +haploinsufficiency O +or O +extra O +dosage O +effects O +, O +in O +order O +to O +define O +genotype O +- O +phenotype O +correlations O +. O + + +A O +Taiwanese O +boy O +with O +congenital O +generalized O +lipodystrophy O +caused O +by O +homozygous O +Ile262fs O +mutation O +in O +the O +BSCL2 O +gene O +. O + +Congenital O +generalized O +lipodystrophy O +( O +CGL O +) O +is O +a O +rare O +autosomal O +recessive O +disease O +that O +is O +characterized O +by O +a O +near O +- O +complete O +absence O +of O +adipose O +tissue O +from O +birth O +or O +early O +infancy O +. O + +Mutations O +in O +the O +BSCL2 O +gene O +are O +known O +to O +result O +in O +CGL2 O +, O +a O +more O +severe O +phenotype O +than O +CGL1 O +, O +with O +earlier O +onset O +, O +more O +extensive O +fat O +loss O +and O +biochemical O +changes O +, O +more O +severe O +intellectual O +impairment O +, O +and O +more O +severe O +cardiomyopathy O +. O + +We O +report O +a O +3 O +- O +month O +- O +old O +Taiwanese O +boy O +with O +initial O +presentation O +of O +a O +lack O +of O +subcutaneous O +fat O +, O +prominent O +musculature O +, O +generalized O +eruptive O +xanthomas O +, O +and O +extreme O +hypertriglyceridemia O +. O + +Absence O +of O +mechanical O +adipose O +tissue O +in O +the O +orbits O +and O +scalp O +was O +revealed O +by O +head O +magnetic O +resonance O +imaging O +. O + +Hepatomegaly O +was O +noticed O +, O +and O +histological O +examination O +of O +a O +liver O +biopsy O +specimen O +suggested O +severe O +hepatic O +steatosis O +and O +periportal O +necrosis O +. O + +However O +, O +echocardiography O +indicated O +no O +sign O +of O +cardiomyopathy O +and O +he O +showed O +no O +distinct O +intellectual O +impairment O +that O +interfered O +with O +daily O +life O +. O + +About O +1 O +year O +later O +, O +abdominal O +computed O +tomography O +revealed O +enlargement O +of O +kidneys O +. O + +He O +had O +a O +homozygous O +insertion O +of O +a O +nucleotide O +, O +783insG O +( O +Ile262fs O +mutation O +), O +in O +exon O +7 O +of O +the O +BSCL2 O +gene O +. O + +We O +reviewed O +the O +genotype O +of O +CGL O +cases O +from O +Japan O +, O +India O +, O +China O +and O +Taiwan O +, O +and O +found O +that O +BSCL2 O +is O +a O +major O +causative O +gene O +for O +CGL O +in O +Asian O +. O + + +Concordance O +between O +PIK3CA O +mutations O +in O +endoscopic O +biopsy O +and O +surgically O +resected O +specimens O +of O +esophageal O +squamous O +cell O +carcinoma O +. O + +BACKGROUND O +: O +PIK3CA O +mutations O +are O +expected O +to O +be O +potential O +therapeutic O +targets O +for O +esophageal O +squamous O +cell O +carcinoma O +( O +ESCC O +). O + +We O +aimed O +to O +clarify O +the O +concordance O +between O +PIK3CA O +mutations O +detected O +in O +endoscopic O +biopsy O +specimens O +and O +corresponding O +surgically O +resected O +specimens O +. O + +METHODS O +: O +We O +examined O +five O +hotspot O +mutations O +in O +the O +PIK3CA O +gene O +( O +E542K O +, O +E545K O +, O +E546K O +, O +H1047R O +, O +and O +H1047L O +) O +in O +formalin B +- O +fixed O +and O +paraffin B +- O +embedded O +tissue O +sections O +of O +paired O +endoscopic O +biopsy O +and O +surgically O +resected O +specimens O +from O +181 O +patients O +undergoing O +curative O +resection O +for O +ESCC O +between O +2000 O +and O +2011 O +using O +a O +Luminex O +technology O +- O +based O +multiplex O +gene O +mutation O +detection O +kit O +. O + +RESULTS O +: O +Mutation O +analyses O +were O +successfully O +performed O +for O +both O +endoscopic O +biopsy O +and O +surgically O +resected O +specimens O +in O +all O +the O +cases O +. O + +A O +PIK3CA O +mutation O +was O +detected O +in O +either O +type O +of O +specimen O +in O +13 O +cases O +( O +7 O +. O +2 O +%, O +95 O +% O +confidence O +interval O +: O +3 O +. O +9 O +- O +12 O +. O +0 O +). O + +The O +overall O +concordance O +rate O +, O +positive O +predictive O +value O +, O +and O +negative O +predictive O +value O +were O +98 O +. O +3 O +% O +( O +178 O +/ O +181 O +), O +90 O +. O +9 O +% O +( O +10 O +/ O +11 O +), O +and O +98 O +. O +8 O +% O +( O +168 O +/ O +170 O +), O +respectively O +. O + +Among O +patients O +with O +a O +PIK3CA O +mutation O +detected O +in O +both O +types O +of O +specimens O +, O +the O +concordance O +between O +PIK3CA O +mutation O +genotypes O +was O +100 O +%. O + +There O +were O +three O +cases O +with O +a O +discordant O +mutation O +status O +between O +the O +types O +of O +specimens O +( O +PIK3CA O +mutation O +in O +surgically O +resected O +specimen O +and O +wild O +- O +type O +in O +biopsy O +specimen O +in O +two O +cases O +, O +and O +the O +opposite O +pattern O +in O +one O +case O +), O +suggesting O +possible O +intratumoral O +heterogeneity O +in O +the O +PIK3CA O +mutation O +status O +. O + +CONCLUSIONS O +: O +The O +PIK3CA O +mutation O +status O +was O +highly O +concordant O +between O +endoscopic O +biopsy O +and O +surgically O +resected O +specimens O +from O +the O +same O +patient O +, O +suggesting O +that O +endoscopic O +biopsy O +specimens O +can O +be O +clinically O +used O +to O +detect O +PIK3CA O +mutations O +in O +patients O +with O +ESCC O +. O + + +Polymorphisms O +of O +the O +DNA O +mismatch O +repair O +gene O +HMSH2 O +in O +breast O +cancer O +occurence O +and O +progression O +. O + +The O +response O +of O +the O +cell O +to O +DNA O +damage O +and O +its O +ability O +to O +maintain O +genomic O +stability O +by O +DNA O +repair O +are O +crucial O +in O +preventing O +cancer O +initiation O +and O +progression O +. O + +Therefore O +, O +polymorphism O +of O +DNA O +repair O +genes O +may O +affect O +the O +process O +of O +carcinogenesis O +. O + +The O +importance O +of O +genetic O +variability O +of O +the O +components O +of O +mismatch O +repair O +( O +MMR O +) O +genes O +is O +well O +documented O +in O +colorectal O +cancer O +, O +but O +little O +is O +known O +about O +its O +role O +in O +breast O +cancer O +. O + +hMSH2 O +is O +one O +of O +the O +crucial O +proteins O +of O +MMR O +. O + +We O +performed O +a O +case O +- O +control O +study O +to O +test O +the O +association O +between O +two O +polymorphisms O +in O +the O +hMSH2 O +gene O +: O +an O +A O +--> O +G O +transition O +at O +127 O +position O +producing O +an O +Asn O +--> O +Ser O +substitution O +at O +codon O +127 O +( O +the O +Asn127Ser O +polymorphism O +) O +and O +a O +G O +--> O +A O +transition O +at O +1032 O +position O +resulting O +in O +a O +Gly O +--> O +Asp O +change O +at O +codon O +322 O +( O +the O +Gly322Asp O +polymorphism O +) O +and O +breast O +cancer O +risk O +and O +cancer O +progression O +. O + +Genotypes O +were O +determined O +in O +DNA O +from O +peripheral O +blood O +lymphocytes O +of O +150 O +breast O +cancer O +patients O +and O +150 O +age O +- O +matched O +women O +( O +controls O +) O +by O +restriction O +fragment O +length O +polymorphism O +and O +allele O +- O +specific O +PCR O +. O + +We O +did O +not O +observe O +any O +correlation O +between O +studied O +polymorphisms O +and O +breast O +cancer O +progression O +evaluated O +by O +node O +- O +metastasis O +, O +tumor O +size O +and O +Bloom O +- O +Richardson O +grading O +. O + +A O +strong O +association O +between O +breast O +cancer O +occurrence O +and O +the O +Gly O +/ O +Gly O +phenotype O +of O +the O +Gly322Asp O +polymorphism O +( O +odds O +ratio O +8 O +. O +39 O +; O +95 O +% O +confidence O +interval O +1 O +. O +44 O +- O +48 O +. O +8 O +) O +was O +found O +. O + +Therefore O +, O +MMR O +may O +play O +a O +role O +in O +the O +breast O +carcinogenesis O +and O +the O +Gly322Asp O +polymorphism O +of O +the O +hMSH2 O +gene O +may O +be O +considered O +as O +a O +potential O +marker O +in O +breast O +cancer O +. O + + +Atorvastatin B +prevented O +and O +reversed O +dexamethasone B +- O +induced O +hypertension O +in O +the O +rat O +. O + +To O +assess O +the O +antioxidant O +effects O +of O +atorvastatin B +( O +atorva B +) O +on O +dexamethasone B +( O +dex B +)- O +induced O +hypertension O +, O +60 O +male O +Sprague O +- O +Dawley O +rats O +were O +treated O +with O +atorva B +30 O +mg O +/ O +kg O +/ O +day O +or O +tap O +water O +for O +15 O +days O +. O + +Dex B +increased O +systolic O +blood O +pressure O +( O +SBP O +) O +from O +109 O ++/- O +1 O +. O +8 O +to O +135 O ++/- O +0 O +. O +6 O +mmHg O +and O +plasma O +superoxide B +( O +5711 O ++/- O +284 O +. O +9 O +saline O +, O +7931 O ++/- O +392 O +. O +8 O +U O +/ O +ml O +dex B +, O +P O +< O +0 O +. O +1 O +). O + +In O +this O +prevention O +study O +, O +SBP O +in O +the O +atorva B ++ O +dex B +group O +was O +increased O +from O +115 O ++/- O +0 O +. O +4 O +to O +124 O ++/- O +1 O +. O +5 O +mmHg O +, O +but O +this O +was O +significantly O +lower O +than O +in O +the O +dex B +- O +only O +group O +( O +P O +' O +< O +0 O +. O +5 O +). O + +Atorva O +reversed O +dex B +- O +induced O +hypertension O +( O +129 O ++/- O +0 O +. O +6 O +mmHg O +, O +vs O +. O + +135 O ++/- O +0 O +. O +6 O +mmHg O +P O +' O +< O +0 O +. O +5 O +) O +and O +decreased O +plasma O +superoxide B +( O +7931 O ++/- O +392 O +. O +8 O +dex B +, O +1187 O ++/- O +441 O +. O +2 O +atorva O ++ O +dex B +, O +P O +< O +0 O +. O +1 O +). O + +Plasma O +nitrate O +/ O +nitrite B +( O +NOx B +) O +was O +decreased O +in O +dex B +- O +treated O +rats O +compared O +to O +saline O +- O +treated O +rats O +( O +11 O +. O +2 O ++/- O +1 O +. O +8 O +microm O +, O +15 O +. O +3 O ++/- O +1 O +. O +17 O +microm O +, O +respectively O +, O +P O +< O +0 O +. O +5 O +). O + +Atorva O +affected O +neither O +plasma O +NOx O +nor O +thymus O +weight O +. O + +Thus O +, O +atorvastatin B +prevented O +and O +reversed O +dexamethasone B +- O +induced O +hypertension O +in O +the O +rat O +. O + + +Gene O +polymorphisms O +implicated O +in O +influencing O +susceptibility O +to O +venous O +and O +arterial O +thromboembolism O +: O +frequency O +distribution O +in O +a O +healthy O +German O +population O +. O + +Evolvement O +and O +progression O +of O +cardiovascular O +diseases O +affecting O +the O +venous O +and O +arterial O +system O +are O +influenced O +by O +a O +multitude O +of O +environmental O +and O +hereditary O +factors O +. O + +Many O +of O +these O +hereditary O +factors O +consist O +of O +defined O +gene O +polymorphisms O +, O +such O +as O +single O +nucleotide O +polymorphisms O +( O +SNPs O +) O +or O +insertion O +- O +deletion O +polymorphisms O +, O +which O +directly O +or O +indirectly O +affect O +the O +hemostatic O +system O +. O + +The O +frequencies O +of O +individual O +hemostatic O +gene O +polymorphisms O +in O +different O +normal O +populations O +are O +well O +defined O +. O + +However O +, O +descriptions O +of O +patterns O +of O +genetic O +variability O +of O +a O +larger O +extent O +of O +different O +factors O +of O +hereditary O +hypercoagulability O +in O +single O +populations O +are O +scarce O +. O + +The O +aim O +of O +this O +study O +was O +i O +) O +to O +give O +a O +detailed O +description O +of O +the O +frequencies O +of O +factors O +of O +hereditary O +thrombophilia O +and O +their O +combinations O +in O +a O +German O +population O +( O +n O += O +282 O +) O +and O +ii O +) O +to O +compare O +their O +distributions O +with O +those O +reported O +for O +other O +regions O +. O + +Variants O +of O +coagulation O +factors O +[ O +factor O +V O +1691G O +> O +A O +( O +factor O +V O +Leiden O +), O +factor O +V O +4070A O +> O +G O +( O +factor O +V O +HR2 O +haplotype O +), O +factor O +VII O +Arg353Gln O +, O +factor O +XIII O +Val34Leu O +, O +beta O +- O +fibrinogen O +- O +455G O +> O +A O +, O +prothrombin O +20210G O +> O +A O +], O +coagulation O +inhibitors O +[ O +tissue O +factor O +pathway O +inhibitor O +536C O +> O +T O +, O +thrombomodulin O +127G O +> O +A O +], O +fibrinolytic O +factors O +[ O +angiotensin O +converting O +enzyme O +intron O +16 O +insertion O + +/ O +deletion O +, O +factor O +VII O +- O +activating O +protease O +1601G O +> O +A O +( O +FSAP O +Marburg O +I O +), O +plasminogen O +activator O +inhibitor O +1 O +- O +675 O +insertion O +/ O +deletion O +( O +5G O +/ O +4G O +), O +tissue O +plasminogen O +activator O +intron O +h O +deletion O +/ O +insertion O +], O +and O +other O +factors O +implicated O +in O +influencing O +susceptibility O +to O +thromboembolic O +diseases O +[ O +apolipoprotein O +E2 O +/ O +E3 O +/ O +E4 O +, O +glycoprotein O +Ia O +807C O +> O +T O +, O + +methylenetetrahydrofolate O +reductase O +677C O +> O +T O +] O +were O +included O +. O + +The O +distribution O +of O +glycoprotein O +Ia O +807C O +> O +T O +deviated O +significantly O +from O +the O +Hardy O +- O +Weinberg O +equilibrium O +, O +and O +a O +comparison O +with O +previously O +published O +data O +indicates O +marked O +region O +and O +ethnicity O +dependent O +differences O +in O +the O +genotype O +distributions O +of O +some O +other O +factors O +. O + + +Necrotising O +fasciitis O +after O +bortezomib B +and O +dexamethasone B +- O +containing O +regimen O +in O +an O +elderly O +patient O +of O +Waldenstrom O +macroglobulinaemia O +. O + +Bortezomib B +and O +high O +- O +dose O +dexamethasone B +- O +containing O +regimens O +are O +considered O +to O +be O +generally O +tolerable O +with O +few O +severe O +bacterial O +infections O +in O +patients O +with O +B O +- O +cell O +malignancies O +. O + +However O +, O +information O +is O +limited O +concerning O +the O +safety O +of O +the O +regimen O +in O +elderly O +patients O +. O + +We O +report O +a O +case O +of O +a O +76 O +- O +year O +- O +old O +man O +with O +Waldenstrom O +macroglobulinaemia O +who O +suffered O +necrotising O +fasciitis O +without O +neutropenia O +after O +the O +combination O +treatment O +with O +bortezomib B +, O +high O +- O +dose O +dexamethasone B +and O +rituximab B +. O + +Despite O +immediate O +intravenous O +antimicrobial O +therapy O +, O +he O +succumbed O +23 O +h O +after O +the O +onset O +. O + +Physicians O +should O +recognise O +the O +possibility O +of O +fatal O +bacterial O +infections O +related O +to O +bortezomib B +plus O +high O +- O +dose O +dexamethasone B +in O +elderly O +patients O +, O +and O +we O +believe O +this O +case O +warrants O +further O +investigation O +. O + + +rTMS O +of O +supplementary O +motor O +area O +modulates O +therapy O +- O +induced O +dyskinesias O +in O +Parkinson O +disease O +. O + +The O +neural O +mechanisms O +and O +circuitry O +involved O +in O +levodopa B +- O +induced O +dyskinesia O +are O +unclear O +. O + +Using O +repetitive O +transcranial O +magnetic O +stimulation O +( O +rTMS O +) O +over O +the O +supplementary O +motor O +area O +( O +SMA O +) O +in O +a O +group O +of O +patients O +with O +advanced O +Parkinson O +disease O +, O +the O +authors O +investigated O +whether O +modulation O +of O +SMA O +excitability O +may O +result O +in O +a O +modification O +of O +a O +dyskinetic O +state O +induced O +by O +continuous O +apomorphine B +infusion O +. O + +rTMS O +at O +1 O +Hz O +was O +observed O +to O +markedly O +reduce O +drug O +- O +induced O +dyskinesias O +, O +whereas O +5 O +- O +Hz O +rTMS O +induced O +a O +slight O +but O +not O +significant O +increase O +. O + + +Angiotensin O +converting O +enzyme O +gene O +polymorphism O +in O +Turkish O +asthmatic O +patients O +. O + +Asthma O +is O +a O +chronic O +inflammatory O +disease O +of O +the O +airways O +. O + +Several O +candidate O +genes O +have O +been O +identified O +with O +a O +potential O +role O +in O +the O +pathogenesis O +of O +asthma O +, O +including O +the O +angiotensin O +converting O +enzyme O +( O +ACE O +) O +gene O +. O + +We O +aimed O +to O +investigate O +the O +frequency O +of O +an O +ACE O +gene O +polymorphism O +in O +Turkish O +asthmatic O +patients O +and O +to O +determine O +its O +impact O +on O +clinical O +parameters O +and O +disease O +severity O +. O + +Ninety O +- O +seven O +asthmatic O +patients O +( O +M O +/ O +F O +25 O +/ O +72 O +, O +mean O +age O +39 O ++/- O +13 O +years O +) O +and O +96 O +healthy O +subjects O +( O +M O +/ O +F O +26 O +/ O +70 O +, O +mean O +age O +38 O ++/- O +12 O +years O +) O +were O +included O +. O + +At O +baseline O +, O +all O +participants O +completed O +a O +questionnaire O +on O +demographics O +, O +symptoms O +, O +triggering O +factors O +, O +severity O +of O +asthma O +, O +and O +the O +presence O +of O +atopism O +. O + +Blood O +samples O +were O +obtained O +from O +all O +patients O +and O +genomic O +DNA O +was O +isolated O +. O + +The O +frequency O +of O +the O +ACE O +genotypes O +( O +I O += O +insertion O +and O +D O += O +deletion O +) O +among O +asthmatics O +and O +controls O +were O +compared O +: O +asthmatics O +showed O +a O +40 O +. O +2 O +% O +prevalence O +of O +the O +DD O +genotype O +( O +n O += O +39 O +), O +ID O +was O +45 O +. O +4 O +% O +( O +n O += O +44 O +), O +and O +II O +was O +14 O +. O +4 O +% O +( O +n O += O +14 O +. O +4 O +). O + +In O +the O +control O +subjects O +, O +the O +frequency O +of O +DD O +was O +18 O +. O +8 O +% O +( O +n O += O +18 O +), O +ID O +was O +50 O +% O +( O +n O += O +48 O +) O +and O +II O +was O +31 O +. O +3 O +% O +( O +n O += O +30 O +). O + +The O +DD O +ACE O +genotype O +was O +significantly O +more O +frequent O +in O +asthmatics O +compared O +with O +controls O +( O +p O +< O +0 O +. O +1 O +). O + +Asthmatics O +with O +the O +ID O +ACE O +genotype O +showed O +a O +higher O +frequency O +of O +drug O +allergies O +, O +although O +this O +was O +not O +statistically O +significant O +( O +p O += O +0 O +. O +8 O +). O + +Asthmatics O +with O +the O +DD O +genotype O +appeared O +to O +have O +a O +higher O +incidence O +of O +asthmatic O +episode O +exacerbations O +due O +to O +viral O +infections O +, O +but O +again O +this O +was O +not O +statistically O +significant O +( O +p O += O +0 O +. O +8 O +). O + +Patients O +with O +mild O +or O +moderate O +- O +severe O +asthma O +had O +similar O +frequencies O +of O +these O +mutations O +. O + +We O +found O +a O +higher O +frequency O +of O +the O +ACE O +DD O +gene O +mutation O +in O +Turkish O +asthmatic O +patients O +compared O +with O +non O +- O +asthmatics O +, O +suggesting O +that O +this O +ACE O +gene O +polymorphism O +may O +be O +a O +risk O +factor O +for O +asthma O +but O +does O +not O +increase O +the O +severity O +of O +the O +disease O +. O + + +The O +impact O +of O +PPARa O +activation O +on O +whole O +genome O +gene O +expression O +in O +human O +precision O +cut O +liver O +slices O +. O + +BACKGROUND O +: O +Studies O +in O +mice O +have O +shown O +that O +PPARa O +is O +an O +important O +regulator O +of O +lipid B +metabolism O +in O +liver O +and O +key O +transcription O +factor O +involved O +in O +the O +adaptive O +response O +to O +fasting O +. O + +However O +, O +much O +less O +is O +known O +about O +the O +role O +of O +PPARa O +in O +human O +liver O +. O + +METHODS O +: O +Here O +we O +set O +out O +to O +study O +the O +function O +of O +PPARa O +in O +human O +liver O +via O +analysis O +of O +whole O +genome O +gene O +regulation O +in O +human O +liver O +slices O +treated O +with O +the O +PPARa O +agonist O +Wy14643 O +. O + +RESULTS O +: O +Quantitative O +PCR O +indicated O +that O +PPARa O +is O +well O +expressed O +in O +human O +liver O +and O +human O +liver O +slices O +and O +that O +the O +classical O +PPARa O +targets O +PLIN2 O +, O +VLDLR O +, O +ANGPTL4 O +, O +CPT1A O +and O +PDK4 O +are O +robustly O +induced O +by O +PPARa O +activation O +. O + +Transcriptomics O +analysis O +indicated O +that O +617 O +genes O +were O +upregulated O +and O +665 O +genes O +were O +downregulated O +by O +PPARa O +activation O +( O +q O +value O +< O +0 O +. O +5 O +). O + +Many O +genes O +induced O +by O +PPARa O +activation O +were O +involved O +in O +lipid B +metabolism O +( O +ACSL5 O +, O +AGPAT9 O +, O +FADS1 O +, O +SLC27A4 O +), O +xenobiotic O +metabolism O +( O +POR O +, O +ABCC2 O +, O +CYP3A5 O +) O +or O +the O +unfolded O +protein O +response O +, O +whereas O +most O +of O +the O +downregulated O +genes O +were O +involved O +in O +immune O +- O +related O +pathways O +. O + +Among O +the O +most O +highly O +repressed O +genes O +upon O +PPARa O +activation O +were O +several O +chemokines O +( O +e O +. O +g O +. O + +CXCL9 O +- O +11 O +, O +CCL8 O +, O +CX3CL1 O +, O +CXCL6 O +), O +interferon O +g O +- O +induced O +genes O +( O +e O +. O +g O +. O + +IFITM1 O +, O +IFIT1 O +, O +IFIT2 O +, O +IFIT3 O +) O +and O +numerous O +other O +immune O +- O +related O +genes O +( O +e O +. O +g O +. O + +TLR3 O +, O +NOS2 O +, O +and O +LCN2 O +). O + +Comparative O +analysis O +of O +gene O +regulation O +by O +Wy14643 O +between O +human O +liver O +slices O +and O +primary O +human O +hepatocytes O +showed O +that O +down O +- O +regulation O +of O +gene O +expression O +by O +PPARa O +is O +much O +better O +captured O +by O +liver O +slices O +as O +compared O +to O +primary O +hepatocytes O +. O + +In O +particular O +, O +PPARa O +activation O +markedly O +suppressed O +immunity O +/ O +inflammation O +- O +related O +genes O +in O +human O +liver O +slices O +but O +not O +in O +primary O +hepatocytes O +. O + +Finally O +, O +several O +putative O +new O +target O +genes O +of O +PPARa O +were O +identified O +that O +were O +commonly O +induced O +by O +PPARa O +activation O +in O +the O +two O +human O +liver O +model O +systems O +, O +including O +TSKU O +, O +RHOF O +, O +CA12 O +and O +VSIG10L O +. O + +CONCLUSION O +: O +Our O +paper O +demonstrates O +the O +suitability O +and O +superiority O +of O +human O +liver O +slices O +over O +primary O +hepatocytes O +for O +studying O +the O +functional O +role O +of O +PPARa O +in O +human O +liver O +. O + +Our O +data O +underscore O +the O +major O +role O +of O +PPARa O +in O +regulation O +of O +hepatic O +lipid B +and O +xenobiotic B +metabolism O +in O +human O +liver O +and O +reveal O +a O +marked O +immuno O +- O +suppressive O +/ O +anti O +- O +inflammatory O +effect O +of O +PPARa O +in O +human O +liver O +slices O +that O +may O +be O +therapeutically O +relevant O +for O +non O +- O +alcoholic O +fatty O +liver O +disease O +. O + + +Oncogenic O +activity O +of O +amplified O +miniature O +chromosome O +maintenance O +8 O +in O +human O +malignancies O +. O + +Miniature O +chromosome O +maintenance O +( O +MCM O +) O +proteins O +play O +critical O +roles O +in O +DNA O +replication O +licensing O +, O +initiation O +and O +elongation O +. O + +MCM8 O +, O +one O +of O +the O +MCM O +proteins O +playing O +a O +critical O +role O +in O +DNA O +repairing O +and O +recombination O +, O +was O +found O +to O +have O +overexpression O +and O +increased O +DNA O +copy O +number O +in O +a O +variety O +of O +human O +malignancies O +. O + +The O +gain O +of O +MCM8 O +is O +associated O +with O +aggressive O +clinical O +features O +of O +several O +human O +cancers O +. O + +Increased O +expression O +of O +MCM8 O +in O +prostate O +cancer O +is O +associated O +with O +cancer O +recurrence O +. O + +Forced O +expression O +of O +MCM8 O +in O +RWPE1 O +cells O +, O +the O +immortalized O +but O +non O +- O +transformed O +prostate O +epithelial O +cell O +line O +, O +exhibited O +fast O +cell O +growth O +and O +transformation O +, O +while O +knock O +down O +of O +MCM8 O +in O +PC3 O +, O +DU145 O +and O +LNCaP O +cells O +induced O +cell O +growth O +arrest O +, O +and O +decreased O +tumour O +volumes O +and O +mortality O +of O +severe O +combined O +immunodeficiency O +mice O +xenografted O +with O +PC3 O +and O +DU145 O +cells O +. O + +MCM8 O +bound O +cyclin O +D1 O +and O +activated O +Rb O +protein O +phosphorylation O +by O +cyclin O +- O +dependent O +kinase O +4 O +in O +vitro O +and O +in O +vivo O +. O + +The O +cyclin O +D1 O +/ O +MCM8 O +interaction O +is O +required O +for O +Rb O +phosphorylation O +and O +S O +- O +phase O +entry O +in O +cancer O +cells O +. O + +As O +a O +result O +, O +our O +study O +showed O +that O +copy O +number O +increase O +and O +overexpression O +of O +MCM8 O +may O +play O +critical O +roles O +in O +human O +cancer O +development O +. O + + +Enhanced O +isoproterenol B +- O +induced O +cardiac O +hypertrophy O +in O +transgenic O +rats O +with O +low O +brain O +angiotensinogen O +. O + +We O +have O +previously O +shown O +that O +a O +permanent O +deficiency O +in O +the O +brain O +renin O +- O +angiotensin O +system O +( O +RAS O +) O +may O +increase O +the O +sensitivity O +of O +the O +baroreflex O +control O +of O +heart O +rate O +. O + +In O +this O +study O +we O +aimed O +at O +studying O +the O +involvement O +of O +the O +brain O +RAS O +in O +the O +cardiac O +reactivity O +to O +the O +beta O +- O +adrenoceptor O +( O +beta O +- O +AR O +) O +agonist O +isoproterenol B +( O +Iso B +). O + +Transgenic O +rats O +with O +low O +brain O +angiotensinogen O +( O +TGR O +) O +were O +used O +. O + +In O +isolated O +hearts O +, O +Iso B +induced O +a O +significantly O +greater O +increase O +in O +left O +ventricular O +( O +LV O +) O +pressure O +and O +maximal O +contraction O +(+ O +dP O +/ O +dt O +( O +max O +)) O +in O +the O +TGR O +than O +in O +the O +Sprague O +- O +Dawley O +( O +SD O +) O +rats O +. O + +LV B +hypertrophy O +induced O +by O +Iso O +treatment O +was O +significantly O +higher O +in O +TGR O +than O +in O +SD O +rats O +( O +in O +g O +LV O +wt O +/ O +100 O +g O +body O +wt O +, O +0 O +. O +28 O ++/- O +0 O +. O +4 O +vs O +. O + +0 O +. O +24 O ++/- O +0 O +. O +4 O +, O +respectively O +). O + +The O +greater O +LV O +hypertrophy O +in O +TGR O +rats O +was O +associated O +with O +more O +pronounced O +downregulation O +of O +beta O +- O +AR O +and O +upregulation O +of O +LV O +beta O +- O +AR O +kinase O +- O +1 O +mRNA O +levels O +compared O +with O +those O +in O +SD O +rats O +. O + +The O +decrease O +in O +the O +heart O +rate O +( O +HR O +) O +induced O +by O +the O +beta B +- I +AR I +antagonist I +metoprolol B +in O +conscious O +rats O +was O +significantly O +attenuated O +in O +TGR O +compared O +with O +SD O +rats O +(- O +9 O +. O +9 O ++/- O +1 O +. O +7 O +% O +vs O +. O + +- O +18 O +. O +1 O ++/- O +1 O +. O +5 O +%), O +whereas O +the O +effect O +of O +parasympathetic O +blockade O +by O +atropine B +on O +HR O +was O +similar O +in O +both O +strains O +. O + +These O +results O +indicate O +that O +TGR O +are O +more O +sensitive O +to O +beta O +- O +AR O +agonist O +- O +induced O +cardiac O +inotropic O +response O +and O +hypertrophy O +, O +possibly O +due O +to O +chronically O +low O +sympathetic O +outflow O +directed O +to O +the O +heart O +. O + + +Intronic O +deletions O +in O +the O +SLC34A3 O +gene O +cause O +hereditary O +hypophosphatemic O +rickets O +with O +hypercalciuria O +. O + +CONTEXT O +: O +Hereditary O +hypophosphatemic O +rickets O +with O +hypercalciuria O +( O +HHRH O +) O +is O +a O +rare O +metabolic O +disorder O +, O +characterized O +by O +hypophosphatemia O +and O +rickets O +/ O +osteomalacia O +with O +increased O +serum O +1 O +, O +25 B +- I +dihydroxyvitamin I +D O +[ O +1 O +, O +25 O +-( O +OH O +)( O +2 O +) O +D O +] O +resulting O +in O +hypercalciuria O +. O + +OBJECTIVE O +: O +Our O +objective O +was O +to O +determine O +whether O +mutations O +in O +the O +SLC34A3 O +gene O +, O +which O +encodes O +sodium O +- O +phosphate O +cotransporter O +type O +IIc O +, O +are O +responsible O +for O +the O +occurrence O +of O +HHRH O +. O + +DESIGN O +AND O +SETTING O +: O +Mutation O +analysis O +of O +exons O +and O +adjacent O +introns O +in O +the O +SLC34A3 O +gene O +was O +conducted O +at O +an O +academic O +research O +laboratory O +and O +medical O +center O +. O + +PATIENTS O +OR O +OTHER O +PARTICIPANTS O +: O +Members O +of O +two O +unrelated O +families O +with O +HHRH O +participated O +in O +the O +study O +. O + +RESULTS O +: O +Two O +affected O +siblings O +in O +one O +family O +were O +homozygous O +for O +a O +101 O +- O +bp O +deletion O +in O +intron O +9 O +. O + +Haplotype O +analysis O +of O +the O +SLC34A3 O +locus O +in O +the O +family O +showed O +that O +the O +two O +deletions O +are O +on O +different O +haplotypes O +. O + +An O +unrelated O +individual O +with O +HHRH O +was O +a O +compound O +heterozygote O +for O +an O +85 O +- O +bp O +deletion O +in O +intron O +10 O +and O +a O +G O +- O +to O +- O +A O +substitution O +at O +the O +last O +nucleotide O +in O +exon O +7 O +. O + +The O +intron O +9 O +deletion O +( O +and O +likely O +the O +other O +two O +mutations O +) O +identified O +in O +this O +study O +causes O +aberrant O +RNA O +splicing O +. O + +Sequence O +analysis O +of O +the O +deleted O +regions O +revealed O +the O +presence O +of O +direct O +repeats O +of O +homologous O +sequences O +. O + +CONCLUSION O +: O +HHRH O +is O +caused O +by O +biallelic O +mutations O +in O +the O +SLC34A3 O +gene O +. O + +Haplotype O +analysis O +suggests O +that O +the O +two O +intron O +9 O +deletions O +arose O +independently O +. O + +The O +identification O +of O +three O +independent O +deletions O +in O +introns O +9 O +and O +10 O +suggests O +that O +the O +SLC34A3 O +gene O +may O +be O +susceptible O +to O +unequal O +crossing O +over O +because O +of O +sequence O +misalignment O +during O +meiosis O +. O + + +Vitamin B +D O +receptor O +expression O +is O +associated O +with O +PIK3CA O +and O +KRAS O +mutations O +in O +colorectal O +cancer O +. O + +Vitamin B +D I +is O +associated O +with O +decreased O +risks O +of O +various O +cancers O +, O +including O +colon O +cancer O +. O + +The O +vitamin O +D O +receptor O +( O +VDR O +) O +is O +a O +transcription O +factor O +, O +which O +plays O +an O +important O +role O +in O +cellular O +differentiation O +and O +inhibition O +of O +proliferation O +. O + +A O +link O +between O +VDR O +and O +the O +RAS O +- O +mitogen O +- O +activated O +protein O +kinase O +( O +MAPK O +) O +or O +phosphatidylinositol O +3 O +- O +kinase O +( O +PI3K O +)- O +AKT O +pathway O +has O +been O +suggested O +. O + +However O +, O +the O +prognostic O +role O +of O +VDR O +expression O +or O +its O +relationship O +with O +PIK3CA O +or O +KRAS O +mutation O +remains O +uncertain O +. O + +Among O +619 O +colorectal O +cancers O +in O +two O +prospective O +cohort O +studies O +, O +233 O +( O +38 O +%) O +tumors O +showed O +VDR O +overexpression O +by O +immunohistochemistry O +. O + +We O +analyzed O +for O +PIK3CA O +and O +KRAS O +mutations O +and O +LINE O +- O +1 O +methylation O +by O +Pyrosequencing O +, O +microsatellite O +instability O +( O +MSI O +), O +and O +DNA O +methylation O +( O +epigenetic O +changes O +) O +in O +eight O +CpG O +island O +methylator O +phenotype O +( O +CIMP O +)- O +specific O +promoters O +[ O +CACNA1G O +, O +CDKN2A O +( O +p16 O +), O +CRABP1 O +, O +IGF2 O +, O +MLH1 O +, O +NEUROG1 O +, O +RUNX3 O +, O +and O +SOCS1 O +] O +by O +MethyLight O +( O +real O + +- O +time O +PCR O +). O + +VDR O +overexpression O +was O +significantly O +associated O +with O +KRAS O +mutation O +( O +odds O +ratio O +, O +1 O +. O +55 O +; O +95 O +% O +confidence O +interval O +, O +1 O +. O +11 O +- O +2 O +. O +16 O +) O +and O +PIK3CA O +mutation O +( O +odds O +ratio O +, O +2 O +. O +17 O +; O +95 O +% O +confidence O +interval O +, O +1 O +. O +36 O +- O +3 O +. O +47 O +), O +both O +of O +which O +persisted O +in O +multivariate O +logistic O +regression O +analysis O +. O + +VDR O +was O +not O +independently O +associated O +with O +body O +mass O +index O +, O +family O +history O +of O +colorectal O +cancer O +, O +tumor O +location O +( O +colon O +versus O +rectum O +), O +stage O +, O +tumor O +grade O +, O +signet O +ring O +cells O +, O +CIMP O +, O +MSI O +, O +LINE O +- O +1 O +hypomethylation O +, O +BRAF O +, O +p53 O +, O +p21 O +, O +beta O +- O +catenin O +, O +or O +cyclooxygenase O +- O +2 O +. O + +VDR O +expression O +was O +not O +significantly O +related O +with O +patient O +survival O +, O +prognosis O +, O +or O +clinical O +outcome O +. O + +In O +conclusion O +, O +VDR O +overexpression O +in O +colorectal O +cancer O +is O +independently O +associated O +with O +PIK3CA O +and O +KRAS O +mutations O +. O + +Our O +data O +support O +potential O +interactions O +between O +the O +VDR O +, O +RAS O +- O +MAPK O +and O +PI3K O +- O +AKT O +pathways O +, O +and O +possible O +influence O +by O +KRAS O +or O +PIK3CA O +mutation O +on O +therapy O +or O +chemoprevention O +targeting O +VDR O +. O + + +Cultured O +mycelium O +Cordyceps O +sinensis O +protects O +liver O +sinusoidal O +endothelial O +cells O +in O +acute O +liver O +injured O +mice O +. O + +Cultured O +mycelium O +Cordyceps O +sinensis O +( O +CMCS B +) O +was O +widely O +used O +for O +a O +variety O +of O +diseases O +including O +liver O +injury O +, O +the O +current O +study O +aims O +to O +investigate O +the O +protective O +effects O +of O +CMCS O +on O +liver O +sinusoidal O +endothelial O +cells O +( O +LSECs O +) O +in O +acute O +injury O +liver O +and O +related O +action O +mechanisms O +. O + +The O +mice O +were O +injected O +intraperitoneally O +with O +lipopolysaccharide B +( O +LPS B +) O +and O +D B +- I +galactosamine I +( O +D B +- O +GalN O +). O + +39 O +male O +BABL O +/ O +c O +mice O +were O +randomly O +divided O +into O +four O +groups O +: O +normal O +control O +, O +model O +control O +, O +CMCS O +treatment O +and O +1 O +, O +10 O +- O +phenanthroline B +treatment O +groups O +. O + +The O +Serum O +liver O +function O +parameters O +including O +alanine B +aminotransferase I +( O +ALT O +) O +and O +aspartate B +aminotransferase I +( O +AST O +) O +levels O +were O +assayed O +with O +the O +commercial O +kit O +. O + +The O +inflammation O +and O +scaffold O +structure O +in O +liver O +were O +stained O +with O +hematoxylin O +and O +eosin O +and O +silver O +staining O +respectively O +. O + +The O +LSECs O +and O +sub O +- O +endothelial O +basement O +membrane O +were O +observed O +with O +the O +scanning O +and O +transmission O +electronic O +microscope O +. O + +The O +protein O +expressions O +of O +intercellular O +adhesion O +molecule O +- O +1 O +( O +ICAM O +- O +1 O +) O +and O +vascular O +cell O +adhesion O +molecule O +- O +1 O +( O +VCAM O +- O +1 O +) O +in O +liver O +were O +analyzed O +with O +Western O +blotting O +. O + +Expression O +of O +von O +Willebrand O +factor O +( O +vWF O +) O +was O +investigated O +with O +immunofluorescence O +staining O +. O + +The O +lipid B +peroxidation O +indicators O +including O +antisuperoxideanion O +( O +ASAFR O +), O +hydroxyl B +free I +radical I +(. O +OH O +), O +superoxide O +dismutase O +( O +SOD O +), O +malondialdehyde B +and O +glutathione O +S O +- O +transferase O +( O +GST O +) O +were O +determined O +with O +kits O +, O +and O +matrix O +metalloproteinase O +- O +2 O +and O +9 O +( O +MMP O +- O +2 O +/ O +9 O +) O +activities O +in O +liver O +were O +analyzed O +with O +gelatin O +zymography O +and O +in O +situ O +fluorescent O +zymography O +respectively O +. O + +The O +model O +mice O +had O +much O +higher O +serum O +levels O +of O +ALT O +and O +AST O +than O +the O +normal O +mice O +. O + +Compared O +to O +that O +in O +the O +normal O +control O +, O +more O +severe O +liver O +inflammation O +and O +hepatocyte O +apoptosis O +, O +worse O +hepatic O +lipid B +peroxidation O +demonstrated O +by O +the O +increased O +ASAFR O +, O +. O +OH O +and O +MDA B +, O +but O +decreased O +SOD O +and O +GST O +, O +increased O +MMP O +- O +2 O +/ O +9 O +activities O +and O +VCAM O +- O +1 O +, O +ICAM O +- O +1 O +and O +vWF O +expressions O +, O +which O +revealed O +obvious O +LSEC O +injury O +and O +scaffold O +structure O +broken O +, O +were O +shown O +in O +the O +model O +control O +. O + +Compared O +with O +the O +model O +group O +, O +CMCS O +and O +1 O +, O +10 O +- O +phenanthroline O +significantly O +improved O +serum O +ALT O +/ O +AST O +, O +attenuated O +hepatic O +inflammation O +and O +improved O +peroxidative O +injury O +in O +liver O +, O +decreased O +MMP O +- O +2 O +/ O +9 O +activities O +in O +liver O +tissue O +, O +improved O +integration O +of O +scaffold O +structure O +, O +and O +decreased O +protein O +expression O +of O +VCAM O +- O +1 O +and O +ICAM O +- O +1 O +. O + +CMCS O +could O +protect O +LSECs O +from O +injury O +and O +maintain O +the O +microvasculature O +integration O +in O +acute O +injured O +liver O +of O +mice O +induced O +by O +LPS B +/ O +D O +- I +GalN O +. O + +Its O +action O +mechanism O +was O +associated O +with O +the O +down O +- O +regulation O +of O +MMP O +- O +2 O +/ O +9 O +activities O +and O +inhibition O +of O +peroxidation O +in O +injured O +liver O +. O + + +A O +Type O +2 O +Diabetes O +- O +Associated O +Functional O +Regulatory O +Variant O +in O +a O +Pancreatic O +Islet O +Enhancer O +at O +the O +ADCY5 O +Locus O +. O + +Molecular O +mechanisms O +remain O +unknown O +for O +most O +type O +2 O +diabetes O +genome O +- O +wide O +association O +study O +identified O +loci O +. O + +Variants O +associated O +with O +type O +2 O +diabetes O +and O +fasting O +glucose B +levels O +reside O +in O +introns O +of O +ADCY5 O +, O +a O +gene O +that O +encodes O +adenylate O +cyclase O +5 O +. O + +Adenylate O +cyclase O +5 O +catalyzes O +the O +production O +of O +cyclic B +AMP I +, O +which O +is O +a O +second O +messenger O +molecule O +involved O +in O +cell O +signaling O +and O +pancreatic O +b O +- O +cell O +insulin O +secretion O +. O + +We O +demonstrated O +that O +type O +2 O +diabetes O +risk O +alleles O +are O +associated O +with O +decreased O +ADCY5 O +expression O +in O +human O +islets O +and O +examined O +candidate O +variants O +for O +regulatory O +function O +. O + +rs11708067 O +overlaps O +a O +predicted O +enhancer O +region O +in O +pancreatic O +islets O +. O + +The O +type O +2 O +diabetes O +risk O +rs11708067 O +- O +A O +allele O +showed O +fewer O +H3K27ac O +ChIP O +- O +seq O +reads O +in O +human O +islets O +, O +lower O +transcriptional O +activity O +in O +reporter O +assays O +in O +rodent O +b O +- O +cells O +( O +rat O +832 O +/ O +13 O +and O +mouse O +MIN6 O +), O +and O +increased O +nuclear O +protein O +binding O +compared O +with O +the O +rs11708067 O +- O +G O +allele O +. O + +Homozygous O +deletion O +of O +the O +orthologous O +enhancer O +region O +in O +832 O +/ O +13 O +cells O +resulted O +in O +a O +64 O +% O +reduction O +in O +expression O +level O +of O +Adcy5 O +, O +but O +not O +adjacent O +gene O +Sec22a O +, O +and O +a O +39 O +% O +reduction O +in O +insulin O +secretion O +. O + +Together O +, O +these O +data O +suggest O +that O +rs11708067 O +- O +A O +risk O +allele O +contributes O +to O +type O +2 O +diabetes O +by O +disrupting O +an O +islet O +enhancer O +, O +which O +results O +in O +reduced O +ADCY5 O +expression O +and O +impaired O +insulin O +secretion O +. O + + +Homozygously O +deleted O +gene O +DACH1 O +regulates O +tumor O +- O +initiating O +activity O +of O +glioma O +cells O +. O + +Loss O +or O +reduction O +in O +function O +of O +tumor O +suppressor O +genes O +contributes O +to O +tumorigenesis O +. O + +Here O +, O +by O +allelic O +DNA O +copy O +number O +analysis O +using O +single O +- O +nucleotide O +polymorphism O +genotyping O +array O +and O +mass O +spectrometry O +, O +we O +report O +homozygous O +deletion O +in O +glioblastoma O +multiformes O +at O +chromosome O +13q21 O +, O +where O +DACH1 O +gene O +is O +located O +. O + +We O +found O +decreased O +cell O +proliferation O +of O +a O +series O +of O +glioma O +cell O +lines O +by O +forced O +expression O +of O +DACH1 O +. O + +We O +then O +generated O +U87TR O +- O +Da O +glioma O +cells O +, O +where O +DACH1 O +expression O +could O +be O +activated O +by O +exposure O +of O +the O +cells O +to O +doxycycline B +. O + +Both O +ex O +vivo O +cellular O +proliferation O +and O +in O +vivo O +growth O +of O +s O +. O +c O +. O + +transplanted O +tumors O +in O +mice O +are O +reduced O +in O +U87TR O +- O +Da O +cells O +with O +DACH1 O +expression O +( O +U87 O +- O +DACH1 O +- O +high O +), O +compared O +with O +DACH1 O +- O +nonexpressing O +U87TR O +- O +Da O +cells O +( O +U87 O +- O +DACH1 O +- O +low O +). O + +U87 O +- O +DACH1 O +- O +low O +cells O +form O +spheroids O +with O +CD133 O +and O +Nestin O +expression O +in O +serum O +- O +free O +medium O +but O +U87 O +- O +DACH1 O +- O +high O +cells O +do O +not O +. O + +Compared O +with O +spheroid O +- O +forming O +U87 O +- O +DACH1 O +- O +low O +cells O +, O +adherent O +U87 O +- O +DACH1 O +- O +high O +cells O +display O +lower O +tumorigenicity O +, O +indicating O +DACH1 B +decreases O +the O +number O +of O +tumor O +- O +initiating O +cells O +. O + +Gene O +expression O +analysis O +and O +chromatin O +immunoprecipitation O +assay O +reveal O +that O +fibroblast O +growth O +factor O +2 O +( O +FGF2 O +/ O +bFGF O +) O +is O +transcriptionally O +repressed O +by O +DACH1 O +, O +especially O +in O +cells O +cultured O +in O +serum O +- O +free O +medium O +. O + +Exogenous O +bFGF O +rescues O +spheroid O +- O +forming O +activity O +and O +tumorigenicity O +of O +the O +U87 O +- O +DACH1 O +- O +high O +cells O +, O +suggesting O +that O +loss O +of O +DACH1 O +increases O +the O +number O +of O +tumor O +- O +initiating O +cells O +through O +transcriptional O +activation O +of O +bFGF O +. O + +These O +results O +illustrate O +that O +DACH1 B +is O +a O +distinctive O +tumor O +suppressor O +, O +which O +does O +not O +only O +suppress O +growth O +of O +tumor O +cells O +but O +also O +regulates O +bFGF O +- O +mediated O +tumor O +- O +initiating O +activity O +of O +glioma O +cells O +. O + + +Definition O +and O +management O +of O +anemia O +in O +patients O +infected O +with O +hepatitis O +C O +virus O +. O + +Chronic O +infection O +with O +hepatitis O +C O +virus O +( O +HCV O +) O +can O +progress O +to O +cirrhosis O +, O +hepatocellular O +carcinoma O +, O +and O +end O +- O +stage O +liver O +disease O +. O + +The O +current O +best O +treatment O +for O +HCV O +infection O +is O +combination O +therapy O +with O +pegylated O +interferon O +and O +ribavirin B +. O + +Although O +this O +regimen O +produces O +sustained O +virologic O +responses O +( O +SVRs O +) O +in O +approximately O +50 O +% O +of O +patients O +, O +it O +can O +be O +associated O +with O +a O +potentially O +dose O +- O +limiting O +hemolytic O +anemia O +. O + +Hemoglobin O +concentrations O +decrease O +mainly O +as O +a O +result O +of O +ribavirin B +- O +induced O +hemolysis O +, O +and O +this O +anemia O +can O +be O +problematic O +in O +patients O +with O +HCV O +infection O +, O +especially O +those O +who O +have O +comorbid O +renal O +or O +cardiovascular O +disorders O +. O + +In O +general O +, O +anemia O +can O +increase O +the O +risk O +of O +morbidity O +and O +mortality O +, O +and O +may O +have O +negative O +effects O +on O +cerebral O +function O +and O +quality O +of O +life O +. O + +Although O +ribavirin B +- O +associated O +anemia O +can O +be O +reversed O +by O +dose O +reduction O +or O +discontinuation O +, O +this O +approach O +compromises O +outcomes O +by O +significantly O +decreasing O +SVR O +rates O +. O + +Recombinant O +human O +erythropoietin O +has O +been O +used O +to O +manage O +ribavirin O +- O +associated O +anemia O +but O +has O +other O +potential O +disadvantages O +. O + +Viramidine B +, O +a O +liver O +- O +targeting O +prodrug O +of O +ribavirin B +, O +has O +the O +potential O +to O +maintain O +the O +virologic O +efficacy O +of O +ribavirin B +while O +decreasing O +the O +risk O +of O +hemolytic O +anemia O +in O +patients O +with O +chronic O +hepatitis O +C O +. O + + +Association O +between O +an O +endoglin O +gene O +polymorphism O +and O +systemic O +sclerosis O +- O +related O +pulmonary O +arterial O +hypertension O +. O + +Systemic O +sclerosis O +( O +SSc O +) O +is O +a O +connective O +tissue O +disorder O +characterized O +by O +early O +generalized O +microangiopathy O +with O +disturbed O +angiogenesis O +. O + +Endoglin O +gene O +( O +ENG O +) O +encodes O +a O +transmembrane O +glycoprotein O +which O +acts O +as O +an O +accessory O +receptor O +for O +the O +transforming O +growth O +factor O +- O +beta O +( O +TGF O +- O +beta O +) O +superfamily O +, O +and O +is O +crucial O +for O +maintaining O +vascular O +integrity O +. O + +A O +6 O +- O +base O +insertion O +in O +intron O +7 O +( O +6bINS O +) O +of O +ENG O +has O +been O +reported O +to O +be O +associated O +with O +microvascular O +disturbance O +. O + +OBJECTIVES O +: O +Our O +objective O +was O +to O +investigate O +the O +relationship O +between O +6bINS O +and O +the O +vascular O +complication O +pulmonary O +arterial O +hypertension O +( O +PAH O +) O +in O +SSc O +in O +a O +French O +Caucasian O +population O +. O + +METHODS O +: O +Two O +hundred O +eighty O +SSc O +cases O +containing O +29 O +/ O +280 O +having O +PAH O +diagnosed O +by O +catheterism O +were O +compared O +with O +140 O +patients O +with O +osteoarthritis O +. O + +Genotyping O +was O +performed O +by O +polymerase O +- O +chain O +- O +reaction O +- O +based O +fluorescence O +and O +direct O +sequencing O +of O +genomic O +DNA O +. O + +RESULTS O +: O +The O +polymorphism O +was O +in O +Hardy O +- O +Weinberg O +equilibrium O +. O + +We O +observed O +a O +significant O +lower O +frequency O +of O +6bINS O +allele O +in O +SSc O +patients O +with O +associated O +PAH O +compared O +with O +controls O +[ O +10 O +. O +3 O +vs O +23 O +. O +9 O +%, O +P O += O +0 O +. O +1 O +; O +odds O +ratio O +( O +OR O +) O +0 O +. O +37 O +, O +95 O +% O +confidence O +interval O +( O +CI O +) O +0 O +. O +15 O +- O +0 O +. O +89 O +], O +and O +a O +trend O +in O +comparison O +with O +SSc O +patients O +without O +PAH O +( O +10 O +. O +3 O +vs O +20 O +. O +3 O +%, O +P O += O +0 O +. O +5 O +; O +OR O +: O +0 O +. O +45 O +, O +95 O +% O +CI O +: O +0 O +. O +19 O +- O +1 O +. O +8 O +). O + +Genotypes O +carrying O +allele O +6bINS O +were O +also O +less O +frequent O +in O +SSc O +patients O +with O +PAH O +than O +in O +controls O +( O +20 O +. O +7 O +vs O +42 O +. O +9 O +%, O +P O += O +0 O +. O +2 O +). O + +CONCLUSIONS O +: O +Thus O +the O +frequency O +of O +6bINS O +differs O +between O +SSc O +patients O +with O +or O +without O +PAH O +, O +suggesting O +the O +implication O +of O +ENG O +in O +this O +devastating O +vascular O +complication O +of O +SSc O +. O + + +Assessment O +of O +a O +new O +non O +- O +invasive O +index O +of O +cardiac O +performance O +for O +detection O +of O +dobutamine B +- O +induced O +myocardial O +ischemia O +. O + +BACKGROUND O +: O +Electrocardiography O +has O +a O +very O +low O +sensitivity O +in O +detecting O +dobutamine B +- O +induced O +myocardial O +ischemia O +. O + +OBJECTIVES O +: O +To O +assess O +the O +added O +diagnostic O +value O +of O +a O +new O +cardiac O +performance O +index O +( O +dP O +/ O +dtejc O +) O +measurement O +, O +based O +on O +brachial O +artery O +flow O +changes O +, O +as O +compared O +to O +standard O +12 O +- O +lead O +ECG O +, O +for O +detecting O +dobutamine B +- O +induced O +myocardial O +ischemia O +, O +using O +Tc99m O +- O +Sestamibi O +single O +- O +photon O +emission O +computed O +tomography O +as O +the O +gold O +standard O +of O +comparison O +to O +assess O +the O +presence O +or O +absence O +of O +ischemia O +. O + +METHODS O +: O +The O +study O +group O +comprised O +40 O +patients O +undergoing O +Sestamibi O +- O +SPECT O +/ O +dobutamine B +stress O +test O +. O + +Simultaneous O +measurements O +of O +ECG O +and O +brachial O +artery O +dP O +/ O +dtejc O +were O +performed O +at O +each O +dobutamine B +level O +. O + +In O +19 O +of O +the O +40 O +patients O +perfusion O +defects O +compatible O +with O +ischemia O +were O +detected O +on O +SPECT O +. O + +The O +increase O +in O +dP B +/ O +dtejc O +during O +infusion O +of O +dobutamine B +in O +this O +group O +was O +severely O +impaired O +as O +compared O +to O +the O +non O +- O +ischemic O +group O +. O + +dP O +/ O +dtejc O +outcome O +was O +combined O +with O +the O +ECG O +results O +, O +giving O +an O +ECG O +- O +enhanced O +value O +, O +and O +compared O +to O +ECG O +alone O +. O + +RESULTS O +: O +The O +sensitivity O +improved O +dramatically O +from O +16 O +% O +to O +79 O +%, O +positive O +predictive O +value O +increased O +from O +60 O +% O +to O +68 O +% O +and O +negative O +predictive O +value O +from O +54 O +% O +to O +78 O +%, O +and O +specificity O +decreased O +from O +90 O +% O +to O +67 O +%. O + +CONCLUSIONS O +: O +If O +ECG O +alone O +is O +used O +for O +specificity O +, O +the O +combination O +with O +dP O +/ O +dtejc O +improved O +the O +sensitivity O +of O +the O +test O +and O +could O +be O +a O +cost O +- O +savings O +alternative O +to O +cardiac O +imaging O +or O +perfusion O +studies O +to O +detect O +myocardial O +ischemia O +, O +especially O +in O +patients O +unable O +to O +exercise O +. O + + +Effects O +of O +common O +germline O +genetic O +variation O +in O +cell O +cycle O +control O +genes O +on O +breast O +cancer O +survival O +: O +results O +from O +a O +population O +- O +based O +cohort O +. O + +INTRODUCTION O +: O +Somatic O +alterations O +have O +been O +shown O +to O +correlate O +with O +breast O +cancer O +prognosis O +and O +survival O +, O +but O +less O +is O +known O +about O +the O +effects O +of O +common O +inherited O +genetic O +variation O +. O + +Of O +particular O +interest O +are O +genes O +involved O +in O +cell O +cycle O +pathways O +, O +which O +regulate O +cell O +division O +. O + +METHODS O +: O +We O +examined O +associations O +between O +common O +germline O +genetic O +variation O +in O +13 O +genes O +involved O +in O +cell O +cycle O +control O +( O +CCND1 O +, O +CCND2 O +, O +CCND3 O +, O +CCNE1 O +, O +CDK2 O +[ O +p33 O +], O +CDK4 O +, O +CDK6 O +, O +CDKN1A O +[ O +p21 O +, O +Cip1 O +], O +CDKN1B O +[ O +p27 O +, O +Kip1 O +], O +CDKN2A O +[ O +p16 O +], O +CDKN2B O +[ O +p15 O +], O +CDKN2C O +[ O +p18 O +], O +and O +CDKN2D O +[ O +p19 O +]) O + +and O +survival O +among O +women O +diagnosed O +with O +invasive O +breast O +cancer O +participating O +in O +the O +SEARCH O +( O +Studies O +of O +Epidemiology O +and O +Risk O +factors O +in O +Cancer O +Heredity O +) O +breast O +cancer O +study O +. O + +DNA O +from O +up O +to O +4 O +, O +470 O +women O +was O +genotyped O +for O +85 O +polymorphisms O +that O +tag O +the O +known O +common O +polymorphisms O +( O +minor O +allele O +frequency O +> O +0 O +. O +5 O +) O +in O +the O +genes O +. O + +The O +genotypes O +of O +each O +polymorphism O +were O +tested O +for O +association O +with O +survival O +using O +Cox O +regression O +analysis O +. O + +RESULTS O +: O +The O +rare O +allele O +of O +the O +tagging O +single O +nucleotide O +polymorphism O +( O +SNP O +) O +rs2479717 O +is O +associated O +with O +an O +increased O +risk O +of O +death O +( O +hazard O +ratio O += O +1 O +. O +26 O +per O +rare O +allele O +carried O +, O +95 O +% O +confidence O +interval O +: O +1 O +. O +12 O +to O +1 O +. O +42 O +; O +P O += O +0 O +. O +1 O +), O +which O +was O +not O +attenuated O +after O +adjusting O +for O +tumour O +stage O +, O +grade O +, O +and O +treatment O +. O + +This O +SNP O +is O +part O +of O +a O +large O +linkage O +disequilibrium O +block O +, O +which O +contains O +CCND3 O +, O +BYSL O +, O +TRFP O +, O +USP49 O +, O +C6ofr49 O +, O +FRS3 O +, O +and O +PGC O +. O + +We O +evaluated O +the O +association O +of O +survival O +and O +somatic O +expression O +of O +these O +genes O +in O +breast O +tumours O +using O +expression O +microarray O +data O +from O +seven O +published O +datasets O +. O + +Elevated O +expression O +of O +the O +C6orf49 O +transcript O +was O +associated O +with O +breast O +cancer O +survival O +, O +adding O +biological O +interest O +to O +the O +finding O +. O + +CONCLUSION O +: O +It O +is O +possible O +that O +CCND3 O +rs2479717 O +, O +or O +another O +variant O +it O +tags O +, O +is O +associated O +with O +prognosis O +after O +a O +diagnosis O +of O +breast O +cancer O +. O + +Further O +study O +is O +required O +to O +validate O +this O +finding O +. O + + +Upregulation O +of O +centrosomal O +protein O +55 O +is O +associated O +with O +unfavorable O +prognosis O +and O +tumor O +invasion O +in O +epithelial O +ovarian O +carcinoma O +. O + +Centrosomal O +protein O +55 O +( O +CEP55 O +) O +is O +a O +cell O +cycle O +regulator O +implicated O +in O +development O +of O +certain O +cancers O +. O + +However O +, O +characteristics O +of O +CEP55 O +expression O +and O +its O +clinical O +/ O +prognostic O +significance O +are O +unclear O +in O +human O +epithelial O +ovarian O +carcinoma O +( O +EOC O +). O + +Therefore O +, O +we O +investigated O +the O +expression O +and O +clinicopathological O +significance O +of O +CEP55 B +in O +patients O +with O +EOC O +and O +its O +role O +in O +regulating O +invasion O +and O +metastasis O +of O +ovarian O +cell O +lines O +. O + +CEP55 O +mRNA O +and O +protein O +expression O +levels O +were O +detected O +by O +quantitative O +real O +- O +time O +PCR O +( O +qRT O +- O +PCR O +), O +Western O +blotting O +, O +and O +immunohistochemistry O +( O +IHC O +). O + +Potential O +associations O +of O +CEP55 O +expression O +scores O +with O +clinical O +parameters O +and O +patient O +survival O +were O +evaluated O +. O + +CEP55 O +function O +was O +investigated O +further O +using O +RNA O +interference O +, O +wound O +healing O +assay O +, O +transwell O +assay O +, O +immunofluorescence O +analysis O +, O +qRT O +- O +PCR O +, O +and O +Western O +blotting O +. O + +CEP55 B +was O +significantly O +upregulated O +in O +ovarian O +cancer O +cell O +lines O +and O +lesions O +compared O +with O +normal O +cells O +and O +adjacent O +noncancerous O +ovarian O +tissues O +. O + +In O +the O +213 O +EOC O +samples O +, O +CEP55 O +protein O +levels O +were O +positively O +correlated O +with O +clinical O +stage O +( O +P O +< O +0 O +. O +1 O +), O +lymph O +node O +metastasis O +( O +P O +< O +0 O +. O +1 O +), O +intraperitoneal O +metastasis O +( O +P O +< O +0 O +. O +1 O +), O +tumor O +recurrence O +( O +P O +< O +0 O +. O +1 O +), O +differentiation O +grade O +( O +P O +< O +0 O +. O +1 O +), O +residual O +tumor O +size O +( O +P O +< O +0 O +. O +1 O +), O +ascites O +see O +tumor O +cells O +( O +P O += O +0 O +. O +20 O +), O +and O +serum O +CA153 O +level O +( O +P O +< O +0 O +. O +1 O +). O + +Moreover O +, O +patients O +with O +aberrant O +CEP55 O +protein O +expression O +showed O +tendencies O +to O +receive O +neoadjuvant O +chemotherapy O +( O +P O +< O +0 O +. O +1 O +) O +and O +cytoreductive O +surgery O +( O +P O += O +0 O +. O +20 O +). O + +By O +contrast O +, O +no O +significant O +correlation O +was O +detected O +between O +the O +protein O +levels O +and O +patient O +age O +, O +histological O +type O +, O +or O +serum O +CA125 O +, O +CA199 O +, O +CA724 O +, O +NSE O +, O +CEA B +, O +and O +b O +- I +HCG I +levels O +. O + +Patients O +with O +high O +CEP55 B +protein O +expression O +had O +shorter O +overall O +survival O +and O +disease O +- O +free O +survival O +compared O +with O +those O +with O +low O +CEP55 O +expression O +. O + +Multivariate O +analysis O +implicated O +CEP55 O +as O +an O +independent O +prognostic O +indicator O +for O +EOC O +patients O +. O + +Additionally O +, O +downregulation O +of O +CEP55 O +in O +ovarian O +cancer O +cells O +remarkably O +inhibited O +cellular O +motility O +and O +invasion O +. O + +Aberrant O +CEP55 O +expression O +may O +predict O +unfavorable O +clinical O +outcomes O +in O +EOC O +patients O +and O +play O +an O +important O +role O +in O +regulating O +invasion O +in O +ovarian O +cancer O +cells O +. O + +Thus O +, O +CEP55 O +may O +serve O +as O +a O +prognostic O +marker O +and O +therapeutic O +target O +for O +EOC O +. O + + +Male O +11b O +- O +HSD1 O +Knockout O +Mice O +Fed O +Trans O +- O +Fats O +and O +Fructose O +Are O +Not O +Protected O +From O +Metabolic O +Syndrome O +or O +Nonalcoholic O +Fatty O +Liver O +Disease O +. O + +Nonalcoholic O +fatty O +liver O +disease O +( O +NAFLD O +) O +defines O +a O +spectrum O +of O +conditions O +from O +simple O +steatosis O +to O +nonalcoholic O +steatohepatitis O +( O +NASH O +) O +and O +cirrhosis O +and O +is O +regarded O +as O +the O +hepatic O +manifestation O +of O +the O +metabolic O +syndrome O +. O + +Glucocorticoids B +can O +promote O +steatosis O +by O +stimulating O +lipolysis O +within O +adipose O +tissue O +, O +free O +fatty B +acid I +delivery O +to O +liver O +and O +hepatic O +de O +novo O +lipogenesis O +. O + +Glucocorticoids B +can O +be O +reactivated O +in O +liver O +through O +11b O +- O +hydroxysteroid O +dehydrogenase O +type O +1 O +( O +11b O +- O +HSD1 O +) O +enzyme O +activity O +. O + +Inhibition O +of O +11b O +- O +HSD1 O +has O +been O +suggested O +as O +a O +potential O +treatment O +for O +NAFLD O +. O + +To O +test O +this O +, O +male O +mice O +with O +global O +( O +11b O +- O +HSD1 O +knockout O +[ O +KO O +]) O +and O +liver O +- O +specific O +( O +LKO O +) O +11b O +- O +HSD1 O +loss O +of O +function O +were O +fed O +the O +American O +Lifestyle O +Induced O +Obesity O +Syndrome O +( O +ALIOS O +) O +diet O +, O +known O +to O +recapitulate O +the O +spectrum O +of O +NAFLD O +, O +and O +metabolic O +and O +liver O +phenotypes O +assessed O +. O + +Body O +weight O +, O +muscle O +and O +adipose O +tissue O +masses O +, O +and O +parameters O +of O +glucose B +homeostasis O +showed O +that O +11b O +- O +HSD1KO O +and O +LKO O +mice O +were O +not O +protected O +from O +systemic O +metabolic O +disease O +. O + +Evaluation O +of O +hepatic O +histology O +, O +triglyceride B +content O +, O +and O +blinded O +NAFLD O +activity O +score O +assessment O +indicated O +that O +levels O +of O +steatosis O +were O +similar O +between O +11b O +- O +HSD1KO O +, O +LKO O +, O +and O +control O +mice O +. O + +Unexpectedly O +, O +histological O +analysis O +revealed O +significantly O +increased O +levels O +of O +immune O +foci O +present O +in O +livers O +of O +11b O +- O +HSD1KO O +but O +not O +LKO O +or O +control O +mice O +, O +suggestive O +of O +a O +transition O +to O +NASH O +. O + +This O +was O +endorsed O +by O +elevated O +hepatic O +expression O +of O +key O +immune O +cell O +and O +inflammatory O +markers O +. O + +These O +data O +indicate O +that O +11b O +- O +HSD1 O +- O +deficient O +mice O +are O +not O +protected O +from O +metabolic O +disease O +or O +hepatosteatosis O +in O +the O +face O +of O +a O +NAFLD O +- O +inducing O +diet O +. O + +However O +, O +global O +deficiency O +of O +11b O +- O +HSD1 O +did O +increase O +markers O +of O +hepatic O +inflammation O +and O +suggests O +a O +critical O +role O +for O +11b O +- O +HSD1 O +in O +restraining O +the O +transition O +to O +NASH O +. O + + +Single O +- O +strand O +conformation O +polymorphism O +analysis O +of O +the O +FMR1 O +gene O +in O +autistic O +and O +mentally O +retarded O +children O +in O +Japan O +. O + +Fragile O +X O +syndrome O +is O +one O +of O +the O +most O +common O +causes O +of O +mental O +retardation O +in O +males O +, O +and O +patients O +with O +fragile O +X O +syndrome O +occasionally O +develop O +autism O +. O + +It O +is O +usually O +caused O +by O +an O +expansion O +of O +the O +trinucleotide O +repeat O +in O +the O +5 O +'- O +untranslated O +region O +of O +the O +FMR1 O +gene O +, O +but O +in O +a O +small O +number O +of O +patients O +deletions O +and O +point O +mutations O +have O +been O +identified O +. O + +We O +screened O +all O +17 O +exons O +of O +the O +FMR1 O +gene O +for O +mutations O +in O +90 O +autistic O +or O +mentally O +retarded O +children O +using O +polymerase O +chain O +reaction O +( O +PCR O +)- O +single O +strand O +conformation O +polymorphism O +( O +SSCP O +) O +analysis O +. O + +No O +mutations O +were O +found O +in O +76 O +male O +patients O +. O + +However O +, O +one O +female O +patient O +was O +heterozygous O +for O +a O +normal O +allele O +and O +a O +mutant O +allele O +with O +an O +A O +to O +C O +substitution O +at O +nucleotide O +879 O +in O +exon O +9 O +. O + +This O +mutation O +was O +not O +found O +in O +50 O +controls O +. O + +Reverse O +transcription O +- O +PCR O +revealed O +that O +a O +large O +proportion O +of O +the O +mutant O +transcripts O +were O +spliced O +aberrantly O +, O +causing O +premature O +termination O +of O +the O +protein O +synthesis O +. O + +Although O +uncommon O +, O +point O +mutations O +in O +the O +FMR1 O +gene O +may O +be O +a O +cause O +of O +autism O +and O +mental O +retardation O +in O +Japanese O +patients O +. O + + +Pheochromocytoma O +unmasked O +by O +amisulpride B +and O +tiapride O +. O + +OBJECTIVE O +: O +To O +describe O +the O +unmasking O +of O +pheochromocytoma O +in O +a O +patient O +treated O +with O +amisulpride B +and O +tiapride O +. O + +CASE O +SUMMARY O +: O +A O +42 O +- O +year O +- O +old O +white O +man O +developed O +acute O +hypertension O +with O +severe O +headache O +and O +vomiting O +2 O +hours O +after O +the O +first O +doses O +of O +amisulpride B +100 O +mg O +and O +tiapride B +100 O +mg O +. O + +Both O +drugs O +were O +immediately O +discontinued O +, O +and O +the O +patient O +recovered O +after O +subsequent O +nicardipine I +and O +verapamil B +treatment O +. O + +Abdominal O +ultrasound O +showed O +an O +adrenal O +mass O +, O +and O +postoperative O +histologic O +examination O +confirmed O +the O +diagnosis O +of O +pheochromocytoma O +. O + +DISCUSSION O +: O +Drug O +- O +induced O +symptoms O +of O +pheochromocytoma O +are O +often O +associated O +with O +the O +use O +of O +substituted B +benzamide B +drugs O +, O +but O +the O +underlying O +mechanism O +is O +unknown O +. O + +In O +our O +case O +, O +use O +of O +the O +Naranjo O +probability O +scale O +indicated O +a O +possible O +relationship O +between O +the O +hypertensive O +crisis O +and O +amisulpride B +and O +tiapride B +therapy O +. O + +CONCLUSIONS O +: O +As O +of O +March O +24 O +, O +2005 O +, O +this O +is O +the O +first O +reported O +case O +of O +amisulpride B +- O +and O +tiapride B +- O +induced O +hypertensive O +crisis O +in O +a O +patient O +with O +pheochromocytoma O +. O + +Physicians O +and O +other O +healthcare O +professionals O +should O +be O +aware O +of O +this O +potential O +adverse O +effect O +of O +tiapride B +and O +amisulpride B +. O + + +Phenylephrine O +but O +not O +ephedrine O +reduces O +frontal O +lobe O +oxygenation B +following O +anesthesia O +- O +induced O +hypotension O +. O + +BACKGROUND O +: O +Vasopressor O +agents O +are O +used O +to O +correct O +anesthesia O +- O +induced O +hypotension O +. O + +We O +describe O +the O +effect O +of O +phenylephrine O +and O +ephedrine O +on O +frontal O +lobe O +oxygenation O +( O +S O +( O +c O +) O +O O +( O +2 O +)) O +following O +anesthesia O +- O +induced O +hypotension O +. O + +METHODS O +: O +Following O +induction O +of O +anesthesia O +by O +fentanyl B +( O +0 O +. O +15 O +mg O +kg O +(- O +1 O +)) O +and O +propofol B +( O +2 O +. O +0 O +mg O +kg O +(- O +1 O +)), O +13 O +patients O +received O +phenylephrine B +( O +0 O +. O +1 O +mg O +iv O +) O +and O +12 O +patients O +received O +ephedrine O +( O +10 O +mg O +iv O +) O +to O +restore O +mean O +arterial O +pressure O +( O +MAP O +). O + +Heart O +rate O +( O +HR O +), O +MAP O +, O +stroke O +volume O +( O +SV O +), O +cardiac O +output O +( O +CO O +), O +and O +frontal O +lobe O +oxygenation O +( O +S O +( O +c O +) O +O O +( O +2 O +)) O +were O +registered O +. O + +RESULTS O +: O +Induction O +of O +anesthesia O +was O +followed O +by O +a O +decrease O +in O +MAP O +, O +HR O +, O +SV O +, O +and O +CO O +concomitant O +with O +an O +elevation O +in O +S O +( O +c O +) O +O O +( O +2 O +). O + +After O +administration O +of O +phenylephrine B +, O +MAP O +increased O +( O +51 O ++/- O +12 O +to O +81 O ++/- O +13 O +mmHg O +; O +P O +< O +0 O +. O +1 O +; O +mean O ++/- O +SD O +). O + +However O +, O +a O +14 O +% O +( O +from O +70 O ++/- O +8 O +% O +to O +60 O ++/- O +7 O +%) O +reduction O +in O +S O +( O +c O +) O +O O +( O +2 O +) O +( O +P O +< O +0 O +. O +5 O +) O +followed O +with O +no O +change O +in O +CO O +( O +3 O +. O +7 O ++/- O +1 O +. O +1 O +to O +3 O +. O +4 O ++/- O +0 O +. O +9 O +l O +min O +(- O +1 O +)). O + +The O +administration O +of O +ephedrine O +led O +to O +a O +similar O +increase O +in O +MAP O +( O +53 O ++/- O +9 O +to O +79 O ++/- O +8 O +mmHg O +; O +P O +< O +0 O +. O +1 O +), O +restored O +CO O +( O +3 O +. O +2 O ++/- O +1 O +. O +2 O +to O +5 O +. O +0 O ++/- O +1 O +. O +3 O +l O +min O +(- O +1 O +)), O +and O +preserved O +S O +( O +c O +) O +O O +( O +2 O +). O + +CONCLUSIONS O +: O +The O +utilization O +of O +phenylephrine O +to O +correct O +hypotension O +induced O +by O +anesthesia O +has O +a O +negative O +impact O +on O +S O +( O +c O +) O +O O +( O +2 O +) O +while O +ephedrine O +maintains O +frontal O +lobe O +oxygenation O +potentially O +related O +to O +an O +increase O +in O +CO O +. O + + +Somatic O +and O +gonadal O +mosaicism O +in O +X O +- O +linked O +retinitis O +pigmentosa O +. O + +The O +g O +. O +ORF15 O ++ O +652 O +- O +653delAG O +mutation O +in O +the O +RPGR O +gene O +is O +the O +most O +frequent O +mutation O +in O +X O +- O +linked O +retinitis O +pigmentosa O +( O +XLRP O +). O + +The O +objective O +of O +this O +study O +was O +to O +investigate O +the O +possibility O +of O +mosaicism O +in O +an O +XLRP O +family O +. O + +Eight O +subjects O +in O +the O +RP O +family O +were O +recruited O +. O + +Blood O +samples O +were O +collected O +for O +DNA O +extraction O +. O + +Haplotype O +analysis O +and O +mutational O +screening O +on O +the O +RPGR O +gene O +were O +performed O +. O + +Additionally O +, O +samples O +of O +hair O +follicles O +and O +buccal O +cells O +from O +the O +mother O +of O +the O +proband O +were O +acquired O +for O +DNA O +extraction O +and O +molecular O +analysis O +. O + +Phenotype O +was O +characterized O +with O +routine O +ophthalmic O +examination O +, O +Goldmann O +perimetry O +, O +electroretinography O +, O +and O +color O +fundus O +photography O +. O + +A O +g O +. O +ORF15 O ++ O +652 O +- O +653delAG O +mutation O +was O +identified O +in O +second O +- O +and O +third O +- O +generation O +patients O +/ O +carriers O +. O + +A O +first O +- O +generation O +female O +, O +who O +was O +considered O +to O +be O +an O +obligate O +carrier O +, O +demonstrated O +a O +normal O +phenotype O +as O +well O +as O +a O +normal O +genotype O +in O +lymphocytic O +DNA O +, O +indicating O +the O +gonadal O +mosaicism O +; O +however O +, O +a O +heterozygous O +AG O +- O +deletion O +at O +nucleotide O +652 O +and O +653 O +was O +identified O +in O +the O +genomic O +DNA O +of O +hair O +follicles O +, O +hair O +shaft O +, O +and O +buccal O +cells O +, O +indicating O +that O +the O +mutation O +is O +somatic O +. O + +In O +conclusion O +, O +we O +reported O +on O +a O +family O +in O +which O +an O +asymptomatic O +woman O +with O +somatic O +- O +gonadal O +mosaicism O +for O +a O +RPGR O +gene O +mutation O +transmitted O +the O +mutation O +to O +an O +asymptomatic O +daughter O +and O +to O +a O +son O +with O +XLRP O +. O + +Gonadal O +mosaicism O +may O +be O +responsible O +for O +a O +proportion O +of O +multiplex O +or O +simplex O +RP O +families O +, O +in O +which O +more O +than O +50 O +% O +of O +all O +cases O +of O +RP O +are O +found O +. O + +( O +c O +) O +2007 O +Wiley O +- O +Liss O +, O +Inc O +. O + + +Complete O +atrioventricular O +block O +secondary O +to O +lithium B +therapy O +. O + +Sinus O +node O +dysfunction O +has O +been O +reported O +most O +frequently O +among O +the O +adverse O +cardiovascular O +effects O +of O +lithium B +. O + +In O +the O +present O +case O +, O +complete O +atrioventricular O +( O +AV O +) O +block O +with O +syncopal O +attacks O +developed O +secondary O +to O +lithium B +therapy O +, O +necessitating O +permanent O +pacemaker O +implantation O +. O + +Serum O +lithium B +levels O +remained O +under O +or O +within O +the O +therapeutic O +range O +during O +the O +syncopal O +attacks O +. O + +Lithium B +should O +be O +used O +with O +extreme O +caution O +, O +especially O +in O +patients O +with O +mild O +disturbance O +of O +AV O +conduction O +. O + + +Organophosphate B +- O +induced O +convulsions O +and O +prevention O +of O +neuropathological O +damages O +. O + +Such O +organophosphorus B +( O +OP O +) O +compounds O +as O +diisopropylfluorophosphate B +( O +DFP O +), O +sarin B +and O +soman O +are O +potent O +inhibitors O +of O +acetylcholinesterases O +( O +AChEs O +) O +and O +butyrylcholinesterases O +( O +BChEs O +). O + +The O +acute O +toxicity O +of O +OPs O +is O +the O +result O +of O +their O +irreversible O +binding O +with O +AChEs O +in O +the O +central O +nervous O +system O +( O +CNS O +), O +which O +elevates O +acetylcholine B +( O +ACh B +) O +levels O +. O + +The O +protective O +action O +of O +subcutaneously O +( O +SC O +) O +administered O +antidotes O +or O +their O +combinations O +in O +DFP O +( O +2 O +. O +0 O +mg O +/ O +kg O +BW O +) O +intoxication O +was O +studied O +in O +9 O +- O +10 O +- O +weeks O +- O +old O +Han O +- O +Wistar O +male O +rats O +. O + +The O +rats O +received O +AChE O +reactivator O +pralidoxime B +- O +2 B +- I +chloride I +( O +2PAM O +) O +( O +30 O +. O +0 O +mg O +/ O +kg O +BW O +), O +anticonvulsant O +diazepam B +( O +2 O +. O +0 O +mg O +/ O +kg O +BW O +), O +A O +( O +1 O +)- O +adenosine O +receptor O +agonist O +N O +( O +6 O +)- O +cyclopentyl B +adenosine I +( O +CPA B +) O +( O +2 O +. O +0 O +mg O +/ O +kg O +BW O +), O +NMDA O +- O +receptor O +antagonist O +dizocilpine O +maleate B +(+- O +MK801 B +hydrogen O +maleate B +) O +( O +2 O +. O +0 O +mg O +/ O + +kg O +BW O +) O +or O +their O +combinations O +with O +cholinolytic B +drug I +atropine B +sulfate O +( O +50 O +. O +0 O +mg O +/ O +kg O +BW O +) O +immediately O +or O +30 O +min O +after O +the O +single O +SC O +injection O +of O +DFP O +. O + +The O +control O +rats O +received O +atropine B +sulfate O +, O +but O +also O +saline O +and O +olive O +oil O +instead O +of O +other O +antidotes O +and O +DFP O +, O +respectively O +. O + +All O +rats O +were O +terminated O +either O +24 O +h O +or O +3 O +weeks O +after O +the O +DFP O +injection O +. O + +The O +rats O +treated O +with O +DFP O +- O +atropine B +showed O +severe O +typical O +OP O +- O +induced O +toxicity O +signs O +. O + +When O +CPA B +, O +diazepam B +or O +2PAM O +was O +given O +immediately O +after O +DFP O +- O +atropine B +, O +these O +treatments O +prevented O +, O +delayed O +or O +shortened O +the O +occurrence O +of O +serious O +signs O +of O +poisoning O +. O + +Atropine O +- O +MK801 O +did O +not O +offer O +any O +additional O +protection O +against O +DFP O +toxicity O +. O + +In O +conclusion O +, O +CPA B +, O +diazepam B +and O +2PAM O +in O +combination O +with O +atropine B +prevented O +the O +occurrence O +of O +serious O +signs O +of O +poisoning O +and O +thus O +reduced O +the O +toxicity O +of O +DFP O +in O +rat O +. O + + +The O +activation O +of O +spinal O +N O +- I +methyl I +- O +D O +- O +aspartate O +receptors O +may O +contribute O +to O +degeneration O +of O +spinal O +motor O +neurons O +induced O +by O +neuraxial O +morphine B +after O +a O +noninjurious O +interval O +of O +spinal O +cord O +ischemia O +. O + +We O +investigated O +the O +relationship O +between O +the O +degeneration O +of O +spinal O +motor O +neurons O +and O +activation O +of O +N O +- O +methyl O +- O +d O +- O +aspartate O +( O +NMDA O +) O +receptors O +after O +neuraxial O +morphine B +following O +a O +noninjurious O +interval O +of O +aortic O +occlusion O +in O +rats O +. O + +Spinal O +cord O +ischemia O +was O +induced O +by O +aortic O +occlusion O +for O +6 O +min O +with O +a O +balloon O +catheter O +. O + +In O +a O +microdialysis O +study O +, O +10 O +muL O +of O +saline O +( O +group O +C O +; O +n O += O +8 O +) O +or O +30 O +mug O +of O +morphine B +( O +group O +M O +; O +n O += O +8 O +) O +was O +injected O +intrathecally O +( O +IT O +) O +0 O +. O +5 O +h O +after O +reflow O +, O +and O +30 O +mug O +of O +morphine B +( O +group O +SM O +; O +n O += O +8 O +) O +or O +10 O +muL O +of O +saline O +( O +group O +SC O +; O +n O += O +8 O +) O +was O +injected O +IT O +0 O +. O +5 O +h O +after O +sham O +operation O +. O + +Microdialysis O +samples O +were O +collected O +preischemia O +, O +before O +IT O +injection O +, O +and O +at O +2 O +, O +4 O +, O +8 O +, O +24 O +, O +and O +48 O +h O +of O +reperfusion O +( O +after O +IT O +injection O +). O + +Second O +, O +we O +investigated O +the O +effect O +of O +IT O +MK B +- I +801 I +( O +30 O +mug O +) O +on O +the O +histopathologic O +changes O +in O +the O +spinal O +cord O +after O +morphine B +- O +induced O +spastic O +paraparesis O +. O + +After O +IT O +morphine B +, O +the O +cerebrospinal O +fluid O +( O +CSF O +) O +glutamate B +concentration O +was O +increased O +in O +group O +M O +relative O +to O +both O +baseline O +and O +group O +C O +( O +P O +< O +0 O +. O +5 O +). O + +This O +increase O +persisted O +for O +8 O +hrs O +. O + +IT O +MK B +- I +801 I +significantly O +reduced O +the O +number O +of O +dark O +- O +stained O +alpha O +- O +motoneurons O +after O +morphine B +- O +induced O +spastic O +paraparesis O +compared O +with O +the O +saline O +group O +. O + +These O +data O +indicate O +that O +IT O +morphine B +induces O +spastic O +paraparesis O +with O +a O +concomitant O +increase O +in O +CSF O +glutamate B +, O +which O +is O +involved O +in O +NMDA O +receptor O +activation O +. O + +We O +suggest O +that O +opioids B +may O +be O +neurotoxic O +in O +the O +setting O +of O +spinal O +cord O +ischemia O +via O +NMDA O +receptor O +activation O +. O + + +Growth O +- O +associated O +protein O +43 O +expression O +in O +hippocampal O +molecular O +layer O +of O +chronic O +epileptic O +rats O +treated O +with O +cycloheximide B +. O + +PURPOSE O +: O +GAP43 O +has O +been O +thought O +to O +be O +linked O +with O +mossy O +fiber O +sprouting O +( O +MFS O +) O +in O +various O +experimental O +models O +of O +epilepsy O +. O + +To O +investigate O +how O +GAP43 O +expression O +( O +GAP43 O +- O +ir O +) O +correlates O +with O +MFS O +, O +we O +assessed O +the O +intensity O +( O +densitometry O +) O +and O +extension O +( O +width O +) O +of O +GAP43 O +- O +ir O +in O +the O +inner O +molecular O +layer O +of O +the O +dentate O +gyrus O +( O +IML O +) O +of O +rats O +subject O +to O +status O +epilepticus O +induced O +by O +pilocarpine B +( O +Pilo B +), O +previously O +injected O +or O +not O +with O +cycloheximide B +( O +CHX O +), O +which O +has O +been O +shown O +to O +inhibit O +MFS O +. O + +METHODS O +: O +CHX O +was O +injected O +before O +the O +Pilo O +injection O +in O +adult O +Wistar O +rats O +. O + +The O +Pilo O +group O +was O +injected O +with O +the O +same O +drugs O +, O +except O +for O +CHX O +. O + +Animals O +were O +killed O +between O +30 O +and O +60 O +days O +later O +, O +and O +brain O +sections O +were O +processed O +for O +GAP43 O +immunohistochemistry O +. O + +RESULTS O +: O +Densitometry O +showed O +no O +significant O +difference O +regarding O +GAP43 O +- O +ir O +in O +the O +IML O +between O +Pilo O +, O +CHX O ++ O +Pilo O +, O +and O +control O +groups O +. O + +However O +, O +the O +results O +of O +the O +width O +of O +the O +GAP43 O +- O +ir O +band O +in O +the O +IML O +showed O +that O +CHX O ++ O +Pilo O +and O +control O +animals O +had O +a O +significantly O +larger O +band O +( O +p O += O +0 O +. O +3 O +) O +as O +compared O +with O +that O +in O +the O +Pilo B +group O +. O + +CONCLUSIONS O +: O +Our O +current O +finding O +that O +animals O +in O +the O +CHX O ++ O +Pilo O +group O +have O +a O +GAP43 O +- O +ir O +band O +in O +the O +IML O +, O +similar O +to O +that O +of O +controls O +, O +reinforces O +prior O +data O +on O +the O +blockade O +of O +MFS O +in O +these O +animals O +. O + +The O +change O +in O +GAP43 O +- O +ir O +present O +in O +Pilo B +- O +treated O +animals O +was O +a O +thinning O +of O +the O +band O +to O +a O +very O +narrow O +layer O +just O +above O +the O +granule O +cell O +layer O +that O +is O +likely O +to O +be O +associated O +with O +the O +loss O +of O +hilar O +cell O +projections O +that O +express O +GAP O +- O +43 O +. O + + +Daidzein O +activates O +choline O +acetyltransferase O +from O +MC O +- O +IXC O +cells O +and O +improves O +drug O +- O +induced O +amnesia O +. O + +The O +choline O +acetyltransferase O +( O +ChAT O +) O +activator O +, O +which O +enhances O +cholinergic B +transmission O +via O +an O +augmentation O +of O +the O +enzymatic O +production O +of O +acetylcholine B +( O +ACh B +), O +is O +an O +important O +factor O +in O +the O +treatment O +of O +Alzheimer O +' O +s O +disease O +( O +AD O +). O + +Methanolic B +extracts O +from O +Pueraria O +thunbergiana O +exhibited O +an O +activation O +effect O +( O +46 O +%) O +on O +ChAT O +in O +vitro O +. O + +Via O +the O +sequential O +isolation O +of O +Pueraria O +thunbergiana O +, O +the O +active O +component O +was O +ultimately O +identified O +as O +daidzein O +( O +4 B +', I +7 I +- I +dihydroxy I +- I +isoflavone I +). O + +In O +order O +to O +investigate O +the O +effects O +of O +daidzein O +from O +Pueraria O +thunbergiana O +on O +scopolamine B +- O +induced O +impairments O +of O +learning O +and O +memory O +, O +we O +conducted O +a O +series O +of O +in O +vivo O +tests O +. O + +Administration O +of O +daidzein O +( O +4 O +. O +5 O +mg O +/ O +kg O +body O +weight O +) O +to O +mice O +was O +shown O +significantly O +to O +reverse O +scopolamine B +- O +induced O +amnesia O +, O +according O +to O +the O +results O +of O +a O +Y O +- O +maze O +test O +. O + +Injections O +of O +scopolamine B +into O +mice O +resulted O +in O +impaired O +performance O +on O +Y O +- O +maze O +tests O +( O +a O +37 O +% O +decreases O +in O +alternation O +behavior O +). O + +By O +way O +of O +contrast O +, O +mice O +treated O +with O +daidzein B +prior O +to O +the O +scopolamine B +injections O +were O +noticeably O +protected O +from O +this O +performance O +impairment O +( O +an O +approximately O +12 O +%- O +21 O +% O +decrease O +in O +alternation O +behavior O +). O + +These O +results O +indicate O +that O +daidzein B +might O +play O +a O +role O +in O +acetylcholine O +biosynthesis O +as O +a O +ChAT O +activator O +, O +and O +that O +it O +also O +ameliorates O +scopolamine B +- O +induced O +amnesia O +. O + + +Effect O +of O +alpha O +- O +tocopherol O +and O +deferoxamine O +on O +methamphetamine B +- O +induced O +neurotoxicity O +. O + +Methamphetamine B +( O +MA O +)- O +induced O +dopaminergic O +neurotoxicity O +is O +believed O +to O +be O +associated O +with O +the O +increased O +formation O +of O +free O +radicals O +. O + +This O +study O +examined O +the O +effect O +of O +alpha O +- O +tocopherol O +( O +alpha O +- O +TC O +), O +a O +scavenger O +of O +reactive B +oxygen I +species I +, O +and O +deferoxamine O +( O +DFO O +), O +an O +iron B +chelator O +, O +on O +the O +MA O +- O +induced O +neurotoxicity O +. O + +Male O +rats O +were O +treated O +with O +MA O +( O +10 O +mg O +/ O +kg O +, O +every O +2 O +h O +for O +four O +injections O +). O + +The O +rat O +received O +either O +alpha O +- O +TC O +( O +20 O +mg O +/ O +kg O +) O +intraperitoneally O +for O +3 O +days O +and O +30 O +min O +prior O +to O +MA O +administration O +or O +DFO B +( O +50 O +mg O +/ O +kg O +) O +subcutaneously O +30 O +min O +before O +MA O +administration O +. O + +The O +concentrations O +of O +dopamine B +( O +DA B +), O +serotonin B +and O +their O +metabolites O +decreased O +significantly O +after O +MA O +administration O +, O +which O +was O +inhibited O +by O +the O +alpha B +- I +TC I +and O +DFO O +pretreatment O +. O + +alpha B +- I +TC I +and O +DFO O +attenuated O +the O +MA O +- O +induced O +hyperthermia O +as O +well O +as O +the O +alterations O +in O +the O +locomotor O +activity O +. O + +The O +level O +of O +lipid B +peroxidation O +was O +higher O +and O +the O +reduced O +glutathione B +concentration O +was O +lower O +in O +the O +MA O +- O +treated O +rats O +. O + +These O +changes O +were O +significantly O +attenuated O +by O +alpha O +- O +TC O +and O +DFO O +. O + +This O +suggests O +that O +alpha O +- O +TC O +and O +DFO O +ameliorate O +the O +MA O +- O +induced O +neuronal O +damage O +by O +decreasing O +the O +level O +of O +oxidative O +stress O +. O + + +Cardiac O +Angiography O +in O +Renally O +Impaired O +Patients O +( O +CARE O +) O +study O +: O +a O +randomized O +double O +- O +blind O +trial O +of O +contrast B +- O +induced O +nephropathy O +in O +patients O +with O +chronic O +kidney O +disease O +. O + +BACKGROUND O +: O +No O +direct O +comparisons O +exist O +of O +the O +renal O +tolerability O +of O +the O +low O +- O +osmolality O +contrast B +medium O +iopamidol B +with O +that O +of O +the O +iso O +- O +osmolality O +contrast B +medium O +iodixanol B +in O +high O +- O +risk O +patients O +. O + +METHODS O +AND O +RESULTS O +: O +The O +present O +study O +is O +a O +multicenter O +, O +randomized O +, O +double O +- O +blind O +comparison O +of O +iopamidol B +and O +iodixanol B +in O +patients O +with O +chronic O +kidney O +disease O +( O +estimated O +glomerular O +filtration O +rate O +, O +20 O +to O +59 O +mL O +/ O +min O +) O +who O +underwent O +cardiac O +angiography O +or O +percutaneous O +coronary O +interventions O +. O + +Serum O +creatinine B +( O +SCr O +) O +levels O +and O +estimated O +glomerular O +filtration O +rate O +were O +assessed O +at O +baseline O +and O +2 O +to O +5 O +days O +after O +receiving O +medications O +. O + +The O +primary O +outcome O +was O +a O +postdose O +SCr O +increase O +> O +or O += O +0 O +. O +5 O +mg O +/ O +dL O +( O +44 O +. O +2 O +micromol O +/ O +L O +) O +over O +baseline O +. O + +Secondary O +outcomes O +were O +a O +postdose O +SCr O +increase O +> O +or O += O +25 O +%, O +a O +postdose O +estimated O +glomerular O +filtration O +rate O +decrease O +of O +> O +or O += O +25 O +%, O +and O +the O +mean O +peak O +change O +in O +SCr O +. O + +In O +414 O +patients O +, O +contrast O +volume O +, O +presence O +of O +diabetes O +mellitus O +, O +use O +of O +N O +- O +acetylcysteine O +, O +mean O +baseline O +SCr O +, O +and O +estimated O +glomerular O +filtration O +rate O +were O +comparable O +in O +the O +2 O +groups O +. O + +SCr O +increases O +> O +or O += O +0 O +. O +5 O +mg O +/ O +dL O +occurred O +in O +4 O +. O +4 O +% O +( O +9 O +of O +204 O +patients O +) O +after O +iopamidol B +and O +6 O +. O +7 O +% O +( O +14 O +of O +210 O +patients O +) O +after O +iodixanol B +( O +P O += O +0 O +. O +39 O +), O +whereas O +rates O +of O +SCr O +increases O +> O +or O += O +25 O +% O +were O +9 O +. O +8 O +% O +and O +12 O +. O +4 O +%, O +respectively O +( O +P O += O +0 O +. O +44 O +). O + +In O +patients O +with O +diabetes O +, O +SCr O +increases O +> O +or O += O +0 O +. O +5 O +mg O +/ O +dL O +were O +5 O +. O +1 O +% O +( O +4 O +of O +78 O +patients O +) O +with O +iopamidol B +and O +13 O +. O +0 O +% O +( O +12 O +of O +92 O +patients O +) O +with O +iodixanol B +( O +P O += O +0 O +. O +11 O +), O +whereas O +SCr O +increases O +> O +or O += O +25 O +% O +were O +10 O +. O +3 O +% O +and O +15 O +. O +2 O +%, O +respectively O +( O +P O += O +0 O +. O +37 O +). O + +Mean O +post O +- O +SCr O +increases O +were O +significantly O +less O +with O +iopamidol B +( O +all O +patients O +: O +0 O +. O +7 O +versus O +0 O +. O +12 O +mg O +/ O +dL O +, O +6 O +. O +2 O +versus O +10 O +. O +6 O +micromol O +/ O +L O +, O +P O += O +0 O +. O +3 O +; O +patients O +with O +diabetes O +: O +0 O +. O +7 O +versus O +0 O +. O +16 O +mg O +/ O +dL O +, O +6 O +. O +2 O +versus O +14 O +. O +1 O +micromol O +/ O +L O +, O +P O += O +0 O +. O +1 O +). O + +CONCLUSIONS O +: O +The O +rate O +of O +contrast B +- O +induced O +nephropathy O +, O +defined O +by O +multiple O +end O +points O +, O +is O +not O +statistically O +different O +after O +the O +intraarterial O +administration O +of O +iopamidol B +or O +iodixanol B +to O +high O +- O +risk O +patients O +, O +with O +or O +without O +diabetes O +mellitus O +. O + +Any O +TRUE O +difference O +between O +the O +agents O +is O +small O +and O +not O +likely O +to O +be O +clinically O +significant O +. O + + +Estrogen B +prevents O +cholesteryl B +ester O +accumulation O +in O +macrophages O +induced O +by O +the O +HIV O +protease O +inhibitor O +ritonavir B +. O + +Individuals O +with O +HIV O +can O +now O +live O +long O +lives O +with O +drug O +therapy O +that O +often O +includes O +protease O +inhibitors O +such O +as O +ritonavir B +. O + +Many O +patients O +, O +however O +, O +develop O +negative O +long O +- O +term O +side O +effects O +such O +as O +premature O +atherosclerosis O +. O + +We O +have O +previously O +demonstrated O +that O +ritonavir B +treatment O +increases O +atherosclerotic O +lesion O +formation O +in O +male O +mice O +to O +a O +greater O +extent O +than O +in O +female O +mice O +. O + +Furthermore O +, O +peripheral O +blood O +monocytes O +isolated O +from O +ritonavir O +- O +treated O +females O +had O +less O +cholesteryl B +ester O +accumulation O +. O + +In O +the O +present O +study O +, O +we O +have O +investigated O +the O +molecular O +mechanisms O +by O +which O +female B +hormones I +influence O +cholesterol B +metabolism O +in O +macrophages O +in O +response O +to O +the O +HIV O +protease O +inhibitor O +ritonavir B +. O + +We O +have O +utilized O +the O +human O +monocyte O +cell O +line O +, O +THP B +- O +1 O +as O +a O +model O +to O +address O +this O +question O +. O + +Briefly O +, O +cells O +were O +differentiated O +for O +72 O +h O +with O +100 O +nM O +PMA O +to O +obtain O +a O +macrophage O +- O +like O +phenotype O +in O +the O +presence O +or O +absence O +of O +1 O +nM O +17beta B +- I +estradiol I +( O +E2 O +), O +100 O +nM O +progesterone O +or O +vehicle O +( O +0 O +. O +1 O +% O +ethanol O +). O + +Cells O +were O +then O +treated O +with O +30 O +ng O +/ O +ml O +ritonavir O +or O +vehicle O +in O +the O +presence O +of O +aggregated O +LDL O +for O +24 O +h O +. O +Cell O +extracts O +were O +harvested O +, O +and O +lipid B +or O +total O +RNA O +was O +isolated O +. O + +E2 O +decreased O +the O +accumulation O +of O +cholesteryl B +esters O +in O +macrophages O +following O +ritonavir O +treatment O +. O + +Ritonavir O +increased O +the O +expression O +of O +the O +scavenger O +receptor O +, O +CD36 O +mRNA O +, O +responsible O +for O +the O +uptake O +of O +LDL O +. O + +Additionally O +, O +ritonavir O +treatment O +selectively O +increased O +the O +relative O +levels O +of O +PPARgamma O +mRNA O +, O +a O +transcription O +factor O +responsible O +for O +the O +regulation O +of O +CD36 O +mRNA O +expression O +. O + +Treatment O +with O +E2 O +, O +however O +, O +failed O +to O +prevent O +these O +increases O +at O +the O +mRNA O +level O +. O + +E2 B +did O +, O +however O +, O +significantly O +suppress O +CD36 O +protein O +levels O +as O +measured O +by O +fluorescent O +immunocytochemistry O +. O + +This O +data O +suggests O +that O +E2 O +modifies O +the O +expression O +of O +CD36 O +at O +the O +level O +of O +protein O +expression O +in O +monocyte O +- O +derived O +macrophages O +resulting O +in O +reduced O +cholesteryl B +ester O +accumulation O +following O +ritonavir B +treatment O +. O + + +Clinical O +comparison O +of O +cardiorespiratory O +effects O +during O +unilateral O +and O +conventional O +spinal O +anaesthesia O +. O + +BACKGROUND O +: O +Spinal O +anaesthesia O +is O +widely O +employed O +in O +clinical O +practice O +but O +has O +the O +main O +drawback O +of O +post O +- O +spinal O +block O +hypotension O +. O + +Efforts O +must O +therefore O +continue O +to O +be O +made O +to O +obviate B +this O +setback O +OBJECTIVE O +: O +To O +evaluate O +the O +cardiovascular O +and O +respiratory O +changes O +during O +unilateral O +and O +conventional O +spinal O +anaesthesia O +. O + +METHODS O +: O +With O +ethical O +approval O +, O +we O +studied O +74 O +American O +Society O +of O +Anesthesiologists O +( O +ASA O +), O +physical O +status O +class O +1 O +and O +2 O +patients O +scheduled O +for O +elective O +unilateral O +lower O +limb O +surgery O +. O + +Patients O +were O +randomly O +allocated O +into O +one O +of O +two O +groups O +: O +lateral O +and O +conventional O +spinal O +anaesthesia O +groups O +. O + +In O +the O +lateral O +position O +with O +operative O +side O +down O +, O +patients O +recived O +10 O +mg O +( O +2mls O +) O +of O +0 O +. O +5 O +% O +hyperbaric O +bupivacaine B +through O +a O +25 O +- O +gauge O +spinal O +needle O +. O + +Patients O +in O +the O +unilateral O +group O +were O +maintained O +in O +the O +lateral O +position O +for O +15 O +minutes O +following O +spinal O +injection O +while O +those O +in O +the O +conventional O +group O +were O +turned O +supine B +immediately O +after O +injection O +. O + +Blood O +pressure O +, O +heart O +rate O +, O +respiratory O +rate O +and O +oxygen O +saturation O +were O +monitored O +over O +1 O +hour O +. O + +RESULTS O +: O +Three O +patients O +( O +8 O +. O +1 O +%) O +in O +the O +unilateral O +group O +and O +5 O +( O +13 O +. O +5 O +%) O +in O +the O +conventional O +group O +developed O +hypotension O +, O +P O += O +0 O +. O +71 O +. O + +Four O +( O +10 O +. O +8 O +%) O +patients O +in O +the O +conventional O +group O +and O +1 O +( O +2 O +. O +7 O +%) O +in O +the O +unilateral O +group O +, O +P O += O +0 O +. O +17 O +required O +epinephrine O +infusion O +to O +treat O +hypotension O +. O + +Patients O +in O +the O +conventional O +group O +had O +statistically O +significant O +greater O +fall O +in O +the O +systolic O +blood O +pressures O +at O +15 O +, O +30 O +and O +45 O +minutes O +when O +compared O +to O +the O +baseline O +( O +P O += O +0 O +. O +3 O +, O +0 O +. O +1 O +and O +0 O +. O +4 O +). O + +The O +mean O +respiratory O +rate O +and O +oxygen O +saturations O +in O +the O +two O +groups O +were O +similar O +. O + +CONCLUSION O +: O +Compared O +to O +conventional O +spinal O +anaesthesia O +, O +unilateral O +spinal O +anaesthesia O +was O +associated O +with O +fewer O +cardiovascular O +perturbations O +. O + +Also O +, O +the O +type O +of O +spinal O +block O +instituted O +affected O +neither O +the O +respiratory O +rate O +nor O +the O +arterial O +oxygen O +saturation O +. O + + +Acute O +effects O +of O +N B +-( I +2 I +- I +propylpentanoyl I +) O +urea I +on O +hippocampal O +amino I +acid I +neurotransmitters I +in O +pilocarpine B +- O +induced O +seizure O +in O +rats O +. O + +The O +present O +study O +aimed O +to O +investigate O +the O +anticonvulsant O +activity O +as O +well O +as O +the O +effects O +on O +the O +level O +of O +hippocampal O +amino I +acid I +neurotransmitters I +( O +glutamate B +, O +aspartate B +, O +glycine B +and O +GABA O +) O +of O +N O +-( O +2 O +- O +propylpentanoyl B +) O +urea I +( O +VPU B +) O +in O +comparison O +to O +its O +parent O +compound O +, O +valproic B +acid I +( O +VPA B +). O + +VPU O +was O +more O +potent O +than O +VPA B +, O +exhibiting O +the O +median O +effective O +dose O +( O +ED O +( O +50 O +)) O +of O +49 O +mg O +/ O +kg O +in O +protecting O +rats O +against O +pilocarpine B +- O +induced O +seizure O +whereas O +the O +corresponding O +value O +for O +VPA B +was O +322 O +mg O +/ O +kg O +. O + +In O +vivo O +microdialysis O +demonstrated O +that O +an O +intraperitoneal O +administration O +of O +pilocarpine B +induced O +a O +pronounced O +increment O +of O +hippocampal O +glutamate B +and O +aspartate O +whereas O +no O +significant O +change O +was O +observed O +on O +the O +level O +of O +glycine B +and O +GABA O +. O + +Pretreatment O +with O +either O +VPU B +( O +50 O +and O +100 O +mg O +/ O +kg O +) O +or O +VPA B +( O +300 O +and O +600 O +mg O +/ O +kg O +) O +completely O +abolished O +pilocarpine B +- O +evoked O +increases O +in O +extracellular O +glutamate B +and O +aspartate B +. O + +In O +addition O +, O +a O +statistically O +significant O +reduction O +was O +also O +observed O +on O +the O +level O +of O +GABA O +and O +glycine B +but O +less O +than O +a O +drastic O +reduction O +of O +glutamate B +and O +aspartate B +level O +. O + +Based O +on O +the O +finding O +that O +VPU B +and O +VPA O +could O +protect O +the O +animals O +against O +pilocarpine B +- O +induced O +seizure O +it O +is O +suggested O +that O +the O +reduction O +of O +inhibitory O +amino I +acid I +neurotransmitters I +was O +comparatively O +minor O +and O +offset O +by O +a O +pronounced O +reduction O +of O +glutamate B +and O +aspartate B +. O + +Therefore O +, O +like O +VPA O +, O +the O +finding O +that O +VPU O +could O +drastically O +reduce O +pilocarpine B +- O +induced O +increases O +in O +glutamate B +and O +aspartate B +should O +account O +, O +at O +least O +partly O +, O +for O +its O +anticonvulsant O +activity O +observed O +in O +pilocarpine B +- O +induced O +seizure O +in O +experimental O +animals O +. O + +Some O +other O +mechanism O +than O +those O +being O +reported O +herein O +should O +be O +further O +investigated O +. O + + +Delirium O +in O +a O +patient O +with O +toxic O +flecainide B +plasma O +concentrations O +: O +the O +role O +of O +a O +pharmacokinetic O +drug O +interaction O +with O +paroxetine B +. O + +OBJECTIVE O +: O +To O +describe O +a O +case O +of O +flecainide B +- O +induced O +delirium O +associated O +with O +a O +pharmacokinetic O +drug O +interaction O +with O +paroxetine B +. O + +CASE O +SUMMARY O +: O +A O +69 O +- O +year O +- O +old O +white O +female O +presented O +to O +the O +emergency O +department O +with O +a O +history O +of O +confusion O +and O +paranoia O +over O +the O +past O +several O +days O +. O + +On O +admission O +the O +patient O +was O +taking O +carvedilol O +12 O +mg O +twice O +daily O +, O +warfarin B +2 O +mg O +/ O +day O +, O +folic B +acid I +1 O +mg O +/ O +day O +, O +levothyroxine B +100 O +microg O +/ O +day O +, O +pantoprazole B +40 O +mg O +/ O +day O +, O +paroxetine B +40 O +mg O +/ O +day O +, O +and O +flecainide B +100 O +mg O +twice O +daily O +. O + +Flecainide B +had O +been O +started O +2 O +weeks O +prior O +for O +atrial O +fibrillation O +. O + +Laboratory O +test O +findings O +on O +admission O +were O +notable O +only O +for O +a O +flecainide B +plasma O +concentration O +of O +1360 O +microg O +/ O +L O +( O +reference O +range O +200 O +- O +1000 O +). O + +A O +metabolic O +drug O +interaction O +between O +flecainide B +and O +paroxetine B +, O +which O +the O +patient O +had O +been O +taking O +for O +more O +than O +5 O +years O +, O +was O +considered O +. O + +Paroxetine B +was O +discontinued O +and O +the O +dose O +of O +flecainide B +was O +reduced O +to O +50 O +mg O +twice O +daily O +. O + +Her O +delirium O +resolved O +3 O +days O +later O +. O + +DISCUSSION O +: O +Flecainide O +and O +pharmacologically O +similar O +agents O +that O +interact O +with O +sodium B +channels O +may O +cause O +delirium O +in O +susceptible O +patients O +. O + +A O +MEDLINE O +search O +( O +1966 O +- O +January O +2009 O +) O +revealed O +one O +in O +vivo O +pharmacokinetic O +study O +on O +the O +interaction O +between O +flecainide B +, O +a O +CYP2D6 O +substrate O +, O +and O +paroxetine B +, O +a O +CYP2D6 O +inhibitor O +, O +as O +well O +as O +3 O +case O +reports O +of O +flecainide B +- O +induced O +delirium O +. O + +According O +to O +the O +Naranjo O +probability O +scale O +, O +flecainide B +was O +the O +probable O +cause O +of O +the O +patient O +' O +s O +delirium O +; O +the O +Horn O +Drug O +Interaction O +Probability O +Scale O +indicates O +a O +possible O +pharmacokinetic O +drug O +interaction O +between O +flecainide B +and O +paroxetine B +. O + +CONCLUSIONS O +: O +Supratherapeutic O +flecainide B +plasma O +concentrations O +may O +cause O +delirium O +. O + +Because O +toxicity O +may O +occur O +when O +flecainide B +is O +prescribed O +with O +paroxetine B +and O +other O +potent O +CYP2D6 O +inhibitors I +, O +flecainide B +plasma O +concentrations O +should O +be O +monitored O +closely O +with O +commencement O +of O +CYP2D6 O +inhibitors O +. O + + +Depression O +, O +impulsiveness O +, O +sleep O +, O +and O +memory O +in O +past O +and O +present O +polydrug O +users O +of O +3 B +, I +4 I +- I +methylenedioxymethamphetamine I +( O +MDMA B +, O +ecstasy B +). O + +RATIONALE O +: O +Ecstasy B +( O +3 B +, I +4 I +- I +methylenedioxymethamphetamine I +, O +MDMA B +) O +is O +a O +worldwide O +recreational O +drug O +of O +abuse O +. O + +Unfortunately O +, O +the O +results O +from O +human O +research O +investigating O +its O +psychological O +effects O +have O +been O +inconsistent O +. O + +OBJECTIVES O +: O +The O +present O +study O +aimed O +to O +be O +the O +largest O +to O +date O +in O +sample O +size O +and O +5HT O +- O +related O +behaviors O +; O +the O +first O +to O +compare O +present O +ecstasy B +users O +with O +past B +users O +after O +an O +abstinence O +of O +4 O +or O +more O +years O +, O +and O +the O +first O +to O +include O +robust O +controls O +for O +other O +recreational O +substances O +. O + +METHODS O +: O +A O +sample O +of O +997 O +participants O +( O +52 O +% O +male O +) O +was O +recruited O +to O +four O +control O +groups O +( O +non O +- O +drug O +( O +ND O +), O +alcohol B +/ O +nicotine O +( O +AN O +), O +cannabis O +/ O +alcohol B +/ O +nicotine O +( O +CAN O +), O +non O +- O +ecstasy B +polydrug O +( O +PD O +)), O +and O +two O +ecstasy B +polydrug O +groups O +( O +present O +( O +MDMA B +) O +and O +past O +users O +( O +EX O +- O +MDMA B +). O + +Participants O +completed O +a O +drug O +history O +questionnaire O +, O +Beck O +Depression O +Inventory O +, O +Barratt O +Impulsiveness O +Scale O +, O +Pittsburgh O +Sleep O +Quality O +Index O +, O +and O +Wechsler O +Memory O +Scale O +- O +Revised O +which O +, O +in O +total O +, O +provided O +13 O +psychometric O +measures O +. O + +RESULTS O +: O +While O +the O +CAN O +and O +PD O +groups O +tended O +to O +record O +greater O +deficits O +than O +the O +non O +- O +drug O +controls O +, O +the O +MDMA B +and O +EX O +- O +MDMA B +groups O +recorded O +greater O +deficits O +than O +all O +the O +control O +groups O +on O +ten O +of O +the O +13 O +psychometric O +measures O +. O + +Strikingly O +, O +despite O +prolonged O +abstinence O +( O +mean O +, O +4 O +. O +98 O +; O +range O +, O +4 O +- O +9 O +years O +), O +past O +ecstasy B +users O +showed O +few O +signs O +of O +recovery O +. O + +Compared O +with O +present O +ecstasy B +users O +, O +the O +past B +users O +showed O +no O +change O +for O +ten O +measures O +, O +increased O +impairment O +for O +two O +measures O +, O +and O +improvement O +on O +just O +one O +measure O +. O + +CONCLUSIONS O +: O +Given O +this O +record O +of O +impaired O +memory O +and O +clinically O +significant O +levels O +of O +depression O +, O +impulsiveness O +, O +and O +sleep O +disturbance O +, O +the O +prognosis O +for O +the O +current O +generation O +of O +ecstasy B +users O +is O +a O +major O +cause O +for O +concern O +. O + + +A O +comparison O +of O +severe O +hemodynamic O +disturbances O +between O +dexmedetomidine B +and O +propofol B +for O +sedation O +in O +neurocritical O +care O +patients O +. O + +OBJECTIVE O +: O +Dexmedetomidine B +and O +propofol B +are O +commonly O +used O +sedatives O +in O +neurocritical O +care O +as O +they O +allow O +for O +frequent O +neurologic O +examinations O +. O + +However O +, O +both O +agents O +are O +associated O +with O +significant O +hemodynamic O +side O +effects O +. O + +The O +primary O +objective O +of O +this O +study O +is O +to O +compare O +the O +prevalence O +of O +severe O +hemodynamic O +effects O +in O +neurocritical O +care O +patients O +receiving O +dexmedetomidine B +and O +propofol B +. O + +DESIGN O +: O +Multicenter O +, O +retrospective O +, O +propensity O +- O +matched O +cohort O +study O +. O + +SETTING O +: O +Neurocritical O +care O +units O +at O +two O +academic O +medical O +centers O +with O +dedicated O +neurocritical O +care O +teams O +and O +board O +- O +certified O +neurointensivists O +. O + +PATIENTS O +: O +Neurocritical O +care O +patients O +admitted O +between O +July O +2009 O +and O +September O +2012 O +were O +evaluated O +and O +then O +matched O +1 O +: O +1 O +based O +on O +propensity O +scoring O +of O +baseline O +characteristics O +. O + +INTERVENTIONS O +: O +Continuous O +sedation O +with O +dexmedetomidine B +or O +propofol B +. O + +MEASUREMENTS O +AND O +MAIN O +RESULTS O +: O +A O +total O +of O +342 O +patients O +( O +105 O +dexmedetomidine B +and O +237 O +propofol B +) O +were O +included O +in O +the O +analysis O +, O +with O +190 O +matched O +( O +95 O +in O +each O +group O +) O +by O +propensity O +score O +. O + +The O +primary O +outcome O +of O +this O +study O +was O +a O +composite O +of O +severe O +hypotension O +( O +mean O +arterial O +pressure O +< O +60 O +mm O +Hg O +) O +and O +bradycardia O +( O +heart O +rate O +< O +50 O +beats O +/ O +min O +) O +during O +sedative O +infusion O +. O + +No O +difference O +in O +the O +primary O +composite O +outcome O +in O +both O +the O +unmatched O +( O +30 O +% O +vs O +30 O +%, O +p O += O +0 O +. O +94 O +) O +or O +matched O +cohorts O +( O +28 O +% O +vs O +34 O +%, O +p O += O +0 O +. O +35 O +) O +could O +be O +found O +. O + +When O +analyzed O +separately O +, O +no O +differences O +could O +be O +found O +in O +the O +prevalence O +of O +severe O +hypotension O +or O +bradycardia O +in O +either O +the O +unmatched O +or O +matched O +cohorts O +. O + +CONCLUSIONS O +: O +Severe O +hypotension O +and O +bradycardia O +occur O +at O +similar O +prevalence O +in O +neurocritical O +care O +patients O +who O +receive O +dexmedetomidine B +or O +propofol B +. O + +Providers O +should O +similarly O +consider O +the O +likelihood O +of O +hypotension O +or O +bradycardia O +before O +starting O +either O +sedative O +. O + + +Effects O +of O +dehydroepiandrosterone B +in O +amphetamine B +- O +induced O +schizophrenia O +models O +in O +mice O +. O + +OBJECTIVE O +: O +To O +examine O +the O +effects O +of O +dehydroepiandrosterone B +( O +DHEA B +) O +on O +animal O +models O +of O +schizophrenia O +. O + +METHODS O +: O +Seventy O +Swiss O +albino O +female O +mice O +( O +25 O +- O +35 O +g O +) O +were O +divided O +into O +4 O +groups O +: O +amphetamine B +- O +free O +( O +control O +), O +amphetamine B +, O +50 O +, O +and O +100 O +mg O +/ O +kg O +DHEA O +. O + +The O +DHEA O +was O +administered O +intraperitoneally O +( O +ip O +) O +for O +5 O +days O +. O + +Amphetamine B +( O +3 O +mg O +/ O +kg O +ip O +) O +induced O +hyper O +locomotion O +, O +apomorphine B +( O +1 O +. O +5 O +mg O +/ O +kg O +subcutaneously O +[ O +sc O +]) O +induced O +climbing O +, O +and O +haloperidol B +( O +1 O +. O +5 O +mg O +/ O +kg O +sc O +) O +induced O +catalepsy O +tests O +were O +used O +as O +animal O +models O +of O +schizophrenia O +. O + +The O +study O +was O +conducted O +at O +the O +Animal O +Experiment O +Laboratories O +, O +Department O +of O +Pharmacology O +, O +Medical O +School O +, O +Eskisehir O +Osmangazi B +University O +, O +Eskisehir O +, O +Turkey O +between O +March O +and O +May O +2012 O +. O + +Statistical O +analysis O +was O +carried O +out O +using O +Kruskal O +- O +Wallis O +test O +for O +hyper O +locomotion O +, O +and O +one O +- O +way O +ANOVA O +for O +climbing O +and O +catalepsy O +tests O +. O + +RESULTS O +: O +In O +the O +amphetamine B +- O +induced O +locomotion O +test O +, O +there O +were O +significant O +increases O +in O +all O +movements O +compared O +with O +the O +amphetamine B +- O +free O +group O +. O + +Both O +DHEA B +50 O +mg O +/ O +kg O +( O +p O +< O +0 O +. O +5 O +), O +and O +100 O +mg O +/ O +kg O +( O +p O +< O +0 O +. O +1 O +) O +significantly O +decreased O +all O +movements O +compared O +with O +the O +amphetamine B +- O +induced O +locomotion O +group O +. O + +There O +was O +a O +significant O +difference O +between O +groups O +in O +the O +haloperidol B +- O +induced O +catalepsy O +test O +( O +p O +< O +0 O +. O +5 O +). O + +There O +was O +no O +significant O +difference O +between O +groups O +in O +terms O +of O +total O +climbing O +time O +in O +the O +apomorphine B +- O +induced O +climbing O +test O +( O +p O +> O +0 O +. O +5 O +). O + +CONCLUSION O +: O +We O +observed O +that O +DHEA O +reduced O +locomotor O +activity O +and O +increased O +catalepsy O +at O +both O +doses O +, O +while O +it O +had O +no O +effect O +on O +climbing O +behavior O +. O + +We O +suggest O +that O +DHEA B +displays O +typical O +neuroleptic O +- O +like O +effects O +, O +and O +may O +be O +used O +in O +the O +treatment O +of O +schizophrenia O +. O + + +Aconitine B +- O +induced O +Ca2 B ++ I +overload O +causes O +arrhythmia O +and O +triggers O +apoptosis O +through O +p38 O +MAPK O +signaling O +pathway O +in O +rats O +. O + +Aconitine B +is O +a O +major O +bioactive O +diterpenoid B +alkaloid O +with O +high O +content O +derived O +from O +herbal B +aconitum B +plants O +. O + +Emerging O +evidence O +indicates O +that O +voltage O +- O +dependent O +Na O +(+) O +channels O +have O +pivotal O +roles O +in O +the O +cardiotoxicity O +of O +aconitine B +. O + +However O +, O +no O +reports O +are O +available O +on O +the O +role O +of O +Ca B +( I +2 I ++) I +in O +aconitine O +poisoning O +. O + +In O +this O +study O +, O +we O +explored O +the O +importance O +of O +pathological O +Ca B +( I +2 I ++) I +signaling O +in O +aconitine O +poisoning O +in O +vitro O +and O +in O +vivo O +. O + +We O +found O +that O +Ca B +( I +2 I ++) I +overload O +lead O +to O +accelerated O +beating O +rhythm O +in O +adult O +rat O +ventricular O +myocytes O +and O +caused O +arrhythmia O +in O +conscious O +freely O +moving O +rats O +. O + +To O +investigate O +effects O +of O +aconitine B +on O +myocardial O +injury O +, O +we O +performed O +cytotoxicity O +assay O +in O +neonatal O +rat O +ventricular O +myocytes O +( O +NRVMs O +), O +as O +well O +as O +measured O +lactate O +dehydrogenase O +level O +in O +the O +culture O +medium O +of O +NRVMs O +and O +activities O +of O +serum O +cardiac O +enzymes O +in O +rats O +. O + +The O +results O +showed O +that O +aconitine B +resulted O +in O +myocardial O +injury O +and O +reduced O +NRVMs O +viability O +dose O +- O +dependently O +. O + +To O +confirm O +the O +pro O +- O +apoptotic O +effects O +, O +we O +performed O +flow O +cytometric O +detection O +, O +cardiac O +histology O +, O +transmission O +electron O +microscopy O +and O +terminal O +deoxynucleotidyl O +transferase O +- O +mediated O +dUTP B +- O +biotin O +nick O +end O +labeling O +assay O +. O + +The O +results O +showed O +that O +aconitine B +stimulated O +apoptosis O +time O +- O +dependently O +. O + +The O +expression O +analysis O +of O +Ca B +( I +2 I ++) I +handling O +proteins O +demonstrated O +that O +aconitine B +promoted O +Ca B +( I +2 I ++) I +overload O +through O +the O +expression O +regulation O +of O +Ca B +( I +2 I ++) I +handling O +proteins O +. O + +The O +expression O +analysis O +of O +apoptosis O +- O +related O +proteins O +revealed O +that O +pro O +- O +apoptotic O +protein O +expression O +was O +upregulated O +, O +and O +anti O +- O +apoptotic O +protein O +BCL O +- O +2 O +expression O +was O +downregulated O +. O + +Furthermore O +, O +increased O +phosphorylation O +of O +MAPK O +family O +members O +, O +especially O +the O +P O +- O +P38 O +/ O +P38 O +ratio O +was O +found O +in O +cardiac O +tissues O +. O + +Hence O +, O +our O +results O +suggest O +that O +aconitine B +significantly O +aggravates O +Ca B +( I +2 I ++) I +overload O +and O +causes O +arrhythmia O +and O +finally O +promotes O +apoptotic O +development O +via O +phosphorylation O +of O +P38 O +mitogen O +- O +activated O +protein O +kinase O +. O +