diff --git "a/test_predictions.txt" "b/test_predictions.txt" new file mode 100644--- /dev/null +++ "b/test_predictions.txt" @@ -0,0 +1,154995 @@ +Clustering O +of O +missense O +mutations O +in O +the O +ataxia B +- I +telangiectasia I +gene O +in O +a O +sporadic B +T I +- I +cell I +leukaemia I +. O + +Ataxia B +- I +telangiectasia I +( O +A B +- I +T I +) O +is O +a O +recessive B +multi I +- I +system I +disorder I +caused O +by O +mutations O +in O +the O +ATM O +gene O +at O +11q22 O +- O +q23 O +( O +ref O +. O +3 O +) O +. O + +The O +risk O +of O +cancer B +, O +especially O +lymphoid B +neoplasias I +, O +is O +substantially O +elevated O +in O +A B +- I +T I +patients O +and O +has O +long O +been O +associated O +with O +chromosomal O +instability O +. O + +By O +analysing O +tumour O +DNA O +from O +patients O +with O +sporadic B +T I +- I +cell I +prolymphocytic I +leukaemia I +( O +T B +- I +PLL I +) O +, O +a O +rare O +clonal B +malignancy I +with O +similarities O +to O +a O +mature B +T I +- I +cell I +leukaemia I +seen O +in O +A B +- I +T I +, O +we O +demonstrate O +a O +high O +frequency O +of O +ATM O +mutations O +in O +T B +- I +PLL I +. O + +In O +marked O +contrast O +to O +the O +ATM O +mutation O +pattern O +in O +A B +- I +T I +, O +the O +most O +frequent O +nucleotide O +changes O +in O +this O +leukaemia B +were O +missense O +mutations O +. O + +These O +clustered O +in O +the O +region O +corresponding O +to O +the O +kinase O +domain O +, O +which O +is O +highly O +conserved O +in O +ATM O +- O +related O +proteins O +in O +mouse O +, O +yeast O +and O +Drosophila O +. O + +The O +resulting O +amino O +- O +acid O +substitutions O +are O +predicted O +to O +interfere O +with O +ATP O +binding O +or O +substrate O +recognition O +. O + +Two O +of O +seventeen O +mutated O +T O +- O +PLL O +samples O +had O +a O +previously O +reported O +A B +- I +T I +allele O +. O + +In O +contrast O +, O +no O +mutations O +were O +detected O +in O +the O +p53 O +gene O +, O +suggesting O +that O +this O +tumour B +suppressor O +is O +not O +frequently O +altered O +in O +this O +leukaemia B +. O + +Occasional O +missense O +mutations O +in O +ATM O +were O +also O +found O +in O +tumour B +DNA O +from O +patients O +with O +B B +- I +cell I +non I +- I +Hodgkins I +lymphomas I +( O +B B +- I +NHL I +) O +and O +a O +B B +- I +NHL I +cell O +line O +. O + +The O +evidence O +of O +a O +significant O +proportion O +of O +loss O +- O +of O +- O +function O +mutations O +and O +a O +complete O +absence O +of O +the O +normal O +copy O +of O +ATM O +in O +the O +majority O +of O +mutated O +tumours I +establishes O +somatic O +inactivation O +of O +this O +gene O +in O +the O +pathogenesis O +of O +sporadic B +T I +- I +PLL I +and O +suggests O +that O +ATM O +acts O +as O +a O +tumour B +suppressor O +. O + +As O +constitutional O +DNA O +was O +not O +available O +, O +a O +putative O +hereditary O +predisposition O +to O +T B +- I +PLL I +will O +require O +further O +investigation O +. O +. O + +Myotonic B +dystrophy I +protein O +kinase O +is O +involved O +in O +the O +modulation O +of O +the O +Ca2 O ++ O +homeostasis O +in O +skeletal O +muscle O +cells O +. O + +Myotonic B +dystrophy I +( O +DM B +) O +, O +the O +most O +prevalent O +muscular B +disorder I +in O +adults O +, O +is O +caused O +by O +( O +CTG O +) O +n O +- O +repeat O +expansion O +in O +a O +gene O +encoding O +a O +protein O +kinase O +( O +DM B +protein O +kinase O +; O +DMPK O +) O +and O +involves O +changes O +in O +cytoarchitecture O +and O +ion O +homeostasis O +. O + +To O +obtain O +clues O +to O +the O +normal O +biological O +role O +of O +DMPK O +in O +cellular O +ion O +homeostasis O +, O +we O +have O +compared O +the O +resting O +[ O +Ca2 O ++ O +] O +i O +, O +the O +amplitude O +and O +shape O +of O +depolarization O +- O +induced O +Ca2 O ++ O +transients O +, O +and O +the O +content O +of O +ATP O +- O +driven O +ion O +pumps O +in O +cultured O +skeletal O +muscle O +cells O +of O +wild O +- O +type O +and O +DMPK O +[ O +- O +/ O +- O +] O +knockout O +mice O +. O + +In O +vitro O +- O +differentiated O +DMPK O +[ O +- O +/ O +- O +] O +myotubes O +exhibit O +a O +higher O +resting O +[ O +Ca2 O ++ O +] O +i O +than O +do O +wild O +- O +type O +myotubes O +because O +of O +an O +altered O +open O +probability O +of O +voltage O +- O +dependent O +l O +- O +type O +Ca2 O ++ O +and O +Na O ++ O +channels O +. O + +The O +mutant O +myotubes O +exhibit O +smaller O +and O +slower O +Ca2 O ++ O +responses O +upon O +triggering O +by O +acetylcholine O +or O +high O +external O +K O ++ O +. O + +In O +addition O +, O +we O +observed O +that O +these O +Ca2 O ++ O +transients O +partially O +result O +from O +an O +influx O +of O +extracellular O +Ca2 O ++ O +through O +the O +l O +- O +type O +Ca2 O ++ O +channel O +. O + +Neither O +the O +content O +nor O +the O +activity O +of O +Na O ++ O +/ O +K O ++ O +ATPase O +and O +sarcoplasmic O +reticulum O +Ca2 O ++ O +- O +ATPase O +are O +affected O +by O +DMPK O +absence O +. O + +In O +conclusion O +, O +our O +data O +suggest O +that O +DMPK O +is O +involved O +in O +modulating O +the O +initial O +events O +of O +excitation O +- O +contraction O +coupling O +in O +skeletal O +muscle O +. O +. O + +Constitutional O +RB1 O +- O +gene O +mutations O +in O +patients O +with O +isolated B +unilateral I +retinoblastoma I +. O + +In O +most O +patients O +with O +isolated B +unilateral I +retinoblastoma I +, O +tumor B +development O +is O +initiated O +by O +somatic O +inactivation O +of O +both O +alleles O +of O +the O +RB1 O +gene O +. O + +However O +, O +some O +of O +these O +patients O +can O +transmit O +retinoblastoma B +predisposition O +to O +their O +offspring O +. O + +To O +determine O +the O +frequency O +and O +nature O +of O +constitutional O +RB1 O +- O +gene O +mutations O +in O +patients O +with O +isolated B +unilateral I +retinoblastoma I +, O +we O +analyzed O +DNA O +from O +peripheral O +blood O +and O +from O +tumor B +tissue O +. O + +The O +analysis O +of O +tumors B +from O +54 O +( O +71 O +% O +) O +of O +76 O +informative O +patients O +showed O +loss O +of O +constitutional O +heterozygosity O +( O +LOH O +) O +at O +intragenic O +loci O +. O + +Three O +of O +13 O +uninformative O +patients O +had O +constitutional O +deletions O +. O + +For O +39 O +randomly O +selected O +tumors B +, O +SSCP O +, O +hetero O +- O +duplex O +analysis O +, O +sequencing O +, O +and O +Southern O +blot O +analysis O +were O +used O +to O +identify O +mutations O +. O + +Mutations O +were O +detected O +in O +21 O +( O +91 O +% O +) O +of O +23 O +tumors B +with O +LOH B +. O + +In O +6 O +( O +38 O +% O +) O +of O +16 O +tumors B +without O +LOH B +, O +one O +mutation O +was O +detected O +, O +and O +in O +9 O +( O +56 O +% O +) O +of O +the O +tumors B +without O +LOH B +, O +both O +mutations O +were O +found O +. O + +Thus O +, O +a O +total O +of O +45 O +mutations O +were O +identified O +in O +tumors B +of O +36 O +patients O +. O + +Thirty O +- O +nine O +of O +the O +mutations O +- O +including O +34 O +small O +mutations O +, O +2 O +large O +structural O +alterations O +, O +and O +hypermethylation O +in O +3 O +tumors B +- O +were O +not O +detected O +in O +the O +corresponding O +peripheral O +blood O +DNA O +. O + +In O +6 O +( O +17 O +% O +) O +of O +the O +36 O +patients O +, O +a O +mutation O +was O +detected O +in O +constitutional O +DNA O +, O +and O +1 O +of O +these O +mutations O +is O +known O +to O +be O +associated O +with O +reduced O +expressivity O +. O + +The O +presence O +of O +a O +constitutional O +mutation O +was O +not O +associated O +with O +an O +early O +age O +at O +treatment O +. O + +In O +1 O +patient O +, O +somatic O +mosaicism O +was O +demonstrated O +by O +molecular O +analysis O +of O +DNA O +and O +RNA O +from O +peripheral O +blood O +. O + +In O +2 O +patients O +without O +a O +detectable O +mutation O +in O +peripheral O +blood O +, O +mosaicism O +was O +suggested O +because O +1 O +of O +the O +patients O +showed O +multifocal B +tumors I +and O +the O +other O +later O +developed O +bilateral B +retinoblastoma I +. O + +In O +conclusion O +, O +our O +results O +emphasize O +that O +the O +manifestation O +and O +transmissibility O +of O +retinoblastoma B +depend O +on O +the O +nature O +of O +the O +first O +mutation O +, O +its O +time O +in O +development O +, O +and O +the O +number O +and O +types O +of O +cells O +that O +are O +affected O +. O +. O + +Hereditary O +deficiency B +of I +the I +fifth I +component I +of I +complement I +in O +man O +. O + +I O +. O + +Clinical O +, O +immunochemical O +, O +and O +family O +studies O +. O + +The O +first O +recognized O +human O +kindred O +with O +hereditary B +deficiency B +of I +the I +fifth I +component I +of I +complement I +( O +C5 O +) O +is O +described O +. O + +The O +proband O +, O +a O +20 O +- O +year O +- O +old O +black O +female O +with O +systemic B +lupus I +erythematosus I +since O +age O +11 O +, O +lacked O +serum O +hemolytic O +complement O +activity O +, O +even O +during O +remission O +. O + +C5 O +was O +undetectable O +in O +her O +serum O +by O +both O +immunodiffusion O +and O +hemolytic O +assays O +. O + +Other O +complement O +components O +were O +normal O +during O +remission O +of O +lupus B +, O +but O +C1 O +, O +C4 O +, O +C2 O +, O +and O +C3 O +levels O +fell O +during O +exacerbations O +. O + +A O +younger O +half O +- O +sister O +, O +who O +had O +no O +underlying O +disease O +, O +was O +also O +found O +to O +lack O +immunochemically O +detectable O +C5 O +. O + +By O +hemolytic O +assay O +, O +she O +exhibited O +1 O +- O +2 O +% O +of O +the O +normal O +serum O +C5 O +level O +and O +normal O +concentrations O +of O +other O +complement O +components O +. O + +C5 O +levels O +of O +other O +family O +members O +were O +either O +normal O +or O +approximately O +half O +- O +normal O +, O +consistent O +with O +autosomal O +codominant O +inheritance O +of O +the O +gene O +determining O +C5 B +deficiency I +. O + +Normal O +hemolytic O +titers O +were O +restored O +to O +both O +homozygous O +C5 B +- I +deficient I +( O +C5D B +) O +sera O +by O +addition O +of O +highly O +purified O +human O +C5 O +. O + +In O +specific O +C5 O +titrations O +, O +however O +, O +it O +was O +noted O +that O +when O +limited O +amounts O +of O +C5 O +were O +assayed O +in O +the O +presence O +of O +low O +dilutions O +of O +either O +C5D B +serum O +, O +curving O +rather O +than O +linear O +dose O +- O +response O +plots O +were O +consistently O +obtained O +, O +suggesting O +some O +inhibitory O +effect O +. O + +Further O +studies O +suggested O +that O +low O +dilutions O +of O +C5D B +serum O +contain O +a O +factor O +( O +or O +factors O +) O +interfering O +at O +some O +step O +in O +the O +hemolytic O +assay O +of O +C5 O +, O +rather O +than O +a O +true O +C5 O +inhibitor O +or O +inactivator O +. O + +Of O +clinical O +interest O +are O +( O +a O +) O +the O +documentation O +of O +membranous B +glomerulonephritis I +, O +vasculitis B +, O +and O +arthritis B +in O +an O +individual O +lacking O +C5 O +( O +and O +its O +biologic O +functions O +) O +, O +and O +( O +b O +) O +a O +remarkable O +propensity O +to O +bacterial B +infections I +in O +the O +proband O +, O +even O +during O +periods O +of O +low O +- O +dose O +or O +alternate O +- O +day O +corticosteroid O +therapy O +. O + +Other O +observations O +indicate O +that O +the O +C5D B +state O +is O +compatible O +with O +normal O +coagulation O +function O +and O +the O +capacity O +to O +mount O +a O +neutrophilic B +leukocytosis I +during O +pyogenic B +infection I +. O +. O + +Susceptibility O +to O +ankylosing B +spondylitis I +in O +twins O +: O +the O +role O +of O +genes O +, O +HLA O +, O +and O +the O +environment O +. O + +OBJECTIVE O +To O +determine O +the O +relative O +effects O +of O +genetic O +and O +environmental O +factors O +in O +susceptibility O +to O +ankylosing B +spondylitis I +( O +AS B +) O +. O + +METHODS O +Twins O +with O +AS B +were O +identified O +from O +the O +Royal O +National O +Hospital O +for O +Rheumatic B +Diseases I +database O +. O + +Clinical O +and O +radiographic O +examinations O +were O +performed O +to O +establish O +diagnoses O +, O +and O +disease O +severity O +was O +assessed O +using O +a O +combination O +of O +validated O +scoring O +systems O +. O + +HLA O +typing O +for O +HLA O +- O +B27 O +, O +HLA O +- O +B60 O +, O +and O +HLA O +- O +DR1 O +was O +performed O +by O +polymerase O +chain O +reaction O +with O +sequence O +- O +specific O +primers O +, O +and O +zygosity O +was O +assessed O +using O +microsatellite O +markers O +. O + +Genetic O +and O +environmental O +variance O +components O +were O +assessed O +with O +the O +program O +Mx O +, O +using O +data O +from O +this O +and O +previous O +studies O +of O +twins O +with O +AS B +. O + +RESULTS O +Six O +of O +8 O +monozygotic O +( O +MZ O +) O +twin O +pairs O +were O +disease O +concordant O +, O +compared O +with O +4 O +of O +15 O +B27 O +- O +positive O +dizygotic O +( O +DZ O +) O +twin O +pairs O +( O +27 O +% O +) O +and O +4 O +of O +32 O +DZ O +twin O +pairs O +overall O +( O +12 O +. O +5 O +% O +) O +. O + +Nonsignificant O +increases O +in O +similarity O +with O +regard O +to O +age O +at O +disease O +onset O +and O +all O +of O +the O +disease O +severity O +scores O +assessed O +were O +noted O +in O +disease O +- O +concordant O +MZ O +twins O +compared O +with O +concordant O +DZ O +twins O +. O + +HLA O +- O +B27 O +and O +B60 O +were O +associated O +with O +the O +disease O +in O +probands O +, O +and O +the O +rate O +of O +disease O +concordance O +was O +significantly O +increased O +among O +DZ O +twin O +pairs O +in O +which O +the O +co O +- O +twin O +was O +positive O +for O +both O +B27 O +and O +DR1 O +. O + +Additive O +genetic O +effects O +were O +estimated O +to O +contribute O +97 O +% O +of O +the O +population O +variance O +. O + +CONCLUSION O +Susceptibility O +to O +AS B +is O +largely O +genetically O +determined O +, O +and O +the O +environmental O +trigger O +for O +the O +disease O +is O +probably O +ubiquitous O +. O + +HLA O +- O +B27 O +accounts O +for O +a O +minority O +of O +the O +overall O +genetic O +susceptibility O +to O +AS B +. O + +Cell O +cycle O +- O +dependent O +colocalization O +of O +BARD1 O +and O +BRCA1 O +proteins O +in O +discrete O +nuclear O +domains O +. O + +Germ O +- O +line O +mutations O +of O +the O +BRCA1 O +gene O +predispose O +women O +to O +early O +- O +onset O +breast B +and I +ovarian I +cancer I +by O +compromising O +the O +genes O +presumptive O +function O +as O +a O +tumor B +suppressor O +. O + +Although O +the O +biochemical O +properties O +of O +BRCA1 O +polypeptides O +are O +not O +understood O +, O +their O +expression O +pattern O +and O +subcellular O +localization O +suggest O +a O +role O +in O +cell O +- O +cycle O +regulation O +. O + +When O +resting O +cells O +are O +induced O +to O +proliferate O +, O +the O +steady O +- O +state O +levels O +of O +BRCA1 O +increase O +in O +late O +G1 O +and O +reach O +a O +maximum O +during O +S O +phase O +. O + +Moreover O +, O +in O +S O +phase O +cells O +, O +BRCA1 O +polypeptides O +are O +hyperphosphorylated O +and O +accumulate O +into O +discrete O +subnuclear O +foci O +termed O +" O +BRCA1 O +nuclear O +dots O +. O + +" O +BRCA1 O +associates O +in O +vivo O +with O +a O +structurally O +related O +protein O +termed O +BARD1 O +. O + +Here O +we O +show O +that O +the O +steady O +- O +state O +levels O +of O +BARD1 O +, O +unlike O +those O +of O +BRCA1 O +, O +remain O +relatively O +constant O +during O +cell O +cycle O +progression O +. O + +However O +, O +immunostaining O +revealed O +that O +BARD1 O +resides O +within O +BRCA1 O +nuclear O +dots O +during O +S O +phase O +of O +the O +cell O +cycle O +, O +but O +not O +during O +the O +G1 O +phase O +. O + +Nevertheless O +, O +BARD1 O +polypeptides O +are O +found O +exclusively O +in O +the O +nuclear O +fractions O +of O +both O +G1 O +- O +and O +S O +- O +phase O +cells O +. O + +Therefore O +, O +progression O +to O +S O +phase O +is O +accompanied O +by O +the O +aggregation O +of O +nuclear O +BARD1 O +polypeptides O +into O +BRCA1 O +nuclear O +dots O +. O + +This O +cell O +cycle O +- O +dependent O +colocalization O +of O +BARD1 O +and O +BRCA1 O +indicates O +a O +role O +for O +BARD1 O +in O +BRCA1 O +- O +mediated O +tumor B +suppression O +. O + +Ethnic O +differences O +in O +the O +HFE O +codon O +282 O +( O +Cys O +/ O +Tyr O +) O +polymorphism O +. O + +Recent O +studies O +have O +shown O +that O +hereditary B +hemochromatosis I +( O +HH B +) O +is O +likely O +to O +be O +caused O +by O +homozygosity O +for O +a O +Cys282Tyr O +mutation O +in O +the O +HFE O +gene O +located O +4 O +. O + +5 O +Mb O +telomeric O +to O +HLA O +- O +A O +. O + +Population O +studies O +of O +this O +polymorphism O +are O +facilitated O +by O +the O +fact O +that O +the O +Cys282Tyr O +mutation O +creates O +a O +Rsal O +restriction O +site O +. O + +We O +have O +studied O +the O +codon O +282 O +( O +Cys O +/ O +Tyr O +) O +polymorphism O +in O +different O +ethnic O +groups O +. O + +In O +agreement O +with O +previous O +observations O +the O +Tyr O +allele O +appeared O +to O +be O +rare O +or O +absent O +in O +Asiatic O +( O +Indian O +, O +Chinese O +) O +populations O +. O + +The O +highest O +allele O +frequency O +( O +7 O +. O +5 O +% O +) O +was O +found O +in O +Swedes O +. O + +Saamis O +( O +2 O +% O +) O +and O +Mordvinians O +( O +1 O +. O +8 O +% O +) O +had O +significantly O +lower O +frequencies O +of O +the O +Tyr O +allele O +. O + +Comparisons O +with O +allele O +frequencies O +based O +on O +prevalence O +estimates O +of O +HH B +showed O +some O +disagreements O +with O +the O +RFLP O +data O +, O +particularly O +in O +Finns O +. O + +The O +newly O +described O +HFE O +marker O +provides O +a O +new O +approach O +to O +the O +screening O +of O +HH B +as O +well O +as O +studies O +of O +the O +relationship O +between O +the O +HFE O +Tyr O +allele O +and O +different O +disorders O +including O +cancer B + +Autosomal B +dominant I +neurohypophyseal I +diabetes I +insipidus I +associated O +with O +a O +missense O +mutation O +encoding O +Gly23 O +- O +- O +> O +Val O +in O +neurophysin O +II O +. O + +Autosomal B +dominant I +neurohypophyseal I +diabetes I +insipidus I +( O +ADNDI B +) O +is O +an O +inherited B +disease I +caused O +by O +progressive O +degeneration O +of O +the O +magnocellular O +neurons O +of O +the O +hypothalamus O +leading O +to O +decreased O +ability O +to O +produce O +the O +hormone O +arginine O +vasopressin O +( O +AVP O +) O +. O + +Affected O +individuals O +are O +not O +symptomatic O +at O +birth O +, O +but O +usually O +develop O +diabetes B +insipidus I +at O +1 O +- O +6 O +yr O +of O +age O +. O + +The O +genetic O +locus O +of O +the O +disease O +is O +the O +AVP O +- O +neurophysin O +II O +( O +NPII O +) O +gene O +, O +and O +mutations O +that O +cause O +ADNDI B +have O +been O +found O +in O +both O +the O +signal O +peptide O +of O +the O +prepro O +- O +AVP O +- O +NPII O +precursor O +and O +within O +NPII O +itself O +. O + +An O +affected O +girl O +who O +presented O +at O +9 O +months O +of O +age O +and O +her O +similarly O +affected O +younger O +brother O +and O +father O +were O +all O +found O +to O +have O +a O +novel O +missense O +mutation O +( O +G1758 O +- O +- O +> O +T O +) O +encoding O +the O +amino O +acid O +substitution O +Gly23 O +- O +- O +> O +Val O +within O +NPII O +. O + +The O +mutation O +was O +confirmed O +by O +restriction O +endonuclease O +analysis O +. O + +A O +T1 O +- O +weighted O +magnetic O +resonance O +imaging O +of O +the O +fathers O +pituitary O +gland O +demonstrates O +an O +attenuated O +posterior O +pituitary O +bright O +spot O +. O + +This O +mutation O +may O +be O +valuable O +for O +developing O +models O +of O +dominantly O +inherited I +neurodegeneration I +, O +as O +the O +early O +age O +of O +onset O +of O +symptoms O +suggests O +that O +this O +mutation O +may O +be O +particularly O +deleterious O +to O +the O +magnocellular O +neuron O +. O +. O + +Frequent O +inactivation O +of O +PTEN O +/ O +MMAC1 O +in O +primary B +prostate I +cancer I +. O + +Sporadic B +prostate I +carcinoma I +is O +the O +most O +common O +male B +cancer I +in O +the O +Western O +world O +, O +yet O +many O +of O +the O +major O +genetic O +events O +involved O +in O +the O +progression O +of O +this O +often O +fatal O +cancer B +remain O +to O +be O +elucidated O +. O + +Numerous O +cytogenetic O +and O +allelotype O +studies O +have O +reported O +frequent O +loss O +of O +heterozygosity O +on O +chromosomal O +arm O +10q O +in O +sporadic B +prostate I +cancer I +. O + +Deletion O +mapping O +studies O +have O +unambiguously O +identified O +a O +region O +of O +chromosome O +10q23 O +to O +be O +the O +minimal O +area O +of O +loss O +. O + +A O +new O +tumor B +suppressor O +gene O +, O +PTEN O +/ O +MMAC1 O +, O +was O +isolated O +recently O +at O +this O +region O +of O +chromosome O +10q23 O +and O +found O +to O +be O +inactivated O +by O +mutation O +in O +three O +prostate B +cancer I +cell O +lines O +. O + +We O +screened O +80 O +prostate B +tumors I +by O +microsatellite O +analysis O +and O +found O +chromosome O +10q23 O +to O +be O +deleted O +in O +23 O +cases O +. O + +We O +then O +proceeded O +with O +sequence O +analysis O +of O +the O +entire O +PTEN O +/ O +MMAC1 O +coding O +region O +and O +tested O +for O +homozygous O +deletion O +with O +new O +intragenic O +markers O +in O +these O +23 O +cases O +with O +10q23 O +loss O +of O +heterozygosity O +. O + +The O +identification O +of O +the O +second O +mutational O +event O +in O +10 O +( O +43 O +% O +) O +tumors B +establishes O +PTEN O +/ O +MMAC1 O +as O +a O +main O +inactivation O +target O +of O +10q O +loss O +in O +sporadic B +prostate I +cancer I +. O +. O + +Risk O +reversals O +in O +predictive O +testing O +for O +Huntington B +disease I +. O + +The O +first O +predictive O +testing O +for O +Huntington B +disease I +( O +HD B +) O +was O +based O +on O +analysis O +of O +linked O +polymorphic O +DNA O +markers O +to O +estimate O +the O +likelihood O +of O +inheriting O +the O +mutation O +for O +HD B +. O + +Limits O +to O +accuracy O +included O +recombination O +between O +the O +DNA O +markers O +and O +the O +mutation O +, O +pedigree O +structure O +, O +and O +whether O +DNA O +samples O +were O +available O +from O +family O +members O +. O + +With O +direct O +tests O +for O +the O +HD B +mutation O +, O +we O +have O +assessed O +the O +accuracy O +of O +results O +obtained O +by O +linkage O +approaches O +when O +requested O +to O +do O +so O +by O +the O +test O +individuals O +. O + +For O +six O +such O +individuals O +, O +there O +was O +significant O +disparity O +between O +the O +tests O +. O + +Three O +went O +from O +a O +decreased O +risk O +to O +an O +increased O +risk O +, O +while O +in O +another O +three O +the O +risk O +was O +decreased O +. O + +Knowledge O +of O +the O +potential O +reasons O +for O +these O +changes O +in O +results O +and O +impact O +of O +these O +risk O +reversals O +on O +both O +patients O +and O +the O +counseling O +team O +can O +assist O +in O +the O +development O +of O +strategies O +for O +the O +prevention O +and O +, O +where O +necessary O +, O +management O +of O +a O +risk O +reversal O +in O +any O +predictive O +testing O +program O +. O +. O + +A O +novel O +common O +missense O +mutation O +G301C O +in O +the O +N O +- O +acetylgalactosamine O +- O +6 O +- O +sulfate O +sulfatase O +gene O +in O +mucopolysaccharidosis B +IVA I +. O + +Mucopolysaccharidosis B +IVA I +( O +MPS B +IVA I +) O +is O +an O +autosomal B +recessive I +lysosomal I +storage I +disorder I +caused O +by O +a O +genetic B +defect I +in I +N I +- I +acetylgalactosamine I +- I +6 I +- I +sulfate I +sulfatase I +( O +GALNS O +) O +. O + +In O +previous O +studies O +, O +we O +have O +found O +two O +common O +mutations O +in O +Caucasians O +and O +Japanese O +, O +respectively O +. O + +To O +characterize O +the O +mutational O +spectrum O +in O +various O +ethnic O +groups O +, O +mutations O +in O +the O +GALNS O +gene O +in O +Colombian O +MPS B +IVA I +patients O +were O +investigated O +, O +and O +genetic O +backgrounds O +were O +extensively O +analyzed O +to O +identify O +racial O +origin O +, O +based O +on O +mitochondrial O +DNA O +( O +mtDNA O +) O +lineages O +. O + +Three O +novel O +missense O +mutations O +never O +identified O +previously O +in O +other O +populations O +and O +found O +in O +16 O +out O +of O +19 O +Colombian O +MPS B +IVA I +unrelated O +alleles O +account O +for O +84 O +. O + +2 O +% O +of O +the O +alleles O +in O +this O +study O +. O + +The O +G301C O +and O +S162F O +mutations O +account O +for O +68 O +. O + +4 O +% O +and O +10 O +. O + +5 O +% O +of O +mutations O +, O +respectively O +, O +whereas O +the O +remaining O +F69V O +is O +limited O +to O +a O +single O +allele O +. O + +The O +skewed O +prevalence O +of O +G301C O +in O +only O +Colombian O +patients O +and O +haplotype O +analysis O +by O +restriction O +fragment O +length O +polymorphisms O +in O +the O +GALNS O +gene O +suggest O +that O +G301C O +originated O +from O +a O +common O +ancestor O +. O + +Investigation O +of O +the O +genetic O +background O +by O +means O +of O +mtDNA O +lineages O +indicate O +that O +all O +our O +patients O +are O +probably O +of O +native O +American O +descent O + +Low O +frequency O +of O +BRCA1 O +germline O +mutations O +in O +45 O +German O +breast B +/ I +ovarian I +cancer I +families O +. O + +In O +this O +study O +we O +investigated O +45 O +German O +breast B +/ I +ovarian I +cancer I +families O +for O +germline O +mutations O +in O +the O +BRCA1 O +gene O +. O + +We O +identified O +four O +germline O +mutations O +in O +three O +breast B +cancer I +families O +and O +in O +one O +breast B +- I +ovarian I +cancer I +family O +. O +among O +these O +were O +one O +frameshift O +mutation O +, O +one O +nonsense O +mutation O +, O +one O +novel O +splice O +site O +mutation O +, O +and O +one O +missense O +mutation O +. O + +The O +missense O +mutation O +was O +also O +found O +in O +2 O +. O + +8 O +% O +of O +the O +general O +population O +, O +suggesting O +that O +it O +is O +not O +disease O +associated O +. O + +The O +average O +age O +of O +disease O +onset O +in O +those O +families O +harbouring O +causative O +mutations O +was O +between O +32 O +. O + +3 O +and O +37 O +. O + +4 O +years O +, O +whereas O +the O +family O +harbouring O +the O +missense O +mutation O +had O +an O +average O +age O +of O +onset O +of O +51 O +. O + +2 O +years O +. O + +These O +findings O +show O +that O +BRCA1 O +is O +implicated O +in O +a O +small O +fraction O +of O +breast B +/ I +ovarian I +cancer I +families O +suggesting O +the O +involvement O +of O +another O +susceptibility O +gene O +( O +s O +) O + +Paternal O +transmission O +of O +congenital B +myotonic I +dystrophy I +. O + +We O +report O +a O +rare O +case O +of O +paternally O +transmitted O +congenital B +myotonic I +dystrophy I +( O +DM B +) O +. O + +The O +proband O +is O +a O +23 O +year O +old O +, O +mentally B +retarded I +male O +who O +suffers O +severe O +muscular B +weakness I +. O + +He O +presented O +with O +respiratory O +and O +feeding O +difficulties O +at O +birth O +. O + +His O +two O +sibs O +suffer O +from O +childhood O +onset O +DM B +. O + +Their O +late O +father O +had O +the O +adult O +type O +of O +DM B +, O +with O +onset O +around O +30 O +years O +. O + +Only O +six O +other O +cases O +of O +paternal O +transmission O +of O +congenital O +DM B +have O +been O +reported O +recently O +. O + +We O +review O +the O +sex O +related O +effects O +on O +transmission O +of O +congenital O +DM B +. O + +Decreased O +fertility O +of O +males O +with O +adult O +onset O +DM B +and O +contraction O +of O +the O +repeat O +upon O +male O +transmission O +contribute O +to O +the O +almost O +absent O +occurrence O +of O +paternal O +transmission O +of O +congenital O +DM B +. O + +Also O +the O +fathers O +of O +the O +reported O +congenitally O +affected O +children O +showed O +, O +on O +average O +, O +shorter O +CTG O +repeat O +lengths O +and O +hence O +less O +severe O +clinical O +symptoms O +than O +the O +mothers O +of O +children O +with O +congenital B +DM B +. O + +We O +conclude O +that O +paternal O +transmission O +of O +congenital O +DM B +is O +rare O +and O +preferentially O +occurs O +with O +onset O +of O +DM B +past O +30 O +years O +in O +the O +father O +. O +. O + +The O +RB1 O +gene O +mutation O +in O +a O +child O +with O +ectopic B +intracranial I +retinoblastoma I +. O + +The O +RB1 O +gene O +mutation O +was O +investigated O +in O +a O +child O +with O +ectopic B +intracranial I +retinoblastoma I +using O +DNA O +obtained O +from O +both O +the O +pineal B +and I +retinal I +tumours I +of O +the O +patient O +. O + +A O +nonsense O +mutation O +in O +exon O +17 O +( O +codon O +556 O +) O +of O +the O +RB1 O +gene O +was O +found O +to O +be O +present O +homozygously O +in O +both O +the O +retinal B +and I +the I +pineal I +tumours I +. O + +The O +same O +mutation O +was O +present O +heterozygously O +in O +the O +DNA O +from O +the O +constitutional O +cells O +of O +the O +patient O +, O +proving O +it O +to O +be O +of O +germline O +origin O +. O + +The O +initial O +mutation O +was O +shown O +to O +have O +occurred O +in O +the O +paternally O +derived O +RB1 O +allele O +. O + +The O +mutation O +is O +in O +an O +area O +of O +the O +gene O +that O +encodes O +the O +protein O +- O +binding O +region O +known O +as O +the O +pocket O +region O +and O +has O +been O +detected O +in O +other O +cases O +of O +retinoblastoma B +. O +. O + +Low O +levels O +of O +beta O +hexosaminidase O +A O +in O +healthy O +individuals O +with O +apparent O +deficiency O +of O +this O +enzyme O +. O + +Appreciable O +beta O +hexosaminidase O +A O +( O +hex O +A O +) O +activity O +has O +been O +detected O +in O +cultured O +skin O +fibroblasts O +and O +melanoma B +tissue O +from O +healthy O +individuals O +previously O +reported O +as O +having O +deficiency B +of I +hex I +A I +activity I +indistinguishable O +from O +that O +of O +patients O +with O +Tay B +- I +Sachs I +disease I +( O +TSD B +) O +. O + +Identification O +and O +quantitation O +of O +hex O +A O +, O +amounting O +to O +3 O +. O + +5 O +% O +- O +6 O +. O + +9 O +% O +of O +total O +beta O +hexosaminidase O +activity O +, O +has O +been O +obtained O +by O +cellulose O +acetate O +gel O +electrophoresis O +, O +DEAE O +- O +cellulose O +ion O +- O +exchange O +chromatography O +, O +radial O +immunodiffusion O +, O +and O +radioimmunoassay O +. O + +Previous O +family O +studies O +suggested O +that O +these O +individuals O +may O +be O +compound O +heterozygotes O +for O +the O +common O +mutant O +TSD B +gene O +and O +a O +rare O +( O +allelic O +) O +mutant O +gene O +. O + +Thus O +, O +the O +postulated O +rate O +mutant O +gene O +appears O +to O +code O +for O +the O +expression O +of O +low O +amounts O +of O +hex O +A O +. O + +Heterozygotes O +for O +the O +rare O +mutant O +may O +be O +indistinguishable O +from O +heterozygotes O +for O +the O +common O +TSD B +mutant O +. O + +However O +, O +direct O +visualization O +and O +quantitation O +of O +hex O +A O +by O +the O +methods O +described O +may O +prevent O +false O +- O +positive O +prenatal O +diagnosis O +of O +TSD B +in O +fetuses O +having O +the O +incomplete O +hex B +A I +deficiency I +of I +the I +type I +described O +in O +the O +four O +healthy O +individuals O + +The O +tumor B +suppressor O +gene O +Smad4 O +/ O +Dpc4 O +is O +required O +for O +gastrulation O +and O +later O +for O +anterior O +development O +of O +the O +mouse O +embryo O +. O + +Mutations O +in O +the O +SMAD4 O +/ O +DPC4 O +tumor B +suppressor O +gene O +, O +a O +key O +signal O +transducer O +in O +most O +TGFbeta O +- O +related O +pathways O +, O +are O +involved O +in O +50 O +% O +of O +pancreatic B +cancers I +. O + +Homozygous O +Smad4 O +mutant O +mice O +die O +before O +day O +7 O +. O + +5 O +of O +embryogenesis O +. O + +Mutant O +embryos O +have O +reduced O +size O +, O +fail O +to O +gastrulate O +or O +express O +a O +mesodermal O +marker O +, O +and O +show O +abnormal O +visceral O +endoderm O +development O +. O + +Growth B +retardation I +of O +the O +Smad4 O +- O +deficient O +embryos O +results O +from O +reduced O +cell O +proliferation O +rather O +than O +increased O +apoptosis O +. O + +Aggregation O +of O +mutant O +Smad4 O +ES O +cells O +with O +wild O +- O +type O +tetraploid O +morulae O +rescues O +the O +gastrulation O +defect O +. O + +These O +results O +indicate O +that O +Smad4 O +is O +initially O +required O +for O +the O +differentiation O +of O +the O +visceral O +endoderm O +and O +that O +the O +gastrulation O +defect O +in O +the O +epiblast O +is O +secondary O +and O +non O +- O +cell O +autonomous O +. O + +Rescued O +embryos O +show O +severe O +anterior O +truncations O +, O +indicating O +a O +second O +important O +role O +for O +Smad4 O +in O +anterior O +patterning O +during O +embryogenesis O +. O + +Prevalence O +of O +p16 O +and O +CDK4 O +germline O +mutations O +in O +48 O +melanoma B +- O +prone O +families O +in O +France O +. O + +The O +French O +Familial O +Melanoma I +Study O +Group O +. O + +Germline O +mutations O +in O +the O +p16 O +and O +CDK4 O +genes O +have O +been O +reported O +in O +a O +subset O +of O +melanoma B +pedigrees O +, O +but O +their O +prevalence O +is O +not O +well O +known O +. O + +We O +searched O +for O +such O +germline O +mutations O +in O +48 O +French O +melanoma B +- O +prone O +families O +selected O +according O +to O +two O +major O +criteria O +families O +with O +at O +least O +three O +affected O +members O +( O +n O += O +20 O +) O +or O +families O +with O +two O +affected O +members O +, O +one O +of O +them O +affected O +before O +the O +age O +of O +50 O +( O +n O += O +28 O +) O +, O +and O +one O +additional O +minor O +criterion O +. O + +Sixteen O +different O +p16 O +germline O +mutations O +were O +found O +in O +21 O +families O +, O +while O +one O +germline O +mutation O +, O +Arg24His O +, O +was O +detected O +in O +the O +CDK4 O +gene O +. O + +The O +frequency O +of O +p16 O +gene O +mutation O +in O +our O +sample O +( O +44 O +% O +) O +is O +among O +the O +highest O +rates O +yet O +reported O +and O +the O +CDK4 O +mutation O +is O +the O +second O +mutation O +detected O +in O +this O +gene O +worldwide O +. O + +In O +summary O +, O +our O +results O +show O +frequent O +involvement O +of O +the O +p16 O +gene O +in O +familial B +melanoma I +and O +confirm O +the O +role O +of O +the O +CDK4 O +gene O +as O +a O +melanoma B +- O +predisposing O +gene O +. O +. O + +Progression O +of O +somatic O +CTG O +repeat O +length O +heterogeneity O +in O +the O +blood O +cells O +of O +myotonic B +dystrophy I +patients O +. O + +The O +genetic O +basis O +of O +myotonic B +dystrophy I +( O +DM B +) O +is O +the O +expansion O +of O +an O +unstable O +CTG O +repeat O +in O +the O +34 O +UTR O +of O +the O +DM B +protein O +kinase O +gene O +on O +chromosome O +19 O +. O + +One O +of O +the O +principal O +features O +of O +the O +DM B +mutation O +is O +an O +extraordinarily O +high O +level O +of O +somatic O +mosaicism O +, O +due O +to O +an O +extremely O +high O +degree O +of O +somatic O +instability O +both O +within O +and O +between O +different O +tissues O +. O + +This O +instability O +appears O +to O +be O +biased O +towards O +further O +expansion O +and O +continuous O +throughout O +the O +life O +of O +an O +individual O +, O +features O +that O +could O +be O +associated O +with O +the O +progressive O +nature O +of O +the O +disease O +. O + +Although O +increasing O +measured O +allele O +size O +between O +patients O +clearly O +correlates O +with O +an O +increased O +severity O +of O +symptoms O +and O +an O +earlier O +age O +of O +onset O +, O +this O +correlation O +is O +not O +precise O +and O +measured O +allele O +length O +cannot O +be O +used O +as O +an O +accurate O +predictor O +of O +age O +of O +onset O +. O + +In O +order O +to O +further O +characterize O +the O +dynamics O +of O +DM B +CTG O +repeat O +somatic O +instability O +, O +we O +have O +studied O +repeat O +length O +changes O +over O +time O +in O +111 O +myotonic B +dystrophy I +patients O +with O +varying O +clinical O +severity O +and O +CTG O +repeat O +size O +over O +time O +intervals O +of O +1 O +- O +7 O +years O +. O + +We O +have O +found O +a O +direct O +progression O +of O +the O +size O +heterogeneity O +over O +time O +related O +to O +initial O +CTG O +repeat O +size O +and O +the O +time O +interval O +and O +always O +biased O +towards O +further O +expansion O +. O + +Attempts O +to O +mathematically O +model O +the O +dynamics O +have O +proved O +only O +partially O +successful O +suggesting O +that O +individual O +specific O +genetic O +and O +/ O +or O +environmental O +factors O +also O +play O +a O +role O +in O +somatic O +mosaicism O +. O +. O + +Aspartylglucosaminuria B +among O +Palestinian O +Arabs O +. O + +Aspartylglucosaminuria B +( O +AGU B +) O +is O +a O +rare O +disorder B +of I +glycoprotein I +metabolism I +caused O +by O +the O +deficiency B +of I +the I +lysosomal I +enzyme I +aspartylglucosaminidase I +( O +AGA O +) O +. O + +AGU B +is O +inherited O +as O +an O +autosomal O +recessive O +trait O +and O +occurs O +with O +a O +high O +frequency O +in O +Finland O +because O +of O +a O +founder O +effect O +. O + +While O +very O +few O +patients O +with O +AGU B +have O +been O +reported O +from O +non O +- O +Finnish O +origin O +, O +we O +diagnosed O +the O +disorder O +in O +8 O +patients O +originating O +from O +3 O +unrelated O +families O +, O +all O +Palestinian O +Arabs O +from O +the O +region O +of O +Jerusalem O +. O + +The O +clinical O +diagnosis O +of O +AGU B +is O +often O +difficult O +, O +in O +particular O +early O +in O +the O +course O +of O +the O +disease O +, O +and O +most O +of O +the O +patients O +are O +diagnosed O +after O +the O +age O +of O +5 O +years O +. O + +However O +, O +since O +these O +patients O +excrete O +early O +large O +amounts O +of O +aspartylglucosamine O +in O +urine O +, O +biochemical O +screening O +is O +easy O +by O +urine O +chromatography O +. O +. O + +Detection O +of O +heterozygous O +carriers O +of O +the O +ataxia B +- I +telangiectasia I +( O +ATM O +) O +gene O +by O +G2 O +phase O +chromosomal O +radiosensitivity O +of O +peripheral O +blood O +lymphocytes O +. O + +In O +ataxia B +- I +telangiectasia I +( O +A B +- I +T I +) O +patients O +, O +mutations O +in O +a O +single O +gene O +, O +ATM O +, O +result O +in O +an O +autosomal B +recessive I +syndrome I +that O +embraces O +a O +variety O +of O +clinical O +features O +and O +manifests O +extreme O +radiosensitivity O +and O +a O +strong O +pre O +- O +disposition O +to O +malignancy B +. O + +Heterozygotes O +for O +the O +ATM O +gene O +have O +no O +clinical O +expression O +of O +A B +- I +T I +but O +may O +be O +cancer B +prone O +with O +a O +moderate O +increase O +in O +in O +vitro O +radiosensitivity O +. O + +We O +performed O +a O +blind O +chromosomal O +analysis O +on O +G2 O +- O +phase O +lymphocytes O +from O +7 O +unrelated O +A B +- I +T I +patients O +, O +13 O +obligate O +A B +- I +T I +heterozygotes O +( O +parents O +of O +the O +patients O +) O +, O +and O +14 O +normal O +controls O +following O +X O +- O +irradiation O +with O +1 O +Gy O +in O +order O +to O +evaluate O +this O +cytogenetic O +method O +as O +a O +tool O +for O +detection O +of O +ATM O +carriers O +. O + +Both O +A B +- I +T I +homozygotes O +and O +heterozygotes O +showed O +significantly O +increased O +levels O +of O +radiation O +- O +induced O +chromatid O +damage O +relative O +to O +that O +of O +normal O +controls O +. O + +These O +results O +show O +that O +the O +G2 O +- O +phase O +chromosomal O +radiosensitivity O +assay O +can O +be O +used O +for O +the O +detection O +of O +A B +- I +T I +heterozygotes O +. O + +In O +combination O +with O +molecular O +genetic O +analyses O +, O +this O +test O +may O +be O +of O +value O +in O +studies O +of O +familial B +and I +sporadic I +cancers I +aimed O +at O +determination O +of O +the O +potential O +involvement O +of O +ATM O +mutations O +in O +tumor B +risk O +or O +development O +. O +. O + +Ataxia B +- I +telangiectasia I +: O +identification O +and O +detection O +of O +founder O +- O +effect O +mutations O +in O +the O +ATM O +gene O +in O +ethnic O +populations O +. O + +To O +facilitate O +the O +evaluation O +of O +ATM O +heterozygotes O +for O +susceptibility O +to O +other O +diseases O +, O +such O +as O +breast B +cancer I +, O +we O +have O +attempted O +to O +define O +the O +most O +common O +mutations O +and O +their O +frequencies O +in O +ataxia B +- I +telangiectasia I +( O +A B +- I +T I +) O +homozygotes O +from O +10 O +ethnic O +populations O +. O + +Both O +genomic O +mutations O +and O +their O +effects O +on O +cDNA O +were O +characterized O +. O + +Protein O +- O +truncation O +testing O +of O +the O +entire O +ATM O +cDNA O +detected O +92 O +( O +66 O +% O +) O +truncating O +mutations O +in O +140 O +mutant O +alleles O +screened O +. O + +The O +haplotyping O +of O +patients O +with O +identical O +mutations O +indicates O +that O +almost O +all O +of O +these O +represent O +common O +ancestry O +and O +that O +very O +few O +spontaneously O +recurring O +ATM O +mutations O +exist O +. O + +Assays O +requiring O +minimal O +amounts O +of O +genomic O +DNA O +were O +designed O +to O +allow O +rapid O +screening O +for O +common O +ethnic O +mutations O +. O + +These O +rapid O +assays O +detected O +mutations O +in O +76 O +% O +of O +Costa O +Rican O +patients O +( O +3 O +) O +, O +50 O +% O +of O +Norwegian O +patients O +( O +1 O +) O +, O +25 O +% O +of O +Polish O +patients O +( O +4 O +) O +, O +and O +14 O +% O +of O +Italian O +patients O +( O +1 O +) O +, O +as O +well O +as O +in O +patients O +of O +Amish O +/ O +Mennonite O +and O +Irish O +English O +backgrounds O +. O + +Additional O +mutations O +were O +observed O +in O +Japanese O +, O +Utah O +Mormon O +, O +and O +African O +American O +patients O +. O + +These O +assays O +should O +facilitate O +screening O +for O +A B +- I +T I +heterozygotes O +in O +the O +populations O +studied O +. O +. O + +The O +von B +Hippel I +- I +Lindau I +tumor I +suppressor O +gene O +is O +required O +for O +cell O +cycle O +exit O +upon O +serum O +withdrawal O +. O + +The O +inactivation O +of O +the O +von B +Hippel I +- I +Lindau I +( I +VHL B +) I +tumor I +suppressor O +gene O +predisposes O +affected O +individuals O +to O +the O +human O +VHL B +cancer I +syndrome I +and O +is O +associated O +with O +sporadic B +renal I +cell I +carcinomas I +( O +RCC B +) O +and O +brain B +hemangioblastomas I +. O + +VHL O +- O +negative O +786 O +- O +0 O +RCC O +cells O +are O +tumorigenic O +in O +nude O +mice O +which O +is O +suppressed O +by O +the O +reintroduction O +of O +VHL O +. O + +Remarkably O +, O +this O +occurs O +without O +affecting O +the O +growth O +rate O +and O +cell O +cycle O +profile O +of O +these O +cells O +in O +culture O +. O + +The O +786 O +- O +0 O +cell O +line O +, O +like O +many O +cancer B +cells O +, O +fails O +to O +exit O +the O +cell O +cycle O +upon O +serum O +withdrawal O +. O + +Here O +, O +it O +is O +shown O +that O +reintroduction O +of O +the O +wild O +- O +type O +VHL B +gene O +restores O +the O +ability O +of O +VHL B +- O +negative O +RCC B +cancer I +cells O +to O +exit O +the O +cell O +cycle O +and O +enter O +G0 O +/ O +quiescence O +in O +low O +serum O +. O + +Both O +VHL O +- O +positive O +and O +VHL O +- O +negative O +RCC O +cells O +exit O +the O +cell O +cycle O +by O +contact O +inhibition O +. O + +The O +cyclin O +- O +dependent O +kinase O +inhibitor O +, O +p27 O +, O +accumulates O +upon O +serum O +withdrawal O +, O +only O +in O +the O +presence O +of O +VHL O +, O +as O +a O +result O +of O +the O +stabilization O +of O +the O +protein O +. O + +We O +propose O +that O +the O +loss O +of O +wild O +- O +type O +VHL B +gene O +results O +in O +a O +specific O +cellular O +defect O +in O +serum O +- O +dependent O +growth O +control O +, O +which O +may O +initiate O +tumor B +formation O +. O + +This O +is O +corrected O +by O +the O +reintroduction O +of O +wild O +- O +type O +VHL O +, O +implicating O +VHL O +as O +the O +first O +tumor B +suppressor O +involved O +in O +the O +regulation O +of O +cell O +cycle O +exit O +, O +which O +is O +consistent O +with O +its O +gatekeeper O +function O +in O +the O +kidney O +. O +. O + +Piebaldism B +with O +deafness B +: O +molecular O +evidence O +for O +an O +expanded O +syndrome O +. O + +In O +a O +South O +African O +girl O +of O +Xhosa O +stock O +with O +severe O +piebaldism B +and O +profound O +congenital B +sensorineural I +deafness I +we O +identified O +a O +novel O +missense O +substitution O +at O +a O +highly O +conserved O +residue O +in O +the O +intracellular O +kinase O +domain O +of O +the O +KIT O +proto O +- O +oncogene O +, O +R796G O +. O + +Though O +auditory B +anomalies I +have O +been O +observed O +in O +mice O +with O +dominant O +white O +spotting O +( O +W O +) O +due O +to O +KIT O +mutations O +, O +deafness B +is O +not O +typical O +in O +human O +piebaldism B +. O + +Thus O +, O +the O +occurrence O +of O +sensorineural B +deafness I +in O +this O +patient O +extends O +considerably O +the O +phenotypic O +range O +of O +piebaldism B +due O +to O +KIT O +gene O +mutation O +in O +humans O +and O +tightens O +the O +clinical O +similarity O +between O +piebaldism B +and O +the O +various O +forms O +of O +Waardenburg B +syndrome I +. O +. O + +Cycloheximide O +facilitates O +the O +identification O +of O +aberrant O +transcripts O +resulting O +from O +a O +novel O +splice O +- O +site O +mutation O +in O +COL17A1 O +in O +a O +patient O +with O +generalized O +atrophic B +benign I +epidermolysis I +bullosa I +. O + +Patients O +with O +generalized O +atrophic B +benign I +epidermolysis I +bullosa I +often O +show O +decreased O +expression O +of O +type O +XVII O +collagen O +, O +a O +transmembrane O +hemidesmosomal O +protein O +encoded O +by O +COL17A1 O +. O + +This O +report O +documents O +a O +novel O +splice O +- O +site O +mutation O +in O +COL17A1 O +in O +a O +patient O +with O +generalized O +atrophic B +benign I +epidermolysis I +bullosa I +, O +and O +applies O +a O +new O +methodology O +to O +define O +and O +characterize O +the O +resulting O +mRNA O +splice O +variants O +. O + +Mutational O +analysis O +of O +COL17A1 O +identified O +a O +maternally O +inherited O +G O +- O +to O +- O +T O +transversion O +at O +the O +- O +1 O +position O +of O +exon O +32 O +. O + +This O +acceptor O +splice O +- O +site O +mutation O +led O +to O +the O +formation O +of O +aberrant O +transcripts O +present O +at O +extremely O +low O +levels O +. O + +Based O +on O +our O +recent O +finding O +that O +cycloheximide O +stabilized O +mutant O +COL17A1 O +transcripts O +in O +keratinocytes O +homozygous O +for O +a O +frameshift O +mutation O +, O +the O +effects O +of O +the O +splice O +- O +site O +mutation O +on O +splicing O +of O +COL17A1 O +transcripts O +were O +determined O +using O +reverse O +transcriptase O +polymerase O +chain O +reaction O +of O +total O +RNA O +from O +keratinocytes O +incubated O +for O +2 O +. O + +5 O +h O +in O +the O +presence O +or O +absence O +of O +10 O +microg O +cycloheximide O +per O +ml O +. O + +Using O +this O +approach O +, O +an O +abnormally O +spliced O +transcript O +was O +identified O +that O +contains O +an O +extra O +264 O +bases O +upstream O +from O +exon O +32 O +, O +resulting O +in O +a O +premature O +termination O +codon O +27 O +bp O +downstream O +from O +the O +cryptic O +splice O +site O +. O + +Three O +other O +splice O +variants O +, O +including O +one O +derived O +from O +the O +skipping O +of O +exon O +32 O +, O +were O +also O +identified O +. O + +These O +results O +indicate O +the O +usefulness O +of O +cycloheximide O +treatment O +in O +evaluating O +the O +abnormal O +processing O +of O +mRNA O +due O +to O +splice O +- O +site O +mutations O +, O +because O +( O +i O +) O +aberrant O +splicing O +often O +generates O +a O +premature O +termination O +codon O +, O +( O +ii O +) O +transcripts O +with O +premature O +termination O +codons O +can O +occur O +at O +low O +or O +undetectable O +levels O +due O +to O +nonsense O +- O +mediated O +mRNA O +decay O +, O +and O +( O +iii O +) O +the O +levels O +of O +these O +transcripts O +can O +be O +increased O +by O +cycloheximide O +. O + +A O +deletion O +mutation O +in O +COL17A1 O +in O +five O +Austrian O +families O +with O +generalized O +atrophic B +benign I +epidermolysis I +bullosa I +represents O +propagation O +of O +an O +ancestral O +allele O +. O + +Patients O +with O +generalized O +atrophic B +benign I +epidermolysis I +bullosa I +, O +a O +usually O +nonlethal O +form O +of O +junctional B +epidermolysis I +bullosa I +, O +have O +generalized O +blistering B +, O +nail B +dystrophy I +, O +patchy O +alopecia B +, O +and O +dental B +abnormalities I +. O + +Skin B +fragility I +in O +most O +cases O +is O +due O +to O +mutations O +in O +the O +gene O +encoding O +type O +XVII O +collagen O +( O +COL17A1 O +) O +. O + +Recently O +, O +we O +reported O +five O +Austrian O +families O +with O +generalized O +atrophic B +benign I +epidermolysis I +bullosa I +who O +share O +the O +same O +COL17A1 O +mutation O +. O + +Affected O +individuals O +in O +three O +families O +are O +homozygous O +for O +4003delTC O +, O +whereas O +those O +in O +two O +others O +are O +compound O +heterozygotes O +. O + +To O +determine O +if O +the O +occurrence O +of O +4003delTC O +in O +these O +unrelated O +families O +signifies O +propagation O +of O +an O +ancestral O +allele O +or O +a O +mutational O +hot O +spot O +, O +haplotypes O +were O +determined O +for O +polymorphisms O +both O +within O +and O +flanking O +COL17A1 O +. O + +Five O +intragenic O +polymorphisms O +were O +chosen O +based O +on O +their O +informativeness O +. O + +One O +of O +these O +, O +not O +previously O +reported O +, O +was O +2988 O +A O +or O +C O +that O +introduces O +a O +new O +restriction O +site O +for O +Eco0109 O +I O +. O + +All O +the O +4003delTC O +alleles O +showed O +the O +same O +haplotype O +for O +these O +five O +polymorphic O +markers O +. O + +Fourteen O +microsatellite O +polymorphisms O +were O +selected O +based O +on O +their O +high O +heterozygosity O +and O +their O +location O +within O +10q23 O +- O +q25 O +near O +COL17A1 O +. O + +Three O +families O +shared O +microsatellite O +polymorphisms O +covering O +at O +most O +19 O +cM O +, O +whereas O +the O +others O +shared O +smaller O +regions O +consistent O +with O +cross O +- O +over O +events O +during O +passage O +of O +this O +mutation O +through O +several O +generations O +. O + +These O +results O +indicate O +that O +4003delTC O +occurs O +on O +a O +single O +ancestral O +allele O +. O +. O + +The O +haptoglobin O +- O +gene O +deletion O +responsible O +for O +anhaptoglobinemia B +. O + +We O +have O +found O +an O +allelic O +deletion O +of O +the O +haptoglobin O +( O +Hp O +) O +gene O +from O +an O +individual O +with O +anhaptoglobinemia B +. O + +The O +Hp O +gene O +cluster O +consists O +of O +coding O +regions O +of O +the O +alpha O +chain O +and O +beta O +chain O +of O +the O +haptoglobin O +gene O +( O +Hp O +) O +and O +of O +the O +alpha O +chain O +and O +beta O +chain O +of O +the O +haptoglobin O +- O +related O +gene O +( O +Hpr O +) O +, O +in O +tandem O +from O +the O +5 O +side O +. O + +Southern O +blot O +and O +PCR O +analyses O +have O +indicated O +that O +the O +individual O +with O +anhaptoglobinemia B +was O +homozygous O +for O +the O +gene O +deletion O +and O +that O +the O +gene O +deletion O +was O +included O +at O +least O +from O +the O +promoter O +region O +of O +Hp O +to O +Hpr O +alpha O +but O +not O +to O +Hpr O +beta O +( O +Hpdel O +) O +. O + +In O +addition O +, O +we O +found O +seven O +individuals O +with O +hypohaptoglobinemia B +in O +three O +families O +, O +and O +the O +genotypes O +of O +six O +of O +the O +seven O +individuals O +were O +found O +to O +be O +Hp2 O +/ O +Hpdel O +. O + +The O +phenotypes O +and O +genotypes O +in O +one O +of O +these O +three O +families O +showed O +the O +father O +to O +be O +hypohaptoglobinemic B +( O +Hp2 O +) O +and O +Hp2 O +/ O +Hpdel O +, O +the O +mother O +to O +be O +Hp2 O +- O +1 O +and O +Hp1 O +/ O +Hp2 O +, O +one O +of O +the O +two O +children O +to O +be O +hypohaptoglobinemic B +( O +Hp2 O +) O +and O +Hp2 O +/ O +Hpdel O +, O +and O +the O +other O +child O +to O +be O +Hp1 O +and O +Hp1 O +/ O +Hpdel O +, O +showing O +an O +anomalous O +inheritance O +of O +Hp B +phenotypes O +in O +the O +child O + +with O +Hp1 O +. O + +The O +Hp2 O +/ O +Hpdel O +individuals O +had O +an O +extremely O +low O +level O +of O +Hp O +( O +mean O ++ O +/ O +- O +SD O += O +0 O +. O +049 O ++ O +/ O +- O +0 O +. O +043 O +mg O +/ O +ml O +; O +n O += O +6 O +) O +, O +compared O +with O +the O +level O +( O +1 O +. O +64 O ++ O +/ O +- O +1 O +. O +07 O +mg O +/ O +ml O +) O +obtained O +from O +52 O +healthy O +volunteers O +having O +phenotype O +Hp2 O +, O +whereas O +the O +serum O +Hp O +level O +of O +an O +individual O +with O +Hp1 O +/ O +Hpdel B +was O +0 O +. O + +50 O +mg O +/ O +ml O +, O +which O +was O +approximately O +half O +the O +level O +of O +Hp O +in O +control O +sera O +from O +the O +Hp1 O +phenotype O +( O +1 O +. O +26 O ++ O +/ O +- O +0 O +. O +33 O +mg O +/ O +ml O +; O +n O += O +9 O +) O +, O +showing O +a O +gene O +- O +dosage O +effect O +. O + +The O +other O +allele O +( O +Hp2 O +) O +of O +individuals O +with O +Hp2 O +/ O +Hpdel O +was O +found O +to O +have O +, O +in O +all O +exons O +, O +no O +mutation O +, O +by O +DNA O +sequencing O +. O + +On O +the O +basis O +of O +the O +present O +study O +, O +the O +mechanism O +of O +anhaptoglobinemia B +and O +the O +mechanism O +of O +anomalous O +inheritance O +of O +Hp B +phenotypes O +were O +well O +explained O +. O + +However O +, O +the O +mechanism O +of O +hypohaptoglobinemia B +remains O +unknown O + +ATM O +mutations O +and O +phenotypes O +in O +ataxia B +- I +telangiectasia I +families O +in O +the O +British O +Isles O +: O +expression O +of O +mutant O +ATM O +and O +the O +risk O +of O +leukemia B +, O +lymphoma B +, O +and O +breast B +cancer I +. O + +We O +report O +the O +spectrum O +of O +59 O +ATM O +mutations O +observed O +in O +ataxia B +- I +telangiectasia I +( O +A B +- I +T I +) O +patients O +in O +the O +British O +Isles O +. O + +Of O +51 O +ATM O +mutations O +identified O +in O +families O +native O +to O +the O +British O +Isles O +, O +11 O +were O +founder O +mutations O +, O +and O +2 O +of O +these O +11 O +conferred O +a O +milder O +clinical O +phenotype O +with O +respect O +to O +both O +cerebellar B +degeneration I +and O +cellular O +features O +. O + +We O +report O +, O +in O +two O +A B +- I +T I +families O +, O +an O +ATM O +mutation O +( O +7271T O +- O +- O +> O +G O +) O +that O +may O +be O +associated O +with O +an O +increased O +risk O +of O +breast B +cancer I +in O +both O +homozygotes O +and O +heterozygotes O +( O +relative O +risk O +12 O +. O +7 O +; O +P O += O +. O +0025 O +) O +, O +although O +there O +is O +a O +less O +severe O +A B +- I +T I +phenotype O +in O +terms O +of O +the O +degree O +of O +cerebellar B +degeneration I +. O + +This O +mutation O +( O +7271T O +- O +- O +> O +G O +) O +also O +allows O +expression O +of O +full O +- O +length O +ATM O +protein O +at O +a O +level O +comparable O +with O +that O +in O +unaffected O +individuals O +. O + +In O +addition O +, O +we O +have O +studied O +18 O +A B +- I +T I +patients O +, O +in O +15 O +families O +, O +who O +developed O +leukemia B +, O +lymphoma B +, O +preleukemic O +T O +- O +cell O +proliferation O +, O +or O +Hodgkin B +lymphoma I +, O +mostly O +in O +childhood O +. O + +A O +wide O +variety O +of O +ATM O +mutation O +types O +, O +including O +missense O +mutations O +and O +in O +- O +frame O +deletions O +, O +were O +seen O +in O +these O +patients O +. O + +We O +also O +show O +that O +25 O +% O +of O +all O +A B +- I +T I +patients O +carried O +in O +- O +frame O +deletions O +or O +missense O +mutations O +, O +many O +of O +which O +were O +also O +associated O +with O +expression O +of O +mutant O +ATM O +protein O +. O + +The O +DMPK O +gene O +of O +severely O +affected O +myotonic B +dystrophy I +patients O +is O +hypermethylated O +proximal O +to O +the O +largely O +expanded O +CTG O +repeat O +. O + +Using O +methylation O +- O +sensitive O +restriction O +enzymes O +, O +we O +characterized O +the O +methylation O +pattern O +on O +the O +5 O +side O +of O +the O +CTG O +repeat O +in O +the O +DMPK O +gene O +of O +normal O +individuals O +and O +of O +patients O +affected O +with O +myotonic B +dystrophy I +, O +showing O +expansions O +of O +the O +repetitive O +sequence O +. O + +The O +gene O +segment O +analyzed O +corresponds O +to O +the O +genomic O +SacI O +- O +HindIII O +fragment O +carrying O +exons O +11 O +- O +15 O +. O + +There O +is O +constitutive O +methylation O +in O +intron O +12 O +at O +restriction O +sites O +of O +SacII O +and O +HhaI O +, O +localized O +1 O +, O +159 O +- O +1 O +, O +232 O +bp O +upstream O +of O +the O +CTG O +repeat O +, O +whereas O +most O +, O +if O +not O +all O +, O +of O +the O +other O +sites O +of O +SacII O +, O +HhaI O +, O +and O +HpaII O +in O +this O +region O +are O +unmethylated O +, O +in O +normal O +individuals O +and O +most O +of O +the O +patients O +. O + +In O +a O +number O +of O +young O +and O +severely O +affected O +patients O +, O +however O +, O +complete O +methylation O +of O +these O +restriction O +sites O +was O +found O +in O +the O +mutated O +allele O +. O + +In O +most O +of O +these O +patients O +, O +the O +onset O +of O +the O +disease O +was O +congenital O +. O + +Preliminary O +in O +vivo O +footprinting O +data O +gave O +evidence O +for O +protein O +- O +DNA O +contact O +in O +normal O +genes O +at O +an O +Sp1 O +consensus O +binding O +site O +upstream O +of O +the O +CTG O +repeat O +and O +for O +a O +significant O +reduction O +of O +this O +interaction O +in O +cells O +with O +a O +hypermethylated O +DMPK O +gene O +. O +. O + +The O +hemochromatosis B +gene O +product O +complexes O +with O +the O +transferrin O +receptor O +and O +lowers O +its O +affinity O +for O +ligand O +binding O +. O + +We O +recently O +reported O +the O +positional O +cloning O +of O +a O +candidate O +gene O +for O +hereditary B +hemochromatosis I +called O +HFE O +. O + +The O +gene O +product O +, O +a O +member O +of O +the O +major O +histocompatibility O +complex O +class O +I O +- O +like O +family O +, O +was O +found O +to O +have O +a O +mutation O +, O +Cys O +- O +282 O +- O +- O +> O +Tyr O +( O +C282Y O +) O +, O +in O +85 O +% O +of O +patient O +chromosomes O +. O + +This O +mutation O +eliminates O +the O +ability O +of O +HFE O +to O +associate O +with O +beta2 O +- O +microglobulin O +( O +beta2m O +) O +and O +prevents O +cell O +- O +surface O +expression O +. O + +A O +second O +mutation O +that O +has O +no O +effect O +on O +beta2m O +association O +, O +H63D O +, O +was O +found O +in O +eight O +out O +of O +nine O +patients O +heterozygous O +for O +the O +C282Y O +mutant O +. O + +In O +this O +report O +, O +we O +demonstrate O +in O +cultured O +293 O +cells O +overexpressing O +wild O +- O +type O +or O +mutant O +HFE O +proteins O +that O +both O +the O +wild O +- O +type O +and O +H63D O +HFE O +proteins O +form O +stable O +complexes O +with O +the O +transferrin O +receptor O +( O +TfR O +) O +. O + +The O +C282Y O +mutation O +nearly O +completely O +prevents O +the O +association O +of O +the O +mutant O +HFE O +protein O +with O +the O +TfR O +. O + +Studies O +on O +cell O +- O +associated O +transferrin O +at O +37 O +degrees O +C O +suggest O +that O +the O +overexpressed O +wild O +- O +type O +HFE O +protein O +decreases O +the O +affinity O +of O +the O +TfR O +for O +transferrin O +. O + +The O +overexpressed O +H63D O +protein O +does O +not O +have O +this O +effect O +, O +providing O +the O +first O +direct O +evidence O +for O +a O +functional O +consequence O +of O +the O +H63D O +mutation O +. O + +Addition O +of O +soluble O +wild O +- O +type O +HFE O +/ O +beta2m O +heterodimers O +to O +cultured O +cells O +also O +decreased O +the O +apparent O +affinity O +of O +the O +TfR O +for O +its O +ligand O +under O +steady O +- O +state O +conditions O +, O +both O +in O +293 O +cells O +and O +in O +HeLa O +cells O +. O + +Furthermore O +, O +at O +4 O +degrees O +C O +, O +the O +added O +soluble O +complex O +of O +HFE O +/ O +beta2m O +inhibited O +binding O +of O +transferrin O +to O +HeLa O +cell O +TfR O +in O +a O +concentration O +- O +dependent O +manner O +. O + +Scatchard O +plots O +of O +these O +data O +indicate O +that O +the O +added O +heterodimer O +substantially O +reduced O +the O +affinity O +of O +TfR O +for O +transferrin O +. O + +These O +results O +establish O +a O +molecular O +link O +between O +HFE O +and O +a O +key O +protein O +involved O +in O +iron O +transport O +, O +the O +TfR O +, O +and O +raise O +the O +possibility O +that O +alterations O +in O +this O +regulatory O +mechanism O +may O +play O +a O +role O +in O +the O +pathogenesis O +of O +hereditary B +hemochromatosis I +. O +. O + +Genomic O +organization O +of O +the O +UBE3A O +/ O +E6 O +- O +AP O +gene O +and O +related O +pseudogenes O +. O + +The O +UBE3A O +gene O +encodes O +the O +E6 O +- O +AP O +ubiquitin O +- O +protein O +ligase O +and O +has O +recently O +been O +shown O +to O +be O +mutated O +in O +Angelman B +syndrome I +patients O +who O +lack O +15q11 O +- O +q13 O +deletions O +or O +chromosome O +15 O +paternal B +uniparental I +disomy I +. O + +Previous O +UBE3A O +cDNA O +analysis O +has O +shown O +a O +coding O +region O +of O +approximately O +2 O +. O + +6 O +kb O +and O +a O +3 O +- O +untranslated O +region O +( O +UTR O +) O +of O +< O +50 O +bp O +, O +whereas O +Northern O +analysis O +has O +indicated O +mRNA O +sizes O +of O +5 O +- O +8 O +kb O +. O + +We O +have O +analyzed O +additional O +cDNA O +clones O +and O +provide O +evidence O +for O +an O +additional O +0 O +. O + +5 O +kb O +of O +5 O +- O +UTR O +and O +> O +2 O +kb O +of O +3 O +- O +UTR O +. O + +We O +have O +established O +the O +genomic O +organization O +of O +UBE3A O +and O +the O +sequence O +of O +intron O +- O +exon O +borders O +. O + +We O +have O +also O +mapped O +two O +highly O +homologous O +processed O +pseudogenes O +, O +UBE3AP1 O +and O +UBE3AP2 O +, O +to O +chromosomes O +2 O +and O +21 O +, O +respectively O +, O +and O +determined O +their O +genomic O +organization O +. O + +These O +results O +will O +form O +the O +basis O +for O +studies O +of O +mutation O +and O +imprinting O +of O +UBE3A O +. O + +Mutation O +spectrum O +and O +genotype O +- O +phenotype O +analyses O +in O +Cowden B +disease I +and O +Bannayan B +- I +Zonana I +syndrome I +, O +two O +hamartoma B +syndromes I +with O +germline O +PTEN O +mutation O +. O + +The O +tumour B +suppressor O +gene O +PTEN O +, O +which O +maps O +to O +10q23 O +. O + +3 O +and O +encodes O +a O +403 O +amino O +acid O +dual O +specificity O +phosphatase O +( O +protein O +tyrosine O +phosphatase O +; O +PTPase O +) O +, O +was O +shown O +recently O +to O +play O +a O +broad O +role O +in O +human O +malignancy B +. O + +Somatic O +PTEN O +deletions O +and O +mutations O +were O +observed O +in O +sporadic B +breast I +, I +brain I +, I +prostate I +and I +kidney I +cancer I +cell O +lines O +and O +in O +several O +primary B +tumours B +such O +as O +endometrial B +carcinomas I +, O +malignant B +melanoma I +and O +thyroid B +tumours I +. O + +In O +addition O +, O +PTEN O +was O +identified O +as O +the O +susceptibility O +gene O +for O +two O +hamartoma B +syndromes I +Cowden B +disease I +( O +CD B +; O +MIM O +158350 O +) O +and O +Bannayan B +- I +Zonana I +( O +BZS B +) O +or O +Ruvalcaba B +- I +Riley I +- I +Smith I +syndrome I +( O +MIM O +153480 O +) O +. O + +Constitutive O +DNA O +from O +37 O +CD B +families O +and O +seven O +BZS B +families O +was O +screened O +for O +germline O +PTEN O +mutations O +. O + +PTEN O +mutations O +were O +identified O +in O +30 O +of O +37 O +( O +81 O +% O +) O +CD B +families O +, O +including O +missense O +and O +nonsense O +point O +mutations O +, O +deletions O +, O +insertions O +, O +a O +deletion O +/ O +insertion O +and O +splice O +site O +mutations O +. O + +These O +mutations O +were O +scattered O +over O +the O +entire O +length O +of O +PTEN O +, O +with O +the O +exception O +of O +the O +first O +, O +fourth O +and O +last O +exons O +. O + +A O +hot O +spot O +for O +PTEN O +mutation O +in O +CD B +was O +identified O +in O +exon O +5 O +that O +contains O +the O +PTPase O +core O +motif O +, O +with O +13 O +of O +30 O +( O +43 O +% O +) O +CD B +mutations O +identified O +in O +this O +exon O +. O + +Seven O +of O +30 O +( O +23 O +% O +) O +were O +within O +the O +core O +motif O +, O +the O +majority O +( O +five O +of O +seven O +) O +of O +which O +were O +missense O +mutations O +, O +possibly O +pointing O +to O +the O +functional O +significance O +of O +this O +region O +. O + +Germline O +PTEN O +mutations O +were O +identified O +in O +four O +of O +seven O +( O +57 O +% O +) O +BZS B +families O +studied O +. O + +Interestingly O +, O +none O +of O +these O +mutations O +was O +observed O +in O +the O +PTPase O +core O +motif O +. O + +It O +is O +also O +worthy O +of O +note O +that O +a O +single O +nonsense O +point O +mutation O +, O +R233X O +, O +was O +observed O +in O +the O +germline O +DNA O +from O +two O +unrelated O +CD B +families O +and O +one O +BZS B +family O +. O + +Genotype O +- O +phenotype O +studies O +were O +not O +performed O +on O +this O +small O +group O +of O +BZS B +families O +. O + +However O +, O +genotype O +- O +phenotype O +analysis O +inthe O +group O +of O +CD B +families O +revealed O +two O +possible O +associations O +worthy O +of O +follow O +- O +up O +in O +independent O +analyses O +. O + +The O +first O +was O +an O +association O +noted O +in O +the O +group O +of O +CD B +families O +with O +breast B +disease I +. O + +A O +correlation O +was O +observed O +between O +the O +presence O +/ O +absence O +of O +a O +PTEN O +mutation O +and O +the O +type O +of O +breast O +involvement O +( O +unaffected O +versus O +benign O +versus O +malignant O +) O +. O + +Specifically O +and O +more O +directly O +, O +an O +association O +was O +also O +observed O +between O +the O +presence O +of O +a O +PTEN O +mutation O +and O +malignant B +breast I +disease I +. O + +Secondly O +, O +there O +appeared O +to O +be O +an O +interdependent O +association O +between O +mutations O +upstream O +and O +within O +the O +PTPase O +core O +motif O +, O +the O +core O +motif O +containing O +the O +majority O +of O +missense O +mutations O +, O +and O +the O +involvement O +of O +all O +major O +organ O +systems O +( O +central O +nervous O +system O +, O +thyroid O +, O +breast O +, O +skin O +and O +gastrointestinal O +tract O +) O +. O + +However O +, O +these O +observations O +would O +need O +to O +be O +confirmed O +by O +studying O +a O +larger O +number O +of O +CD B +families O +. O + +Molecular B +defects I +leading O +to O +human B +complement I +component I +C6 I +deficiency I +in O +an O +African O +- O +American O +family O +. O + +Complement B +component I +C6 I +deficiency I +( O +C6D B +) O +was O +diagnosed O +in O +a O +16 O +- O +year O +- O +old O +African O +- O +American O +male O +with O +meningococcal B +meningitis I +. O + +The O +patients O +father O +and O +two O +brothers O +also O +had O +C6D B +, O +but O +gave O +no O +history O +of O +meningitis B +or O +other O +neisserial B +infection I +. O + +By O +using O +exon O +- O +specific O +polymerase O +chain O +reaction O +( O +PCR O +) O +/ O +single O +- O +strand O +conformation O +polymorphism O +as O +a O +screening O +step O +and O +nucleotide O +sequencing O +of O +target O +exons O +, O +we O +determined O +that O +the O +proband O +was O +a O +compound O +heterozygote O +for O +two O +C6 O +gene O +mutations O +. O + +The O +first O +, O +1195delC O +located O +in O +exon O +7 O +, O +is O +a O +novel O +mutation O +, O +while O +the O +second O +, O +1936delG O +in O +exon O +12 O +, O +has O +been O +described O +before O +to O +cause O +C6D B +in O +an O +unrelated O +African O +- O +American O +individual O +. O + +Both O +mutations O +result O +in O +premature O +termination O +codons O +and O +C6 O +null O +alleles O +. O + +Allele O +- O +specific O +PCR O +indicated O +that O +the O +probands O +two O +brothers O +also O +inherited O +the O +1195delC O +mutation O +from O +their O +heterozygous O +mother O +and O +the O +1936delG O +mutation O +from O +their O +homozygous O +father O +. O +. O + +PAX6 O +mutations O +reviewed O +. O + +Mutations O +in O +PAX6 O +are O +responsible O +for O +human O +aniridia B +and O +have O +also O +been O +found O +in O +patients O +with O +Peters B +anomaly I +, O +with O +congenital B +cataracts I +, O +with O +autosomal B +dominant I +keratitis I +, O +and O +with O +isolated B +foveal I +hypoplasia I +. O + +No O +locus O +other O +than O +chromosome O +11p13 O +has O +been O +implicated O +in O +aniridia B +, O +and O +PAX6 O +is O +clearly O +the O +major O +, O +if O +not O +only O +, O +gene O +responsible O +. O + +Twenty O +- O +eight O +percent O +of O +identified O +PAX6 O +mutations O +are O +C O +- O +T O +changes O +at O +CpG O +dinucleotides O +, O +20 O +% O +are O +splicing O +errors O +, O +and O +more O +than O +30 O +% O +are O +deletion O +or O +insertion O +events O +. O + +There O +is O +a O +noticeably O +elevated O +level O +of O +mutation O +in O +the O +paired O +domain O +compared O +with O +the O +rest O +of O +the O +gene O +. O + +Increased O +mutation O +in O +the O +homeodomain O +is O +accounted O +for O +by O +the O +hypermutable O +CpG O +dinucleotide O +in O +codon O +240 O +. O + +Very O +nearly O +all O +mutations O +appear O +to O +cause O +loss O +of O +function O +of O +the O +mutant O +allele O +, O +and O +more O +than O +80 O +% O +of O +exonic O +substitutions O +result O +in O +nonsense O +codons O +. O + +In O +a O +gene O +with O +such O +extraordinarily O +high O +sequence O +conservation O +throughout O +evolution O +, O +there O +are O +presumed O +undiscovered O +missense O +mutations O +, O +these O +are O +hypothesized O +to O +exist O +in O +as O +- O +yet O +unidentified O +phenotypes O +. O +. O + +Genetic O +heterogeneity O +and O +penetrance O +analysis O +of O +the O +BRCA1 O +and O +BRCA2 O +genes O +in O +breast B +cancer I +families O +. O + +The O +Breast B +Cancer I +Linkage O +Consortium O +. O + +The O +contribution O +of O +BRCA1 O +and O +BRCA2 O +to O +inherited B +breast I +cancer I +was O +assessed O +by O +linkage O +and O +mutation O +analysis O +in O +237 O +families O +, O +each O +with O +at O +least O +four O +cases O +of O +breast B +cancer I +, O +collected O +by O +the O +Breast B +Cancer I +Linkage O +Consortium O +. O + +Families O +were O +included O +without O +regard O +to O +the O +occurrence O +of O +ovarian B +or I +other I +cancers I +. O + +Overall O +, O +disease O +was O +linked O +to O +BRCA1 O +in O +an O +estimated O +52 O +% O +of O +families O +, O +to O +BRCA2 O +in O +32 O +% O +of O +families O +, O +and O +to O +neither O +gene O +in O +16 O +% O +( O +95 O +% O +confidence O +interval O +[ O +CI O +] O +6 O +% O +- O +28 O +% O +) O +, O +suggesting O +other O +predisposition O +genes O +. O + +The O +majority O +( O +81 O +% O +) O +of O +the O +breast B +- I +ovarian I +cancer I +families O +were O +due O +to O +BRCA1 O +, O +with O +most O +others O +( O +14 O +% O +) O +due O +to O +BRCA2 O +. O + +Conversely O +, O +the O +majority O +of O +families O +with O +male B +and O +female I +breast I +cancer I +were O +due O +to O +BRCA2 O +( O +76 O +% O +) O +. O + +The O +largest O +proportion O +( O +67 O +% O +) O +of O +families O +due O +to O +other O +genes O +was O +found O +in O +families O +with O +four O +or O +five O +cases O +of O +female B +breast I +cancer I +only O +. O + +These O +estimates O +were O +not O +substantially O +affected O +either O +by O +changing O +the O +assumed O +penetrance O +model O +for O +BRCA1 O +or O +by O +including O +or O +excluding O +BRCA1 O +mutation O +data O +. O + +Among O +those O +families O +with O +disease O +due I +to I +BRCA1 O +that O +were O +tested O +by O +one O +of O +the O +standard O +screening O +methods O +, O +mutations O +were O +detected O +in O +the O +coding O +sequence O +or O +splice O +sites O +in O +an O +estimated O +63 O +% O +( O +95 O +% O +CI O +51 O +% O +- O +77 O +% O +) O +. O + +The O +estimated O +sensitivity O +was O +identical O +for O +direct O +sequencing O +and O +other O +techniques O +. O + +The O +penetrance O +of O +BRCA2 O +was O +estimated O +by O +maximizing O +the O +LOD O +score O +in O +BRCA2 O +- O +mutation O +families O +, O +over O +all O +possible O +penetrance O +functions O +. O + +The O +estimated O +cumulative O +risk O +of O +breast B +cancer I +reached O +28 O +% O +( O +95 O +% O +CI O +9 O +% O +- O +44 O +% O +) O +by O +age O +50 O +years O +and O +84 O +% O +( O +95 O +% O +CI O +43 O +% O +- O +95 O +% O +) O +by O +age O +70 O +years O +. O + +The O +corresponding O +ovarian B +cancer I +risks O +were O +0 O +. O + +4 O +% O +( O +95 O +% O +CI O +0 O +% O +- O +1 O +% O +) O +by O +age O +50 O +years O +and O +27 O +% O +( O +95 O +% O +CI O +0 O +% O +- O +47 O +% O +) O +by O +age O +70 O +years O +. O + +The O +lifetime O +risk O +of O +breast B +cancer I +appears O +similar O +to O +the O +risk O +in O +BRCA1 O +carriers O +, O +but O +there O +was O +some O +suggestion O +of O +a O +lower O +risk O +in O +BRCA2 O +carriers O +< O +50 O +years O +of O +age O +. O + +Eye B +movement I +abnormalities I +correlate O +with O +genotype O +in O +autosomal B +dominant I +cerebellar I +ataxia I +type I +I I +. O + +We O +compared O +horizontal O +eye O +movements O +( O +visually O +guided O +saccades O +, O +antisaccades O +, O +and O +smooth O +pursuit O +) O +in O +control O +subjects O +( O +n O += O +14 O +) O +and O +patients O +with O +three O +forms O +of O +autosomal B +dominant I +cerebellar I +ataxias I +type I +I I +spinocerebellar B +ataxias I +1 I +and I +2 I +( O +SCA1 B +, O +n O += O +11 O +; O +SCA2 B +, O +n O += O +10 O +) O +and O +SCA3 B +/ I +Machado I +- I +Joseph I +disease I +( O +MJD B +) O +( O +n O += O +16 O +) O +. O + +In O +SCA1 O +, O +saccade O +amplitude O +was O +significantly O +increased O +, O +resulting O +in O +hypermetria B +. O + +The O +smooth O +pursuit O +gain O +was O +decreased O +. O + +In O +SCA2 O +, O +saccade O +velocity O +was O +markedly O +decreased O +. O + +The O +percentage O +of O +errors O +in O +antisaccades O +was O +greatly O +increased O +and O +was O +significantly O +correlated O +with O +age O +at O +disease O +onset O +. O + +In O +addition O +, O +a O +correlation O +between O +smooth O +pursuit O +gain O +and O +the O +number O +of O +trinucleotide O +repeats O +was O +found O +. O + +In O +SCA3 O +, O +gaze O +- O +evoked O +nystagmus B +was O +often O +present O +as O +was O +saccade O +hypometria I +and O +smooth O +pursuit O +gain O +was O +markedly O +decreased O +. O + +Three O +major O +criteria O +, O +saccade O +amplitude O +, O +saccade O +velocity O +, O +and O +presence O +of O +gaze O +- O +evoked O +nystagmus B +, O +permitted O +the O +correct O +assignment O +of O +90 O +% O +of O +the O +SCA1 O +, O +90 O +% O +of O +the O +SCA2 O +, O +and O +93 O +% O +of O +the O +patients O +with O +SCA3 B +to O +their O +genetically O +confirmed O +patient O +group O +and O +, O +therefore O +, O +may O +help O +orient O +diagnoses O +of O +SCA1 O +, O +SCA2 O +, O +and O +SCA3 O +at O +early O +clinical O +stages O +of O +the O +diseases O +. O +. O + +Genetic O +basis O +and O +molecular O +mechanism O +for O +idiopathic O +ventricular B +fibrillation I +. O + +Ventricular B +fibrillation I +causes O +more O +than O +300 O +, O +000 O +sudden B +deaths I +each O +year O +in O +the O +USA O +alone O +. O + +In O +approximately O +5 O +- O +12 O +% O +of O +these O +cases O +, O +there O +are O +no O +demonstrable O +cardiac O +or O +non O +- O +cardiac O +causes O +to O +account O +for O +the O +episode O +, O +which O +is O +therefore O +classified O +as O +idiopathic B +ventricular I +fibrillation I +( O +IVF B +) O +. O + +A O +distinct O +group O +of O +IVF B +patients O +has O +been O +found O +to O +present O +with O +a O +characteristic O +electrocardiographic O +pattern O +. O + +Because O +of O +the O +small O +size O +of O +most O +pedigrees O +and O +the O +high O +incidence O +of O +sudden B +death I +, O +however O +, O +molecular O +genetic O +studies O +of O +IVF B +have O +not O +yet O +been O +done O +. O + +Because O +IVF B +causes O +cardiac B +rhythm I +disturbance I +, O +we O +investigated O +whether O +malfunction O +of O +ion O +channels O +could O +cause O +the O +disorder O +by O +studying O +mutations O +in O +the O +cardiac O +sodium O +channel O +gene O +SCN5A O +. O + +We O +have O +now O +identified O +a O +missense O +mutation O +, O +a O +splice O +- O +donor O +mutation O +, O +and O +a O +frameshift O +mutation O +in O +the O +coding O +region O +of O +SCN5A O +in O +three O +IVF B +families O +. O + +We O +show O +that O +sodium O +channels O +with O +the O +missense O +mutation O +recover O +from O +inactivation O +more O +rapidly O +than O +normal O +and O +that O +the O +frameshift O +mutation O +causes O +the O +sodium O +channel O +to O +be O +non O +- O +functional O +. O + +Our O +results O +indicate O +that O +mutations O +in O +cardiac O +ion O +- O +channel O +genes O +contribute O +to O +the O +risk O +of O +developing O +IVF B +. O +. O + +Molecular O +heterogeneity O +in O +mucopolysaccharidosis B +IVA I +in O +Australia O +and O +Northern O +Ireland O +: O +nine O +novel O +mutations O +including O +T312S O +, O +a O +common O +allele O +that O +confers O +a O +mild O +phenotype O +. O + +Mucopolysaccharidosis B +IVA I +( O +MPS B +IVA I +) O +is O +an O +autosomal B +recessive I +lysosomal I +storage I +disorder I +caused O +by O +a O +genetic B +defect I +in I +N I +- I +acetylgalactosamine I +- I +6 I +- I +sulfate I +sulfatase I +( O +GALNS O +) O +. O + +Previous O +studies O +of O +patients O +from O +a O +British O +- O +Irish O +population O +showed O +that O +the O +I113F O +mutation O +is O +the O +most O +common O +single O +mutation O +among O +MPS B +IVA I +patients O +and O +produces O +a O +severe O +clinical O +phenotype O +. O + +We O +studied O +mutations O +in O +the O +GALNS O +gene O +from O +23 O +additional O +MPS B +IVA I +patients O +( O +15 O +from O +Australia O +, O +8 O +from O +Northern O +Ireland O +) O +, O +with O +various O +clinical O +phenotypes O +( O +severe O +, O +16 O +cases O +; O +intermediate O +, O +4 O +cases O +; O +mild O +, O +3 O +cases O +) O +. O + +We O +found O +two O +common O +mutations O +that O +together O +accounted O +for O +32 O +% O +of O +the O +44 O +unrelated O +alleles O +in O +these O +patients O +. O + +One O +is O +the O +T312S O +mutation O +, O +a O +novel O +mutation O +found O +exclusively O +in O +milder O +patients O +. O + +The O +other O +is O +the O +previously O +described O +I113F O +that O +produces O +a O +severe O +phenotype O +. O + +The O +I113F O +and O +T312S O +mutations O +accounted O +for O +8 O +( O +18 O +% O +) O +and O +6 O +( O +14 O +% O +) O +of O +44 O +unrelated O +alleles O +, O +respectively O +. O + +The O +relatively O +high O +residual O +GALNS O +activity O +seen O +when O +the O +T312S O +mutant O +cDNA O +is O +overexpressed O +in O +mutant O +cells O +provides O +an O +explanation O +for O +the O +mild O +phenotype O +in O +patients O +with O +this O +mutation O +. O + +The O +distribution O +and O +relative O +frequencies O +of O +the O +I113F O +and O +T312S O +mutations O +in O +Australia O +corresponded O +to O +those O +observed O +in O +Northern O +Ireland O +and O +are O +unique O +to O +these O +two O +populations O +, O +suggesting O +that O +both O +mutations O +were O +probably O +introduced O +to O +Australia O +by O +Irish O +migrants O +during O +the O +19th O +century O +. O + +Haplotype O +analysis O +using O +6 O +RFLPs O +provides O +additional O +data O +that O +the O +I113F O +mutation O +originated O +from O +a O +common O +ancestor O +. O + +The O +other O +9 O +novel O +mutations O +identified O +in O +these O +23 O +patients O +were O +each O +limited O +to O +a O +single O +family O +. O + +These O +data O +provide O +further O +evidence O +for O +extensive O +allelic O +heterogeneity O +in O +MPS B +IVA I +in O +British O +- O +Irish O +patients O +and O +provide O +evidence O +for O +their O +transmission O +to O +Australia O +by O +British O +- O +Irish O +migrants O +. O +. O + +Identification O +of O +constitutional O +WT1 O +mutations O +, O +in O +patients O +with O +isolated O +diffuse I +mesangial I +sclerosis I +, O +and O +analysis O +of O +genotype O +/ O +phenotype O +correlations O +by O +use O +of O +a O +computerized O +mutation O +database O +. O + +Constitutional O +mutations O +of O +the O +WT1 O +gene O +, O +encoding O +a O +zinc O +- O +finger O +transcription O +factor O +involved O +in O +renal O +and O +gonadal O +development O +, O +are O +found O +in O +most O +patients O +with O +Denys B +- I +Drash I +syndrome I +( O +DDS B +) O +, O +or O +diffuse B +mesangial I +sclerosis I +( O +DMS B +) O +associated O +with O +pseudohermaphroditism B +and O +/ O +or O +Wilms B +tumor I +( O +WT B +) O +. O + +Most O +mutations O +in O +DDS B +patients O +lie O +in O +exon O +8 O +or O +exon O +9 O +, O +encoding O +zinc O +finger O +2 O +or O +zinc O +finger O +3 O +, O +respectively O +, O +with O +a O +hot O +spot O +( O +R394W O +) O +in O +exon O +9 O +. O + +We O +analyzed O +a O +series O +of O +24 O +patients O +, O +10 O +with O +isolated O +DMS B +( O +IDMS B +) O +, O +10 O +with O +DDS B +, O +and O +4 O +with O +urogenital B +abnormalities I +and O +/ O +or O +WT B +. O + +We O +report O +WT1 O +heterozygous O +mutations O +in O +16 O +patients O +, O +4 O +of O +whom O +presented O +with O +IDMS B +. O + +One O +male O +and O +two O +female O +IDMS B +patients O +with O +WT1 O +mutations O +underwent O +normal O +puberty O +. O + +Two O +mutations O +associated O +with O +IDMS B +are O +different O +from O +those O +described O +in O +DDS B +patients O +. O + +No O +WT1 O +mutations O +were O +detected O +in O +the O +six O +other O +IDMS B +patients O +, O +suggesting O +genetic O +heterogeneity O +of O +this O +disease O +. O + +We O +analyzed O +genotype O +/ O +phenotype O +correlations O +, O +on O +the O +basis O +of O +the O +constitution O +of O +a O +WT1 O +mutation O +database O +of O +84 O +germ O +- O +line O +mutations O +, O +to O +compare O +the O +distribution O +and O +type O +of O +mutations O +, O +according O +to O +the O +different O +symptoms O +. O + +This O +demonstrated O +( O +1 O +) O +the O +association O +between O +mutations O +in O +exons O +8 O +and O +9 O +and O +DMS B +; O +( O +2 O +) O +among O +patients O +with O +DMS B +, O +a O +higher O +frequency O +of O +exon O +8 O +mutations O +among O +46 O +, O +XY O +patients O +with O +female O +phenotype O +than O +among O +46 O +, O +XY O +patients O +with O +sexual O +ambiguity O +or O +male O +phenotype O +; O +and O +( O +3 O +) O +statistically O +significant O +evidence O +that O +mutations O +in O +exons O +8 O +and O +9 O +preferentially O +affect O +amino O +acids O +with O +different O +functions O +. O +. O + +The O +185delAG O +BRCA1 O +mutation O +originated O +before O +the O +dispersion O +of O +Jews O +in O +the O +diaspora O +and O +is O +not O +limited O +to O +Ashkenazim O +. O + +The O +185delAG O +mutation O +in O +BRCA1 O +is O +detected O +in O +Ashkenazi O +Jews O +both O +in O +familial B +breast I +and I +ovarian I +cancer I +and O +in O +the O +general O +population O +. O + +All O +tested O +Ashkenazi O +mutation O +carriers O +share O +the O +same O +allelic O +pattern O +at O +the O +BRCA1 O +locus O +. O + +Our O +previous O +study O +showed O +that O +this O +Ashkenazi O +mutation O +also O +occurs O +in O +Iraqi O +Jews O +with O +a O +similar O +allelic O +pattern O +. O + +We O +extended O +our O +analysis O +to O +other O +non O +- O +Ashkenazi O +subsets O +354 O +of O +Moroccan O +origin O +, O +200 O +Yemenites O +and O +150 O +Iranian O +Jews O +. O + +Heteroduplex O +analysis O +complemented O +by O +direct O +DNA O +sequencing O +of O +abnormally O +migrating O +bands O +were O +employed O +. O + +Four O +of O +Moroccan O +origin O +( O +1 O +. O +1 O +% O +) O +and O +none O +of O +the O +Yemenites O +or O +Iranians O +was O +a O +carrier O +of O +the O +185delAG O +mutation O +. O + +BRCA1 O +allelic O +patterns O +were O +determined O +for O +four O +of O +these O +individuals O +and O +for O +12 O +additional O +non O +- O +Ashkenazi O +185delAG O +mutation O +carriers O +who O +had O +breast B +/ I +ovarian I +cancer I +. O + +Six O +non O +- O +Ashkenazi O +individuals O +shared O +the O +common O +Ashkenazi O +haplotype O +, O +four O +had O +a O +closely O +related O +pattern O +, O +and O +the O +rest O +( O +n O += O +6 O +) O +displayed O +a O +distinct O +BRCA1 O +allelic O +pattern O +. O + +We O +conclude O +that O +the O +185delAG O +BRCA1 O +mutation O +occurs O +in O +some O +non O +- O +Ashkenazi O +populations O +at O +rates O +comparable O +with O +that O +of O +Ashkenazim O +. O + +The O +majority O +of O +Jewish O +185delAG O +mutation O +carriers O +have O +a O +common O +allelic O +pattern O +, O +supporting O +the O +founder O +effect O +notion O +, O +but O +dating O +the O +mutations O +origin O +to O +an O +earlier O +date O +than O +currently O +estimated O +. O + +However O +, O +the O +different O +allelic O +pattern O +at O +the O +BRCA1 O +locus O +even O +in O +some O +Jewish O +mutation O +carriers O +, O +might O +suggest O +that O +the O +mutation O +arose O +independently O +. O +. O + +Crystal O +structure O +of O +the O +hemochromatosis B +protein O +HFE O +and O +characterization O +of O +its O +interaction O +with O +transferrin O +receptor O +. O + +HFE O +is O +an O +MHC O +- O +related O +protein O +that O +is O +mutated O +in O +the O +iron B +- I +overload I +disease I +hereditary B +hemochromatosis I +. O + +HFE O +binds O +to O +transferrin O +receptor O +( O +TfR O +) O +and O +reduces O +its O +affinity O +for O +iron O +- O +loaded O +transferrin O +, O +implicating O +HFE O +in O +iron O +metabolism O +. O + +The O +2 O +. O + +6 O +A O +crystal O +structure O +of O +HFE O +reveals O +the O +locations O +of O +hemochromatosis B +mutations O +and O +a O +patch O +of O +histidines O +that O +could O +be O +involved O +in O +pH O +- O +dependent O +interactions O +. O + +We O +also O +demonstrate O +that O +soluble O +TfR O +and O +HFE O +bind O +tightly O +at O +the O +basic O +pH O +of O +the O +cell O +surface O +, O +but O +not O +at O +the O +acidic O +pH O +of O +intracellular O +vesicles O +. O + +TfR O +HFE O +stoichiometry O +( O +2 O +1 O +) O +differs O +from O +TfR O +transferrin O +stoichiometry O +( O +2 O +2 O +) O +, O +implying O +a O +different O +mode O +of O +binding O +for O +HFE O +and O +transferrin O +to O +TfR O +, O +consistent O +with O +our O +demonstration O +that O +HFE O +, O +transferrin O +, O +and O +TfR O +form O +a O +ternary O +complex O +. O + +Identification O +of O +three O +novel O +mutations O +and O +a O +high O +frequency O +of O +the O +Arg778Leu O +mutation O +in O +Korean O +patients O +with O +Wilson B +disease I +. O + +Four O +mutations O +- O +- O +R778L O +, O +A874V O +, O +L1083F O +, O +and O +2304delC O +- O +- O +in O +the O +copper O +- O +transporting O +enzyme O +, O +P O +- O +type O +ATPase O +( O +ATP7B O +) O +, O +were O +identified O +in O +Korean O +Patients O +with O +Wilson B +disease I +. O + +Arg778Leu O +, O +the O +most O +frequently O +reported O +mutation O +of O +this O +enzyme O +, O +was O +found O +in O +six O +of O +eight O +unrelated O +patients O +studied O +, O +an O +allele O +frequency O +of O +37 O +. O + +5 O +% O +, O +which O +is O +considerably O +higher O +than O +those O +in O +other O +Asian O +populations O +. O + +The O +novel O +single O +nucleotide O +deletion O +, O +2304delC O +, O +was O +found O +in O +one O +patient O +. O + +Since O +a O +mutation O +at O +cDNA O +nucleotide O +2302 O +( O +2302insC O +) O +had O +been O +previously O +described O +, O +this O +region O +of O +the O +ATP7B O +gene O +may O +be O +susceptible O +to O +gene O +rearrangements O +causing O +Wilson B +disease I +. O + +Disruption O +of O +splicing O +regulated O +by O +a O +CUG O +- O +binding O +protein O +in O +myotonic B +dystrophy I +. O + +Myotonic B +dystrophy I +( O +DM B +) O +is O +caused O +by O +a O +CTG O +expansion O +in O +the O +3 O +untranslated O +region O +of O +the O +DM B +gene O +. O + +One O +model O +of O +DM B +pathogenesis O +suggests O +that O +RNAs O +from O +the O +expanded O +allele O +create O +a O +gain O +- O +of O +- O +function O +mutation O +by O +the O +inappropriate O +binding O +of O +proteins O +to O +the O +CUG O +repeats O +. O + +Data O +presented O +here O +indicate O +that O +the O +conserved O +heterogeneous O +nuclear O +ribonucleoprotein O +, O +CUG O +- O +binding O +protein O +( O +CUG O +- O +BP O +) O +, O +may O +mediate O +the O +trans O +- O +dominant O +effect O +of O +the O +RNA O +. O + +CUG O +- O +BP O +was O +found O +to O +bind O +to O +the O +human O +cardiac O +troponin O +T O +( O +cTNT O +) O +pre O +- O +messenger O +RNA O +and O +regulate O +its O +alternative O +splicing O +. O + +Splicing O +of O +cTNT O +was O +disrupted O +in O +DM B +striated O +muscle O +and O +in O +normal O +cells O +expressing O +transcripts O +that O +contain O +CUG O +repeats O +. O + +Altered O +expression O +of O +genes O +regulated O +posttranscriptionally O +by O +CUG O +- O +BP O +therefore O +may O +contribute O +to O +DM B +pathogenesis O +. O +. O + +Identification O +of O +a O +novel O +nonsense O +mutation O +and O +a O +missense O +substitution O +in O +the O +vasopressin O +- O +neurophysin O +II O +gene O +in O +two O +Spanish O +kindreds O +with O +familial B +neurohypophyseal I +diabetes I +insipidus I +. O + +Familial B +neurohypophyseal I +diabetes I +insipidus I +( O +FNDI B +) O +is O +an O +autosomal B +dominant I +disease I +caused O +by O +deficiency B +in I +the I +antidiuretic I +hormone I +arginine I +vasopressin I +( O +AVP O +) O +encoded O +by O +the O +AVP O +- O +neurophysin O +II O +( O +AVP O +- O +NPII O +) O +gene O +on O +chromosome O +20p13 O +. O + +In O +this O +study O +, O +we O +analyzed O +two O +families O +with O +FNDI B +using O +direct O +automated O +fluorescent O +, O +solid O +phase O +, O +single O +- O +stranded O +DNA O +sequencing O +of O +PCR O +- O +amplified O +AVP O +- O +NPII O +DNA O +. O + +In O +one O +of O +the O +families O +, O +affected O +individuals O +presented O +a O +novel O +nonsense O +mutation O +in O +exon O +3 O +of O +the O +gene O +, O +consisting O +in O +a O +G O +to O +T O +transition O +at O +nucleotide O +2101 O +, O +which O +produces O +a O +stop O +signal O +in O +codon O +82 O +( O +Glu O +) O +of O +NPII O +. O + +The O +premature O +termination O +eliminates O +part O +of O +the O +C O +- O +terminal O +domain O +of O +NPII O +, O +including O +a O +cysteine O +residue O +in O +position O +85 O +, O +which O +could O +be O +involved O +in O +the O +correct O +folding O +of O +the O +prohormone O +. O + +In O +the O +second O +family O +, O +a O +G279A O +substitution O +at O +position O +- O +1 O +of O +the O +signal O +peptide O +was O +observed O +in O +all O +affected O +individuals O +. O + +This O +missense O +mutation O +, O +which O +replaces O +Ala O +with O +Thr O +, O +is O +frequent O +among O +FNDI B +patients O +and O +is O +thought O +to O +reduce O +the O +efficiency O +of O +cleavage O +by O +signal O +peptidases O +. O +. O + +Genetic O +heterogeneity O +of O +Saethre B +- I +Chotzen I +syndrome I +, O +due O +to O +TWIST O +and O +FGFR O +mutations O +. 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O + +More O +than O +35 O +different O +TWIST O +mutations O +are O +now O +known O +in O +the O +literature O +. O + +The O +most O +common O +phenotypic O +features O +, O +present O +in O +more O +than O +a O +third O +of O +our O +patients O +with O +TWIST O +mutations O +, O +are O +coronal B +synostosis I +, O +brachycephaly B +, O +low B +frontal I +hairline I +, O +facial B +asymmetry I +, O +ptosis B +, O +hypertelorism B +, O +broad B +great I +toes I +, O +and O +clinodactyly B +. O + +Significant O +intra O +- O +and O +interfamilial O +phenotypic O +variability O +is O +present O +for O +either O +TWIST O +mutations O +or O +FGFR O +mutations O +. O + +The O +overlap O +in O +clinical O +features O +and O +the O +presence O +, O +in O +the O +same O +genes O +, O +of O +mutations O +for O +more O +than O +one O +craniosynostotic B +condition I +- O +such O +as O +Saethre B +- I +Chotzen I +, I +Crouzon I +, I +and I +Pfeiffer I +syndromes I +- O +support O +the O +hypothesis O +that O +TWIST O +and O +FGFRs O +are O +components O +of O +the O +same O +molecular O +pathway O +involved O +in O +the O +modulation O +of O +craniofacial O +and O +limb O +development O +in O +humans O +. O +. O + +Mutation O +analysis O +of O +UBE3A O +in O +Angelman B +syndrome I +patients O +. O + +Angelman B +syndrome I +( O +AS B +) O +is O +caused O +by O +chromosome O +15q11 O +- O +q13 O +deletions O +of O +maternal O +origin O +, O +by O +paternal B +uniparental I +disomy I +( O +UPD B +) O +15 I +, O +by O +imprinting O +defects O +, O +and O +by O +mutations O +in O +the O +UBE3A O +gene O +. O + +UBE3A O +encodes O +a O +ubiquitin O +- O +protein O +ligase O +and O +shows O +brain O +- O +specific O +imprinting O +. O + +Here O +we O +describe O +UBE3A O +coding O +- O +region O +mutations O +detected O +by O +SSCP O +analysis O +in O +13 O +AS B +individuals O +or O +families O +. O + +Two O +identical O +de O +novo O +5 O +- O +bp O +duplications O +in O +exon O +16 O +were O +found O +. O + +Among O +the O +other O +11 O +unique O +mutations O +, O +8 O +were O +small O +deletions O +or O +insertions O +predicted O +to O +cause O +frameshifts O +, O +1 O +was O +a O +mutation O +to O +a O +stop O +codon O +, O +1 O +was O +a O +missense O +mutation O +, O +and O +1 O +was O +predicted O +to O +cause O +insertion O +of O +an O +isoleucine O +in O +the O +hect O +domain O +of O +the O +UBE3A O +protein O +, O +which O +functions O +in O +E2 O +binding O +and O +ubiquitin O +transfer O +. O + +Eight O +of O +the O +cases O +were O +familial O +, O +and O +five O +were O +sporadic O +. O + +In O +two O +familial O +cases O +and O +one O +sporadic O +case O +, O +mosaicism O +for O +UBE3A O +mutations O +was O +detected O +in O +the O +mother O +of O +three O +AS O +sons O +, O +in O +the O +maternal O +grandfather O +of O +two O +AS O +first O +cousins O +, O +and O +in O +the O +mother O +of O +an O +AS B +daughter O +. O + +The O +frequencies O +with O +which O +we O +detected O +mutations O +were O +5 O +( O +14 O +% O +) O +of O +35 O +in O +sporadic O +cases O +and O +8 O +( O +80 O +% O +) O +of O +10 O +in O +familial O +cases O +. O +. O + +The O +hemochromatosis B +845 O +G O +- O +- O +> O +A O +and O +187 O +C O +- O +- O +> O +G O +mutations O +: O +prevalence O +in O +non O +- O +Caucasian O +populations O +. O + +Hemochromatosis B +, O +the O +inherited B +disorder I +of I +iron I +metabolism I +, O +leads O +, O +if O +untreated O +, O +to O +progressive O +iron B +overload I +and O +premature O +death I +. O + +The O +hemochromatosis B +gene O +, O +HFE O +, O +recently O +has O +been O +identified O +, O +and O +characterization O +of O +this O +gene O +has O +shown O +that O +it O +contains O +two O +mutations O +that O +result O +in O +amino O +acid O +substitutions O +- O +cDNA O +nucleotides O +845 O +G O +- O +- O +> O +A O +( O +C282Y O +) O +and O +187 O +C O +- O +- O +> O +G O +( O +H63D O +) O +. O + +Although O +hemochromatosis B +is O +common O +in O +Caucasians O +, O +affecting O +> O += O +1 O +/ O +300 O +individuals O +of O +northern O +European O +origin O +, O +it O +has O +not O +been O +recognized O +in O +other O +populations O +. O + +The O +present O +study O +used O +PCR O +and O +restriction O +- O +enzyme O +digestion O +to O +analyze O +the O +frequency O +of O +the O +845 O +G O +- O +- O +> O +A O +and O +187 O +C O +- O +- O +> O +G O +mutations O +in O +HLA O +- O +typed O +samples O +from O +non O +- O +Caucasian O +populations O +, O +comprising O +Australian O +Aboriginal O +, O +Chinese O +, O +and O +Pacific O +Islanders O +. O + +Results O +showed O +that O +the O +845 O +G O +- O +- O +> O +A O +mutation O +was O +present O +in O +these O +populations O +( O +allele O +frequency O +0 O +. O +32 O +% O +) O +, O +and O +, O +furthermore O +, O +it O +was O +always O +seen O +in O +conjunction O +with O +HLA O +haplotypes O +common O +in O +Caucasians O +, O +suggesting O +that O +845 O +G O +- O +- O +> O +A O +may O +have O +been O +introduced O +into O +these O +populations O +by O +Caucasian O +admixture O +. O + +187 O +C O +- O +- O +> O +G O +was O +present O +at O +an O +allele O +frequency O +of O +2 O +. O + +68 O +% O +in O +the O +two O +populations O +analyzed O +( O +Australian O +Aboriginal O +and O +Chinese O +) O +. O + +In O +the O +Australian O +Aboriginal O +samples O +, O +187 O +C O +- O +- O +> O +G O +was O +found O +to O +be O +associated O +with O +HLA O +haplotypes O +common O +in O +Caucasians O +, O +suggesting O +that O +it O +was O +introduced O +by O +recent O +admixture O +. O + +In O +the O +Chinese O +samples O +analyzed O +, O +187 O +C O +- O +- O +> O +G O +was O +present O +in O +association O +with O +a O +wide O +variety O +of O +HLA O +haplotypes O +, O +showing O +this O +mutation O +to O +be O +widespread O +and O +likely O +to O +predate O +the O +more O +genetically O +restricted O +845 O +G O +- O +- O +> O +A O +mutation O +. O + +Genotype O +- O +phenotype O +correlations O +in O +attenuated B +adenomatous I +polyposis I +coli I +. 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O + +Five O +novel O +germ O +- O +line O +APC B +mutations O +were O +identified O +in O +seven O +kindreds O +. O + +Mutations O +were O +located O +in O +three O +different O +regions O +of O +the O +APC B +gene O +( O +1 O +) O +at O +the O +5 O +end O +spanning O +exons O +4 O +and O +5 O +, O +( O +2 O +) O +within O +exon O +9 O +, O +and O +( O +3 O +) O +at O +the O +3 O +distal O +end O +of O +the O +gene O +. O + +Variability O +in O +the O +number O +of O +colorectal B +adenomas I +was O +most O +apparent O +in O +individuals O +with O +mutations O +in O +region O +1 O +, O +and O +upper O +- O +gastrointestinal O +manifestations O +were O +more O +severe O +in O +them O +. O + +In O +individuals O +with O +mutations O +in O +either O +region O +2 O +or O +region O +3 O +, O +the O +average O +number O +of O +adenomas B +tended O +to O +be O +lower O +than O +those O +in O +individuals O +with O +mutations O +in O +region O +1 O +, O +although O +age O +at O +diagnosis O +was O +similar O +. O + +In O +all O +AAPC B +kindreds O +, O +a O +predominance O +of O +right O +- O +sided O +colorectal B +adenomas I +and O +rectal B +polyp I +sparing O +was O +observed O +. O + +No O +desmoid B +tumors I +were O +found O +in O +these O +kindreds O +. O + +Our O +data O +suggest O +that O +, O +in O +AAPC B +families O +, O +the O +location O +of O +the O +APC B +mutation O +may O +partially O +predict O +specific O +phenotypic O +expression O +. O + +This O +should O +help O +in O +the O +design O +of O +tailored O +clinical O +- O +management O +protocols O +in O +this O +subset O +of O +FAP B +patients O +. O +. O + +Wilms B +' I +tumor I +1 O +and O +Dax O +- O +1 O +modulate O +the O +orphan O +nuclear O +receptor O +SF O +- O +1 O +in O +sex O +- O +specific O +gene O +expression O +. O + +Products O +of O +steroidogenic O +factor O +1 O +( O +SF O +- O +1 O +) O +and O +Wilms B +tumor I +1 O +( O +WT1 O +) O +genes O +are O +essential O +for O +mammalian O +gonadogenesis O +prior O +to O +sexual O +differentiation O +. O + +In O +males O +, O +SF O +- O +1 O +participates O +in O +sexual O +development O +by O +regulating O +expression O +of O +the O +polypeptide O +hormone O +Mullerian O +inhibiting O +substance O +( O +MIS O +) O +. O + +Here O +, O +we O +show O +that O +WT1 O +- O +KTS O +isoforms O +associate O +and O +synergize O +with O +SF O +- O +1 O +to O +promote O +MIS O +expression O +. O + +In O +contrast O +, O +WT1 O +missense O +mutations O +, O +associated O +with O +male B +pseudohermaphroditism I +in O +Denys B +- I +Drash I +syndrome I +, O +fail O +to O +synergize O +with O +SF O +- O +1 O +. O + +Additionally O +, O +the O +X O +- O +linked O +, O +candidate O +dosage O +- O +sensitive O +sex O +- O +reversal O +gene O +, O +Dax O +- O +1 O +, O +antagonizes O +synergy O +between O +SF O +- O +1 O +and O +WT1 O +, O +most O +likely O +through O +a O +direct O +interaction O +with O +SF O +- O +1 O +. O + +We O +propose O +that O +WT1 O +and O +Dax O +- O +1 O +functionally O +oppose O +each O +other O +in O +testis O +development O +by O +modulating O +SF O +- O +1 O +- O +mediated O +transactivation O +. O +. O + +A O +mouse O +model O +for O +Prader B +- I +Willi I +syndrome I +imprinting O +- O +centre O +mutations O +. O + +Imprinting O +in O +the O +15q11 O +- O +q13 O +region O +involves O +an O +imprinting O +centre O +( O +IC O +) O +, O +mapping O +in O +part O +to O +the O +promoter O +and O +first O +exon O +of O +SNRPN O +. O + +Deletion O +of O +this O +IC O +abolishes O +local O +paternally O +derived O +gene O +expression O +and O +results O +in O +Prader B +- I +Willi I +syndrome I +( O +PWS B +) O +. O + +We O +have O +created O +two O +deletion O +mutations O +in O +mice O +to O +understand O +PWS B +and O +the O +mechanism O +of O +this O +IC O +. O + +Mice O +harbouring O +an O +intragenic O +deletion O +in O +Snrpn O +are O +phenotypically O +normal O +, O +suggesting O +that O +mutations O +of O +SNRPN O +are O +not O +sufficient O +to O +induce O +PWS B +. O + +Mice O +with O +a O +larger O +deletion O +involving O +both O +Snrpn O +and O +the O +putative O +PWS B +- O +IC O +lack O +expression O +of O +the O +imprinted O +genes O +Zfp127 O +( O +mouse O +homologue O +of O +ZNF127 O +) O +, O +Ndn O +and O +Ipw O +, O +and O +manifest O +several O +phenotypes O +common O +to O +PWS B +infants O +. O + +These O +data O +demonstrate O +that O +both O +the O +position O +of O +the O +IC O +and O +its O +role O +in O +the O +coordinate O +expression O +of O +genes O +is O +conserved O +between O +mouse O +and O +human O +, O +and O +indicate O +that O +the O +mouse O +is O +a O +suitable O +model O +system O +in O +which O +to O +investigate O +the O +molecular O +mechanisms O +of O +imprinting O +in O +this O +region O +of O +the O +genome O +. O +. O + +Mutations O +of O +the O +ATM O +gene O +detected O +in O +Japanese O +ataxia B +- I +telangiectasia I +patients O +: O +possible O +preponderance O +of O +the O +two O +founder O +mutations O +4612del165 O +and O +7883del5 O +. O + +The O +ATM O +( O +A B +- I +T O +, O +mutated O +) O +gene O +on O +human O +chromosome O +11q22 O +. O + +3 O +has O +recently O +been O +identified O +as O +the O +gene O +responsible O +for O +the O +human O +recessive B +disease I +ataxia B +- I +telangiectasia I +( O +A B +- I +T I +) O +. 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O + +The O +others O +were O +minute O +deletions O +, O +4649delA O +in O +exon O +33 O +and O +7883del5 O +in O +exon O +55 O +. O + +The O +mutations O +4612del165 O +and O +7883del5 O +were O +found O +in O +more O +than O +two O +unrelated O +families O +; O +44 O +% O +( O +7 O +of O +16 O +) O +of O +the O +mutant O +alleles O +had O +one O +of O +the O +two O +mutations O +. O + +The O +4612del165 O +mutations O +in O +three O +different O +families O +were O +all O +ascribed O +to O +the O +same O +T O +- O +- O +> O +A O +substitution O +at O +the O +splice O +donor O +site O +in O +intron O +33 O +. O + +Microsatellite O +genotyping O +around O +the O +ATM O +locus O +also O +indicated O +that O +a O +common O +haplotype O +was O +shared O +by O +the O +mutant O +alleles O +in O +both O +mutations O +. O + +This O +suggests O +that O +these O +two O +founder O +mutations O +may O +be O +predominant O +among O +Japanese O +ATM O +mutant O +alleles O +. O + +W474C O +amino O +acid O +substitution O +affects O +early O +processing O +of O +the O +alpha O +- O +subunit O +of O +beta O +- O +hexosaminidase O +A O +and O +is O +associated O +with O +subacute O +G B +( I +M2 I +) I +gangliosidosis I +. O + +Mutations O +in O +the O +HEXA O +gene O +, O +encoding O +the O +alpha O +- O +subunit O +of O +beta O +- O +hexosaminidase O +A O +( O +Hex O +A O +) O +, O +that O +abolish O +Hex O +A O +enzyme O +activity O +cause O +Tay B +- I +Sachs I +disease I +( O +TSD B +) O +, O +the O +fatal O +infantile O +form O +of O +G B +( I +M2 I +) I +gangliosidosis I +, I +Type I +1 I +. O + +Less O +severe O +, O +subacute O +( O +juvenile O +- O +onset O +) O +and O +chronic O +( O +adult O +- O +onset O +) O +variants O +are O +characterized O +by O +a O +broad O +spectrum O +of O +clinical O +manifestations O +and O +are O +associated O +with O +residual O +levels O +of O +Hex O +A O +enzyme O +activity O +. O + +We O +identified O +a O +1422 O +G O +- O +- O +> O +C O +( O +amino O +acid O +W474C O +) O +substitution O +in O +the O +first O +position O +of O +exon O +13 O +of O +HEXA O +of O +a O +non O +- O +Jewish O +proband O +who O +manifested O +a O +subacute O +variant O +of O +G B +( I +M2 I +) I +gangliosidosis I +. O + +On O +the O +second O +maternally O +inherited O +allele O +, O +we O +identified O +the O +common O +infantile O +disease I +- O +causing O +4 O +- O +bp O +insertion O +, O ++ O +TATC O +1278 O +, O +in O +exon O +11 O +. O + +Pulse O +- O +chase O +analysis O +using O +proband O +fibroblasts O +revealed O +that O +the O +W474C O +- O +containing O +alpha O +- O +subunit O +precursor O +was O +normally O +synthesized O +, O +but O +not O +phosphorylated O +or O +secreted O +, O +and O +the O +mature O +lysosomal O +alpha O +- O +subunit O +was O +not O +detected O +. O + +When O +the O +W474C O +- O +containing O +alpha O +- O +subunit O +was O +transiently O +co O +- O +expressed O +with O +the O +beta O +- O +subunit O +to O +produce O +Hex O +A O +( O +alphabeta O +) O +in O +COS O +- O +7 O +cells O +, O +the O +mature O +alpha O +- O +subunit O +was O +present O +, O +but O +its O +level O +was O +much O +lower O +than O +that O +from O +normal O +alpha O +- O +subunit O +transfections O +, O +although O +higher O +than O +in O +those O +cells O +transfected O +with O +an O +alpha O +- O +subunit O +associated O +with O +infantile O +TSD B +. O + +Furthermore O +, O +the O +precursor O +level O +of O +the O +W474C O +alpha O +- O +subunit O +was O +found O +to O +accumulate O +in O +comparison O +to O +the O +normal O +alpha O +- O +subunit O +precursor O +levels O +. O + +We O +conclude O +that O +the O +1422 O +G O +- O +- O +> O +C O +mutation O +is O +the O +cause O +of O +Hex B +A I +enzyme I +deficiency I +in O +the O +proband O +. O + +The O +resulting O +W474C O +substitution O +clearly O +interferes O +with O +alpha O +- O +subunit O +processing O +, O +but O +because O +the O +base O +substitution O +falls O +at O +the O +first O +position O +of O +exon O +13 O +, O +aberrant O +splicing O +may O +also O +contribute O +to O +Hex B +A I +deficiency I +in O +this O +proband O +. O +. O + +Two O +frequent O +missense O +mutations O +in O +Pendred B +syndrome I +. O + +Pendred B +syndrome I +is O +an O +autosomal B +recessive I +disorder I +characterized O +by O +early O +childhood O +deafness B +and O +goiter B +. O + +A O +century O +after O +its O +recognition O +as O +a O +syndrome O +by O +Vaughan O +Pendred O +, O +the O +disease O +gene O +( O +PDS B +) O +was O +mapped O +to O +chromosome O +7q22 O +- O +q31 O +. O + +1 O +and O +, O +recently O +, O +found O +to O +encode O +a O +putative O +sulfate O +transporter O +. O + +We O +performed O +mutation O +analysis O +of O +the O +PDS B +gene O +in O +patients O +from O +14 O +Pendred B +families O +originating O +from O +seven O +countries O +and O +identified O +all O +mutations O +. O + +The O +mutations O +include O +three O +single O +base O +deletions O +, O +one O +splice O +site O +mutation O +and O +10 O +missense O +mutations O +. O + +One O +missense O +mutation O +( O +L236P O +) O +was O +found O +in O +a O +homozygous O +state O +in O +two O +consanguineous O +families O +and O +in O +a O +heterozygous O +state O +in O +five O +additional O +non O +- O +consanguineous O +families O +. O + +Another O +missense O +mutation O +( O +T416P O +) O +was O +found O +in O +a O +homozygous O +state O +in O +one O +family O +and O +in O +a O +heterozygous O +state O +in O +four O +families O +. O + +Pendred B +patients O +in O +three O +non O +- O +consanguineous O +families O +were O +shown O +to O +be O +compound O +heterozygotes O +for O +L236P O +and O +T416P O +. O + +In O +total O +, O +one O +or O +both O +of O +these O +mutations O +were O +found O +in O +nine O +of O +the O +14 O +families O +analyzed O +. O + +The O +identification O +of O +two O +frequent O +PDS B +mutations O +will O +facilitate O +the O +molecular O +diagnosis O +of O +Pendred B +syndrome I +. O + +Insertional O +mutation O +by O +transposable O +element O +, O +L1 O +, O +in O +the O +DMD B +gene O +results O +in O +X B +- I +linked I +dilated I +cardiomyopathy I +. O + +X B +- I +linked I +dilated I +cardiomyopathy I +( O +XLDCM B +) O +is O +a O +clinical O +phenotype O +of O +dystrophinopathy B +which O +is O +characterized O +by O +preferential O +myocardial O +involvement O +without O +any O +overt O +clinical O +signs O +of O +skeletal B +myopathy I +. O + +To O +date O +, O +several O +mutations O +in O +the O +Duchenne B +muscular I +dystrophy I +gene O +, O +DMD O +, O +have O +been O +identified O +in O +patients O +with O +XLDCM B +, O +but O +a O +pathogenic O +correlation O +of O +these O +cardiospecific O +mutations O +in O +DMD B +with O +the O +XLDCM B +phenotype O +has O +remained O +to O +be O +elucidated O +. O + +We O +report O +here O +the O +identification O +of O +a O +unique O +de O +novo O +L1 O +insertion O +in O +the O +muscle O +exon O +1 O +in O +DMD B +in O +three O +XLDCM B +patients O +from O +two O +unrelated O +Japanese O +families O +. O + +The O +insertion O +was O +a O +5 O +- O +truncated O +form O +of O +human O +L1 O +inversely O +integrated O +in O +the O +5 O +- O +untranslated O +region O +in O +the O +muscle O +exon O +1 O +, O +which O +affected O +the O +transcription O +or O +the O +stability O +of O +the O +muscle O +form O +of O +dystrophin O +transcripts O +but O +not O +that O +of O +the O +brain O +or O +Purkinje O +cell O +form O +, O +probably O +due O +to O +its O +unique O +site O +of O +integration O +. O + +We O +speculate O +that O +this O +insertion O +of O +an O +L1 O +sequence O +in O +DMD B +is O +responsible O +for O +some O +of O +the O +population O +of O +Japanese O +patients O +with O +XLDCM B +. O +. O + +Severe O +early O +- O +onset O +obesity B +, O +adrenal B +insufficiency I +and O +red B +hair I +pigmentation I +caused O +by O +POMC O +mutations O +in O +humans O +. O + +Sequential O +cleavage O +of O +the O +precursor O +protein O +pre O +- O +pro O +- O +opiomelanocortin O +( O +POMC O +) O +generates O +the O +melanocortin O +peptides O +adrenocorticotrophin O +( O +ACTH O +) O +, O +melanocyte O +- O +stimulating O +hormones O +( O +MSH O +) O +alpha O +, O +beta O +and O +gamma O +as O +well O +as O +the O +opioid O +- O +receptor O +ligand O +beta O +- O +endorphin O +. O + +While O +a O +few O +cases O +of O +isolated O +ACTH B +deficiency I +have O +been O +reported O +( O +OMIM O +201400 O +) O +, O +an O +inherited O +POMC B +defect I +has O +not O +been O +described O +so O +far O +. O + +Recent O +studies O +in O +animal O +models O +elucidated O +a O +central O +role O +of O +alpha O +- O +MSH O +in O +the O +regulation O +of O +food O +intake O +by O +activation O +of O +the O +brain O +melanocortin O +- O +4 O +- O +receptor O +( O +MC4 O +- O +R O +; O +refs O +3 O +- O +5 O +) O +and O +the O +linkage O +of O +human O +obesity B +to O +chromosome O +2 O +in O +close O +proximity O +to O +the O +POMC O +locus O +, O +led O +to O +the O +proposal O +of O +an O +association O +of O +POMC O +with O +human O +obesity B +. O + +The O +dual O +role O +of O +alpha O +- O +MSH O +in O +regulating O +food O +intake O +and O +influencing O +hair O +pigmentation O +predicts O +that O +the O +phenotype O +associated O +with O +a O +defect O +in O +POMC O +function O +would O +include O +obesity B +, O +alteration O +in O +pigmentation O +and O +ACTH B +deficiency I +. O + +The O +observation O +of O +these O +symptoms O +in O +two O +probands O +prompted O +us O +to O +search O +for O +mutations O +within O +their O +POMC B +genes O +. O + +Patient O +1 O +was O +found O +to O +be O +a O +compound O +heterozygote O +for O +two O +mutations O +in O +exon O +3 O +( O +G7013T O +, O +C7133delta O +) O +which O +interfere O +with O +appropriate O +synthesis O +of O +ACTH O +and O +alpha O +- O +MSH O +. O + +Patient O +2 O +was O +homozygous O +for O +a O +mutation O +in O +exon O +2 O +( O +C3804A O +) O +which O +abolishes O +POMC O +translation O +. O + +These O +findings O +represent O +the O +first O +examples O +of O +a O +genetic B +defect I +within O +the O +POMC B +gene O +and O +define O +a O +new O +monogenic B +endocrine I +disorder I +resulting O +in O +early O +- O +onset O +obesity B +, O +adrenal B +insufficiency I +and O +red B +hair I +pigmentation I +. O +. O + +A O +European O +multicenter O +study O +of O +phenylalanine B +hydroxylase I +deficiency I +: O +classification O +of O +105 O +mutations O +and O +a O +general O +system O +for O +genotype O +- O +based O +prediction O +of O +metabolic O +phenotype O +. O + +Phenylketonuria B +( O +PKU B +) O +and O +mild B +hyperphenylalaninemia I +( O +MHP B +) O +are O +allelic B +disorders I +caused O +by O +mutations O +in O +the O +gene O +encoding O +phenylalanine O +hydroxylase O +( O +PAH O +) O +. O + +Previous O +studies O +have O +suggested O +that O +the O +highly O +variable O +metabolic O +phenotypes O +of O +PAH B +deficiency I +correlate O +with O +PAH O +genotypes O +. O + +We O +identified O +both O +causative O +mutations O +in O +686 O +patients O +from O +seven O +European O +centers O +. O + +On O +the O +basis O +of O +the O +phenotypic O +characteristics O +of O +297 O +functionally O +hemizygous O +patients O +, O +105 O +of O +the O +mutations O +were O +assigned O +to O +one O +of O +four O +arbitrary O +phenotype O +categories O +. O + +We O +proposed O +and O +tested O +a O +simple O +model O +for O +correlation O +between O +genotype O +and O +phenotypic O +outcome O +. O + +The O +observed O +phenotype O +matched O +the O +predicted O +phenotype O +in O +79 O +% O +of O +the O +cases O +, O +and O +in O +only O +5 O +of O +184 O +patients O +was O +the O +observed O +phenotype O +more O +than O +one O +category O +away O +from O +that O +expected O +. O + +Among O +the O +seven O +contributing O +centers O +, O +the O +proportion O +of O +patients O +for O +whom O +the O +observed O +phenotype O +did O +not O +match O +the O +predicted O +phenotype O +was O +4 O +% O +- O +23 O +% O +( O +P O +< O +. O +0001 O +) O +, O +suggesting O +that O +differences O +in O +methods O +used O +for O +mutation O +detection O +or O +phenotype O +classification O +may O +account O +for O +a O +considerable O +proportion O +of O +genotype O +- O +phenotype O +inconsistencies O +. O + +Our O +data O +indicate O +that O +the O +PAH O +- O +mutation O +genotype O +is O +the O +main O +determinant O +of O +metabolic O +phenotype O +in O +most O +patients O +with O +PAH B +deficiency I +. O + +In O +the O +present O +study O +, O +the O +classification O +of O +105 O +PAH O +mutations O +may O +allow O +the O +prediction O +of O +the O +biochemical O +phenotype O +in O +> O +10 O +, O +000 O +genotypes O +, O +which O +may O +be O +useful O +for O +the O +management O +of O +hyperphenylalaninemia B +in O +newborns O +. O + +Somatic O +instability O +of O +the O +CTG O +repeat O +in O +mice O +transgenic O +for O +the O +myotonic B +dystrophy I +region O +is O +age O +dependent O +but O +not O +correlated O +to O +the O +relative O +intertissue O +transcription O +levels O +and O +proliferative O +capacities O +. O + +A O +( O +CTG O +) O +nexpansion O +in O +the O +3 O +- O +untranslated O +region O +( O +UTR O +) O +of O +the O +DM B +protein O +kinase O +gene O +( O +DMPK O +) O +is O +responsible O +for O +causing O +myotonic B +dystrophy I +( O +DM B +) O +. O + +Major O +instability O +, O +with O +very O +large O +expansions O +between O +generations O +and O +high O +levels O +of O +somatic O +mosaicism O +, O +is O +observed O +in O +patients O +. O + +There O +is O +a O +good O +correlation O +between O +repeat O +size O +( O +at O +least O +in O +leucocytes O +) O +, O +clinical O +severity O +and O +age O +of O +onset O +. O + +The O +trinucleotide O +repeat O +instability O +mechanisms O +involved O +in O +DM B +and O +other O +human O +genetic B +diseases I +are O +unknown O +. O + +We O +studied O +somatic O +instability O +by O +measuring O +the O +CTG O +repeat O +length O +at O +several O +ages O +in O +various O +tissues O +of O +transgenic O +mice O +carrying O +a O +( O +CTG O +) O +55expansion O +surrounded O +by O +45 O +kb O +of O +the O +human O +DM B +region O +, O +using O +small O +- O +pool O +PCR O +. O + +These O +mice O +have O +been O +shown O +to O +reproduce O +the O +intergenerational O +and O +somatic O +instability O +of O +the O +55 O +CTG O +repeat O +suggesting O +that O +surrounding O +sequences O +and O +the O +chromatin O +environment O +are O +involved O +in O +instability O +mechanisms O +. O + +As O +observed O +in O +some O +of O +the O +tissues O +of O +DM B +patients O +, O +there O +is O +a O +tendency O +for O +repeat O +length O +and O +somatic O +mosaicism O +to O +increase O +with O +the O +age O +of O +the O +mouse O +. O + +Furthermore O +, O +we O +observed O +no O +correlation O +between O +the O +somatic O +mutation O +rate O +and O +tissue O +proliferation O +capacity O +. O + +The O +somatic O +mutation O +rates O +in O +different O +tissues O +were O +also O +not O +correlated O +to O +the O +relative O +inter O +- O +tissue O +difference O +in O +transcriptional O +levels O +of O +the O +three O +genes O +( O +DMAHP O +, O +DMPK O +and O +59 O +) O +surrounding O +the O +repeat O +. O +. O + +A O +novel O +missense O +mutation O +in O +patients O +from O +a O +retinoblastoma B +pedigree O +showing O +only O +mild O +expression O +of O +the O +tumor B +phenotype O +. O + +We O +have O +used O +single O +strand O +conformation O +polymorphism O +analysis O +to O +study O +the O +27 O +exons O +of O +the O +RB1 O +gene O +in O +individuals O +from O +a O +family O +showing O +mild O +expression O +of O +the O +retinoblastoma B +phenotype O +. O + +In O +this O +family O +affected O +individuals O +developed O +unilateral B +tumors I +and O +, O +as O +a O +result O +of O +linkage O +analysis O +, O +unaffected O +mutation O +carriers O +were O +also O +identified O +within O +the O +pedigree O +. O + +A O +single O +band O +shift O +using O +SSCP O +was O +identified O +in O +exon O +21 O +which O +resulted O +in O +a O +missense O +mutation O +converting O +a O +cys O +- O +- O +> O +arg O +at O +nucleotide O +position O +28 O +in O +the O +exon O +. O + +The O +mutation O +destroyed O +an O +NdeI O +restriction O +enzyme O +site O +. O + +Analysis O +of O +all O +family O +members O +demonstrated O +that O +the O +missense O +mutation O +co O +- O +segregated O +with O +patients O +with O +tumors B +or O +who O +, O +as O +a O +result O +of O +linkage O +analysis O +had O +been O +predicted O +to O +carry O +the O +predisposing O +mutation O +. O + +These O +observations O +point O +to O +another O +region O +of O +the O +RB1 O +gene O +where O +mutations O +only O +modify O +the O +function O +of O +the O +gene O +and O +raise O +important O +questions O +for O +genetic O +counseling O +in O +families O +with O +these O +distinctive O +phenotypes O +. O +. O + +Maternal B +disomy I +and O +Prader B +- I +Willi I +syndrome I +consistent O +with O +gamete O +complementation O +in O +a O +case O +of O +familial O +translocation O +( O +3 O +; O +15 O +) O +( O +p25 O +; O +q11 O +. O +2 O +) O +. O + +Maternal B +uniparental I +disomy I +( O +UPD B +) O +for I +chromosome I +15 I +is O +responsible O +for O +an O +estimated O +30 O +% O +of O +cases O +of O +Prader B +- I +Willi I +syndrome I +( O +PWS B +) O +. O + +We O +report O +on O +an O +unusual O +case O +of O +maternal B +disomy I +15 I +in O +PWS B +that O +is O +most O +consistent O +with O +adjacent O +- O +1 O +segregation O +of O +a O +paternal O +t O +( O +3 O +; O +15 O +) O +( O +p25 O +; O +q11 O +. O +2 O +) O +with O +simultaneous O +maternal O +meiotic O +nondisjunction O +for O +chromosome O +15 O +. O + +The O +patient O +( O +J O +. O +B O +. O +) O +, O +a O +17 O +- O +year O +- O +old O +white O +male O +with O +PWS B +, O +was O +found O +to O +have O +47 O +chromosomes O +with O +a O +supernumerary O +, O +paternal O +der O +( O +15 O +) O +consisting O +of O +the O +short O +arm O +and O +the O +proximal O +long O +arm O +of O +chromosome O +15 O +, O +and O +distal O +chromosome O +arm O +3p O +. O + +The O +t O +( O +3 O +; O +15 O +) O +was O +present O +in O +the O +balanced O +state O +in O +the O +patients O +father O +and O +a O +sister O +. O + +Fluorescent O +in O +situ O +hybridization O +analysis O +demonstrated O +that O +the O +PWS B +critical O +region O +resided O +on O +the O +derivative O +chromosome O +3 O +and O +that O +there O +was O +no O +deletion O +of O +the O +PWS B +region O +on O +the O +normal O +pair O +of O +15s O +present O +in O +J O +. O + +B O +. O + +Methylation O +analysis O +at O +exon O +alpha O +of O +the O +small O +nuclear O +ribonucleoprotein O +- O +associated O +polypeptide O +N O +( O +SNRPN O +) O +gene O +showed O +a O +pattern O +characteristic O +of O +only O +the O +maternal O +chromosome O +15 O +in O +J O +. O + +B O +. O + +Maternal O +disomy O +was O +confirmed O +by O +polymerase O +chain O +reaction O +analysis O +of O +microsatellite O +repeats O +at O +the O +gamma O +- O +aminobutyric O +acid O +receptor O +beta3 O +subunit O +( O +GABRB3 O +) O +locus O +. O + +A O +niece O +( O +B O +. O +B O +. O +) O +with O +45 O +chromosomes O +and O +the O +derivative O +3 O +but O +without O +the O +der O +( O +15 O +) O +demonstrated O +a O +phenotype O +consistent O +with O +that O +reported O +for O +haploinsufficiency B +of I +distal I +3 I +p I +. O + +Uniparental B +disomy I +associated O +with O +unbalanced O +segregation O +of O +non O +- O +Robertsonian O +translocations O +has O +been O +reported O +previously O +but O +has O +not O +, O +to O +our O +knowledge O +, O +been O +observed O +in O +a O +case O +of O +PWS B +. O + +Furthermore O +, O +our O +findings O +are O +best O +interpreted O +as O +true O +gamete O +complementation O +resulting O +in O +maternal O +UPD B +15 I +and O +PWS B + +Schwartz B +- I +Jampel I +syndrome I +type I +2 I +and O +Stuve B +- I +Wiedemann I +syndrome I +: O +a O +case O +for O +" O +lumping O +" O +. O + +Recent O +studies O +demonstrated O +the O +existence O +of O +a O +genetically O +distinct O +, O +usually O +lethal O +form O +of O +the O +Schwartz B +- I +Jampel I +syndrome I +( O +SJS B +) O +of O +myotonia B +and O +skeletal B +dysplasia I +, O +which O +we O +called O +SJS B +type I +2 I +. O + +This O +disorder O +is O +reminiscent O +of O +another O +rare O +condition O +, O +the O +Stuve B +- I +Wiedemann I +syndrome I +( O +SWS B +) O +, O +which O +comprises O +campomelia B +at O +birth O +with O +skeletal B +dysplasia I +, O +contractures B +, O +and O +early O +death O +. O + +To O +test O +for O +possible O +nosologic O +identity O +between O +these O +disorders O +, O +we O +reviewed O +the O +literature O +and O +obtained O +a O +follow O +- O +up O +of O +the O +only O +two O +surviving O +patients O +, O +one O +with O +SJS B +type I +2 I +at O +age O +10 O +years O +and O +another O +with O +SWS B +at O +age O +7 O +years O +. O + +Patients O +reported O +as O +having O +either O +neonatal O +SJS B +or O +SWS B +presented O +a O +combination O +of O +a O +severe O +, O +prenatal O +- O +onset O +neuromuscular B +disorder I +( O +with O +congenital B +joint I +contractures I +, O +respiratory O +and O +feeding O +difficulties O +, O +tendency O +to O +hyperthermia B +, O +and O +frequent O +death O +in O +infancy O +) O +with O +a O +distinct O +campomelic B +- I +metaphyseal I +skeletal I +dysplasia I +. O + +The O +similarity O +of O +the O +clinical O +and O +radiographic O +findings O +is O +so O +extensive O +that O +these O +disorders O +appear O +to O +be O +a O +single O +entity O +. O + +The O +follow O +- O +up O +observation O +of O +an O +identical O +and O +unique O +pattern O +of O +progressive O +bone B +dysplasia I +in O +the O +two O +patients O +( O +one O +with O +SJS B +type I +2 I +, O +one O +with O +SWS B +) O +surviving O +beyond O +infancy O +adds O +to O +the O +evidence O +in O +favor O +of O +identity O +. O + +The O +hypothesis O +that O +SWS B +and O +SJS B +type I +2 I +are O +the O +same O +disorder O +should O +be O +testable O +by O +molecular O +methods O +. O +. O + +A O +mouse O +model O +of O +severe B +von I +Willebrand I +disease I +: O +defects O +in O +hemostasis I +and O +thrombosis B +. O + +von B +Willebrand I +factor I +( I +vWf I +) I +deficiency I +causes O +severe O +von B +Willebrand I +disease I +in O +humans O +. O + +We O +generated O +a O +mouse O +model O +for O +this O +disease O +by O +using O +gene O +targeting O +. O + +vWf B +- I +deficient I +mice O +appeared O +normal O +at O +birth O +; O +they O +were O +viable O +and O +fertile O +. O + +Neither O +vWf O +nor O +vWf O +propolypeptide O +( O +von B +Willebrand I +antigen O +II O +) O +were O +detectable O +in O +plasma O +, O +platelets O +, O +or O +endothelial O +cells O +of O +the O +homozygous O +mutant O +mice O +. O + +The O +mutant O +mice O +exhibited O +defects O +in O +hemostasis O +with O +a O +highly O +prolonged O +bleeding O +time O +and O +spontaneous O +bleeding B +events O +in O +approximately O +10 O +% O +of O +neonates O +. O + +As O +in O +the O +human O +disease O +, O +the O +factor O +VIII O +level O +in O +these O +mice O +was O +reduced O +strongly O +as O +a O +result O +of O +the O +lack O +of O +protection O +provided O +by O +vWf O +. O + +Defective O +thrombosis B +in O +mutant O +mice O +was O +also O +evident O +in O +an O +in O +vivo O +model O +of O +vascular B +injury I +. O + +In O +this O +model O +, O +the O +exteriorized O +mesentery O +was O +superfused O +with O +ferric O +chloride O +and O +the O +accumulation O +of O +fluorescently O +labeled O +platelets O +was O +observed O +by O +intravital O +microscopy O +. O + +We O +conclude O +that O +these O +mice O +very O +closely O +mimic O +severe O +human O +von B +Willebrand I +disease I +and O +will O +be O +very O +useful O +for O +investigating O +the O +role O +of O +vWf O +in O +normal O +physiology O +and O +in O +disease O +models O +. O +. O + +Oral O +contraceptives O +and O +the O +risk O +of O +hereditary B +ovarian I +cancer I +. O + +Hereditary B +Ovarian I +Cancer I +Clinical O +Study O +Group O +. O + +BACKGROUND O +Women O +with O +mutations O +in O +either O +the O +BRCA1 O +or O +the O +BRCA2 O +gene O +have O +a O +high O +lifetime O +risk O +of O +ovarian B +cancer I +. O + +Oral O +contraceptives O +protect O +against O +ovarian B +cancer I +in O +general O +, O +but O +it O +is O +not O +known O +whether O +they O +also O +protect O +against O +hereditary O +forms O +of I +ovarian B +cancer I +. O + +METHODS O +We O +enrolled O +207 O +women O +with O +hereditary B +ovarian I +cancer I +and O +161 O +of O +their O +sisters O +as O +controls O +in O +a O +case O +- O +control O +study O +. O + +All O +the O +patients O +carried O +a O +pathogenic O +mutation O +in O +either O +BRCA1 O +( O +179 O +women O +) O +or O +BRCA2 O +( O +28 O +women O +) O +. O + +The O +control O +women O +were O +enrolled O +regardless O +of O +whether O +or O +not O +they O +had O +either O +mutation O +. O + +Lifetime O +histories O +of O +oral O +- O +contraceptive O +use O +were O +obtained O +by O +interview O +or O +by O +written O +questionnaire O +and O +were O +compared O +between O +patients O +and O +control O +women O +, O +after O +adjustment O +for O +year O +of O +birth O +and O +parity O +. O + +RESULTS O +The O +adjusted O +odds O +ratio O +for O +ovarian B +cancer I +associated O +with O +any O +past O +use O +of O +oral O +contraceptives O +was O +0 O +. O + +5 O +( O +95 O +percent O +confidence O +interval O +, O +0 O +. O +3 O +to O +0 O +. O +8 O +) O +. O + +The O +risk O +decreased O +with O +increasing O +duration O +of O +use O +( O +P O +for O +trend O +, O +< O +0 O +. O +001 O +) O +; O +use O +for O +six O +or O +more O +years O +was O +associated O +with O +a O +60 O +percent O +reduction O +in O +risk O +. O + +Oral O +- O +contraceptive O +use O +protected O +against O +ovarian B +cancer I +both O +for O +carriers O +of O +the O +BRCA1 O +mutation O +( O +odds O +ratio O +, O +0 O +. O +5 O +; O +95 O +percent O +confidence O +interval O +, O +0 O +. O +3 O +to O +0 O +. O +9 O +) O +and O +for O +carriers O +of O +the O +BRCA2 O +mutation O +( O +odds O +ratio O +, O +0 O +. O +4 O +; O +95 O +percent O +confidence O +interval O +, O +0 O +. O +2 O +to O +1 O +. O +1 O +) O +. O + +CONCLUSIONS O +Oral O +- O +contraceptive O +use O +may O +reduce O +the O +risk O +of O +ovarian B +cancer I +in O +women O +with O +pathogenic O +mutations O +in O +the O +BRCA1 O +or O +BRCA2 O +gene O + +A O +Japanese O +family O +with O +adrenoleukodystrophy B +with O +a O +codon O +291 O +deletion O +: O +a O +clinical O +, O +biochemical O +, O +pathological O +, O +and O +genetic O +report O +. O + +We O +report O +a O +Japanese O +family O +with O +adrenoleukodystrophy B +( O +ALD B +) O +with O +a O +three O +base O +pair O +deletion O +( O +delGAG O +291 O +) O +in O +the O +ALD B +gene O +. O + +A O +variety O +of O +phenotypes O +were O +observed O +within O +this O +family O +. O + +While O +the O +proband O +( O +patient O +1 O +) O +was O +classified O +as O +having O +a O +rare O +intermediate O +type O +of O +adult O +cerebral O +and O +cerebello O +- O +brain O +stem O +forms O +, O +his O +younger O +brother O +( O +patient O +2 O +) O +and O +nephew O +( O +patient O +3 O +) O +had O +a O +childhood O +ALD B +type O +. O + +Another O +nephew O +( O +patient O +4 O +) O +of O +patient O +1 O +was O +classified O +as O +having O +an O +adolescent O +form O +. O + +The O +tau O +level O +in O +the O +cerebrospinal O +fluid O +( O +CSF O +) O +in O +patient O +1 O +was O +as O +high O +as O +that O +of O +patients O +with O +Alzheimers B +disease I +( O +AD B +) O +. O + +His O +brain O +magnetic O +resonance O +image O +( O +MRI O +) O +showed O +abnormalities O +in O +the O +bilateral O +cerebellar O +hemispheres O +and O +brain O +stem O +, O +but O +not O +in O +the O +cerebral O +white O +matter O +, O +where O +marked O +reductions O +of O +the O +cerebral O +blood O +flow O +and O +oxygen O +metabolism O +were O +clearly O +demonstrated O +by O +positron O +emission O +tomography O +( O +PET O +) O +. O + +In O +patients O +2 O +and O +3 O +, O +the O +autopsy O +findings O +showed O +massive O +demyelination B +of I +the I +cerebral I +white I +matter I +with O +sparing O +of O +the O +U O +- O +fibers O +, O +compatible O +with O +the O +findings O +of O +childhood O +ALD B +. O + +Oleic O +and O +erucic O +acids O +( O +Lorenzos O +Oil O +) O +were O +administered O +to O +patients O +1 O +and O +4 O +, O +but O +sufficient O +effectiveness O +was O +not O +obtained O +. O + +The O +findings O +in O +this O +family O +suggest O +that O +delGAG291 O +is O +part O +of O +the O +cause O +of O +Japanese O +ALD B +with O +phenotypic O +variations O +. O + +Moreover O +, O +although O +the O +scale O +of O +the O +study O +is O +limited O +, O +there O +is O +a O +possibility O +that O +PET O +can O +detect O +an O +insidious O +lesion O +which O +is O +undetectable O +by O +computed O +tomogram O +( O +CT O +) O +or O +MRI O +analysis O +, O +and O +that O +the O +higher O +level O +of O +tau O +reflects O +the O +process O +of O +neuronal B +degeneration I +in O +ALD B +. O + +Lorenzos O +Oil O +should O +be O +given O +in O +the O +early O +stage O +. O +. O + +Nonsense O +mutation O +in O +exon O +4 O +of O +human O +complement O +C9 O +gene O +is O +the O +major O +cause O +of O +Japanese O +complement B +C9 I +deficiency I +. O + +Deficiency B +of I +the I +ninth I +component I +of I +human I +complement I +( O +C9 O +) O +is O +the O +most O +common O +complement B +deficiency I +in O +Japan O +but O +is O +rare O +in O +other O +countries O +. O + +We O +studied O +the O +molecular O +basis O +of O +C9 B +deficiency I +in O +four O +Japanese O +C9 B +- I +deficient I +patients O +who O +had O +suffered O +from O +meningococcal B +meningitis I +. O + +Direct O +sequencing O +of O +amplified O +C9 O +cDNA O +and O +DNA O +revealed O +a O +nonsense O +substitution O +( O +CGA O +- O +- O +> O +TGA O +) O +at O +codon O +95 O +in O +exon O +4 O +in O +the O +four O +C9 B +- I +deficient I +individuals O +. O + +An O +allele O +- O +specific O +polymerase O +chain O +reaction O +system O +designed O +to O +detect O +exclusively O +only O +one O +of O +the O +normal O +and O +mutant O +alleles O +indicated O +that O +all O +the O +four O +patients O +were O +homozygous O +for O +the O +mutation O +in O +exon O +4 O +and O +that O +the O +parents O +of O +patient O +2 O +were O +heterozygous O +. O + +The O +common O +mutation O +at O +codon O +95 O +in O +exon O +4 O +might O +be O +responsible O +for O +most O +Japanese O +C9 B +deficiency I +. O +. O + +BRCA1 O +required O +for O +transcription O +- O +coupled O +repair O +of O +oxidative O +DNA O +damage O +. O + +The O +breast B +and I +ovarian I +cancer I +susceptibility O +gene O +BRCA1 O +encodes O +a O +zinc O +finger O +protein O +of O +unknown O +function O +. O + +Association O +of O +the O +BRCA1 O +protein O +with O +the O +DNA O +repair O +protein O +Rad51 O +and O +changes O +in O +the O +phosphorylation O +and O +cellular O +localization O +of O +the O +protein O +after O +exposure O +to O +DNA O +- O +damaging O +agents O +are O +consistent O +with O +a O +role O +for O +BRCA1 O +in O +DNA O +repair O +. O + +Here O +, O +it O +is O +shown O +that O +mouse O +embryonic O +stem O +cells O +deficient O +in O +BRCA1 O +are O +defective O +in O +the O +ability O +to O +carry O +out O +transcription O +- O +coupled O +repair O +of O +oxidative O +DNA O +damage O +, O +and O +are O +hypersensitive O +to O +ionizing O +radiation O +and O +hydrogen O +peroxide O +. O + +These O +results O +suggest O +that O +BRCA1 O +participates O +, O +directly O +or O +indirectly O +, O +in O +transcription O +- O +coupled O +repair O +of O +oxidative O +DNA O +damage O +. O +. O + +Truncation O +mutations O +in O +the O +transactivation O +region O +of O +PAX6 O +result O +in O +dominant O +- O +negative O +mutants O +. O + +PAX6 O +is O +a O +transcription O +factor O +with O +two O +DNA O +- O +binding O +domains O +( O +paired O +box O +and O +homeobox O +) O +and O +a O +proline O +- O +serine O +- O +threonine O +( O +PST O +) O +- O +rich O +transactivation O +domain O +. O + +PAX6 O +regulates O +eye O +development O +in O +animals O +ranging O +from O +jellyfish O +to O +Drosophila O +to O +humans O +. O + +Heterozygous O +mutations O +in O +the O +human O +PAX6 O +gene O +result O +in O +various O +phenotypes O +, O +including O +aniridia B +, O +Peters B +anomaly I +, O +autosomal B +dominant I +keratitis I +, O +and O +familial B +foveal I +dysplasia I +. O + +It O +is O +believed O +that O +the O +mutated O +allele O +of O +PAX6 O +produces O +an O +inactive O +protein O +and O +aniridia B +is O +caused O +due O +to O +genetic B +haploinsufficiency I +. O + +However O +, O +several O +truncation O +mutations O +have O +been O +found O +to O +occur O +in O +the O +C O +- O +terminal O +half O +of O +PAX6 O +in O +patients O +with O +Aniridia B +resulting O +in O +mutant O +proteins O +that O +retain O +the O +DNA O +- O +binding O +domains O +but O +have O +lost O +most O +of O +the O +transactivation O +domain O +. O + +It O +is O +not O +clear O +whether O +such O +mutants O +really O +behave O +as O +loss O +- O +of O +- O +function O +mutants O +as O +predicted O +by O +haploinsufficiency O +. O + +Contrary O +to O +this O +theory O +, O +our O +data O +showed O +that O +these O +mutants O +are O +dominant O +- O +negative O +in O +transient O +transfection O +assays O +when O +they O +are O +coexpressed O +with O +wild O +- O +type O +PAX6 O +. O + +We O +found O +that O +the O +dominant O +- O +negative O +effects O +result O +from O +the O +enhanced O +DNA O +binding O +ability O +of O +these O +mutants O +. O + +Kinetic O +studies O +of O +binding O +and O +dissociation O +revealed O +that O +various O +truncation O +mutants O +have O +3 O +- O +5 O +- O +fold O +higher O +affinity O +to O +various O +DNA O +- O +binding O +sites O +when O +compared O +with O +the O +wild O +- O +type O +PAX6 O +. O + +These O +results O +provide O +a O +new O +insight O +into O +the O +role O +of O +mutant O +PAX6 O +in O +causing O +aniridia B +. O +. O + +Reversal O +of O +severe O +hypertrophic B +cardiomyopathy I +and O +excellent O +neuropsychologic O +outcome O +in O +very B +- I +long I +- I +chain I +acyl I +- I +coenzyme I +A I +dehydrogenase I +deficiency I +. O + +Very B +- I +long I +- I +chain I +acyl I +- I +coenzyme I +A I +dehydrogenase I +( I +VLCAD I +) I +deficiency I +is O +a O +disorder O +of O +fatty O +acid O +beta O +oxidation O +that O +reportedly O +has O +high O +rates O +of O +morbidity O +and O +mortality O +. O + +We O +describe O +the O +outcome O +of O +a O +5 O +- O +year O +- O +old O +girl O +with O +VLCAD B +deficiency I +who O +was O +first O +seen O +at O +5 O +months O +of O +age O +with O +severe O +hypertrophic B +cardiomyopathy I +, O +hepatomegaly B +, O +encephalopathy B +, O +and O +hypotonia B +. O + +Biochemical O +studies O +indicated O +VLCAD B +deficiency I +caused O +by O +a O +stable O +yet O +inactive O +enzyme O +. O + +Molecular O +genetic O +analysis O +of O +her O +VLCAD O +gene O +revealed O +a O +T1372C O +( O +F458L O +) O +missense O +mutation O +and O +a O +1668 O +ACAG O +1669 O +splice O +site O +mutation O +. O + +After O +initial O +treatment O +with O +intravenous O +glucose O +and O +carnitine O +, O +the O +patient O +has O +thrived O +on O +a O +low O +- O +fat O +diet O +supplemented O +with O +medium O +- O +chain O +triglyceride O +oil O +and O +carnitine O +and O +avoidance O +of O +fasting O +. O + +Her O +ventricular B +hypertrophy I +resolved O +significantly O +over O +1 O +year O +, O +and O +cognitively O +, O +she O +is O +in O +the O +superior O +range O +for O +age O +. O + +Clinical O +recognition O +of O +VLCAD B +deficiency I +is O +important O +because O +it O +is O +one O +of O +the O +few O +directly O +treatable O +causes O +of O +cardiomyopathy B +in O +children O +. O +. O + +Cloning O +of O +a O +novel O +member O +of O +the O +low O +- O +density O +lipoprotein O +receptor O +family O +. O + +A O +gene O +encoding O +a O +novel O +transmembrane O +protein O +was O +identified O +by O +DNA O +sequence O +analysis O +within O +the O +insulin B +- I +dependent I +diabetes I +mellitus I +( O +IDDM B +) O +locus O +IDDM4 O +on O +chromosome O +11q13 O +. O + +Based O +on O +its O +chromosomal O +position O +, O +this O +gene O +is O +a O +candidate O +for O +conferring O +susceptibility O +to O +diabetes B +. O + +The O +gene O +, O +termed O +low O +- O +density O +lipoprotein O +receptor O +related O +protein O +5 O +( O +LRP5 O +) O +, O +encodes O +a O +protein O +of O +1615 O +amino O +acids O +that O +contains O +conserved O +modules O +which O +are O +characteristic O +of O +the O +low O +- O +density O +lipoprotein O +( O +LDL O +) O +receptor O +family O +. O + +These O +modules O +include O +a O +putative O +signal O +peptide O +for O +protein O +export O +, O +four O +epidermal O +growth O +factor O +( O +EGF O +) O +repeats O +with O +associated O +spacer O +domains O +, O +three O +LDL O +- O +receptor O +( O +LDLR O +) O +repeats O +, O +a O +single O +transmembrane O +spanning O +domain O +, O +and O +a O +cytoplasmic O +domain O +. O + +The O +encoded O +protein O +has O +a O +unique O +organization O +of O +EGF O +and O +LDLR O +repeats O +; O +therefore O +, O +LRP5 O +likely O +represents O +a O +new O +category O +of O +the O +LDLR O +family O +. O + +Both O +human O +and O +mouse O +LRP5 O +cDNAs O +have O +been O +isolated O +and O +the O +encoded O +mature O +proteins O +are O +95 O +% O +identical O +, O +indicating O +a O +high O +degree O +of O +evolutionary O +conservation O +. O +. O + +The O +APC B +variants O +I1307K O +and O +E1317Q O +are O +associated O +with O +colorectal B +tumors I +, O +but O +not O +always O +with O +a O +family O +history O +. O + +Classical B +familial I +adenomatous I +polyposis I +( O +FAP B +) O +is O +a O +high O +- O +penetrance O +autosomal B +dominant I +disease I +that O +predisposes O +to O +hundreds O +or O +thousands O +of O +colorectal B +adenomas I +and I +carcinoma I +and O +that O +results O +from O +truncating O +mutations O +in O +the O +APC B +gene O +. O + +A O +variant O +of O +FAP B +is O +attenuated B +adenomatous I +polyposis I +coli I +, O +which O +results O +from O +germ O +- O +line O +mutations O +in O +the O +5 O +and O +3 O +regions O +of O +the O +APC B +gene O +. O + +Attenuated B +adenomatous I +polyposis I +coli I +patients O +have O +" O +multiple O +" O +colorectal B +adenomas I +( O +typically O +fewer O +than O +100 O +) O +without O +the O +florid O +phenotype O +of O +classical O +FAP B +. O + +Another O +group O +of O +patients O +with O +multiple O +adenomas B +has O +no O +mutations O +in O +the O +APC B +gene O +, O +and O +their O +phenotype O +probably O +results O +from O +variation O +at O +a O +locus O +, O +or O +loci O +, O +elsewhere O +in O +the O +genome O +. O + +Recently O +, O +however O +, O +a O +missense O +variant O +of O +APC O +( O +I1307K O +) O +was O +described O +that O +confers O +an O +increased O +risk O +of O +colorectal B +tumors I +, O +including O +multiple O +adenomas B +, O +in O +Ashkenazim O +. O + +We O +have O +studied O +a O +set O +of O +164 O +patients O +with O +multiple O +colorectal B +adenomas I +and I +/ I +or O +carcinoma I +and O +analyzed O +codons O +1263 O +- O +1377 O +( O +exon O +15G O +) O +of O +the O +APC B +gene O +for O +germ O +- O +line O +variants O +. O + +Three O +patients O +with O +the O +I1307K O +allele O +were O +detected O +, O +each O +of O +Ashkenazi O +descent O +. O + +Four O +patients O +had O +a O +germ O +- O +line O +E1317Q O +missense O +variant O +of O +APC B +that O +was O +not O +present O +in O +controls O +; O +one O +of O +these O +individuals O +had O +an O +unusually O +large O +number O +of O +metaplastic B +polyps I +of I +the I +colorectum I +. O + +There O +is O +increasing O +evidence O +that O +there O +exist O +germ O +- O +line O +variants O +of O +the O +APC B +gene O +that O +predispose O +to O +the O +development O +of O +multiple O +colorectal B +adenomas I +and O +carcinoma I +, O +but O +without O +the O +florid O +phenotype O +of O +classical O +FAP B +, O +and O +possibly O +with O +importance O +for O +colorectal B +cancer I +risk O +in O +the O +general O +population O +. O +. O + +Genomic O +structure O +of O +the O +human O +congenital B +chloride I +diarrhea I +( O +CLD B +) O +gene O +. O + +Congenital B +chloride I +diarrhea I +( O +CLD B +) O +is O +caused O +by O +mutations O +in O +a O +gene O +which O +encodes O +an O +intestinal O +anion O +transporter O +. O + +We O +report O +here O +the O +complete O +genomic O +organization O +of O +the O +human O +CLD B +gene O +which O +spans O +approximately O +39kb O +, O +and O +comprises O +21 O +exons O +. O + +All O +exon O +/ O +intron O +boundaries O +conform O +to O +the O +GT O +/ O +AG O +rule O +. O + +An O +analysis O +of O +the O +putative O +promoter O +region O +sequence O +shows O +a O +putative O +TATA O +box O +and O +predicts O +multiple O +transcription O +factor O +binding O +sites O +. O + +The O +genomic O +structure O +was O +determined O +using O +DNA O +from O +several O +sources O +including O +multiple O +large O +- O +insert O +libaries O +and O +genomic O +DNA O +from O +Finnish O +CLD B +patients O +and O +controls O +. O + +Exon O +- O +specific O +primers O +developed O +in O +this O +study O +will O +facilitate O +mutation O +screening O +studies O +of O +patients O +with O +the O +disease O +. O + +Genomic O +sequencing O +of O +a O +BAC O +clone O +H O +_ O +RG364P16 O +revealed O +the O +presence O +of O +another O +, O +highly O +homologous O +gene O +3 O +of O +the O +CLD O +gene O +, O +with O +a O +similar O +genomic O +structure O +, O +recently O +identified O +as O +the O +Pendred B +syndrome I +gene O +( O +PDS B +) O +. O +. O + +The O +APCI1307K O +allele O +and O +cancer B +risk O +in O +a O +community O +- O +based O +study O +of O +Ashkenazi O +Jews O +. O + +Mutations O +in O +APC O +are O +classically O +associated O +with O +familial B +adenomatous I +polyposis I +( O +FAP B +) O +, O +a O +highly O +penetrant O +autosomal B +dominant I +disorder I +characterized O +by O +multiple O +intestinal B +polyps I +and O +, O +without O +surgical O +intervention O +, O +the O +development O +of O +colorectal B +cancer I +( O +CRC B +) O +. O + +APC O +is O +a O +tumour B +- O +suppressor O +gene O +, O +and O +somatic O +loss O +occurs O +in O +tumours B +. O + +The O +germline O +T O +- O +to O +- O +A O +transversion O +responsible O +for O +the O +APC B +I1307K O +allele O +converts O +the O +wild O +- O +type O +sequence O +to O +a O +homopolymer O +tract O +( O +A8 O +) O +that O +is O +genetically O +unstable O +and O +prone O +to O +somatic O +mutation O +. O + +The O +I1307K O +allele O +was O +found O +in O +6 O +. O + +1 O +% O +of O +unselected O +Ashkenazi O +Jews O +and O +higher O +proportions O +of O +Ashkenazim O +with O +family O +or O +personal O +histories O +of O +CRC B +( O +ref O +. O +2 O +) O +. O + +To O +evaluate O +the O +role O +of O +I1307K O +in O +cancer B +, O +we O +genotyped O +5 O +, O +081 O +Ashkenazi O +volunteers O +in O +a O +community O +survey O +. O + +Risk O +of O +developing O +colorectal B +, I +breast I +and I +other I +cancers I +were O +compared O +between O +genotyped O +I1307K O +carriers O +and O +non O +- O +carriers O +and O +their O +first O +- O +degree O +relatives O +. O + +Sperm O +DNA O +analysis O +in O +a O +Friedreich B +ataxia I +premutation O +carrier O +suggests O +both O +meiotic O +and O +mitotic O +expansion O +in O +the O +FRDA B +gene O +. O + +Friedreich B +ataxia I +is O +usually O +caused O +by O +an O +expansion O +of O +a O +GAA O +trinucleotide O +repeat O +in O +intron O +1 O +of O +the O +FRDA B +gene O +. O + +Occasionally O +, O +a O +fully O +expanded O +allele O +has O +been O +found O +to O +arise O +from O +a O +premutation O +of O +100 O +or O +less O +triplet O +repeats O +. O + +We O +have O +examined O +the O +sperm O +DNA O +of O +a O +premutation O +carrier O +. O + +This O +mans O +leucocyte O +DNA O +showed O +one O +normal O +allele O +and O +one O +allele O +of O +approximately O +100 O +repeats O +. O + +His O +sperm O +showed O +an O +expanded O +allele O +in O +a O +tight O +range O +centering O +on O +a O +size O +of O +approximately O +320 O +trinucleotide O +repeats O +. O + +His O +affected O +son O +has O +repeat O +sizes O +of O +1040 O +and O +540 O +. O + +These O +data O +suggest O +that O +expansion O +occurs O +in O +two O +stages O +, O +the O +first O +during O +meiosis O +followed O +by O +a O +second O +mitotic O +expansion O +. O + +We O +also O +show O +that O +in O +all O +informative O +carrier O +father O +to O +affected O +child O +transmissions O +, O +with O +the O +notable O +exception O +of O +the O +premutation O +carrier O +, O +the O +expansion O +size O +decreases O +. O +. O + +The O +R496H O +mutation O +of O +arylsulfatase O +A O +does O +not O +cause O +metachromatic B +leukodystrophy I +. O + +Deficiency B +of I +arylsulfatase I +A I +( O +ARSA O +) O +enzyme O +activity O +causes O +metachromatic B +leukodystrophy I +( O +MLD B +) O +. O + +A O +number O +of O +ARSA O +gene O +mutations O +responsible O +for O +MLD B +have O +been O +identified O +. O + +Recently O +, O +the O +R496H O +mutation O +of O +ARSA O +was O +proposed O +to O +be O +a O +cause O +of O +MLD B +( O +Draghia O +et O +al O +. O +, O +1997 O +) O +. O + +We O +have O +investigated O +the O +R496H O +mutation O +and O +found O +this O +mutation O +at O +a O +relatively O +high O +frequency O +in O +an O +African O +American O +population O +( O +f O += O +0 O +. O +09 O +, O +n O += O +61 O +subjects O +) O +. O + +The O +ARSA O +enzyme O +activity O +in O +subjects O +with O +and O +without O +the O +R496H O +mutation O +was O +determined O +and O +found O +to O +be O +normal O +. O + +It O +is O +therefore O +concluded O +that O +the O +R496H O +mutation O +of O +ARSA O +does O +not O +negatively O +influence O +the O +activity O +of O +ARSA O +and O +is O +not O +a O +cause O +of O +MLD B + +Down O +- O +regulation O +of O +transmembrane O +carbonic O +anhydrases O +in O +renal B +cell I +carcinoma I +cell O +lines O +by O +wild O +- O +type O +von B +Hippel I +- I +Lindau I +transgenes O +. O + +To O +discover O +genes O +involved O +in O +von B +Hippel I +- I +Lindau I +( O +VHL B +) O +- O +mediated O +carcinogenesis B +, O +we O +used O +renal B +cell I +carcinoma I +cell O +lines O +stably O +transfected O +with O +wild O +- O +type O +VHL B +- O +expressing O +transgenes O +. O + +Large O +- O +scale O +RNA O +differential O +display O +technology O +applied O +to O +these O +cell O +lines O +identified O +several O +differentially O +expressed O +genes O +, O +including O +an O +alpha O +carbonic O +anhydrase O +gene O +, O +termed O +CA12 O +. O + +The O +deduced O +protein O +sequence O +was O +classified O +as O +a O +one O +- O +pass O +transmembrane O +CA O +possessing O +an O +apparently O +intact O +catalytic O +domain O +in O +the O +extracellular O +CA O +module O +. O + +Reintroduced O +wild O +- O +type O +VHL O +strongly O +inhibited O +the O +overexpression O +of O +the O +CA12 O +gene O +in O +the O +parental O +renal B +cell I +carcinoma I +cell O +lines O +. O + +Similar O +results O +were O +obtained O +with O +CA9 O +, O +encoding O +another O +transmembrane O +CA O +with O +an O +intact O +catalytic O +domain O +. O + +Although O +both O +domains O +of O +the O +VHL B +protein O +contribute O +to O +regulation O +of O +CA12 O +expression O +, O +the O +elongin O +binding O +domain O +alone O +could O +effectively O +regulate O +CA9 O +expression O +. O + +We O +mapped O +CA12 O +and O +CA9 O +loci O +to O +chromosome O +bands O +15q22 O +and O +17q21 O +. O + +2 O +respectively O +, O +regions O +prone O +to O +amplification O +in O +some O +human O +cancers B +. O + +Additional O +experiments O +are O +needed O +to O +define O +the O +role O +of O +CA O +IX O +and O +CA O +XII O +enzymes O +in O +the O +regulation O +of O +pH O +in O +the O +extracellular O +microenvironment O +and O +its O +potential O +impact O +on O +cancer B +cell O +growth O +. O + +A O +gene O +encoding O +a O +transmembrane O +protein O +is O +mutated O +in O +patients O +with O +diabetes B +mellitus I +and O +optic B +atrophy I +( O +Wolfram B +syndrome I +) O +. O + +Wolfram B +syndrome I +( O +WFS B +; O +OMIM O +222300 O +) O +is O +an O +autosomal B +recessive I +neurodegenerative I +disorder I +defined O +by O +young O +- O +onset O +non B +- I +immune I +insulin I +- I +dependent I +diabetes I +mellitus I +and O +progressive O +optic B +atrophy I +. O + +Linkage O +to O +markers O +on O +chromosome O +4p O +was O +confirmed O +in O +five O +families O +. O + +On O +the O +basis O +of O +meiotic O +recombinants O +and O +disease O +- O +associated O +haplotypes O +, O +the O +WFS B +gene O +was O +localized O +to O +a O +BAC O +/ O +P1 O +contig O +of O +less O +than O +250 O +kb O +. O + +Mutations O +in O +a O +novel O +gene O +( O +WFS1 O +) O +encoding O +a O +putative O +transmembrane O +protein O +were O +found O +in O +all O +affected O +individuals O +in O +six O +WFS B +families O +, O +and O +these O +mutations O +were O +associated O +with O +the O +disease O +phenotype O +. O + +WFS1 O +appears O +to O +function O +in O +survival O +of O +islet O +beta O +- O +cells O +and O +neurons O +. O +. O + +Stable O +interaction O +between O +the O +products O +of O +the O +BRCA1 O +and O +BRCA2 O +tumor B +suppressor O +genes O +in O +mitotic O +and O +meiotic O +cells O +. O + +BRCA1 O +and O +BRCA2 O +account O +for O +most O +cases O +of O +familial O +, O +early O +onset O +breast B +and I +/ I +or I +ovarian I +cancer I +and O +encode O +products O +that O +each O +interact O +with O +hRAD51 O +. O + +Results O +presented O +here O +show O +that O +BRCA1 O +and O +BRCA2 O +coexist O +in O +a O +biochemical O +complex O +and O +colocalize O +in O +subnuclear O +foci O +in O +somatic O +cells O +and O +on O +the O +axial O +elements O +of O +developing O +synaptonemal O +complexes O +. O + +Like O +BRCA1 O +and O +RAD51 O +, O +BRCA2 O +relocates O +to O +PCNA O ++ O +replication O +sites O +following O +exposure O +of O +S O +phase O +cells O +to O +hydroxyurea O +or O +UV O +irradiation O +. O + +Thus O +, O +BRCA1 O +and O +BRCA2 O +participate O +, O +together O +, O +in O +a O +pathway O +( O +s O +) O +associated O +with O +the O +activation O +of O +double O +- O +strand O +break O +repair O +and O +/ O +or O +homologous O +recombination O +. O + +Dysfunction O +of O +this O +pathway O +may O +be O +a O +general O +phenomenon O +in O +the O +majority O +of O +cases O +of O +hereditary B +breast I +and I +/ I +or I +ovarian I +cancer I +. O +. O + +A O +novel O +Arg362Ser O +mutation O +in O +the O +sterol O +27 O +- O +hydroxylase O +gene O +( O +CYP27 O +) O +: O +its O +effects O +on O +pre O +- O +mRNA O +splicing O +and O +enzyme O +activity O +. O + +A O +novel O +C O +to O +A O +mutation O +in O +the O +sterol O +27 O +- O +hydroxylase O +gene O +( O +CYP27 O +) O +was O +identified O +by O +sequencing O +amplified O +CYP27 O +gene O +products O +from O +a O +patient O +with O +cerebrotendinous B +xanthomatosis I +( O +CTX B +) O +. O + +The O +mutation O +changed O +the O +adrenodoxin O +cofactor O +binding O +residue O +362Arg O +to O +362Ser O +( O +CGT O +362Arg O +to O +AGT O +362Ser O +) O +, O +and O +was O +responsible O +for O +deficiency O +in O +the O +sterol O +27 O +- O +hydroxylase O +activity O +, O +as O +confirmed O +by O +expression O +of O +mutant O +cDNA O +into O +COS O +- O +1 O +cells O +. O + +Quantitative O +analysis O +showed O +that O +the O +expression O +of O +CYP27 O +gene O +mRNA O +in O +the O +patient O +represented O +52 O +. O + +5 O +% O +of O +the O +normal O +level O +. O + +As O +the O +mutation O +occurred O +at O +the O +penultimate O +nucleotide O +of O +exon O +6 O +( O +- O +2 O +position O +of O +exon O +6 O +- O +intron O +6 O +splice O +site O +) O +of O +the O +gene O +, O +we O +hypothesized O +that O +the O +mutation O +may O +partially O +affect O +the O +normal O +splicing O +efficiency O +in O +exon O +6 O +and O +cause O +alternative O +splicing O +elsewhere O +, O +which O +resulted O +in O +decreased O +transcript O +in O +the O +patient O +. O + +Transfection O +of O +constructed O +minigenes O +, O +with O +or O +without O +the O +mutation O +, O +into O +COS O +- O +1 O +cells O +confirmed O +that O +the O +mutant O +minigene O +was O +responsible O +for O +a O +mRNA O +species O +alternatively O +spliced O +at O +an O +activated O +cryptic O +5 O +splice O +site O +88 O +bp O +upstream O +from O +the O +3 O +end O +of O +exon O +6 O +. O + +Our O +data O +suggest O +that O +the O +C O +to O +A O +mutation O +at O +the O +penultimate O +nucleotide O +of O +exon O +6 O +of O +the O +CYP27 O +gene O +not O +only O +causes O +the O +deficiency O +in I +the O +sterol O +27 O +- O +hydroxylase I +activity O +, O +but O +also O +partially O +leads O +to O +alternative O +pre O +- O +mRNA O +splicing O +of O +the O +gene O +. O + +To O +our O +knowledge O +, O +this O +is O +the O +first O +report O +regarding O +effects O +on O +pre O +- O +mRNA O +splicing O +of O +a O +mutation O +at O +the O +- O +2 O +position O +of O +a O +5 O +splice O +site O +. O + +ATM O +germline O +mutations O +in O +classical O +ataxia B +- I +telangiectasia I +patients O +in O +the O +Dutch O +population O +. O + +Germline O +mutations O +in O +the O +ATM O +gene O +are O +responsible O +for O +the O +autosomal B +recessive I +disorder I +ataxia B +- I +telangiectasia I +( O +A B +- I +T I +) O +. O + +In O +our O +study O +, O +we O +have O +determined O +the O +ATM O +mutation O +spectrum O +in O +19 O +classical O +A B +- I +T I +patients O +, O +including O +some O +immigrant O +populations O +, O +as O +well O +as O +12 O +of O +Dutch O +ethnic O +origin O +. O + +Both O +the O +protein O +truncation O +test O +( O +PTT O +) O +and O +the O +restriction O +endonuclease O +fingerprinting O +( O +REF O +) O +method O +were O +used O +and O +compared O +for O +their O +detection O +efficiency O +, O +identifying O +76 O +% O +and O +60 O +% O +of O +the O +mutations O +, O +respectively O +. O + +Most O +patients O +were O +found O +to O +be O +compound O +heterozygote O +. O + +Seventeen O +mutations O +were O +distinct O +, O +of O +which O +10 O +were O +not O +reported O +previously O +. O + +Mutations O +are O +small O +deletions O +or O +point O +mutations O +frequently O +affecting O +splice O +sites O +. O + +Moreover O +, O +a O +16 O +. O + +7 O +- O +kb O +genomic O +deletion O +of O +the O +3 O +end O +of O +the O +gene O +, O +most O +likely O +a O +result O +of O +recombination O +between O +two O +LINE O +elements O +, O +was O +identified O +. O + +The O +most O +frequently O +found O +mutation O +, O +identified O +in O +three O +unrelated O +Turkish O +A B +- I +T I +individuals O +, O +was O +previously O +described O +to O +be O +a O +Turkish O +A B +- I +T I +founder O +mutation O +. O + +The O +presence O +of O +a O +founder O +mutation O +among O +relatively O +small O +ethnic O +population O +groups O +in O +Western O +Europe O +could O +indicate O +a O +high O +carrier O +frequency O +in O +such O +communities O +. O + +In O +patients O +of O +Dutch O +ethnic O +origin O +, O +however O +, O +no O +significant O +founder O +effect O +could O +be O +identified O +. O + +The O +observed O +genetic O +heterogeneity O +including O +the O +relative O +high O +percentage O +of O +splice O +- O +site O +mutations O +had O +no O +reflection O +on O +the O +phenotype O +. O + +All O +patients O +manifested O +classical O +A B +- I +T I +and O +increased O +cellular O +radioresistant O +DNA O +synthesis O +. O + +Determination O +of O +the O +genomic O +structure O +of O +the O +COL4A4 O +gene O +and O +of O +novel O +mutations O +causing O +autosomal B +recessive I +Alport I +syndrome I +. O + +Autosomal B +recessive I +Alport I +syndrome I +is O +a O +progressive O +hematuric B +glomerulonephritis I +characterized O +by O +glomerular B +basement I +membrane I +abnormalities I +and O +associated O +with O +mutations O +in O +either O +the O +COL4A3 O +or O +the O +COL4A4 O +gene O +, O +which O +encode O +the O +alpha3 O +and O +alpha4 O +type O +IV O +collagen O +chains O +, O +respectively O +. O + +To O +date O +, O +mutation O +screening O +in O +the O +two O +genes O +has O +been O +hampered O +by O +the O +lack O +of O +genomic O +structure O +information O +. O + +We O +report O +here O +the O +complete O +characterization O +of O +the O +48 O +exons O +of O +the O +COL4A4 O +gene O +, O +a O +comprehensive O +gene O +screen O +, O +and O +the O +subsequent O +detection O +of O +10 O +novel O +mutations O +in O +eight O +patients O +diagnosed O +with O +autosomal B +recessive I +Alport I +syndrome I +. O + +Furthermore O +, O +we O +identified O +a O +glycine O +to O +alanine O +substitution O +in O +the O +collagenous O +domain O +that O +is O +apparently O +silent O +in O +the O +heterozygous O +carriers O +, O +in O +11 O +. O + +5 O +% O +of O +all O +control O +individuals O +, O +and O +in O +one O +control O +individual O +homozygous O +for O +this O +glycine O +substitution O +. O + +There O +has O +been O +no O +previous O +finding O +of O +a O +glycine O +substitution O +that O +is O +not O +associated O +with O +any O +obvious O +phenotype O +in O +homozygous O +individuals O +. O + +Founder O +BRCA1 O +and O +BRCA2 O +mutations O +in O +French O +Canadian O +breast B +and I +ovarian I +cancer I +families O +. O + +We O +have O +identified O +four O +mutations O +in O +each O +of O +the O +breast B +cancer I +- O +susceptibility O +genes O +, O +BRCA1 O +and O +BRCA2 O +, O +in O +French O +Canadian O +breast B +cancer I +and O +breast B +/ I +ovarian I +cancer I +families O +from O +Quebec O +. O + +To O +identify O +founder O +effects O +, O +we O +examined O +independently O +ascertained O +French O +Canadian O +cancer B +families O +for O +the O +distribution O +of O +these O +eight O +mutations O +. O + +Mutations O +were O +found O +in O +41 O +of O +97 O +families O +. O + +Six O +of O +eight O +mutations O +were O +observed O +at O +least O +twice O +. O + +The O +BRCA1 O +C4446T O +mutation O +was O +the O +most O +common O +mutation O +found O +, O +followed O +by O +the O +BRCA2 O +8765delAG O +mutation O +. O + +Together O +, O +these O +mutations O +were O +found O +in O +28 O +of O +41 O +families O +identified O +to O +have O +a O +mutation O +. O + +The O +odds O +of O +detection O +of O +any O +of O +the O +four O +BRCA1 O +mutations O +was O +18 O +. O + +7x O +greater O +if O +one O +or O +more O +cases O +of O +ovarian B +cancer I +were O +also O +present O +in O +the O +family O +. O + +The O +odds O +of O +detection O +of O +any O +of O +the O +four O +BRCA2 O +mutations O +was O +5 O +. O + +3x O +greater O +if O +there O +were O +at O +least O +five O +cases O +of O +breast B +cancer I +in O +the O +family O +. O + +Interestingly O +, O +the O +presence O +of O +a O +breast B +cancer I +case O +< O +36 O +years O +of O +age O +was O +strongly O +predictive O +of O +the O +presence O +of O +any O +of O +the O +eight O +mutations O +screened O +. O + +Carriers O +of O +the O +same O +mutation O +, O +from O +different O +families O +, O +shared O +similar O +haplotypes O +, O +indicating O +that O +the O +mutant O +alleles O +were O +likely O +to O +be O +identical O +by O +descent O +for O +a O +mutation O +in O +the O +founder O +population O +. O + +The O +identification O +of O +common O +BRCA1 O +and O +BRCA2 O +mutations O +will O +facilitate O +carrier O +detection O +in O +French O +Canadian O +breast B +cancer I +and O +breast B +/ I +ovarian I +cancer I +families O +. O + +Are O +Dp71 O +and O +Dp140 O +brain O +dystrophin O +isoforms O +related O +to O +cognitive B +impairment I +in O +Duchenne B +muscular I +dystrophy I +? O + +Molecular O +study O +and O +neuropsychological O +analysis O +were O +performed O +concurrently O +on O +49 O +patients O +with O +Duchenne B +muscular I +dystrophy I +( O +DMD B +) O +in O +order O +to O +find O +a O +molecular O +explanation O +for O +the O +cognitive B +impairment I +observed O +in O +most O +DMD B +patients O +. O + +Complete O +analysis O +of O +the O +dystrophin O +gene O +was O +performed O +to O +define O +the O +localization O +of O +deletions O +and O +duplications O +in O +relation O +to O +the O +different O +DMD B +promoters O +. O + +Qualitative O +analysis O +of O +the O +Dp71 O +transcript O +and O +testing O +for O +the O +specific O +first O +exon O +of O +Dp140 O +were O +also O +carried O +out O +. O + +Neuropsychological O +analysis O +assessed O +verbal O +and O +visuospatial O +intelligence O +, O +verbal O +memory O +, O +and O +reading O +skills O +. O + +Comparison O +of O +molecular O +and O +psychometric O +findings O +demonstrated O +that O +deletions O +and O +duplications O +that O +were O +localized O +in O +the O +distal O +part O +of O +the O +gene O +seemed O +to O +be O +preferentially O +associated O +with O +cognitive B +impairment I +. O + +Two O +altered O +Dp71 O +transcripts O +and O +two O +deleted O +Dp140 O +DNA O +sequences O +were O +found O +in O +four O +patients O +with O +severe O +cerebral B +dysfunction I +. O + +These O +findings O +suggest O +that O +some O +sequences O +located O +in O +the O +distal O +part O +of O +the O +gene O +and O +, O +in O +particular O +, O +some O +DMD B +isoforms O +expressed O +in O +the O +brain O +may O +be O +related O +to O +the O +cognitive B +impairment I +associated O +with O +DMD B +. O +. O + +I1307K O +APC B +and O +hMLH1 O +mutations O +in O +a O +non O +- O +Jewish O +family O +with O +hereditary B +non I +- I +polyposis I +colorectal I +cancer I +. O + +We O +describe O +a O +French O +Canadian O +hereditary B +non I +- I +polyposis I +colorectal I +cancer I +( O +HNPCC B +) O +kindred O +which O +carries O +a O +novel O +truncating O +mutation O +in O +hMLH1 O +. O + +Interestingly O +, O +the O +I1307K O +APC B +polymorphism O +, O +associated O +with O +an O +increased O +risk O +of O +colorectal B +cancer I +, O +is O +also O +present O +in O +this O +family O +. O + +The O +I1307K O +polymorphism O +has O +previously O +only O +been O +identified O +in O +individuals O +of O +self O +- O +reported O +Ashkenazi O +Jewish O +origins O +. O + +In O +addition O +, O +in O +this O +family O +, O +there O +appears O +to O +be O +no O +relationship O +between O +the O +I1307K O +polymorphism O +and O +the O +presence O +or O +absence O +of O +cancer B +. O +. O + +Identification O +of O +a O +novel O +mutation O +of O +the O +CPO O +gene O +in O +a O +Japanese O +hereditary B +coproporphyria I +family O +. O + +Hereditary B +coproporphyria I +( O +HCP B +) O +is O +an O +autosomal B +dominant I +disease I +characterized O +by O +a O +deficiency B +of I +coproporphyrinogen I +oxidase I +( O +CPO O +) O +caused O +by O +a O +mutation O +in O +the O +CPO O +gene O +. O + +Only O +11 O +mutations O +of O +the O +gene O +have O +been O +reported O +in O +HCP B +patients O +. O + +We O +report O +another O +mutation O +in O +a O +Japanese O +family O +. O + +Polymerase O +chain O +reaction O +- O +single O +strand O +conformational O +polymorphism O +and O +direct O +sequence O +analyses O +demonstrated O +a O +C O +to O +T O +substitution O +in O +exon O +1 O +of O +the O +CPO O +gene O +at O +nucleotide O +position O +85 O +, O +which O +lies O +in O +the O +putative O +presequence O +for O +targeting O +to O +mitochondria O +. O + +This O +mutation O +changes O +the O +codon O +for O +glutamine O +to O +a O +termination O +codon O +at O +amino O +acid O +position O +29 O +. O + +MaeI O +restriction O +analysis O +showed O +two O +other O +carriers O +in O +the O +family O +. O + +The O +C B +- I +T I +mutation O +is O +located O +within O +a O +recently O +proposed O +putative O +alternative O +translation O +initiation O +codon O +( O +TIC O +- O +1 O +) O +, O +supporting O +that O +TIC O +- O +1 O +is O +the O +real O +TIC O +rather O +than O +TIC O +- O +2 O +. O +. O + +Human B +complement I +factor I +H I +deficiency I +associated O +with O +hemolytic B +uremic I +syndrome I +. O + +This O +study O +reports O +on O +six O +cases O +of O +deficiency B +in I +the I +human I +complement I +regulatory I +protein I +Factor I +H I +( O +FH B +) O +in O +the O +context O +of O +an O +acute B +renal I +disease I +. O + +Five O +of O +the O +cases O +were O +observed O +in O +children O +presenting O +with O +idiopathic B +hemolytic I +uremic I +syndrome I +( O +HUS B +) O +. O + +Two O +of O +the O +children O +exhibited O +a O +homozygous O +deficiency O +characterized O +by O +the O +absence O +of O +the O +150 O +- O +kD O +form O +of O +Factor O +H O +and O +the O +presence O +, O +upon O +immunoblotting O +, O +of O +the O +42 O +- O +kD O +Factor O +H O +- O +like O +protein O +1 O +( O +FHL O +- O +1 O +) O +and O +other O +FH O +- O +related O +protein O +( O +FHR O +) O +bands O +. O + +Southern O +blot O +and O +PCR O +analysis O +of O +DNA O +of O +one O +patient O +with O +homozygous O +deficiency O +ruled O +out O +the O +presence O +of O +a O +large O +deletion O +of O +the O +FH B +gene O +as O +the O +underlying O +defect O +for O +the O +deficiency O +. O + +The O +other O +four O +children O +presented O +with O +heterozygous O +deficiency O +and O +exhibited O +a O +normal O +immunoblotting O +pattern O +of O +proteins O +of O +the O +FH B +family O +. O + +Factor B +H I +deficiency I +is O +the O +only O +complement B +deficiency I +associated O +with O +HUS B +. O + +These O +observations O +suggest O +a O +role O +for O +FH O +and O +/ O +or O +FH O +receptors O +in O +the O +pathogenesis O +of O +idiopathic O +HUS B +. O +. O + +Further O +evidence O +for O +a O +major O +ancient O +mutation O +underlying O +myotonic B +dystrophy I +from O +linkage O +disequilibrium O +studies O +in O +the O +Japanese O +population O +. O + +The O +myotonic B +dystrophy I +( O +DM B +) O +mutation O +is O +an O +unstable O +( O +CTG O +) O +n O +repeat O +, O +present O +at O +a O +copy O +number O +of O +5 O +- O +37 O +repeats O +on O +normal O +chromosomes O +but O +amplified O +to O +50 O +- O +3000 O +copies O +on O +DM B +chromosomes O +. O + +Previous O +findings O +in O +Caucasian O +populations O +of O +a O +DM B +founder O +chromosome O +raise O +a O +question O +about O +the O +molecular O +events O +involved O +in O +the O +expansion O +mutation O +. O + +To O +investigate O +whether O +a O +founder O +chromosome O +for O +the O +DM B +mutation O +exists O +in O +the O +Japanese O +population O +, O +we O +genotyped O +families O +using O +polymorphic O +markers O +near O +the O +( O +CTG O +) O +n O +repeat O +region O +and O +constructed O +haplotypes O +. O + +Six O +different O +haplotypes O +were O +found O +and O +DM B +alleles O +were O +always O +haplotype O +A O +. O + +To O +find O +an O +origin O +of O +the O +( O +CTG O +) O +n O +repeat O +mutation O +and O +to O +investigate O +the O +mechanism O +of O +the O +expansion O +mutation O +in O +the O +Japanese O +population O +we O +have O +studied O +90 O +Japanese O +DM B +families O +comprising O +190 O +affected O +and O +130 O +unaffected O +members O +. O + +The O +results O +suggest O +that O +a O +few O +common O +ancestral O +mutations O +in O +both O +Caucasian O +and O +Japanese O +populations O +have O +originated O +by O +expansion O +of O +an O +ancestral O +n O += O +5 O +repeat O +to O +n O += O +19 O +- O +37 O +copies O +. O + +These O +data O +support O +multistep O +models O +of O +triplet O +repeat O +expansion O +that O +have O +been O +proposed O +for O +both O +DM B +and O +Friedreichs B +ataxia I +. O +. O + +The O +molecular O +basis O +of O +C6 B +deficiency I +in O +the O +western O +Cape O +, O +South O +Africa O +. O + +Deficiency B +of I +the I +sixth I +component I +of I +human I +complement I +( O +C6 O +) O +has O +been O +reported O +in O +a O +number O +of O +families O +from O +the O +western O +Cape O +, O +South O +Africa O +. O + +Meningococcal B +disease I +is O +endemic O +in O +the O +Cape O +and O +almost O +all O +pedigrees O +of O +total B +C6 I +deficiency I +( O +C6Q0 O +) O +have O +been O +ascertained O +because O +of O +recurrent O +disease O +. O + +We O +have O +sequenced O +the O +expressed O +exons O +of O +the O +C6 O +gene O +from O +selected O +cases O +and O +have O +found O +three O +molecular B +defects I +leading O +to O +total B +deficiency I +879delG O +, O +which O +is O +the O +common O +defect O +in O +the O +Cape O +and O +hitherto O +unreported O +, O +and O +1195delC O +and O +1936delG O +, O +which O +have O +been O +previously O +reported O +in O +African O +- O +Americans O +. O + +We O +also O +show O +that O +the O +879delG O +and O +1195delC O +defects O +are O +associated O +with O +characteristic O +C6 O +/ O +C7 O +region O +DNA O +marker O +haplotypes O +, O +although O +small O +variations O +were O +observed O +. O + +The O +1936delG O +defect O +was O +observed O +only O +once O +in O +the O +Cape O +, O +but O +its O +associated O +haplotype O +could O +be O +deduced O +. O + +The O +data O +from O +the O +haplotypes O +indicate O +that O +these O +three O +molecular O +defects O +account O +for O +the O +defects O +in O +all O +the O +38 O +unrelated O +C6Q0 O +individuals O +we O +have O +studied O +from O +the O +Cape O +. O + +We O +have O +also O +observed O +the O +879delG O +defect O +in O +two O +Dutch O +C6 B +- I +deficient I +kindreds O +, O +but O +the O +879delG O +defect O +in O +the O +Cape O +probably O +did O +not O +come O +from O +The O +Netherlands O +. O +. O + +Complement B +C7 I +deficiency I +: O +seven O +further O +molecular O +defects O +and O +their O +associated O +marker O +haplotypes O +. O + +Seven O +further O +molecular O +bases O +of O +C7 B +deficiency I +are O +described O +. O + +All O +these O +new O +molecular B +defects O +involve O +single O +- O +nucleotide O +events O +, O +deletions O +and O +substitutions O +, O +some O +of O +which O +alter O +splice O +sites O +, O +and O +others O +codons O +. O + +They O +are O +distributed O +along O +the O +C7 O +gene O +, O +but O +predominantly O +towards O +the O +3 O +end O +. O + +All O +were O +found O +in O +compound O +heterozygous O +individuals O +. O + +The O +C6 O +/ O +C7 O +marker O +haplotypes O +associated O +with O +most O +C7 B +defects I +are O +tabulated O +. O +. O + +A O +genome O +- O +wide O +search O +for O +chromosomal O +loci O +linked O +to O +mental O +health O +wellness O +in O +relatives O +at O +high O +risk O +for O +bipolar B +affective I +disorder I +among O +the O +Old O +Order O +Amish O +. O + +Bipolar B +affective I +disorder I +( O +BPAD B +; O +manic B +- I +depressive I +illness I +) O +is O +characterized O +by O +episodes O +of O +mania B +and O +/ O +or O +hypomania B +interspersed O +with O +periods O +of O +depression B +. O + +Compelling O +evidence O +supports O +a O +significant O +genetic O +component O +in O +the O +susceptibility O +to O +develop O +BPAD B +. O + +To O +date O +, O +however O +, O +linkage O +studies O +have O +attempted O +only O +to O +identify O +chromosomal O +loci O +that O +cause O +or O +increase O +the O +risk O +of O +developing O +BPAD B +. O + +To O +determine O +whether O +there O +could O +be O +protective O +alleles O +that O +prevent O +or O +reduce O +the O +risk O +of O +developing O +BPAD B +, O +similar O +to O +what O +is O +observed O +in O +other O +genetic B +disorders I +, O +we O +used O +mental O +health O +wellness O +( O +absence O +of O +any O +psychiatric B +disorder I +) O +as O +the O +phenotype O +in O +our O +genome O +- O +wide O +linkage O +scan O +of O +several O +large O +multigeneration O +Old O +Order O +Amish O +pedigrees O +exhibiting O +an O +extremely O +high O +incidence O +of O +BPAD B +. O + +We O +have O +found O +strong O +evidence O +for O +a O +locus O +on O +chromosome O +4p O +at O +D4S2949 O +( O +maximum O +GENEHUNTER O +- O +PLUS O +nonparametric O +linkage O +score O += O +4 O +. O +05 O +, O +P O += O +5 O +. O +22 O +x O +10 O +( O +- O +4 O +) O +; O +SIBPAL O +Pempirical O +value O +< O +3 O +x O +10 O +( O +- O +5 O +) O +) O +and O +suggestive O +evidence O +for O +a O +locus O +on O +chromosome O +4q O +at O +D4S397 O +( O +maximum O +GENEHUNTER O +- O +PLUS O +nonparametric O +linkage O +score O += O +3 O +. O +29 O +, O +P O += O +2 O +. O +57 O +x O +10 O +( O +- O +3 O + +) O +; O +SIBPAL O +Pempirical O +value O +< O +1 O +x O +10 O +( O +- O +3 O +) O +) O +that O +are O +linked O +to O +mental O +health O +wellness O +. O + +These O +findings O +are O +consistent O +with O +the O +hypothesis O +that O +certain O +alleles O +could O +prevent O +or O +modify O +the O +clinical O +manifestations O +of O +BPAD B +and O +perhaps O +other O +related O +affective B +disorders I +. O + +Segregation O +distortion O +in O +myotonic B +dystrophy I +. O + +Myotonic B +dystrophy I +( O +DM B +) O +is O +an O +autosomal B +dominant I +disease I +which O +, O +in O +the O +typical O +pedigree O +, O +shows O +a O +three O +generation O +anticipation O +cascade O +. O + +This O +results O +in O +infertility B +and O +congenital B +myotonic I +dystrophy I +( O +CDM B +) O +with O +the O +disappearance O +of O +DM B +in O +that O +pedigree O +. O + +The O +concept O +of O +segregation O +distortion O +, O +where O +there O +is O +preferential O +transmission O +of O +the O +larger O +allele O +at O +the O +DM B +locus O +, O +has O +been O +put O +forward O +to O +explain O +partially O +the O +maintenance O +of O +DM B +in O +the O +population O +. O + +In O +a O +survey O +of O +DM B +in O +Northern O +Ireland O +, O +59 O +pedigrees O +were O +ascertained O +. O + +Sibships O +where O +the O +status O +of O +all O +the O +members O +had O +been O +identified O +were O +examined O +to O +determine O +the O +transmission O +of O +the O +DM B +expansion O +from O +affected O +parents O +to O +their O +offspring O +. O + +Where O +the O +transmitting O +parent O +was O +male O +, O +58 O +. O + +3 O +% O +of O +the O +offspring O +were O +affected O +, O +and O +in O +the O +case O +of O +a O +female O +transmitting O +parent O +, O +68 O +. O + +7 O +% O +were O +affected O +. O + +Studies O +on O +meiotic O +drive O +in O +DM B +have O +shown O +increased O +transmission O +of O +the O +larger O +allele O +at O +the O +DM B +locus O +in O +non O +- O +DM B +heterozygotes O +for O +CTGn O +. O + +This O +study O +provides O +further O +evidence O +that O +the O +DM B +expansion O +tends O +to O +be O +transmitted O +preferentially O +. O + +Diagnosis O +of O +hemochromatosis B +. O + +If O +untreated O +, O +hemochromatosis B +can O +cause O +serious O +illness O +and O +early O +death O +, O +but O +the O +disease O +is O +still O +substantially O +under O +- O +diagnosed O +. O + +The O +cornerstone O +of O +screening O +and O +case O +detection O +is O +the O +measurement O +of O +serum O +transferrin O +saturation O +and O +the O +serum O +ferritin O +level O +. O + +Once O +the O +diagnosis O +is O +suspected O +, O +physicians O +must O +use O +serum O +ferritin O +levels O +and O +hepatic O +iron O +stores O +on O +liver O +biopsy O +specimens O +to O +assess O +patients O +for O +the O +presence O +of O +iron B +overload I +. O + +Liver O +biopsy O +is O +also O +used O +to O +establish O +the O +presence O +or O +absence O +of O +cirrhosis B +, O +which O +can O +affect O +prognosis O +and O +management O +. O + +A O +DNA O +- O +based O +test O +for O +the O +HFE O +gene O +is O +commercially O +available O +, O +but O +its O +place O +in O +the O +diagnosis O +of O +hemochromatosis B +is O +still O +being O +evaluated O +. O + +Currently O +, O +the O +most O +useful O +role O +for O +this O +test O +is O +in O +the O +detection O +of O +hemochromatosis B +in O +the O +family O +members O +of O +patients O +with O +a O +proven O +case O +of O +the O +disease O +. O + +It O +is O +crucial O +to O +diagnose O +hemochromatosis B +before O +hepatic B +cirrhosis I +develops O +because O +phlebotomy O +therapy O +can O +avert O +serious O +chronic O +disease O +and O +can O +even O +lead O +to O +normal O +life O +expectancy O +. O +. O + +Prevalence O +of O +the O +I1307K O +APC B +gene O +variant O +in O +Israeli O +Jews O +of O +differing O +ethnic O +origin O +and O +risk O +for O +colorectal B +cancer I +. O + +BACKGROUND O +& O +AIMS O +Israeli O +Jews O +of O +European O +birth O +, O +i O +. O +e O +. O +, O +Ashkenazim O +, O +have O +the O +highest O +colorectal B +cancer I +incidence O +of O +any O +Israeli O +ethnic O +group O +. O + +The O +I1307K O +APC B +gene O +variant O +was O +found O +in O +6 O +. O + +1 O +% O +of O +American O +Jews O +, O +28 O +% O +of O +their O +familial B +colorectal I +cancer I +cases O +, O +but O +not O +in O +non O +- O +Jews O +. O + +We O +assessed O +the O +I1307K O +prevalence O +in O +Israeli O +Jews O +of O +differing O +ethnic O +origin O +and O +risk O +for O +colorectal B +cancer I +. O + +METHODS O +DNA O +samples O +from O +500 O +unrelated O +Jews O +of O +European O +or O +non O +- O +European O +origin O +, O +with O +or O +without O +a O +personal O +and O +/ O +or O +family O +history O +of O +neoplasia B +, O +were O +examined O +for O +the O +I1307K O +variant O +by O +the O +allele O +- O +specific O +oligonucleotide O +( O +ASO O +) O +method O +. O + +RESULTS O +In O +persons O +at O +average O +risk O +for O +colorectal B +cancer I +, O +I1307K O +was O +found O +in O +5 O +. O + +0 O +% O +of O +120 O +European O +and O +1 O +. O + +6 O +% O +of O +188 O +non O +- O +European O +Jews O +( O +P O += O +0 O +. O +08 O +) O +. O + +It O +occurred O +in O +15 O +. O + +4 O +% O +of O +52 O +Ashkenazi O +Israelis O +with O +familial B +cancer I +( O +P O += O +0 O +. O +02 O +) O +and O +was O +not O +detected O +in O +51 O +non O +- O +European O +Jews O +at O +increased O +cancer B +risk O +. O + +Colorectal B +neoplasia I +occurred O +personally O +or O +in O +the O +families O +of O +13 O +of O +20 O +Ashkenazi O +I1307K O +carriers O +, O +8 O +of O +whom O +also O +had O +a O +personal O +or O +family O +history O +of O +noncolonic B +neoplasia I +. O + +CONCLUSIONS O +The O +I1307K O +APC B +variant O +may O +represent O +a O +susceptibility O +gene O +for O +colorectal B +, I +or I +other I +, I +cancers I +in O +Ashkenazi O +Jews O +, O +and O +partially O +explains O +the O +higher O +incidence O +of O +colorectal B +cancer I +in O +European O +Israelis O +. O + +Systematic O +analysis O +of O +coproporphyrinogen O +oxidase O +gene I +defects I +in O +hereditary B +coproporphyria I +and O +mutation O +update O +. O + +Hereditary B +coproporphyria I +( O +HC B +) O +is O +an O +acute B +hepatic I +porphyria I +with O +autosomal O +dominant O +inheritance O +caused O +by O +deficient O +activity O +of O +coproporphyrinogen O +III O +oxidase O +( O +CPO O +) O +. O + +Clinical O +manifestations O +of O +the O +disease O +are O +characterized O +by O +acute O +attacks O +of O +neurological B +dysfunction I +often O +precipitated O +by O +drugs O +, O +fasting O +, O +cyclical O +hormonal O +changes O +, O +or O +infectious B +diseases I +. O + +Skin B +photosensitivity I +may O +also O +be O +present O +. O + +The O +seven O +exons O +, O +the O +exon O +/ O +intron O +boundaries O +and O +part O +of O +3 O +noncoding O +sequence O +of O +the O +CPO O +gene O +were O +systematically O +analyzed O +by O +an O +exon O +- O +by O +- O +exon O +denaturing O +gradient O +gel O +electrophoresis O +( O +DGGE O +) O +strategy O +followed O +by O +direct O +sequencing O +in O +seven O +unrelated O +heterozygous O +HC B +patients O +from O +France O +, O +Holland O +, O +and O +Czech O +Republic O +. O + +Seven O +novel O +mutations O +and O +two O +new O +polymorphisms O +were O +detected O +. O + +Among O +these O +mutations O +two O +are O +missense O +( O +G197W O +, O +W427R O +) O +, O +two O +are O +nonsense O +( O +Q306X O +, O +Q385X O +) O +, O +two O +are O +small O +deletions O +( O +662de14bp O +; O +1168del3bp O +removing O +a O +glycine O +at O +position O +390 O +) O +, O +and O +one O +is O +a O +splicing O +mutation O +( O +IVS1 O +- O +15c O +- O +- O +> O +g O +) O +which O +creates O +a O +new O +acceptor O +splice O +site O +. O + +The O +pathological O +significance O +of O +the O +point O +mutations O +G197W O +, O +W427R O +, O +and O +the O +in O +- O +frame O +deletion O +390delGly O +were O +assessed O +by O +their O +respective O +expression O +in O +a O +prokaryotic O +system O +using O +site O +- O +directed O +mutagenesis O +. O + +These O +mutations O +resulted O +in O +the O +absence O +or O +a O +dramatic O +decrease O +of O +CPO O +activity O +. O + +The O +two O +polymorphisms O +were O +localized O +in O +noncoding O +part O +of O +the O +gene O +1 O +) O +a O +C O +/ O +G O +polymorphism O +in O +the O +promotor O +region O +, O +142 O +bp O +upstream O +from O +the O +transcriptional O +initiation O +site O +( O +- O +142C O +/ O +G O +) O +, O +and O +2 O +) O +a O +6 O +bp O +deletion O +polymorphism O +in O +the O +3 O +noncoding O +part O +of O +the O +CPO O +gene O +, O +574 O +bp O +downstream O +of O +the O +last O +base O +of O +the O +normal O +termination O +codon O +( O ++ O +574 O +delATTCTT O +) O +. O + +Five O +intragenic O +dimorphisms O +are O +now O +well O +characterized O +and O +the O +high O +degree O +of O +allelic O +heterogeneity O +in O +HC B +is O +demonstrated O +with O +seven O +new O +different O +mutations O +making O +a O +total O +of O +nineteen O +CPO B +gene I +defects I +reported O +so O +far O +. O +. O + +Coincidence O +of O +two O +novel O +arylsulfatase O +A O +alleles O +and O +mutation O +459 O ++ O +1G O +> O +A O +within O +a O +family O +with O +metachromatic B +leukodystrophy I +: O +molecular O +basis O +of O +phenotypic O +heterogeneity O +. O + +In O +a O +family O +with O +three O +siblings O +, O +one O +developed O +classical O +late B +infantile I +metachromatic I +leukodystrophy I +( O +MLD B +) O +, O +fatal O +at O +age O +5 O +years O +, O +with O +deficient B +arylsulfatase O +A O +( O +ARSA O +) O +activity O +and O +increased O +galactosylsulfatide O +( O +GS O +) O +excretion O +. O + +The O +two O +other O +siblings O +, O +apparently O +healthy O +at O +12 O +( O +1 O +/ O +2 O +) O +and O +15 O +years O +, O +respectively O +, O +and O +their O +father O +, O +apparently O +healthy O +as O +well O +, O +presented O +ARSA O +and O +GS O +values O +within O +the O +range O +of O +MLD B +patients O +. O + +Mutation O +screening O +and O +sequence O +analysis O +disclosed O +the O +involvement O +of O +three O +different O +ARSA O +mutations O +being O +the O +molecular O +basis O +of O +intrafamilial O +phenotypic O +heterogeneity O +. O + +The O +late O +infantile O +patient O +inherited O +from O +his O +mother O +the O +frequent O +0 O +- O +type O +mutation O +459 O ++ O +1G O +> O +A O +, O +and O +from O +his O +father O +a O +novel O +, O +single O +basepair O +microdeletion O +of O +guanine O +at O +nucleotide O +7 O +in O +exon O +1 O +( O +7delG O +) O +. O + +The O +two O +clinically O +unaffected O +siblings O +carried O +the O +maternal O +mutation O +459 O ++ O +1G O +> O +A O +and O +, O +on O +their O +paternal O +allele O +, O +a O +novel O +cytosine O +to O +thymidine O +transition O +at O +nucleotide O +2435 O +in O +exon O +8 O +, O +resulting O +in O +substitution O +of O +alanine O +464 O +by O +valine O +( O +A464V O +) O +. O + +The O +fathers O +genotype O +thus O +was O +7delG O +/ O +A464V O +. O + +Mutation O +A464V O +was O +not O +found O +in O +18 O +unrelated O +MLD B +patients O +and O +50 O +controls O +. O + +A464V O +, O +although O +clearly O +modifying O +ARSA O +and O +GS O +levels O +, O +apparently O +bears O +little O +significance O +for O +clinical O +manifestation O +of O +MLD B +, O +mimicking O +the O +frequent O +ARSA O +pseudodeficiency O +allele O +. O + +Our O +results O +demonstrate O +that O +in O +certain O +genetic O +conditions O +MLD O +- O +like O +ARSA O +and O +GS O +values O +need O +not O +be O +paralleled O +by O +clinical O +disease O +, O +a O +finding O +with O +serious O +diagnostic O +and O +prognostic O +implications O +. O + +Moreover O +, O +further O +ARSA O +alleles O +functionally O +similar O +to O +A464V O +might O +exist O +which O +, O +together O +with O +0 O +- O +type O +mutations O +, O +may O +cause O +pathological O +ARSA O +and O +GS O +levels O +, O +but O +not O +clinical O +outbreak O +of O +the O +disease O +. O +. O + +Human O +MLH1 B +deficiency I +predisposes O +to O +hematological B +malignancy I +and O +neurofibromatosis B +type I +1 I +. O + +Heterozygous O +germ O +- O +line O +mutations O +in O +the O +DNA O +mismatch O +repair O +genes O +lead O +to O +hereditary B +nonpolyposis I +colorectal I +cancer I +. O + +The O +disease O +susceptibility O +of O +individuals O +who O +constitutionally O +lack O +both O +wild O +- O +type O +alleles O +is O +unknown O +. O + +We O +have O +identified O +three O +offspring O +in O +a O +hereditary B +nonpolyposis I +colorectal I +cancer I +family O +who O +developed O +hematological B +malignancy I +at O +a O +very O +early O +age O +, O +and O +at O +least O +two O +of O +them O +displayed O +signs O +of O +neurofibromatosis B +type I +1 I +( O +NF1 B +) O +. O + +DNA O +sequence O +analysis O +and O +allele O +- O +specific O +amplification O +in O +two O +siblings O +revealed O +a O +homozygous O +MLH1 O +mutation O +( O +C676T O +- O +- O +> O +Arg226Stop O +) O +. O + +Thus O +, O +a O +homozygous O +germ O +- O +line O +MLH1 O +mutation O +and O +consequent O +mismatch O +repair O +deficiency O +results O +in O +a O +mutator O +phenotype O +characterized O +by O +leukemia B +and I +/ I +or I +lymphoma I +associated O +with O +neurofibromatosis B +type I +1 I +. O +. O + +Missense O +mutations O +in O +the O +most O +ancient O +residues O +of O +the O +PAX6 O +paired O +domain O +underlie O +a O +spectrum O +of O +human O +congenital B +eye I +malformations I +. O + +Mutations O +of O +the O +human O +PAX6 O +gene O +underlie O +aniridia B +( O +congenital B +absence I +of I +the I +iris I +) O +, O +a O +rare O +dominant B +malformation I +of I +the I +eye I +. O + +The O +spectrum O +of O +PAX6 O +mutations O +in O +aniridia B +patients O +is O +highly O +biased O +, O +with O +92 O +% O +of O +all O +reported O +mutations O +leading O +to O +premature O +truncation O +of O +the O +protein O +( O +nonsense O +, O +splicing O +, O +insertions O +and O +deletions O +) O +and O +just O +2 O +% O +leading O +to O +substitution O +of O +one O +amino O +acid O +by O +another O +( O +missense O +) O +. O + +The O +extraordinary O +conservation O +of O +the O +PAX6 O +protein O +at O +the O +amino O +acid O +level O +amongst O +vertebrates O +predicts O +that O +pathological O +missense O +mutations O +should O +in O +fact O +be O +common O +even O +though O +they O +are O +hardly O +ever O +seen O +in O +aniridia B +patients O +. O + +This O +indicates O +that O +there O +is O +a O +heavy O +ascertainment O +bias O +in O +the O +selection O +of O +patients O +for O +PAX6 O +mutation O +analysis O +and O +that O +the O +missing O +PAX6 O +missense O +mutations O +frequently O +may O +underlie O +phenotypes O +distinct O +from O +textbook O +aniridia B +. O + +Here O +we O +present O +four O +novel O +PAX6 O +missense O +mutations O +, O +two O +in O +association O +with O +atypical O +phenotypes O +ectopia B +pupillae I +( O +displaced B +pupils I +) O +and O +congenital B +nystagmus I +( O +searching O +gaze I +) O +, O +and O +two O +in O +association O +with O +more O +recognizable O +aniridia B +phenotypes O +. O + +Strikingly O +, O +all O +four O +mutations O +are O +located O +within O +the O +PAX6 O +paired O +domain O +and O +affect O +amino O +acids O +which O +are O +highly O +conserved O +in O +all O +known O +paired O +domain O +proteins O +. O + +Our O +results O +support O +the O +hypothesis O +that O +the O +under O +- O +representation O +of O +missense O +mutations O +is O +caused O +by O +ascertainment O +bias O +and O +suggest O +that O +a O +substantial O +burden O +of O +PAX6 B +- I +related I +disease I +remains O +to O +be O +uncovered O +. O +. O + +The O +chromosomal O +order O +of O +genes O +controlling O +the O +major O +histocompatibility O +complex O +, O +properdin O +factor O +B O +, O +and O +deficiency B +of I +the I +second I +component I +of I +complement I +. O + +The O +relationship O +of O +the O +genes O +coding O +for O +HLA O +to O +those O +coding O +for O +properdin O +Factor O +B O +allotypes O +and O +for O +deficiency B +of I +the I +second I +component I +of I +complement I +( O +C2 O +) O +was O +studied O +in O +families O +of O +patients O +with O +connective B +tissue I +disorders I +. O + +Patients O +were O +selected O +because O +they O +were O +heterozygous O +or O +homozygous O +for O +C2 B +deficiency I +. O + +12 O +families O +with O +15 O +matings O +informative O +for O +C2 B +deficiency I +were O +found O +. O + +Of O +57 O +informative O +meioses O +, O +two O +crossovers O +were O +noted O +between O +the O +C2 B +deficiency I +gene O +and O +the O +HLA O +- O +B O +gene O +, O +with O +a O +recombinant O +fraction O +of O +0 O +. O + +035 O +. O + +A O +lod O +score O +of O +13 O +was O +calculated O +for O +linkage O +between O +C2 B +deficiency I +and O +HLA O +- O +B O +at O +a O +maximum O +likelihood O +value O +of O +the O +recombinant O +fraction O +of O +0 O +. O + +04 O +. O + +18 O +families O +with O +21 O +informative O +matings O +for O +both O +properdin O +Factor O +B O +allotype O +and O +HLA O +- O +B O +were O +found O +. O + +Of O +72 O +informative O +meioses O +, O +three O +recombinants O +were O +found O +, O +giving O +a O +recombinant O +fraction O +of O +0 O +. O + +042 O +. O + +A O +lod O +score O +of O +16 O +between O +HLA O +- O +B O +and O +Factor O +B O +allotypes O +was O +calculated O +at O +a O +maximum O +likelihood O +value O +of O +the O +recombinant O +fraction O +of O +0 O +. O + +04 O +. O + +A O +crossover O +was O +shown O +to O +have O +occurred O +between O +genes O +for O +Factor O +B O +and O +HLA O +- O +D O +, O +in O +which O +HLA O +- O +D O +segregared O +with O +HLA O +- O +A O +and O +B O +. O + +These O +studies O +suggest O +that O +the O +genes O +for O +Factor O +B O +and O +C2 B +deficiency I +are O +located O +outside O +those O +for O +HLA O +, O +that O +the O +order O +of O +genese O +is O +HLA O +- O +A O +, O +- O +B O +, O +- O +D O +, O +Factor O +B O +allotype O +, O +C2 B +deficiency I +, O +that O +the O +genes O +coding O +for O +C2 B +deficiency I +and O +Factor O +B O +allotypes O +are O +approximately O +3 O +- O +- O +5 O +centimorgans O +from O +the O +HLA O +- O +A O +and O +HLA O +- O +B O +loci O +, O +and O +that O +the O +apparent O +lack O +of O +recombinants O +between O +the O +Factor O +B O +gene O +and O +C2 B +deficiency I +gene O +suggests O +that O +these O +two O +genes O +lie O +in O +close O +proximity O +to O +one O +another O +. O + +Distribution O +of O +emerin O +and O +lamins O +in O +the O +heart O +and O +implications O +for O +Emery B +- I +Dreifuss I +muscular I +dystrophy I +. O + +Emerin O +is O +a O +nuclear O +membrane O +protein O +which O +is O +missing O +or O +defective O +in O +Emery B +- I +Dreifuss I +muscular I +dystrophy I +( O +EDMD B +) O +. O + +It O +is O +one O +member O +of O +a O +family O +of O +lamina O +- O +associated O +proteins O +which O +includes O +LAP1 O +, O +LAP2 O +and O +lamin O +B O +receptor O +( O +LBR O +) O +. O + +A O +panel O +of O +16 O +monoclonal O +antibodies O +( O +mAbs O +) O +has O +been O +mapped O +to O +six O +specific O +sites O +throughout O +the O +emerin O +molecule O +using O +phage O +- O +displayed O +peptide O +libraries O +and O +has O +been O +used O +to O +localize O +emerin O +in O +human O +and O +rabbit O +heart O +. O + +Several O +mAbs O +against O +different O +emerin O +epitopes O +did O +not O +recognize O +intercalated O +discs O +in O +the O +heart O +, O +though O +they O +recognized O +cardiomyocyte O +nuclei O +strongly O +, O +both O +at O +the O +rim O +and O +in O +intranuclear O +spots O +or O +channels O +. O + +A O +polyclonal O +rabbit O +antiserum O +against O +emerin O +did O +recognize O +both O +nuclear O +membrane O +and O +intercalated O +discs O +but O +, O +after O +affinity O +purification O +against O +a O +pure O +- O +emerin O +band O +on O +a O +western O +blot O +, O +it O +stained O +only O +the O +nuclear O +membrane O +. O + +These O +results O +would O +not O +be O +expected O +if O +immunostaining O +at O +intercalated O +discs O +were O +due O +to O +a O +product O +of O +the O +emerin O +gene O +and O +, O +therefore O +, O +cast O +some O +doubt O +upon O +the O +hypothesis O +that O +cardiac B +defects I +in O +EDMD B +are O +caused O +by O +absence O +of O +emerin O +from O +intercalated O +discs O +. O + +Although O +emerin O +was O +abundant O +in O +the O +membranes O +of O +cardiomyocyte O +nuclei O +, O +it O +was O +absent O +from O +many O +non O +- O +myocyte O +cells O +in O +the O +heart O +. O + +This O +distribution O +of O +emerin O +was O +similar O +to O +that O +of O +lamin O +A O +, O +a O +candidate O +gene O +for O +an O +autosomal O +form O +of O +EDMD B +. O + +In O +contrast O +, O +lamin O +B1 O +was O +absent O +from O +cardiomyocyte O +nuclei O +, O +showing O +that O +lamin O +B1 O +is O +not O +essential O +for O +localization O +of O +emerin O +to O +the O +nuclear O +lamina O +. O + +Lamin O +B1 O +is O +also O +almost O +completely O +absent O +from O +skeletal O +muscle O +nuclei O +. O + +In O +EDMD B +, O +the O +additional O +absence O +of O +lamin O +B1 O +from O +heart O +and O +skeletal O +muscle O +nuclei O +which O +already O +lack O +emerin O +may O +offer O +an O +alternative O +explanation O +of O +why O +these O +tissues O +are O +particularly O +affected O +. O +. O + +Genetic O +mapping O +of O +the O +copper B +toxicosis I +locus O +in O +Bedlington O +terriers O +to O +dog O +chromosome O +10 O +, O +in O +a O +region O +syntenic O +to O +human O +chromosome O +region O +2p13 O +- O +p16 O +. O + +Abnormal O +hepatic I +copper I +accumulation I +is O +recognized O +as O +an O +inherited B +disorder I +in O +man O +, O +mouse O +, O +rat O +and O +dog O +. O + +The O +major O +cause O +of O +hepatic O +copper I +accumulation I +in O +man O +is O +a O +dysfunctional O +ATP7B O +gene O +, O +causing O +Wilson B +disease I +( O +WD B +) O +. O + +Mutations O +in O +the O +ATP7B O +genes O +have O +also O +been O +demonstrated O +in O +mouse O +and O +rat O +. O + +The O +ATP7B O +gene O +has O +been O +excluded O +in O +the O +much O +rarer O +human O +copper B +overload I +disease O +non O +- O +Indian O +childhood O +cirrhosis B +, O +indicating O +genetic O +heterogeneity O +. O + +By O +investigating O +the O +common O +autosomal B +recessive I +copper I +toxicosis I +( O +CT B +) O +in O +Bedlington O +terriers O +, O +we O +have O +identified O +a O +new O +locus O +involved O +in O +progressive O +liver B +disease I +. O + +We O +examined O +whether O +the O +WD B +gene O +ATP7B O +was O +also O +causative O +for O +CT B +by O +investigating O +the O +chromosomal O +co O +- O +localization O +of O +ATP7B O +and O +C04107 O +, O +using O +fluorescence O +in O +situ O +hybridization O +( O +FISH O +) O +. O + +C04107 O +is O +an O +anonymous O +microsatellite O +marker O +closely O +linked O +to O +CT O +. O + +However O +, O +BAC O +clones O +containing O +ATP7B O +and O +C04107 O +mapped O +to O +the O +canine O +chromosome O +regions O +CFA22q11 O +and O +CFA10q26 O +, O +respectively O +, O +demonstrating O +that O +WD B +cannot O +be O +homologous O +to O +CT O +. O + +The O +copper O +transport O +genes O +CTR1 O +and O +CTR2 O +were O +also O +excluded O +as O +candidate O +genes O +for O +CT B +since O +they O +both O +mapped O +to O +canine O +chromosome O +region O +CFA11q22 O +. O + +2 O +- O +22 O +. O + +5 O +. O + +A O +transcribed O +sequence O +identified O +from O +the O +C04107 O +- O +containing O +BAC O +was O +found O +to O +be O +homologous O +to O +a O +gene O +expressed O +from O +human O +chromosome O +2p13 O +- O +p16 O +, O +a O +region O +devoid O +of O +any O +positional O +candidate O +genes O +. O + +Molecular O +analysis O +of O +the O +APC B +gene O +in O +205 O +families O +: O +extended O +genotype O +- O +phenotype O +correlations O +in O +FAP B +and O +evidence O +for O +the O +role O +of O +APC B +amino O +acid O +changes O +in O +colorectal B +cancer I +predisposition O +. O + +BACKGROUND O +/ O +AIMS O +The O +development O +of O +colorectal B +cancer I +and O +a O +variable O +range O +of O +extracolonic O +manifestations O +in O +familial B +adenomatous I +polyposis I +( O +FAP B +) O +is O +the O +result O +of O +the O +dominant O +inheritance O +of O +adenomatous B +polyposis I +coli I +( O +APC B +) O +gene O +mutations O +. O + +In O +this O +study O +, O +direct O +mutation O +analysis O +of O +the O +APC B +gene O +was O +performed O +to O +determine O +genotype O +- O +phenotype O +correlations O +for O +nine O +extracolonic O +manifestations O +and O +to O +investigate O +the O +incidence O +of O +APC B +mutations O +in O +non B +- I +FAP I +colorectal I +cancer I +. O + +METHODS O +The O +APC B +gene O +was O +analysed O +in O +190 O +unrelated O +FAP B +and I +15 O +non O +- I +FAP I +colorectal B +cancer I +patients O +using O +denaturing O +gradient O +gel O +electrophoresis O +, O +the O +protein O +truncation O +test O +, O +and O +direct O +sequencing O +. O + +RESULTS O +Chain O +terminating O +signals O +were O +only O +identified O +in O +patients O +belonging O +to O +the O +FAP B +group O +( O +105 O +patients O +) O +. O + +Amino O +acid O +changes O +were O +identified O +in O +four O +patients O +, O +three O +of O +whom O +belonged O +to O +the O +non O +- O +FAP O +group O +of O +colorectal B +cancer I +patients O +. O + +Genotype O +- O +phenotype O +correlations O +identified O +significant O +differences O +in O +the O +nature O +of O +certain O +extracolonic O +manifestations O +in O +FAP B +patients O +belonging O +to O +three O +mutation O +subgroups O +. O + +CONCLUSIONS O +Extended O +genotype O +- O +phenotype O +correlations O +made O +in O +this O +study O +may O +have O +the O +potential O +to O +determine O +the O +most O +appropriate O +surveillance O +and O +prophylactic O +treatment O +regimens O +for O +those O +patients O +with O +mutations O +associated O +with O +life O +threatening O +conditions O +. O + +This O +study O +also O +provided O +evidence O +for O +the O +pathological O +nature O +of O +amino O +acid O +changes O +in O +APC O +associated O +with O +both O +FAP B +and O +non I +- I +FAP I +colorectal I +cancer I +patients O +. O +. O + +Inherited B +colorectal I +polyposis I +and O +cancer B +risk O +of O +the O +APC B +I1307K O +polymorphism O +. O + +Germ O +- O +line O +and O +somatic O +truncating O +mutations O +of O +the O +APC B +gene O +are O +thought O +to O +initiate O +colorectal B +tumor I +formation O +in O +familial B +adenomatous I +polyposis I +syndrome I +and O +sporadic B +colorectal I +carcinogenesis I +, O +respectively O +. O + +Recently O +, O +an O +isoleucine O +- O +- O +> O +lysine O +polymorphism O +at O +codon O +1307 O +( O +I1307K O +) O +of O +the O +APC B +gene O +has O +been O +identified O +in O +6 O +% O +- O +7 O +% O +of O +the O +Ashkenazi O +Jewish O +population O +. O + +To O +assess O +the O +risk O +of O +this O +common O +APC B +allelic O +variant O +in O +colorectal B +carcinogenesis I +, O +we O +have O +analyzed O +a O +large O +cohort O +of O +unselected O +Ashkenazi O +Jewish O +subjects O +with O +adenomatous B +polyps I +and O +. O +or O +colorectal B +cancer I +, O +for O +the O +APC B +I1307K O +polymorphism O +. O + +The O +APC B +I1307K O +allele O +was O +identified O +in O +48 O +( O +10 O +. O +1 O +% O +) O +of O +476 O +patients O +. O + +Compared O +with O +the O +frequency O +in O +two O +separate O +population O +control O +groups O +, O +the O +APC B +I1307K O +allele O +is O +associated O +with O +an O +estimated O +relative O +risk O +of O +1 O +. O + +5 O +- O +1 O +. O + +7 O +for O +colorectal B +neoplasia I +( O +both O +P O += O +. O +01 O +) O +. O + +Furthermore O +, O +compared O +with O +noncarriers O +, O +APC B +I1307K O +carriers O +had O +increased O +numbers O +of O +adenomas B +and O +colorectal B +cancers I +per O +patient O +( O +P O += O +. O +03 O +) O +, O +as O +well O +as O +a O +younger O +age O +at O +diagnosis O +. O + +We O +conclude O +that O +the O +APC B +I1307K O +variant O +leads O +to O +increased O +adenoma B +formation O +and O +directly O +contributes O +to O +3 O +% O +- O +4 O +% O +of O +all O +Ashkenazi O +Jewish O +colorectal B +cancer I +. O + +The O +estimated O +relative O +risk O +for O +carriers O +may O +justify O +specific O +clinical O +screening O +for O +the O +360 O +, O +000 O +Americans O +expected O +to O +harbor O +this O +allele O +, O +and O +genetic O +testing O +in O +the O +setting O +of O +long O +- O +term O +- O +outcome O +studies O +may O +impact O +significantly O +on O +colorectal B +cancer I +prevention O +in O +this O +population O +. O + +Localization O +of O +human O +BRCA1 O +and O +its O +loss O +in O +high O +- O +grade O +, O +non O +- O +inherited I +breast I +carcinomas I +. O + +Although O +the O +link O +between O +the O +BRCA1 O +tumour B +- O +suppressor O +gene O +and O +hereditary B +breast I +and I +ovarian I +cancer I +is O +established O +, O +the O +role O +, O +if O +any O +, O +of O +BRCA1 O +in O +non B +- I +familial I +cancers I +is O +unclear O +. O + +BRCA1 O +mutations O +are O +rare O +in O +sporadic B +cancers I +, O +but O +loss O +of O +BRCA1 O +resulting O +from O +reduced O +expression O +or O +incorrect O +subcellular O +localization O +is O +postulated O +to O +be O +important O +in O +non B +- I +familial I +breast I +and I +ovarian I +cancers I +. O + +Epigenetic O +loss O +, O +however O +, O +has O +not O +received O +general O +acceptance O +due O +to O +controversy O +regarding O +the O +subcellular O +localization O +of O +BRCA1 O +proteins O +, O +reports O +of O +which O +have O +ranged O +from O +exclusively O +nuclear O +, O +to O +conditionally O +nuclear O +, O +to O +the O +ER O +/ O +golgi O +, O +to O +cytoplasmic O +invaginations O +into O +the O +nucleus O +. O + +In O +an O +attempt O +to O +resolve O +this O +issue O +, O +we O +have O +comprehensively O +characterized O +19 O +anti O +- O +BRCA1 O +antibodies O +. O + +These O +reagents O +detect O +a O +220 O +- O +kD O +protein O +localized O +in O +discrete O +nuclear O +foci O +in O +all O +epithelial O +cell O +lines O +, O +including O +those O +derived O +from O +breast B +malignancies I +. O + +Immunohistochemical O +staining O +of O +human O +breast O +specimens O +also O +revealed O +BRCA1 O +nuclear O +foci O +in O +benign O +breast I +, O +invasive B +lobular I +cancers I +and O +low O +- O +grade O +ductal B +carcinomas I +. O + +Conversely O +, O +BRCA1 O +expression O +was O +reduced O +or O +undetectable O +in O +the O +majority O +of O +high O +- O +grade O +, O +ductal B +carcinomas I +, O +suggesting O +that O +absence O +of O +BRCA1 O +may O +contribute O +to O +the O +pathogenesis O +of O +a O +significant O +percentage O +of O +sporadic B +breast I +cancers I +. O +. O + +Torsade B +de I +pointes I +ventricular B +tachycardia I +during O +low O +dose O +intermittent O +dobutamine O +treatment O +in O +a O +patient O +with O +dilated B +cardiomyopathy I +and O +congestive B +heart I +failure I +. O + +The O +authors O +describe O +the O +case O +of O +a O +56 O +- O +year O +- O +old O +woman O +with O +chronic O +, O +severe O +heart B +failure I +secondary O +to O +dilated B +cardiomyopathy I +and O +absence O +of O +significant O +ventricular B +arrhythmias I +who O +developed O +QT B +prolongation I +and O +torsade B +de I +pointes I +ventricular I +tachycardia I +during O +one O +cycle O +of O +intermittent O +low O +dose O +( O +2 O +. O +5 O +mcg O +/ O +kg O +per O +min O +) O +dobutamine O +. O + +This O +report O +of O +torsade B +de I +pointes I +ventricular B +tachycardia I +during O +intermittent O +dobutamine O +supports O +the O +hypothesis O +that O +unpredictable O +fatal O +arrhythmias B +may O +occur O +even O +with O +low O +doses O +and O +in O +patients O +with O +no O +history O +of O +significant O +rhythm O +disturbances I +. O + +The O +mechanisms O +of O +proarrhythmic O +effects O +of O +Dubutamine O +are O +discussed O +. O + +Positive O +skin O +tests O +in O +late O +reactions O +to O +radiographic O +contrast O +media O +. O + +In O +the O +last O +few O +years O +delayed O +reactions O +several O +hours O +after O +the O +injection O +of O +radiographic O +and O +contrast O +materials O +( O +PRC O +) O +have O +been O +described O +with O +increasing O +frequency O +. O + +The O +authors O +report O +two O +observations O +on O +patients O +with O +delayed O +reactions O +in O +whom O +intradermoreactions O +( O +IDR O +) O +and O +patch O +tests O +to O +a O +series O +of O +ionic O +and O +non O +ionic O +PRC O +were O +studied O +. O + +After O +angiography O +by O +the O +venous O +route O +in O +patient O +n O +degree O +1 O +a O +biphasic O +reaction O +with O +an O +immediate O +reaction O +( O +dyspnea B +, O +loss B +of I +consciousness I +) O +and O +delayed O +macro O +- O +papular O +rash B +appeared O +, O +whilst O +patient O +n O +degree O +2 O +developed O +a O +generalised O +sensation O +of O +heat O +, O +persistent O +pain B +at O +the O +site O +of O +injection O +immediately O +and O +a O +generalised O +macro O +- O +papular O +reaction O +after O +24 O +hours O +. O + +The O +skin O +tests O +revealed O +positive O +delayed O +reactions O +of O +24 O +hours O +and O +48 O +hours O +by O +IDR O +and O +patch O +tests O +to O +only O +some O +PRC O +with O +common O +chains O +in O +their O +structures O +. O + +The O +positive O +skin O +tests O +are O +in O +favour O +of O +immunological O +reactions O +and O +may O +help O +in O +diagnosis O +of O +allergy B +in O +the O +patients O +. O + +Risk O +of O +transient O +hyperammonemic B +encephalopathy B +in O +cancer B +patients O +who O +received O +continuous O +infusion O +of O +5 O +- O +fluorouracil O +with O +the O +complication O +of O +dehydration B +and O +infection B +. O + +From O +1986 O +to O +1998 O +, O +29 O +cancer B +patients O +who O +had O +32 O +episodes O +of O +transient O +hyperammonemic B +encephalopathy B +related O +to O +continuous O +infusion O +of O +5 O +- O +fluorouracil O +( O +5 O +- O +FU O +) O +were O +identified O +. O + +None O +of O +the O +patients O +had O +decompensated O +liver B +disease I +. O + +Onset O +of O +hyperammonemic B +encephalopathy B +varied O +from O +0 O +. O +5 O +to O +5 O +days O +( O +mean O +: O +2 O +. O +6 O ++ O +/ O +- O +1 O +. O +3 O +days O +) O +after O +the O +initiation O +of O +chemotherapy O +. O + +Plasma O +ammonium O +level O +ranged O +from O +248 O +to O +2387 O +microg O +% O +( O +mean O +: O +626 O ++ O +/ O +- O +431 O +microg O +% O +) O +. O + +Among O +the O +32 O +episodes O +, O +26 O +( O +81 O +% O +) O +had O +various O +degrees O +of O +azotemia B +, O +18 O +( O +56 O +% O +) O +occurred O +during O +bacterial B +infections I +and O +14 O +( O +44 O +% O +) O +without O +infection B +occurred O +during O +periods O +of O +dehydration O +. O + +Higher O +plasma O +ammonium O +levels O +and O +more O +rapid O +onset O +of O +hyperammonemia B +were O +seen O +in O +18 O +patients O +with O +bacterial B +infections I +( O +p O += O +0 O +. O +003 O +and O +0 O +. O +0006 O +, O +respectively O +) O +and O +in O +nine O +patients O +receiving O +high O +daily O +doses O +( O +2600 O +or O +1800 O +mg O +/ O +m2 O +) O +of O +5 O +- O +FU O +( O +p O += O +0 O +. O +0001 O +and O +< O +0 O +. O +0001 O +, O +respectively O +) O +. O + +In O +25 O +out O +of O +32 O +episodes O +( O +78 O +% O +) O +, O +plasma O +ammonium O +levels O +and O +mental O +status O +returned O +to O +normal O +within O +2 O +days O +after O +adequate O +management O +. O + +In O +conclusion O +, O +hyperammonemic B +encephalopathy B +can O +occur O +in O +patients O +receiving O +continuous O +infusion O +of O +5 O +- O +FU O +. O + +Azotemia B +, O +body B +fluid I +insufficiency I +and O +bacterial B +infections I +were O +frequently O +found O +in O +these O +patients O +. O + +It O +is O +therefore O +important O +to O +recognize O +this O +condition O +in O +patients O +receiving O +continuous O +infusion O +of O +5 O +- O +FU O +. O + +The O +effects O +of O +quinine O +and O +4 O +- O +aminopyridine O +on O +conditioned O +place O +preference O +and O +changes O +in O +motor O +activity O +induced O +by O +morphine O +in O +rats O +. O + +1 O +. O + +The O +effects O +of O +two O +unselective O +potassium O +( O +K O +( O ++ O +) O +- O +) O +channel O +blockers O +, O +quinine O +( O +12 O +. O +5 O +, O +25 O +and O +50 O +mg O +/ O +kg O +) O +and O +4 O +- O +aminopyridine O +( O +1 O +and O +2 O +mg O +/ O +kg O +) O +, O +on O +conditioned O +place O +preference O +and O +biphasic O +changes O +in O +motor O +activity O +induced O +by O +morphine O +( O +10 O +mg O +/ O +kg O +) O +were O +tested O +in O +Wistar O +rats O +. O + +Quinine O +is O +known O +to O +block O +voltage O +- O +, O +calcium O +- O +and O +ATP O +- O +sensitive O +K O +( O ++ O +) O +- O +channels O +while O +4 O +- O +aminopyridine O +is O +known O +to O +block O +voltage O +- O +sensitive O +K O +( O ++ O +) O +- O +channels O +. O + +2 O +. O + +In O +the O +counterbalanced O +method O +, O +quinine O +attenuated O +morphine O +- O +induced O +place O +preference O +, O +whereas O +4 O +- O +aminopyridine O +was O +ineffective O +. O + +In O +the O +motor O +activity O +test O +measured O +with O +an O +Animex O +- O +activity O +meter O +neither O +of O +the O +K O +( O ++ O +) O +- O +channel O +blockers O +affected O +morphine O +- O +induced O +hypoactivity B +, O +but O +both O +K O +( O ++ O +) O +- O +channel O +blockers O +prevented O +morphine O +- O +induced O +secondary O +hyperactivity B +. O + +3 O +. O + +These O +results O +suggest O +the O +involvement O +of O +quinine O +- O +sensitive O +but O +not O +4 O +- O +aminopyridine O +- O +sensitive O +K O +( O ++ O +) O +- O +channels O +in O +morphine O +reward O +. O + +It O +is O +also O +suggested O +that O +the O +blockade O +of O +K O +( O ++ O +) O +- O +channels O +sensitive O +to O +these O +blockers O +is O +not O +sufficient O +to O +prevent O +morphine O +- O +induced O +hypoactivity B +whereas O +morphine O +- O +induced O +hyperactivity B +seems O +to O +be O +connected O +to O +both O +quinine O +- O +and O +4 O +- O +aminopyridine O +- O +sensitive O +K O +( O ++ O +) O +- O +channels O +. O + +Nociceptin O +/ O +orphanin O +FQ O +and O +nocistatin O +on O +learning B +and I +memory I +impairment I +induced O +by O +scopolamine O +in O +mice O +. O + +1 O +. O + +Nociceptin O +, O +also O +known O +as O +orphanin O +FQ O +, O +is O +an O +endogenous O +ligand O +for O +the O +orphan O +opioid O +receptor O +- O +like O +receptor O +1 O +( O +ORL1 O +) O +and O +involves O +in O +various O +functions O +in O +the O +central O +nervous O +system O +( O +CNS O +) O +. O + +On O +the O +other O +hand O +, O +nocistatin O +is O +recently O +isolated O +from O +the O +same O +precursor O +as O +nociceptin O +and O +blocks O +nociceptin O +- O +induced O +allodynia B +and O +hyperalgesia B +. O + +2 O +. O + +Although O +ORL1 O +receptors O +which O +display O +a O +high O +degree O +of O +sequence O +homology O +with O +classical O +opioid O +receptors O +are O +abundant O +in O +the O +hippocampus O +, O +little O +is O +known O +regarding O +their O +role O +in O +learning O +and O +memory O +. O + +3 O +. O + +The O +present O +study O +was O +designed O +to O +investigate O +whether O +nociceptin O +/ O +orphanin O +FQ O +and O +nocistatin O +could O +modulate O +impairment B +of I +learning I +and I +memory I +induced O +by O +scopolamine O +, O +a O +muscarinic O +cholinergic O +receptor O +antagonist O +, O +using O +spontaneous O +alternation O +of O +Y O +- O +maze O +and O +step O +- O +down O +type O +passive O +avoidance O +tasks O +in O +mice O +. O + +4 O +. O + +While O +nocistatin O +( O +0 O +. O +5 O +- O +5 O +. O +0 O +nmol O +mouse O +- O +1 O +, O +i O +. O +c O +. O +v O +. O +) O +administered O +30 O +min O +before O +spontaneous O +alternation O +performance O +or O +the O +training O +session O +of O +the O +passive O +avoidance O +task O +, O +had O +no O +effect O +on O +spontaneous O +alternation O +or O +passive O +avoidance O +behaviours O +, O +a O +lower O +per O +cent O +alternation O +and O +shorter O +median O +step O +- O +down O +latency O +in O +the O +retention O +test O +were O +obtained O +in O +nociceptin O +( O +1 O +. O +5 O +and O +/ O +or O +5 O +. O +0 O +nmol O +mouse O +- O +1 O +, O +i O +. O +c O +. O +v O +. O +) O +- O +treated O +normal O +mice O +. O + +5 O +. O + +Administration O +of O +nocistatin O +( O +1 O +. O +5 O +and O +/ O +or O +5 O +. O +0 O +nmol O +mouse O +- O +1 O +, O +i O +. O +c O +. O +v O +. O +) O +30 O +min O +before O +spontaneous O +alternation O +performance O +or O +the O +training O +session O +of O +the O +passive O +avoidance O +task O +, O +attenuated O +the O +scopolamine O +- O +induced O +impairment O +of O +spontaneous O +alternation O +and O +passive O +avoidance O +behaviours O +. O + +6 O +. O + +These O +results O +indicated O +that O +nocistatin O +, O +a O +new O +biologically O +active O +peptide O +, O +ameliorates O +impairments O +of O +spontaneous O +alternation O +and O +passive O +avoidance O +induced O +by O +scopolamine O +, O +and O +suggested O +that O +these O +peptides O +play O +opposite O +roles O +in O +learning O +and O +memory O +. O + +Meloxicam O +- O +induced O +liver B +toxicity I +. O + +We O +report O +the O +case O +of O +a O +female O +patient O +with O +rheumatoid B +arthritis I +who O +developed O +acute O +cytolytic B +hepatitis I +due O +to O +meloxicam O +. O + +Recently O +introduced O +in O +Belgium O +, O +meloxicam O +is O +the O +first O +nonsteroidal O +antiinflammatory O +drug O +with O +selective O +action O +on O +the O +inducible O +form O +of O +cyclooxygenase O +2 O +. O + +The O +acute O +cytolytic B +hepatitis I +occurred O +rapidly O +after O +meloxicam O +administration O +and O +was O +associated O +with O +the O +development O +of O +antinuclear O +antibodies O +suggesting O +a O +hypersensitivity B +mechanism O +. O + +This O +first O +case O +of O +meloxicam O +related O +liver B +toxicity I +demonstrates O +the O +potential O +of O +this O +drug O +to O +induce O +hepatic B +damage I +. O + +Induction O +of O +apoptosis O +by O +remoxipride O +metabolites O +in O +HL60 O +and O +CD34 O ++ O +/ O +CD19 O +- O +human O +bone O +marrow O +progenitor O +cells O +: O +potential O +relevance O +to O +remoxipride O +- O +induced O +aplastic B +anemia I +. O + +The O +antipsychotic O +agent O +, O +remoxipride O +[ O +( O +S O +) O +- O +( O +- O +) O +- O +3 O +- O +bromo O +- O +N O +- O +[ O +( O +1 O +- O +ethyl O +- O +2 O +- O +pyrrolidinyl O +) O +methyl O +] O +- O +2 O +, O +6 O +- O +dimethoxybenz O +amide O +] O +has O +been O +associated O +with O +acquired O +aplastic B +anemia I +. O + +We O +have O +examined O +the O +ability O +of O +remoxipride O +, O +three O +pyrrolidine O +ring O +metabolites O +and O +five O +aromatic O +ring O +metabolites O +of O +the O +parent O +compound O +to O +induce O +apoptosis O +in O +HL60 O +cells O +and O +human O +bone O +marrow O +progenitor O +( O +HBMP O +) O +cells O +. O + +Cells O +were O +treated O +for O +0 O +- O +24 O +h O +with O +each O +compound O +( O +0 O +- O +200 O +microM O +) O +. O + +Apoptosis O +was O +assessed O +by O +fluorescence O +microscopy O +in O +Hoechst O +33342 O +- O +and O +propidium O +iodide O +stained O +cell O +samples O +. O + +Results O +were O +confirmed O +by O +determination O +of O +internucleosomal O +DNA O +fragmentation O +using O +gel O +electrophoresis O +for O +HL60 O +cell O +samples O +and O +terminal O +deoxynucleotidyl O +transferase O +assay O +in O +HBMP O +cells O +. O + +The O +catechol O +and O +hydroquinone O +metabolites O +, O +NCQ436 O +and O +NCQ344 O +, O +induced O +apoptosis O +in O +HL60 O +and O +HBMP O +cells O +in O +a O +time O +- O +and O +concentration O +dependent O +manner O +, O +while O +the O +phenols O +, O +NCR181 O +, O +FLA873 O +, O +and O +FLA797 O +, O +and O +the O +derivatives O +formed O +by O +oxidation O +of O +the O +pyrrolidine O +ring O +, O +FLA838 O +, O +NCM001 O +, O +and O +NCL118 O +, O +had O +no O +effect O +. O + +No O +necrosis B +was O +observed O +in O +cells O +treated O +with O +NCQ436 O +but O +NCQ344 O +had O +a O +biphasic O +effect O +in O +both O +cell O +types O +, O +inducing O +apoptosis O +at O +lower O +concentrations O +and O +necrosis B +at O +higher O +concentrations O +. O + +These O +data O +show O +that O +the O +catechol O +and O +hydroquinone O +metabolites O +of O +remoxipride O +have O +direct O +toxic O +effects O +in O +HL60 O +and O +HBMP O +cells O +, O +leading O +to O +apoptosis O +, O +while O +the O +phenol O +metabolites O +were O +inactive O +. O + +Similarly O +, O +benzene O +- O +derived O +catechol O +and O +hydroquinone O +, O +but O +not O +phenol O +, O +induce O +apoptosis O +in O +HBMP O +cells O +[ O +Moran O +et O +al O +. O +, O +Mol O +. O +Pharmacol O +. O +, O +50 O +( O +1996 O +) O +610 O +- O +615 O +] O +. O + +We O +propose O +that O +remoxipride O +and O +benzene O +may O +induce O +aplastic B +anemia I +via O +production O +of O +similar O +reactive O +metabolites O +and O +that O +the O +ability O +of O +NCQ436 O +and O +NCQ344 O +to O +induce O +apoptosis O +in O +HBMP O +cells O +may O +contribute O +to O +the O +mechanism O +underlying O +acquired O +aplastic B +anemia I +that O +has O +been O +associated O +with O +remoxipride O +. O + +Synthesis O +and O +preliminary O +pharmacological O +investigations O +of O +1 O +- O +( O +1 O +, O +2 O +- O +dihydro O +- O +2 O +- O +acenaphthylenyl O +) O +piperazine O +derivatives O +as O +potential O +atypical O +antipsychotic O +agents O +in O +mice O +. O + +In O +research O +towards O +the O +development O +of O +new O +atypical O +antipsychotic O +agents O +, O +one O +strategy O +is O +that O +the O +dopaminergic O +system O +can O +be O +modulated O +through O +manipulation O +of O +the O +serotonergic O +system O +. O + +The O +synthesis O +and O +preliminary O +pharmacological O +evaluation O +of O +a O +series O +of O +potential O +atypical O +antipsychotic O +agents O +based O +on O +the O +structure O +of O +1 O +- O +( O +1 O +, O +2 O +- O +dihydro O +- O +2 O +- O +acenaphthylenyl O +) O +piperazine O +( O +7 O +) O +is O +described O +. O + +Compound O +7e O +, O +5 O +- O +{ O +2 O +- O +[ O +4 O +- O +( O +1 O +, O +2 O +- O +dihydro O +- O +2 O +- O +acenaphthylenyl O +) O +piperazinyl O +] O +ethyl O +} O +- O +2 O +, O +3 O +- O +dihy O +dro O +- O +1H O +- O +indol O +- O +2 O +- O +one O +, O +from O +this O +series O +showed O +significant O +affinities O +at O +the O +5 O +- O +HT1A O +and O +5 O +- O +HT2A O +receptors O +and O +moderate O +affinity O +at O +the O +D2 O +receptor O +. O + +7e O +exhibits O +a O +high O +reversal O +of O +catalepsy B +induced O +by O +haloperidol O +indicating O +its O +atypical O +antipsychotic O +nature O +. O + +Sub O +- O +chronic O +inhibition O +of O +nitric O +- O +oxide O +synthesis O +modifies O +haloperidol O +- O +induced O +catalepsy B +and O +the O +number O +of O +NADPH O +- O +diaphorase O +neurons O +in O +mice O +. O + +RATIONALE O +: O +NG O +- O +nitro O +- O +L O +- O +arginine O +( O +L O +- O +NOARG O +) O +, O +an O +inhibitor O +of O +nitric O +- O +oxide O +synthase O +( O +NOS O +) O +, O +induces O +catalepsy B +in O +mice O +. O + +This O +effect O +undergoes O +rapid O +tolerance O +, O +showing O +a O +significant O +decrease O +after O +2 O +days O +of O +sub O +- O +chronic O +L O +- O +NOARG O +treatment O +. O + +Nitric O +oxide O +( O +NO O +) O +has O +been O +shown O +to O +influence O +dopaminergic O +neurotransmission O +in O +the O +striatum O +. O + +Neuroleptic O +drugs O +such O +as O +haloperidol O +, O +which O +block O +dopamine O +receptors O +, O +also O +cause O +catalepsy B +in O +rodents O +. O + +OBJECTIVES O +: O +To O +investigate O +the O +effects O +of O +subchronic O +L O +- O +NOARG O +treatment O +in O +haloperidol O +- O +induced O +catalepsy B +and O +the O +number O +of O +NOS O +neurons O +in O +areas O +related O +to O +motor O +control O +. O + +METHODS O +: O +Male O +albino O +Swiss O +mice O +were O +treated O +sub O +- O +chronically O +( O +twice O +a O +day O +for O +4 O +days O +) O +with O +L O +- O +NOARG O +( O +40 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +or O +haloperidol O +( O +1 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +. O + +Catalepsy B +was O +evaluated O +at O +the O +beginning O +and O +the O +end O +of O +the O +treatments O +. O + +Reduced O +nicotinamide O +adenine O +dinucleotide O +phosphate O +- O +diaphorase O +( O +NADPH O +- O +d O +) O +histochemistry O +was O +also O +employed O +to O +visualize O +NOS O +as O +an O +index O +of O +enzyme O +expression O +in O +mice O +brain O +regions O +related O +to O +motor O +control O +. O + +RESULTS O +: O +L O +- O +NOARG O +sub O +- O +chronic O +administration O +produced O +tolerance O +of O +L O +- O +NOARG O +and O +of O +haloperidol O +- O +induced O +catalepsy B +. O + +It O +also O +induced O +an O +increase O +in O +the O +number O +of O +NADPH O +- O +d O +- O +positive O +cells O +in O +the O +dorsal O +part O +of O +the O +caudate O +and O +accumbens O +nuclei O +compared O +with O +haloperidol O +and O +in O +the O +pedunculopontine O +tegmental O +nucleus O +compared O +with O +saline O +. O + +In O +contrast O +, O +there O +was O +a O +decrease O +in O +NADPH O +- O +d O +neuron O +number O +in O +the O +substantia O +nigra O +, O +pars O +compacta O +in O +both O +haloperidol O +- O +treated O +and O +L O +- O +NOARG O +- O +treated O +animals O +. O + +CONCLUSIONS O +: O +The O +results O +give O +further O +support O +to O +the O +hypothesis O +that O +NO O +plays O +a O +role O +in O +motor O +behavior O +control O +and O +suggest O +that O +it O +may O +take O +part O +in O +the O +synaptic O +changes O +produced O +by O +antipsychotic O +treatment O +. O + +Prolonged O +left B +ventricular I +dysfunction I +occurs O +in O +patients O +with O +coronary B +artery I +disease I +after O +both O +dobutamine O +and O +exercise O +induced O +myocardial B +ischaemia I +. O + +OBJECTIVE O +: O +To O +determine O +whether O +pharmacological O +stress O +leads O +to O +prolonged O +but O +reversible O +left B +ventricular I +dysfunction I +in O +patients O +with O +coronary B +artery I +disease I +, O +similar O +to O +that O +seen O +after O +exercise O +. O + +DESIGN O +: O +A O +randomised O +crossover O +study O +of O +recovery O +time O +of O +systolic O +and O +diastolic O +left O +ventricular O +function O +after O +exercise O +and O +dobutamine O +induced O +ischaemia B +. O + +SUBJECTS O +: O +10 O +patients O +with O +stable B +angina I +, O +angiographically O +proven O +coronary B +artery I +disease I +, O +and O +normal O +left O +ventricular O +function O +. O + +INTERVENTIONS O +: O +Treadmill O +exercise O +and O +dobutamine O +stress O +were O +performed O +on O +different O +days O +. O + +Quantitative O +assessment O +of O +systolic O +and O +diastolic O +left O +ventricular O +function O +was O +performed O +using O +transthoracic O +echocardiography O +at O +baseline O +and O +at O +regular O +intervals O +after O +each O +test O +. O + +RESULTS O +: O +Both O +forms O +of O +stress O +led O +to O +prolonged O +but O +reversible O +systolic B +and I +diastolic I +dysfunction I +. O + +There O +was O +no O +difference O +in O +the O +maximum O +double O +product O +( O +p O += O +0 O +. O +53 O +) O +or O +ST O +depression B +( O +p O += O +0 O +. O +63 O +) O +with O +either O +form O +of O +stress O +. O + +After O +exercise O +, O +ejection O +fraction O +was O +reduced O +at O +15 O +and O +30 O +minutes O +compared O +with O +baseline O +( O +mean O +( O +SEM O +) O +, O +- O +5 O +. O +6 O +( O +1 O +. O +5 O +) O +% O +, O +p O +< O +0 O +. O +05 O +; O +and O +- O +6 O +. O +1 O +( O +2 O +. O +2 O +) O +% O +, O +p O +< O +0 O +. O +01 O +) O +, O +and O +at O +30 O +and O +45 O +minutes O +after O +dobutamine O +( O +- O +10 O +. O +8 O +( O +1 O +. O +8 O +) O +% O +and O +- O +5 O +. O +5 O +( O +1 O +. O +8 O +) O +% O +, O +both O +p O +< O +0 O +. O +01 O +) O +. O + +Regional O +analysis O +showed O +a O +reduction O +in O +the O +worst O +affected O +segment O +15 O +and O +30 O +minutes O +after O +exercise O +( O +- O +27 O +. O +9 O +( O +7 O +. O +2 O +) O +% O +and O +- O +28 O +. O +6 O +( O +5 O +. O +7 O +) O +% O +, O +both O +p O +< O +0 O +. O +01 O +) O +, O +and O +at O +30 O +minutes O +after O +dobutamine O +( O +- O +32 O +( O +5 O +. O +3 O +) O +% O +, O +p O +< O +0 O +. O +01 O +) O +. O + +The O +isovolumic O +relaxation O +period O +was O +prolonged O +45 O +minutes O +after O +each O +form O +of O +stress O +( O +p O +< O +0 O +. O +05 O +) O +. O + +CONCLUSIONS O +: O +In O +patients O +with O +coronary B +artery I +disease I +, O +dobutamine O +induced O +ischaemia B +results O +in O +prolonged O +reversible O +left B +ventricular I +dysfunction I +, O +presumed O +to O +be O +myocardial B +stunning I +, O +similar O +to O +that O +seen O +after O +exercise O +. O + +Dobutamine O +induced O +ischaemia B +could O +therefore O +be O +used O +to O +study O +the O +pathophysiology O +of O +this O +phenomenon O +further O +in O +patients O +with O +coronary B +artery I +disease I +. O + +Anorexigens O +and O +pulmonary B +hypertension I +in O +the O +United O +States O +: O +results O +from O +the O +surveillance O +of O +North O +American O +pulmonary B +hypertension I +. O + +BACKGROUND O +: O +The O +use O +of O +appetite O +suppressants O +in O +Europe O +has O +been O +associated O +with O +the O +development O +of O +primary B +pulmonary I +hypertension I +( O +PPH B +) O +. O + +Recently O +, O +fenfluramine O +appetite O +suppressants O +became O +widely O +used O +in O +the O +United O +States O +but O +were O +withdrawn O +in O +September O +1997 O +because O +of O +concerns O +over O +adverse O +effects O +. O + +MATERIALS O +AND O +METHODS O +: O +We O +conducted O +a O +prospective O +surveillance O +study O +on O +patients O +diagnosed O +with O +pulmonary B +hypertension I +at O +12 O +large O +referral O +centers O +in O +North O +America O +. O + +Data O +collected O +on O +patients O +seen O +from O +September O +1 O +, O +1996 O +, O +to O +December O +31 O +, O +1997 O +, O +included O +the O +cause O +of O +the O +pulmonary B +hypertension I +and O +its O +severity O +. O + +Patients O +with O +no O +identifiable O +cause O +of O +pulmonary B +hypertension I +were O +classed O +as O +PPH O +. O + +A O +history O +of O +drug O +exposure O +also O +was O +taken O +with O +special O +attention O +on O +the O +use O +of O +antidepressants O +, O +anorexigens O +, O +and O +amphetamines O +. O + +RESULTS O +: O +Five O +hundred O +seventy O +- O +nine O +patients O +were O +studied O +, O +205 O +with O +PPH B +and O +374 O +with O +pulmonary B +hypertension I +from O +other O +causes O +( O +secondary B +pulmonary I +hypertension I +[ O +SPH B +] O +) O +. O + +The O +use O +of O +anorexigens O +was O +common O +in O +both O +groups O +. O + +However O +, O +of O +the O +medications O +surveyed O +, O +only O +the O +fenfluramines O +had O +a O +significant O +preferential O +association O +with O +PPH B +as O +compared O +with O +SPH O +( O +adjusted O +odds O +ratio O +for O +use O +> O +6 O +months O +, O +7 O +. O +5 O +; O +95 O +% O +confidence O +interval O +, O +1 O +. O +7 O +to O +32 O +. O +4 O +) O +. O + +The O +association O +was O +stronger O +with O +longer O +duration O +of O +use O +when O +compared O +to O +shorter O +duration O +of O +use O +and O +was O +more O +pronounced O +in O +recent O +users O +than O +in O +remote O +users O +. O + +An O +unexpectedly O +high O +( O +11 O +. O +4 O +% O +) O +number O +of O +patients O +with O +SPH B +had O +used O +anorexigens O +. O + +CONCLUSION O +: O +The O +magnitude O +of O +the O +association O +with O +PPH O +, O +the O +increase O +of O +association O +with O +increasing O +duration O +of O +use O +, O +and O +the O +specificity O +for O +fenfluramines O +are O +consistent O +with O +previous O +studies O +indicating O +that O +fenfluramines O +are O +causally O +related O +to O +PPH O +. O + +The O +high O +prevalence O +of O +anorexigen O +use O +in O +patients O +with O +SPH B +also O +raises O +the O +possibility O +that O +these O +drugs O +precipitate O +pulmonary B +hypertension I +in O +patients O +with O +underlying O +conditions O +associated O +with O +SPH B +. O + +Clinical O +aspects O +of O +heparin O +- O +induced O +thrombocytopenia B +and O +thrombosis B +and O +other O +side O +effects O +of O +heparin O +therapy O +. O + +Heparin O +, O +first O +used O +to O +prevent O +the O +clotting O +of O +blood O +in O +vitro O +, O +has O +been O +clinically O +used O +to O +treat O +thrombosis B +for O +more O +than O +50 O +years O +. O + +Although O +several O +new O +anticoagulant O +drugs O +are O +in O +development O +, O +heparin O +remains O +the O +anticoagulant O +of O +choice O +to O +treat O +acute O +thrombotic B +episodes I +. O + +The O +clinical O +effects O +of O +heparin O +are O +meritorious O +, O +but O +side O +effects O +do O +exist O +. O + +Bleeding B +is O +the O +primary O +untoward O +effect O +of O +heparin O +. O + +Major O +bleeding B +is O +of O +primary O +concern O +in O +patients O +receiving O +heparin O +therapy O +. O + +However O +, O +additional O +important O +untoward O +effects O +of O +heparin O +therapy O +include O +heparin O +- O +induced O +thrombocytopenia B +, O +heparin O +- O +associated O +osteoporosis B +, O +eosinophilia B +, O +skin O +reactions O +, O +allergic B +reactions I +other O +than O +thrombocytopenia B +, O +alopecia B +, O +transaminasemia B +, O +hyperkalemia B +, O +hypoaldosteronism B +, O +and O +priapism B +. O + +These O +side O +effects O +are O +relatively O +rare O +in O +a O +given O +individual O +, O +but O +given O +the O +extremely O +widespread O +use O +of O +heparin O +, O +some O +are O +quite O +common O +, O +particularly O +HITT B +and O +osteoporosis B +. O + +Although O +reasonable O +incidences O +of O +many O +of O +these O +side O +effects O +can O +be O +" O +softly O +" O +deduced O +from O +current O +reports O +dealing O +with O +unfractionated O +heparin O +, O +at O +present O +the O +incidences O +of O +these O +side O +effects O +with O +newer O +low O +molecular O +weight O +heparins O +appear O +to O +be O +much O +less O +common O +. O + +However O +, O +only O +longer O +experience O +will O +more O +clearly O +define O +the O +incidence O +of O +each O +side O +effect O +with O +low O +molecular O +weight O +preparations O +. O + +A O +case O +of O +bilateral O +optic B +neuropathy I +in O +a O +patient O +on O +tacrolimus O +( O +FK506 O +) O +therapy O +after O +liver O +transplantation O +. O + +PURPOSE O +: O +To O +report O +a O +case O +of O +bilateral O +optic B +neuropathy I +in O +a O +patient O +receiving O +tacrolimus O +( O +FK O +506 O +, O +Prograf O +; O +Fujisawa O +USA O +, O +Inc O +, O +Deerfield O +, O +Illinois O +) O +for O +immunosuppression O +after O +orthotropic O +liver O +transplantation O +. O + +METHOD O +: O +Case O +report O +. O + +In O +a O +58 O +- O +year O +- O +old O +man O +receiving O +tacrolimus O +after O +orthotropic O +liver O +transplantation O +, O +serial O +neuro O +- O +ophthalmologic O +examinations O +and O +laboratory O +studies O +were O +performed O +. O + +RESULTS O +: O +The O +patient O +had O +episodic B +deterioration I +of I +vision I +in O +both O +eyes O +, O +with O +clinical O +features O +resembling O +ischemic B +optic I +neuropathies I +. O + +Deterioration B +of I +vision I +occurred O +despite O +discontinuation O +of O +the O +tacrolimus O +. O + +CONCLUSION O +: O +Tacrolimus O +and O +other O +immunosuppressive O +agents O +may O +be O +associated O +with O +optic B +nerve I +toxicity I +. O + +Hypercalcemia B +, O +arrhythmia B +, O +and O +mood O +stabilizers O +. O + +Recent O +findings O +in O +a O +bipolar B +patient O +receiving O +maintenance O +lithium O +therapy O +who O +developed O +hypercalcemia B +and O +severe O +bradyarrhythmia B +prompted O +the O +authors O +to O +conduct O +a O +retrospective O +study O +of O +bipolar B +patients O +with O +lithium O +- O +associated O +hypercalcemia B +. O + +A O +printout O +of O +all O +cases O +of O +hypercalcemia B +that O +presented O +during O +a O +1 O +- O +year O +period O +was O +generated O +. O + +After O +eliminating O +spurious O +hypercalcemias B +or O +those O +associated O +with O +intravenous O +fluids O +, O +the O +authors O +identified O +18 O +non O +- O +lithium O +- O +treated O +patients O +with O +hypercalcemias B +related O +to O +malignancies B +and O +other O +medical O +conditions O +( O +group O +A O +) O +and O +12 O +patients O +with O +lithium O +- O +associated O +hypercalcemia B +( O +group O +B O +) O +. O + +Patients O +in O +group O +B O +were O +not O +comparable O +to O +those O +in O +group O +A O +, O +as O +the O +latter O +were O +medically O +compromised O +and O +were O +receiving O +multiple O +pharmacotherapies O +. O + +Thus O +, O +two O +control O +groups O +were O +generated O +: O +group O +C1 O +, O +which O +included O +age O +- O +and O +sex O +- O +comparable O +lithium O +- O +treated O +bipolar B +normocalcemic O +patients O +, O +and O +group O +C2 O +, O +which O +included O +bipolar B +normocalcemic O +patients O +treated O +with O +anticonvulsant O +mood O +stabilizers O +. O + +The O +electrocardiographic O +( O +ECG O +) O +findings O +for O +patients O +in O +group O +B O +were O +compared O +with O +those O +of O +patients O +in O +groups O +C1 O +and O +C2 O +. O + +It O +was O +found O +that O +these O +groups O +did O +not O +differ O +in O +their O +overall O +frequency O +of O +ECG B +abnormalities I +; O +however O +, O +there O +were O +significant O +differences O +in O +the O +frequency O +of O +conduction B +defects I +. O + +Patients O +with O +hypercalcemia B +resulting O +from O +medical B +diseases O +and O +bipolar B +patients O +with O +lithium O +- O +associated O +hypercalcemia B +had O +significantly O +higher O +frequencies O +of O +conduction O +defects O +. O + +Patients O +in O +group O +A O +had O +significant O +mortality O +at O +2 O +- O +year O +follow O +- O +up O +( O +28 O +% O +) O +, O +in O +contrast O +to O +zero O +mortality O +in O +the O +other O +three O +groups O +. O + +The O +clinical O +implications O +of O +these O +findings O +are O +discussed O +. O + +Attenuation O +of O +nephrotoxicity B +by O +a O +novel O +lipid O +nanosphere O +( O +NS O +- O +718 O +) O +incorporating O +amphotericin O +B O +. O + +NS O +- O +718 O +, O +a O +lipid O +nanosphere O +incorporating O +amphotericin O +B O +, O +is O +effective O +against O +pathogenic O +fungi O +and O +has O +low O +toxicity B +. O + +We O +compared O +the O +toxicity B +of O +NS O +- O +718 O +with O +that O +of O +Fungizone O +( O +amphotericin O +B O +- O +sodium O +deoxycholate O +; O +D O +- O +AmB O +) O +in O +vitro O +using O +renal O +cell O +cultures O +and O +in O +vivo O +by O +biochemical O +analysis O +, O +histopathological O +study O +of O +the O +kidney O +and O +pharmacokinetic O +study O +of O +amphotericin O +B O +following O +intravenous O +infusion O +of O +the O +formulation O +in O +rats O +. O + +Incubation O +with O +NS O +- O +718 O +resulted O +in O +significantly O +less O +damage O +of O +cultured O +human O +renal O +proximal O +tubular O +epithelial O +cells O +compared O +with O +D O +- O +AmB O +. O + +Serum O +blood O +urea O +and O +creatinine O +concentrations O +increased O +significantly O +in O +rats O +given O +an O +iv O +infusion O +of O +D O +- O +AmB O +3 O +mg O +/ O +kg O +but O +not O +in O +those O +given O +the O +same O +dose O +of O +NS O +- O +718 O +. O + +Histopathological O +examination O +of O +the O +kidney O +showed O +tubular B +necrosis I +in O +D O +- O +AmB O +- O +treated O +rats O +but O +no O +change O +in O +NS O +- O +718 O +- O +treated O +rats O +. O + +Amphotericin O +B O +concentrations O +in O +the O +kidney O +in O +NS O +- O +718 O +- O +treated O +rats O +were O +higher O +than O +those O +in O +D O +- O +AmB O +- O +treated O +rats O +. O + +Our O +in O +vitro O +and O +in O +vivo O +results O +suggest O +that O +incorporation O +of O +amphotericin O +B O +into O +lipid O +nanospheres O +of O +NS O +- O +718 O +attenuates O +the O +nephrotoxicity B +of O +amphotericin O +B O +. O + +Patterns O +of O +sulfadiazine O +acute O +nephrotoxicity B +. O + +Sulfadiazine O +acute O +nephrotoxicity B +is O +reviving O +specially O +because O +of O +its O +use O +in O +toxoplasmosis B +in O +HIV B +- I +positive I +patients O +. O + +We O +report O +4 O +cases O +, O +one O +of O +them O +in O +a O +previously O +healthy O +person O +. O + +Under O +treatment O +with O +sulfadiazine O +they O +developed O +oliguria B +, O +abdominal B +pain I +, O +renal B +failure I +and O +showed O +multiple O +radiolucent O +renal B +calculi I +in O +echography O +. O + +All O +patients O +recovered O +their O +previous O +normal O +renal O +function O +after O +adequate O +hydration O +and O +alcalinization O +. O + +A O +nephrostomy O +tube O +had O +to O +be O +placed O +in O +one O +of O +the O +patients O +for O +ureteral B +lithiasis B +in O +a O +single O +functional O +kidney O +. O + +None O +of O +them O +needed O +dialysis O +or O +a O +renal O +biopsy O +because O +of O +a O +typical O +benign O +course O +. O + +Treatment O +with O +sulfadiazine O +requires O +exquisite O +control O +of O +renal O +function O +, O +an O +increase O +in O +water O +ingestion O +and O +possibly O +the O +alcalinization O +of O +the O +urine O +. O + +We O +communicate O +a O +case O +in O +a O +previously O +healthy O +person O +, O +a O +fact O +not O +found O +in O +the O +recent O +literature O +. O + +Probably O +many O +more O +cases O +are O +not O +detected O +. O + +We O +think O +that O +a O +prospective O +study O +would O +be O +useful O +. O + +Downbeat B +nystagmus B +associated O +with O +intravenous O +patient O +- O +controlled O +administration O +of O +morphine O +. O + +IMPLICATIONS O +: O +This O +case O +documents O +a O +patient O +who O +developed O +dizziness B +with O +downbeating O +nystagmus B +while O +receiving O +a O +relatively O +large O +dose O +of O +IV O +patient O +- O +controlled O +analgesia O +morphine O +. O + +Although O +there O +have O +been O +case O +reports O +of O +epidural O +morphine O +with O +these O +symptoms O +and O +signs O +, O +this O +has O +not O +been O +previously O +documented O +with O +IV O +or O +patient O +- O +controlled O +analgesia O +morphine O +. O + +Hemodynamic O +and O +antiadrenergic O +effects O +of O +dronedarone O +and O +amiodarone O +in O +animals O +with O +a O +healed O +myocardial B +infarction I +. O + +The O +hemodynamic O +and O +antiadrenergic O +effects O +of O +dronedarone O +, O +a O +noniodinated O +compound O +structurally O +related O +to O +amiodarone O +, O +were O +compared O +with O +those O +of O +amiodarone O +after O +prolonged O +oral O +administration O +, O +both O +at O +rest O +and O +during O +sympathetic O +stimulation O +in O +conscious O +dogs O +with O +a O +healed O +myocardial B +infarction I +. O + +All O +dogs O +( O +n O += O +6 O +) O +randomly O +received O +orally O +dronedarone O +( O +10 O +and O +30 O +mg O +/ O +kg O +) O +, O +amiodarone O +( O +10 O +and O +30 O +mg O +/ O +kg O +) O +, O +and O +placebo O +twice O +daily O +for O +7 O +days O +, O +with O +a O +3 O +- O +week O +washout O +between O +consecutive O +treatments O +. O + +Heart O +rate O +( O +HR O +) O +, O +mean O +arterial O +pressure O +( O +MBP O +) O +, O +positive O +rate O +of O +increase O +of O +left O +ventricular O +pressure O +( O ++ O +LVdP O +/ O +dt O +) O +, O +echocardiographically O +assessed O +left O +ventricular O +ejection O +fraction O +( O +LVEF O +) O +, O +and O +fractional O +shortening O +( O +FS O +) O +, O +as O +well O +as O +chronotropic O +response O +to O +isoproterenol O +and O +exercise O +- O +induced O +sympathetic O +stimulation O +were O +evaluated O +under O +baseline O +and O +posttreatment O +conditions O +. O + +Resting O +values O +of O +LVEF O +, O +FS O +, O ++ O +LVdP O +/ O +dt O +, O +and O +MBP O +remained O +unchanged O +whatever O +the O +drug O +and O +the O +dosing O +regimen O +, O +whereas O +resting O +HR O +was O +significantly O +and O +dose O +- O +dependently O +lowered O +after O +dronedarone O +and O +to O +a O +lesser O +extent O +after O +amiodarone O +. O + +Both O +dronedarone O +and O +amiodarone O +significantly O +reduced O +the O +exercise O +- O +induced O +tachycardia B +and O +, O +at O +the O +highest O +dose O +, O +decreased O +the O +isoproterenol O +- O +induced O +tachycardia B +. O + +Thus O +, O +dronedarone O +and O +amiodarone O +displayed O +a O +similar O +level O +of O +antiadrenergic O +effect O +and O +did O +not O +impair O +the O +resting O +left O +ventricular O +function O +. O + +Consequently O +, O +dronedarone O +might O +be O +particularly O +suitable O +for O +the O +treatment O +and O +prevention O +of O +various O +clinical O +arrhythmias B +, O +without O +compromising O +the O +left O +ventricular O +function O +. O + +Phase O +2 O +trial O +of O +liposomal O +doxorubicin O +( O +40 O +mg O +/ O +m O +( O +2 O +) O +) O +in O +platinum O +/ O +paclitaxel O +- O +refractory O +ovarian B +and I +fallopian I +tube I +cancers I +and O +primary B +carcinoma B +of I +the I +peritoneum I +. O + +BACKGROUND O +: O +Several O +studies O +have O +demonstrated O +liposomal O +doxorubicin O +( O +Doxil O +) O +to O +be O +an O +active O +antineoplastic O +agent O +in O +platinum O +- O +resistant I +ovarian B +cancer I +, O +with O +dose O +limiting O +toxicity B +of O +the O +standard O +dosing O +regimen O +( O +50 O +mg O +/ O +m O +( O +2 O +) O +q O +4 O +weeks O +) O +being O +severe O +erythrodysesthesia B +( O +" O +hand B +- I +foot I +syndrome I +" O +) O +and O +stomatitis B +. O + +We O +wished O +to O +develop O +a O +more O +tolerable O +liposomal O +doxorubicin O +treatment O +regimen O +and O +document O +its O +level O +of O +activity O +in O +a O +well O +- O +defined O +patient O +population O +with O +platinum O +/ O +paclitaxel O +- O +refractory O +disease O +. O + +METHODS O +AND O +MATERIALS O +: O +Patients O +with O +ovarian B +or I +fallopian I +tube I +cancers I +or O +primary B +peritoneal B +carcinoma I +with O +platinum O +/ O +paclitaxel O +- O +refractory O +disease O +( O +stable O +or O +progressive O +disease O +following O +treatment O +with O +these O +agents O +or O +previous O +objective O +response O +< O +3 O +months O +in O +duration O +) O +were O +treated O +with O +liposomal O +doxorubicin O +at O +a O +dose O +of O +40 O +mg O +/ O +m O +( O +2 O +) O +q O +4 O +weeks O +. O + +RESULTS O +: O +A O +total O +of O +49 O +patients O +( O +median O +age O +: O +60 O +; O +range O +41 O +- O +81 O +) O +entered O +this O +phase O +2 O +trial O +. O + +The O +median O +number O +of O +prior O +regimens O +was O +2 O +( O +range O +: O +1 O +- O +6 O +) O +. O + +Six O +( O +12 O +% O +) O +and O +4 O +( O +8 O +% O +) O +patients O +experienced O +grade O +2 O +hand B +- I +foot I +syndrome I +and O +stomatitis B +, O +respectively O +( O +no O +episodes O +of O +grade O +3 O +) O +. O + +One O +patient O +developed O +grade O +3 O +diarrhea B +requiring O +hospitalization O +for O +hydration O +. O + +Six O +( O +12 O +% O +) O +individuals O +required O +dose O +reductions O +. O + +The O +median O +number O +of O +courses O +of O +liposomal O +doxorubicin O +administered O +on O +this O +protocol O +was O +2 O +( O +range O +: O +1 O +- O +12 O +) O +. O + +Four O +of O +44 O +patients O +( O +9 O +% O +) O +evaluable O +for O +response O +exhibited O +objective O +and O +subjective O +evidence O +of O +an O +antineoplastic O +effect O +of O +therapy O +. O + +CONCLUSION O +: O +This O +modified O +liposomal O +doxorubicin O +regimen O +results O +in O +less O +toxicity B +( O +stomatitis B +, O +hand B +- I +foot I +syndrome I +) O +than O +the O +standard O +FDA O +- O +approved O +dose O +schedule O +. O + +Definite O +, O +although O +limited O +, O +antineoplastic O +activity O +is O +observed O +in O +patients O +with O +well O +- O +defined O +platinum O +- O +and O +paclitaxel O +- O +refractory O +ovarian B +cancer I +. O + +Efficacy O +of O +olanzapine O +in O +acute O +bipolar B +mania I +: O +a O +double O +- O +blind O +, O +placebo O +- O +controlled O +study O +. O + +The O +Olanzipine O +HGGW O +Study O +Group O +. O + +BACKGROUND O +: O +We O +compared O +the O +efficacy O +and O +safety O +of O +olanzapine O +vs O +placebo O +for O +the O +treatment O +of O +acute O +bipolar B +mania I +. O + +METHODS O +: O +Four O +- O +week O +, O +randomized O +, O +double O +- O +blind O +, O +parallel O +study O +. O + +A O +total O +of O +115 O +patients O +with O +a O +DSM O +- O +IV O +diagnosis O +of O +bipolar B +disorder I +, O +manic B +or O +mixed O +, O +were O +randomized O +to O +olanzapine O +, O +5 O +to O +20 O +mg O +/ O +d O +( O +n O += O +55 O +) O +, O +or O +placebo O +( O +n O += O +60 O +) O +. O + +The O +primary O +efficacy O +measure O +was O +the O +Young O +- O +Mania B +Rating O +Scale O +( O +Y O +- O +MRS O +) O +total O +score O +. O + +Response O +and O +euthymia O +were O +defined O +, O +a O +priori O +, O +as O +at O +least O +a O +50 O +% O +improvement O +from O +baseline O +to O +end O +point O +and O +as O +a O +score O +of O +no O +less O +than O +12 O +at O +end O +point O +in O +the O +Y O +- O +MRS O +total O +score O +, O +respectively O +. O + +Safety O +was O +assessed O +using O +adverse O +events O +, O +Extrapyramidal B +Symptom O +( O +EPS O +) O +rating O +scales O +, O +laboratory O +values O +, O +electrocardiograms O +, O +vital O +signs O +, O +and O +weight O +change O +. O + +RESULTS O +: O +Olanzapine O +- O +treated O +patients O +demonstrated O +a O +statistically O +significant O +greater O +mean O +( O ++ O +/ O +- O +SD O +) O +improvement O +in O +Y O +- O +MRS O +total O +score O +than O +placebo O +- O +treated O +patients O +( O +- O +14 O +. O +8 O ++ O +/ O +- O +12 O +. O +5 O +and O +- O +8 O +. O +1 O ++ O +/ O +- O +12 O +. O +7 O +, O +respectively O +; O +P O +< O +. O +001 O +) O +, O +which O +was O +evident O +at O +the O +first O +postbaseline O +observation O +1 O +week O +after O +randomization O +and O +was O +maintained O +throughout O +the O +study O +( O +last O +observation O +carried O +forward O +) O +. O + +Olanzapine O +- O +treated O +patients O +demonstrated O +a O +higher O +rate O +of O +response O +( O +65 O +% O +vs O +43 O +% O +, O +respectively O +; O +P O += O +. O +02 O +) O +and O +euthymia O +( O +61 O +% O +vs O +36 O +% O +, O +respectively O +; O +P O += O +. O +01 O +) O +than O +placebo O +- O +treated O +patients O +. O + +There O +were O +no O +statistically O +significant O +differences O +in O +EPSs O +between O +groups O +. O + +However O +, O +olanzapine O +- O +treated O +patients O +had O +a O +statistically O +significant O +greater O +mean O +( O ++ O +/ O +- O +SD O +) O +weight B +gain I +than O +placebo O +- O +treated O +patients O +( O +2 O +. O +1 O ++ O +/ O +- O +2 O +. O +8 O +vs O +0 O +. O +45 O ++ O +/ O +- O +2 O +. O +3 O +kg O +, O +respectively O +) O +and O +also O +experienced O +more O +treatment O +- O +emergent O +somnolence B +( O +21 O +patients O +[ O +38 O +. O +2 O +% O +] O +vs O +5 O +[ O +8 O +. O +3 O +% O +] O +, O +respectively O +) O +. O + +CONCLUSION O +: O +Olanzapine O +demonstrated O +greater O +efficacy O +than O +placebo O +in O +the O +treatment O +of O +acute O +bipolar B +mania I +and O +was O +generally O +well O +tolerated O +. O + +The O +effect O +of O +pupil O +dilation O +with O +tropicamide O +on O +vision O +and O +driving O +simulator O +performance O +. O + +PURPOSE O +: O +To O +assess O +the O +effect O +of O +pupil O +dilation O +on O +vision O +and O +driving O +ability O +. O + +METHODS O +: O +A O +series O +of O +tests O +on O +various O +parameters O +of O +visual O +function O +and O +driving O +simulator O +performance O +were O +performed O +on O +12 O +healthy O +drivers O +, O +before O +and O +after O +pupil O +dilation O +using O +guttae O +tropicamide O +1 O +% O +. O + +A O +driving O +simulator O +( O +Transport O +Research O +Laboratory O +) O +was O +used O +to O +measure O +reaction O +time O +( O +RT O +) O +, O +speed O +maintenance O +and O +steering O +accuracy O +. O + +Tests O +of O +basic O +visual O +function O +included O +high O +- O +and O +low O +- O +contrast O +visual O +acuity O +( O +HCVA O +and O +LCVA O +) O +, O +Pelli O +- O +Robson O +contrast O +threshold O +( O +CT O +) O +and O +Goldmann O +perimetry O +( O +FIELDS O +) O +. O + +Useful O +Field O +of O +View O +( O +UFOV O +- O +- O +a O +test O +of O +visual O +attention O +) O +was O +also O +undertaken O +. O + +The O +mean O +differences O +in O +the O +pre O +- O +and O +post O +- O +dilatation O +measurements O +were O +tested O +for O +statistical O +significance O +at O +the O +95 O +% O +level O +using O +one O +- O +tail O +paired O +t O +- O +tests O +. O + +RESULTS O +: O +Pupillary O +dilation O +resulted O +in O +a O +statistically O +significant O +deterioration O +in O +CT O +and O +HCVA O +only O +. O + +Five O +of O +12 O +drivers O +also O +exhibited O +deterioration O +in O +LCVA O +, O +CT O +and O +RT O +. O + +Little O +evidence O +emerged O +for O +deterioration O +in O +FIELDS O +and O +UFOV O +. O + +Also O +, O +7 O +of O +12 O +drivers O +appeared O +to O +adjust O +their O +driving O +behaviour O +by O +reducing O +their O +speed O +on O +the O +driving O +simulator O +, O +leading O +to O +improved O +steering O +accuracy O +. O + +CONCLUSIONS O +: O +Pupillary O +dilation O +may O +lead O +to O +a O +decrease B +in I +vision I +and O +daylight O +driving O +performance O +in O +young O +people O +. O + +A O +larger O +study O +, O +including O +a O +broader O +spectrum O +of O +subjects O +, O +is O +warranted O +before O +guidelines O +can O +be O +recommended O +. O + +A O +case O +of O +isotretinoin O +embryopathy B +with O +bilateral O +anotia B +and O +Taussig B +- I +Bing I +malformation I +. O + +We O +report O +a O +newborn O +infant O +with O +multiple B +congenital I +anomalies I +( O +anotia B +and O +Taussig B +- I +Bing I +malformation I +) O +due O +to O +exposure O +to O +isotretinoin O +within O +the O +first O +trimester O +. O + +In O +this O +paper O +we O +aim O +to O +draw O +to O +the O +fact O +that O +caution O +is O +needed O +when O +prescribing O +vitamin O +A O +- O +containing O +drugs O +to O +women O +of O +childbearing O +years O +. O + +Effect O +of O +methoxamine O +on O +maximum O +urethral O +pressure O +in O +women O +with O +genuine O +stress B +incontinence I +: O +a O +placebo O +- O +controlled O +, O +double O +- O +blind O +crossover O +study O +. O + +The O +aim O +of O +the O +study O +was O +to O +evaluate O +the O +potential O +role O +for O +a O +selective O +alpha1 O +- O +adrenoceptor O +agonist O +in O +the O +treatment O +of O +urinary B +stress I +incontinence I +. O + +A O +randomised O +, O +double O +- O +blind O +, O +placebo O +- O +controlled O +, O +crossover O +study O +design O +was O +employed O +. O + +Half O +log O +incremental O +doses O +of O +intravenous O +methoxamine O +or O +placebo O +( O +saline O +) O +were O +administered O +to O +a O +group O +of O +women O +with O +genuine O +stress B +incontinence I +while O +measuring O +maximum O +urethral O +pressure O +( O +MUP O +) O +, O +blood O +pressure O +, O +heart O +rate O +, O +and O +symptomatic O +side O +effects O +. O + +Methoxamine O +evoked O +non O +- O +significant O +increases O +in O +MUP O +and O +diastolic O +blood O +pressure O +but O +caused O +a O +significant O +rise O +in O +systolic O +blood O +pressure O +and O +significant O +fall O +in O +heart O +rate O +at O +maximum O +dosage O +. O + +Systemic O +side O +effects O +including O +piloerection O +, O +headache B +, O +and O +cold O +extremities O +were O +experienced O +in O +all O +subjects O +. O + +The O +results O +indicate O +that O +the O +clinical O +usefulness O +of O +direct O +, O +peripherally O +acting O +sub O +- O +type O +- O +selective O +alpha1 O +- O +adrenoceptor O +agonists O +in O +the O +medical O +treatment O +of O +stress B +incontinence I +may O +be O +limited O +by O +associated O +piloerection O +and O +cardiovascular O +side O +effects O +. O + +Hyperglycemic B +effect O +of O +amino O +compounds O +structurally O +related O +to O +caproate O +in O +rats O +. O + +The O +chronic O +feeding O +of O +small O +amounts O +( O +0 O +. O +3 O +- O +3 O +% O +of O +diet O +weight O +) O +of O +certain O +amino O +derivatives O +of O +caproate O +resulted O +in O +hyperglycemia B +, O +an O +elevated B +glucose I +tolerance I +curve O +and O +, O +occasionally O +, O +glucosuria B +. O + +Effective O +compounds O +included O +norleucine O +, O +norvaline O +, O +glutamate O +, O +epsilon O +- O +aminocaproate O +, O +methionine O +, O +and O +leucine O +. O + +Toleration O +of O +high O +doses O +of O +angiotensin O +- O +converting O +enzyme O +inhibitors O +in O +patients O +with O +chronic O +heart B +failure I +: O +results O +from O +the O +ATLAS O +trial O +. O + +The O +Assessment O +of O +Treatment O +with O +Lisinopril O +and O +Survival O +. O + +BACKGROUND O +: O +Treatment O +with O +angiotensin O +- O +converting O +enzyme O +( O +ACE O +) O +inhibitors O +reduces O +mortality O +and O +morbidity O +in O +patients O +with O +chronic B +heart B +failure I +( O +CHF B +) O +, O +but O +most O +affected O +patients O +are O +not O +receiving O +these O +agents O +or O +are O +being O +treated O +with O +doses O +lower O +than O +those O +found O +to O +be O +efficacious O +in O +trials O +, O +primarily O +because O +of O +concerns O +about O +the O +safety O +and O +tolerability O +of O +these O +agents O +, O +especially O +at O +the O +recommended O +doses O +. O + +The O +present O +study O +examines O +the O +safety O +and O +tolerability O +of O +high O +- O +compared O +with O +low O +- O +dose O +lisinopril O +in O +CHF B +. O + +METHODS O +: O +The O +Assessment O +of O +Lisinopril O +and O +Survival O +study O +was O +a O +multicenter O +, O +randomized O +, O +double O +- O +blind O +trial O +in O +which O +patients O +with O +or O +without O +previous O +ACE O +inhibitor O +treatment O +were O +stabilized O +receiving O +medium O +- O +dose O +lisinopril O +( O +12 O +. O +5 O +or O +15 O +. O +0 O +mg O +once O +daily O +[ O +OD O +] O +) O +for O +2 O +to O +4 O +weeks O +and O +then O +randomized O +to O +high O +- O +( O +35 O +. O +0 O +or O +32 O +. O +5 O +mg O +OD O +) O +or O +low O +- O +dose O +( O +5 O +. O +0 O +or O +2 O +. O +5 O +mg O +OD O +) O +groups O +. O + +Patients O +with O +New O +York O +Heart O +Association O +classes O +II O +to O +IV O +CHF B +and O +left O +ventricular O +ejection O +fractions O +of O +no O +greater O +than O +0 O +. O +30 O +( O +n O += O +3164 O +) O +were O +randomized O +and O +followed O +up O +for O +a O +median O +of O +46 O +months O +. O + +We O +examined O +the O +occurrence O +of O +adverse O +events O +and O +the O +need O +for O +discontinuation O +and O +dose O +reduction O +during O +treatment O +, O +with O +a O +focus O +on O +hypotension B +and O +renal B +dysfunction I +. O + +RESULTS O +: O +Of O +405 O +patients O +not O +previously O +receiving O +an O +ACE O +inhibitor O +, O +doses O +in O +only O +4 O +. O +2 O +% O +could O +not O +be O +titrated O +to O +the O +medium O +doses O +required O +for O +randomization O +because O +of O +symptoms O +possibly O +related O +to O +hypotension B +( O +2 O +. O +0 O +% O +) O +or O +because O +of O +renal B +dysfunction I +or O +hyperkalemia B +( O +2 O +. O +3 O +% O +) O +. O + +Doses O +in O +more O +than O +90 O +% O +of O +randomized O +patients O +in O +the O +high O +- O +and O +low O +- O +dose O +groups O +were O +titrated O +to O +their O +assigned O +target O +, O +and O +the O +mean O +doses O +of O +blinded O +medication O +in O +both O +groups O +remained O +similar O +throughout O +the O +study O +. O + +Withdrawals O +occurred O +in O +27 O +. O +1 O +% O +of O +the O +high O +- O +and O +30 O +. O +7 O +% O +of O +the O +low O +- O +dose O +groups O +. O + +Subgroups O +presumed O +to O +be O +at O +higher O +risk O +for O +ACE O +inhibitor O +intolerance O +( O +blood O +pressure O +, O +< O +120 O +mm O +Hg O +; O +creatinine O +, O +> O +or O += O +132 O +. O +6 O +micromol O +/ O +L O +[ O +> O +or O += O +1 O +. O +5 O +mg O +/ O +dL O +] O +; O +age O +, O +> O +or O += O +70 O +years O +; O +and O +patients O +with O +diabetes B +) O +generally O +tolerated O +the O +high O +- O +dose O +strategy O +. O + +CONCLUSIONS O +: O +These O +findings O +demonstrate O +that O +ACE O +inhibitor O +therapy O +in O +most O +patients O +with O +CHF B +can O +be O +successfully O +titrated O +to O +and O +maintained O +at O +high O +doses O +, O +and O +that O +more O +aggressive O +use O +of O +these O +agents O +is O +warranted O +. O + +Cocaine O +, O +ethanol O +, O +and O +cocaethylene O +cardiotoxity B +in O +an O +animal O +model O +of O +cocaine O +and O +ethanol O +abuse I +. O + +OBJECTIVES O +: O +Simultaneous O +abuse O +of O +cocaine O +and O +ethanol O +affects O +12 O +million O +Americans O +annually O +. O + +In O +combination O +, O +these O +substances O +are O +substantially O +more O +toxic O +than O +either O +drug O +alone O +. O + +Their O +combined O +cardiac B +toxicity I +may O +be O +due O +to O +independent O +effects O +of O +each O +drug O +; O +however O +, O +they O +may O +also O +be O +due O +to O +cocaethylene O +( O +CE O +) O +, O +a O +cocaine O +metabolite O +formed O +only O +in O +the O +presence O +of O +ethanol O +. O + +The O +purpose O +of O +this O +study O +was O +to O +delineate O +the O +role O +of O +CE O +in O +the O +combined O +cardiotoxicity B +of O +cocaine O +and O +ethanol O +in O +a O +model O +simulating O +their O +abuse O +. O + +METHODS O +: O +Twenty O +- O +three O +dogs O +were O +randomized O +to O +receive O +either O +1 O +) O +three O +intravenous O +( O +IV O +) O +boluses O +of O +cocaine O +7 O +. O +5 O +mg O +/ O +kg O +with O +ethanol O +( O +1 O +g O +/ O +kg O +) O +as O +an O +IV O +infusion O +( O +C O ++ O +E O +, O +n O += O +8 O +) O +, O +2 O +) O +three O +cocaine O +boluses O +only O +( O +C O +, O +n O += O +6 O +) O +, O +3 O +) O +ethanol O +infusion O +only O +( O +E O +, O +n O += O +5 O +) O +, O +or O +4 O +) O +placebo O +boluses O +and O +infusion O +( O +n O += O +4 O +) O +. O + +Hemodynamic O +measurements O +, O +electrocardiograms O +, O +and O +serum O +drug O +concentrations O +were O +obtained O +at O +baseline O +, O +and O +then O +at O +fixed O +time O +intervals O +after O +each O +drug O +was O +administered O +. O + +RESULTS O +: O +Two O +of O +eight O +dogs O +in O +the O +C O ++ O +E O +group O +experienced O +cardiovascular B +collapse I +. O + +The O +most O +dramatic O +hemodynamic O +changes O +occurred O +after O +each O +cocaine O +bolus O +in O +the O +C O ++ O +E O +and O +C O +only O +groups O +; O +however O +, O +persistent O +hemodynamic O +changes O +occurred O +in O +the O +C O ++ O +E O +group O +. O + +Peak O +CE O +levels O +were O +associated O +with O +a O +45 O +% O +( O +SD O ++ O +/ O +- O +22 O +% O +, O +95 O +% O +CI O += O +22 O +% O +to O +69 O +% O +) O +decrease O +in O +cardiac I +output I +( O +p O +< O +0 O +. O +05 O +) O +, O +a O +56 O +% O +( O +SD O ++ O +/ O +- O +23 O +% O +, O +95 O +% O +CI O += O +32 O +% O +to O +80 O +% O +) O +decrease O +in O +dP O +/ O +dt O +( O +max O +) O +( O +p O +< O +. O +006 O +) O +, O +and O +a O +23 O +% O +( O +SD O ++ O +/ O +- O +15 O +% O +, O +95 O +% O +CI O += O +7 O +% O +to O +49 O +% O +) O +decrease O +in O +SVO O +( O +2 O +) O +( O +p O +< O +0 O +. O +025 O +) O +. O + +Ventricular B +arrhythmias I +were O +primarily O +observed O +in O +the O +C O ++ O +E O +group O +, O +in O +which O +four O +of O +eight O +dogs O +experienced O +ventricular B +tachycardia I +. O + +CONCLUSIONS O +: O +Cocaine O +and O +ethanol O +in O +combination O +were O +more O +toxic O +than O +either O +substance O +alone O +. O + +Co O +- O +administration O +resulted O +in O +prolonged O +cardiac B +toxicity I +and O +was O +dysrhythmogenic O +. O + +Peak O +serum O +cocaethylene O +concentrations O +were O +associated O +with O +prolonged O +myocardial B +depression I +. O + +Worsening O +of O +Parkinsonism B +after O +the O +use O +of O +veralipride O +for O +treatment O +of O +menopause O +: O +case O +report O +. O + +We O +describe O +a O +female O +patient O +with O +stable O +Parkinson B +' I +s I +disease I +who O +has O +shown O +a O +marked O +worsening O +of O +her O +motor O +functions O +following O +therapy O +of O +menopause O +related O +symptoms O +with O +veralipride O +, O +as O +well O +as O +the O +improvement O +of O +her O +symptoms O +back O +to O +baseline O +after O +discontinuation O +of O +the O +drug O +. O + +We O +emphasize O +the O +anti O +- O +dopaminergic O +effect O +of O +veralipride O +. O + +Viracept O +and O +irregular O +heartbeat O +warning O +. O + +A O +group O +of O +doctors O +in O +Boston O +warn O +that O +the O +protease O +inhibitor O +Viracept O +may O +cause O +an O +irregular O +heart O +beat I +, O +known O +as O +bradycardia B +, O +in O +people O +with O +HIV B +. O + +Bradycardia B +occurred O +in O +a O +45 O +- O +year O +- O +old O +male O +patient O +who O +was O +Viracept O +in O +combination O +with O +other O +anti O +- O +HIV B +drugs O +. O + +The O +symptoms O +ceased O +after O +switching O +to O +another O +drug O +combination O +. O + +Frequency O +of O +appearance O +of O +myeloperoxidase O +- O +antineutrophil O +cytoplasmic O +antibody O +( O +MPO O +- O +ANCA O +) O +in O +Graves B +' I +disease I +patients O +treated O +with O +propylthiouracil O +and O +the O +relationship O +between O +MPO O +- O +ANCA O +and O +clinical O +manifestations O +. O + +OBJECTIVE O +: O +Myeloperoxidase O +antineutrophil O +cytoplasmic O +antibody O +( O +MPO O +- O +ANCA O +) O +- O +positive O +vasculitis B +has O +been O +reported O +in O +patients O +with O +Graves B +' I +disease I +who O +were O +treated O +with O +propylthiouracil O +( O +PTU O +) O +. O + +The O +appearance O +of O +MPO O +- O +ANCA O +in O +these O +cases O +was O +suspected O +of O +being O +related O +to O +PTU O +because O +the O +titres O +of O +MPO O +- O +ANCA O +decreased O +when O +PTU O +was O +stopped O +. O + +Nevertheless O +, O +there O +have O +been O +no O +studies O +on O +the O +temporal O +relationship O +between O +the O +appearance O +of O +MPO O +- O +ANCA I +and O +vasculitis B +during O +PTU O +therapy O +, O +or O +on O +the O +incidence O +of O +MPO O +- O +ANCA I +in O +untreated O +Graves B +' I +disease I +patients O +. O + +Therefore O +, O +we O +sought O +to O +address O +these O +parameters O +in O +patients O +with O +Graves B +' I +disease I +. O + +PATIENTS O +: O +We O +investigated O +102 O +untreated O +patients O +with O +hyperthyroidism B +due O +to O +Graves B +' I +disease I +for O +the O +presence O +of O +MPO O +- O +ANCA O +, O +and O +for O +the O +development O +vasculitis B +after O +starting O +PTU O +therapy O +. O + +Twenty O +- O +nine O +of O +them O +were O +later O +excluded O +because O +of O +adverse O +effects O +of O +PTU O +or O +because O +the O +observation O +period O +was O +less O +than O +3 O +months O +. O + +The O +remaining O +73 O +patients O +( O +55 O +women O +and O +18 O +men O +) O +, O +all O +of O +whom O +were O +examined O +for O +more O +than O +3 O +months O +, O +were O +adopted O +as O +the O +subjects O +of O +the O +investigation O +. O + +The O +median O +observation O +period O +was O +23 O +. O +6 O +months O +( O +range O +: O +3 O +- O +37 O +months O +) O +. O + +MEASUREMENTS O +: O +MPO O +- O +ANCA O +was O +measured O +at O +intervals O +of O +2 O +- O +6 O +months O +. O + +RESULTS O +: O +Before O +treatment O +, O +the O +MPO O +- O +ANCA O +titres O +of O +all O +102 O +untreated O +Graves B +' I +disease I +patients O +were O +within O +the O +reference O +range O +( O +below O +10 O +U O +/ O +ml O +) O +. O + +Three O +( O +4 O +. O +1 O +% O +) O +of O +the O +73 O +patients O +were O +positive O +for O +MPO O +- O +ANCA O +at O +13 O +, O +16 O +and O +17 O +months O +, O +respectively O +, O +after O +the O +start O +of O +PTU O +therapy O +. O + +In O +two O +of O +them O +, O +the O +MPO O +- O +ANCA O +titres O +transiently O +increased O +to O +12 O +. O +8 O +and O +15 O +. O +0 O +U O +/ O +ml O +, O +respectively O +, O +despite O +continued O +PTU O +therapy O +, O +but O +no O +vasculitic B +disorders I +developed O +. O + +In O +the O +third O +patient O +, O +the O +MPO O +- O +ANCA O +titre O +increased O +to O +204 O +U O +/ O +ml O +and O +she O +developed O +a O +higher O +fever B +, O +oral B +ulcers B +and O +polyarthralgia B +, O +but O +the O +symptoms O +resolved O +2 O +weeks O +after O +stopping O +PTU O +therapy O +, O +and O +the O +MPO O +- O +ANCA O +titre O +decreased O +to O +20 O +. O +7 O +U O +/ O +ml O +by O +4 O +months O +after O +discontinuing O +PTU O +. O + +CONCLUSIONS O +: O +PTU O +therapy O +may O +be O +related O +to O +the O +appearance O +of O +MPO O +- O +ANCA O +, O +but O +MPO O +- O +ANCA O +does O +not O +appear O +to O +be O +closely O +related O +to O +vasculitis B +. O + +Prevalence O +of O +heart B +disease I +in O +asymptomatic O +chronic O +cocaine O +users O +. O + +To O +determine O +the O +prevalence O +of O +heart B +disease I +in O +outpatient O +young O +asymptomatic O +chronic O +cocaine O +users O +, O +35 O +cocaine O +users O +and O +32 O +age O +- O +matched O +controls O +underwent O +resting O +and O +exercise O +electrocardiography O +( O +ECG O +) O +and O +Doppler O +echocardiography O +. O + +Findings O +consistent O +with O +coronary B +artery I +disease I +were O +detected O +in O +12 O +( O +34 O +% O +) O +patients O +and O +3 O +( O +9 O +% O +) O +controls O +( O +p O += O +0 O +. O +01 O +) O +. O + +Decreased B +left I +ventricular I +systolic I +function I +was O +demonstrated O +in O +5 O +( O +14 O +% O +) O +patients O +, O +but O +in O +none O +of O +the O +controls O +( O +p O += O +0 O +. O +055 O +) O +. O + +Finally O +, O +resting O +and O +peak O +exercise O +abnormal O +left I +ventricular I +filling O +was O +detected O +in O +38 O +and O +35 O +% O +of O +patients O +as O +compared O +to O +19 O +and O +9 O +% O +of O +controls O +, O +respectively O +( O +p O += O +0 O +. O +11 O +and O +0 O +. O +02 O +, O +respectively O +) O +. O + +We O +conclude O +that O +coronary B +artery I +or I +myocardial I +disease I +is O +common O +( O +38 O +% O +) O +in O +young O +asymptomatic O +chronic O +cocaine O +users O +. O + +Therefore O +, O +screening O +ECG O +and O +echocardiography O +may O +be O +warranted O +in O +these O +patients O +. O + +Cardioprotective O +effects O +of O +Picrorrhiza O +kurroa O +against O +isoproterenol O +- O +induced O +myocardial B +stress I +in O +rats O +. O + +The O +cardioprotective O +effect O +of O +the O +ethanol O +extract O +of O +Picrorrhiza O +kurroa O +rhizomes O +and O +roots O +( O +PK O +) O +on O +isoproterenol O +- O +induced O +myocardial B +infarction I +in O +rats O +with O +respect O +to O +lipid O +metabolism O +in O +serum O +and O +heart O +tissue O +has O +been O +investigated O +. O + +Oral O +pre O +- O +treatment O +with O +PK O +( O +80 O +mg O +kg O +( O +- O +1 O +) O +day O +( O +- O +1 O +) O +for O +15 O +days O +) O +significantly O +prevented O +the O +isoproterenol O +- O +induced O +myocardial B +infarction I +and O +maintained O +the O +rats O +at O +near O +normal O +status O +. O + +Phase O +2 O +early O +afterdepolarization O +as O +a O +trigger O +of O +polymorphic O +ventricular B +tachycardia I +in O +acquired O +long B +- I +QT I +syndrome I +: O +direct O +evidence O +from O +intracellular O +recordings O +in O +the O +intact O +left O +ventricular O +wall O +. O + +BACKGROUND O +: O +This O +study O +examined O +the O +role O +of O +phase O +2 O +early O +afterdepolarization O +( O +EAD O +) O +in O +producing O +a O +trigger O +to O +initiate O +torsade B +de I +pointes I +( O +TdP B +) O +with O +QT B +prolongation I +induced O +by O +dl O +- O +sotalol O +and O +azimilide O +. O + +The O +contribution O +of O +transmural O +dispersion O +of O +repolarization O +( O +TDR O +) O +to O +transmural O +propagation O +of O +EAD O +and O +the O +maintenance O +of O +TdP B +was O +also O +evaluated O +. O + +METHODS O +AND O +RESULTS O +: O +Transmembrane O +action O +potentials O +from O +epicardium O +, O +midmyocardium O +, O +and O +endocardium O +were O +recorded O +simultaneously O +, O +together O +with O +a O +transmural O +ECG O +, O +in O +arterially O +perfused O +canine O +and O +rabbit O +left O +ventricular O +preparations O +. O + +dl O +- O +Sotalol O +preferentially O +prolonged O +action O +potential O +duration O +( O +APD O +) O +in O +M O +cells O +dose O +- O +dependently O +( O +1 O +to O +100 O +micromol O +/ O +L O +) O +, O +leading O +to O +QT B +prolongation I +and O +an O +increase O +in O +TDR O +. O + +Azimilide O +, O +however O +, O +significantly O +prolonged O +APD O +and O +QT O +interval O +at O +concentrations O +from O +0 O +. O +1 O +to O +10 O +micromol O +/ O +L O +but O +shortened O +them O +at O +30 O +micromol O +/ O +L O +. O + +Unlike O +dl O +- O +sotalol O +, O +azimilide O +( O +> O +3 O +micromol O +/ O +L O +) O +increased O +epicardial O +APD B +markedly O +, O +causing O +a O +diminished O +TDR O +. O + +Although O +both O +dl O +- O +sotalol O +and O +azimilide O +rarely O +induced O +EADs O +in O +canine O +left O +ventricles O +, O +they O +produced O +frequent O +EADs O +in O +rabbits O +, O +in O +which O +more O +pronounced O +QT B +prolongation I +was O +seen O +. O + +An O +increase O +in O +TDR O +by O +dl O +- O +sotalol O +facilitated O +transmural O +propagation O +of O +EADs O +that O +initiated O +multiple O +episodes O +of O +spontaneous O +TdP B +in O +3 O +of O +6 O +rabbit O +left O +ventricles O +. O + +Of O +note O +, O +although O +azimilide O +( O +3 O +to O +10 O +micromol O +/ O +L O +) O +increased O +APD B +more O +than O +dl O +- O +sotalol O +, O +its O +EADs O +often O +failed O +to O +propagate O +transmurally O +, O +probably O +because O +of O +a O +diminished O +TDR O +. O + +CONCLUSIONS O +: O +This O +study O +provides O +the O +first O +direct O +evidence O +from O +intracellular O +action O +potential O +recordings O +that O +phase O +2 O +EAD O +can O +be O +generated O +from O +intact O +ventricular O +wall O +and O +produce O +a O +trigger O +to O +initiate O +the O +onset O +of O +TdP B +under O +QT B +prolongation I +. O + +A O +pilot O +study O +to O +assess O +the O +safety O +of O +dobutamine O +stress O +echocardiography O +in O +the O +emergency O +department O +evaluation O +of O +cocaine O +- O +associated O +chest B +pain I +. O + +STUDY O +OBJECTIVE O +: O +Chest B +pain I +in O +the O +setting O +of O +cocaine O +use O +poses O +a O +diagnostic O +dilemma O +. O + +Dobutamine O +stress O +echocardiography O +( O +DSE O +) O +is O +a O +widely O +available O +and O +sensitive O +test O +for O +evaluating O +cardiac B +ischemia I +. O + +Because O +of O +the O +theoretical O +concern O +regarding O +administration O +of O +dobutamine O +in O +the O +setting O +of O +cocaine O +use O +, O +we O +conducted O +a O +pilot O +study O +to O +assess O +the O +safety O +of O +DSE O +in O +emergency O +department O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +. O + +METHODS O +: O +A O +prospective O +case O +series O +was O +conducted O +in O +the O +intensive O +diagnostic O +and O +treatment O +unit O +in O +the O +ED O +of O +an O +urban O +tertiary O +- O +care O +teaching O +hospital O +. O + +Patients O +were O +eligible O +for O +DSE O +if O +they O +had O +used O +cocaine O +within O +24 O +hours O +preceding O +the O +onset O +of O +chest B +pain I +and O +had O +a O +normal O +ECG O +and O +tropinin O +I O +level O +. O + +Patients O +exhibiting O +signs O +of O +continuing O +cocaine O +toxicity B +were O +excluded O +from O +the O +study O +. O + +All O +patients O +were O +admitted O +to O +the O +hospital O +for O +serial O +testing O +after O +the O +DSE O +testing O +in O +the O +intensive O +diagnostic O +and O +treatment O +unit O +. O + +RESULTS O +: O +Twenty O +- O +four O +patients O +were O +enrolled O +. O + +Two O +patients O +had O +inadequate O +resting O +images O +, O +one O +DSE O +was O +terminated O +because O +of O +inferior O +hypokinesis B +, O +another O +DSE O +was O +terminated O +because O +of O +a O +rate O +- O +related O +atrial B +conduction I +deficit I +, O +and O +1 O +patient O +did O +not O +reach O +the O +target O +heart O +rate O +. O + +Thus O +, O +19 O +patients O +completed O +a O +DSE O +and O +reached O +their O +target O +heart O +rates O +. O + +None O +of O +the O +patients O +experienced O +signs O +of O +exaggerated O +adrenergic O +response O +, O +which O +was O +defined O +as O +a O +systolic O +blood O +pressure O +of O +greater O +than O +200 O +mm O +Hg O +or O +the O +occurrence O +of O +tachydysrhythmias B +( O +excluding O +sinus B +tachycardia I +) O +. O + +Further O +suggesting O +lack O +of O +exaggerated O +adrenergic O +response O +, O +13 O +( O +65 O +% O +) O +of O +20 O +patients O +required O +supplemental O +atropine O +to O +reach O +their O +target O +heart O +rates O +. O + +CONCLUSION O +: O +No O +exaggerated O +adrenergic O +response O +was O +detected O +when O +dobutamine O +was O +administered O +to O +patients O +with O +cocaine O +- O +related O +chest B +pain I +. O + +Prenatal O +cocaine O +exposure O +and O +cranial O +sonographic O +findings O +in O +preterm O +infants O +. O + +PURPOSE O +: O +Prenatal O +cocaine O +exposure O +has O +been O +linked O +with O +subependymal B +hemorrhage I +and O +the O +formation O +of O +cysts B +that O +are O +detectable O +on O +cranial O +sonography O +in O +neonates O +born O +at O +term O +. O + +We O +sought O +to O +determine O +if O +prenatal O +cocaine O +exposure O +increases O +the O +incidence O +of O +subependymal B +cysts I +in O +preterm O +infants O +. O + +METHODS O +: O +We O +retrospectively O +reviewed O +the O +medical O +records O +and O +cranial O +sonograms O +obtained O +during O +a O +1 O +- O +year O +period O +on O +122 O +premature O +( O +< O +36 O +weeks O +of O +gestation O +) O +infants O +. O + +Infants O +were O +categorized O +into O +1 O +of O +2 O +groups O +: O +those O +exposed O +to O +cocaine O +and O +those O +not O +exposed O +to O +cocaine O +. O + +Infants O +were O +assigned O +to O +the O +cocaine O +- O +exposed O +group O +if O +there O +was O +a O +maternal O +history O +of O +cocaine B +abuse I +during O +pregnancy O +or O +if O +maternal O +or O +neonatal O +urine O +toxicology O +results O +were O +positive O +at O +the O +time O +of O +delivery O +. O + +RESULTS O +: O +Five O +of O +the O +122 O +infants O +were O +excluded O +from O +the O +study O +because O +of O +insufficient O +medical O +and O +drug O +histories O +. O + +The O +incidence O +of O +subependymal B +cysts I +in O +the O +117 O +remaining O +infants O +was O +14 O +% O +( O +16 O +of O +117 O +) O +. O + +The O +incidence O +of O +subependymal B +cysts I +in O +infants O +exposed O +to O +cocaine O +prenatally O +was O +44 O +% O +( O +8 O +of O +18 O +) O +compared O +with O +8 O +% O +( O +8 O +of O +99 O +) O +in O +the O +unexposed O +group O +( O +p O +< O +0 O +. O +01 O +) O +. O + +CONCLUSIONS O +: O +We O +found O +an O +increased O +incidence O +of O +subependymal B +cyst I +formation O +in O +preterm O +infants O +who O +were O +exposed O +to O +cocaine O +prenatally O +. O + +This O +result O +is O +consistent O +with O +results O +of O +similar O +studies O +in O +term O +infants O +. O + +Thalidomide O +neuropathy B +in O +patients O +treated O +for O +metastatic O +prostate B +cancer I +. O + +We O +prospectively O +evaluated O +thalidomide O +- O +induced O +neuropathy B +using O +electrodiagnostic O +studies O +. O + +Sixty O +- O +seven O +men O +with O +metastatic O +androgen O +- O +independent O +prostate B +cancer I +in O +an O +open O +- O +label O +trial O +of O +oral O +thalidomide O +underwent O +neurologic O +examinations O +and O +nerve O +conduction O +studies O +( O +NCS O +) O +prior O +to O +and O +at O +3 O +- O +month O +intervals O +during O +treatment O +. O + +NCS O +included O +recording O +of O +sensory O +nerve O +action O +potentials O +( O +SNAPs O +) O +from O +median O +, O +radial O +, O +ulnar O +, O +and O +sural O +nerves O +. O + +SNAP O +amplitudes O +for O +each O +nerve O +were O +expressed O +as O +the O +percentage O +of O +its O +baseline O +, O +and O +the O +mean O +of O +the O +four O +was O +termed O +the O +SNAP O +index O +. O + +A O +40 O +% O +decline O +in O +the O +SNAP O +index O +was O +considered O +clinically O +significant O +. O + +Thalidomide O +was O +discontinued O +in O +55 O +patients O +for O +lack O +of O +therapeutic O +response O +. O + +Of O +67 O +patients O +initially O +enrolled O +, O +24 O +remained O +on O +thalidomide O +for O +3 O +months O +, O +8 O +remained O +at O +6 O +months O +, O +and O +3 O +remained O +at O +9 O +months O +. O + +Six O +patients O +developed O +neuropathy B +. O + +Clinical O +symptoms O +and O +a O +decline O +in O +the O +SNAP O +index O +occurred O +concurrently O +. O + +Older O +age O +and O +cumulative O +dose O +were O +possible O +contributing O +factors O +. O + +Neuropathy B +may O +thus O +be O +a O +common O +complication O +of O +thalidomide O +in O +older O +patients O +. O + +The O +SNAP O +index O +can O +be O +used O +to O +monitor O +peripheral B +neuropathy I +, O +but O +not O +for O +early O +detection O +. O + +Overexpression O +of O +copper O +/ O +zinc O +- O +superoxide O +dismutase O +protects O +from O +kanamycin O +- O +induced O +hearing B +loss I +. O + +The O +participation O +of O +reactive O +oxygen O +species O +in O +aminoglycoside O +- O +induced O +ototoxicity B +has O +been O +deduced O +from O +observations O +that O +aminoglycoside O +- O +iron O +complexes O +catalyze O +the O +formation O +of O +superoxide O +radicals O +in O +vitro O +and O +that O +antioxidants O +attenuate O +ototoxicity B +in O +vivo O +. O + +We O +therefore O +hypothesized O +that O +overexpression O +of O +Cu O +/ O +Zn O +- O +superoxide O +dismutase O +( O +h O +- O +SOD1 O +) O +should O +protect O +transgenic O +mice O +from O +ototoxicity B +. O + +Immunocytochemistry O +confirmed O +expression O +of O +h O +- O +SOD1 O +in O +inner O +ear O +tissues O +of O +transgenic O +C57BL O +/ O +6 O +- O +TgN O +[ O +SOD1 O +] O +3Cje O +mice O +. O + +Transgenic O +and O +nontransgenic O +littermates O +received O +kanamycin O +( O +400 O +mg O +/ O +kg O +body O +weight O +/ O +day O +) O +for O +10 O +days O +beginning O +on O +day O +10 O +after O +birth O +. O + +Auditory O +thresholds O +were O +tested O +by O +evoked O +auditory O +brain O +stem O +responses O +at O +1 O +month O +after O +birth O +. O + +In O +nontransgenic O +animals O +, O +the O +threshold O +in O +the O +kanamycin O +- O +treated O +group O +was O +45 O +- O +50 O +dB O +higher O +than O +in O +saline O +- O +injected O +controls O +. O + +In O +the O +transgenic O +group O +, O +kanamycin O +increased O +the O +threshold O +by O +only O +15 O +dB O +over O +the O +respective O +controls O +. O + +The O +effects O +were O +similar O +at O +12 O +and O +24 O +kHz O +. O + +The O +protection O +by O +overexpression O +of O +superoxide O +dismutase O +supports O +the O +hypothesis O +that O +oxidant O +stress O +plays O +a O +significant O +role O +in O +aminoglycoside O +- O +induced O +ototoxicity B +. O + +The O +results O +also O +suggest O +transgenic O +animals O +as O +suitable O +models O +to O +investigate O +the O +underlying O +mechanisms O +and O +possible O +strategies O +for O +prevention O +. O + +Fatty B +liver I +induced O +by O +tetracycline O +in O +the O +rat O +. O + +Dose O +- O +response O +relationships O +and O +effect O +of O +sex O +. O + +Dose O +- O +response O +relationships O +, O +biochemical O +mechanisms O +, O +and O +sex O +differences O +in O +the O +experimental O +fatty B +liver I +induced O +by O +tetracycline O +were O +studied O +in O +the O +intact O +rat O +and O +with O +the O +isolated O +perfused O +rat O +liver O +in O +vitro O +. O + +In O +the O +intact O +male O +and O +female O +rat O +, O +no O +direct O +relationship O +was O +observed O +between O +dose O +of O +tetracycline O +and O +hepatic O +accumulation O +of O +triglyceride O +. O + +With O +provision O +of O +adequate O +oleic O +acid O +as O +a O +substrate O +for O +the O +isolated O +perfused O +liver O +, O +a O +direct O +relationship O +was O +observed O +between O +dose O +of O +tetracycline O +and O +both O +accumulation O +of O +triglyceride O +in O +the O +liver O +and O +depression O +of O +output O +of O +triglyceride O +by O +livers O +from O +male O +and O +female O +rats O +. O + +Marked O +differences O +were O +observed O +between O +female O +and O +male O +rats O +with O +regard O +to O +base O +line O +( O +control O +) O +hepatic O +concentration O +of O +triglyceride O +and O +output O +of O +triglyceride O +. O + +Accumulation O +of O +hepatic O +triglyceride O +, O +as O +a O +per O +cent O +of O +control O +values O +, O +in O +response O +to O +graded O +doses O +of O +tetracycline O +, O +did O +not O +differ O +significantly O +between O +male O +, O +female O +and O +pregnant O +rat O +livers O +. O + +However O +, O +livers O +from O +female O +, O +and O +especially O +pregnant O +female O +rats O +, O +were O +strikingly O +resistant O +to O +the O +effects O +of O +tetracycline O +on O +depression O +of O +output O +of O +triglyceride O +under O +these O +experimental O +conditions O +. O + +These O +differences O +between O +the O +sexes O +could O +not O +be O +related O +to O +altered O +disposition O +of O +tetracycline O +or O +altered O +uptake O +of O +oleic O +acid O +. O + +Depressed O +hepatic O +secretion O +of O +triglyceride O +accounted O +only O +for O +30 O +to O +50 O +% O +of O +accumulated O +hepatic O +triglyceride O +, O +indicating O +that O +additional O +mechanisms O +must O +be O +involved O +in O +the O +production O +of O +the O +triglyceride O +- O +rich O +fatty B +liver I +in O +response O +to O +tetracycline O +. O + +Prednisone O +induces O +anxiety B +and O +glial O +cerebral O +changes O +in O +rats O +. O + +OBJECTIVE O +: O +To O +assess O +whether O +prednisone O +( O +PDN O +) O +produces O +anxiety B +and O +/ O +or O +cerebral O +glial O +changes O +in O +rats O +. O + +METHODS O +: O +Male O +Wistar O +rats O +were O +studied O +and O +3 O +groups O +were O +formed O +( O +8 O +rats O +per O +group O +) O +. O + +The O +moderate O +- O +dose O +group O +received O +5 O +mg O +/ O +kg O +/ O +day O +PDN O +released O +from O +a O +subcutaneous O +implant O +. O + +In O +the O +high O +- O +dose O +group O +, O +implants O +containing O +PDN O +equivalent O +to O +60 O +mg O +/ O +kg O +/ O +day O +were O +applied O +. O + +In O +the O +control O +group O +implants O +contained O +no O +PDN O +. O + +Anxiety B +was O +assessed O +using O +an O +open O +field O +and O +elevated O +plus O +- O +maze O +devices O +. O + +The O +number O +of O +cells O +and O +cytoplasmic O +transformation O +of O +astrocytes O +and O +microglia O +cells O +were O +assessed O +by O +immunohistochemical O +analyses O +. O + +RESULTS O +: O +Anxiety B +was O +documented O +in O +both O +groups O +of O +PDN O +treated O +rats O +compared O +with O +controls O +. O + +The O +magnitude O +of O +transformation O +of O +the O +microglia O +assessed O +by O +the O +number O +of O +intersections O +was O +significantly O +higher O +in O +the O +PDN O +groups O +than O +in O +controls O +in O +the O +prefrontal O +cortex O +( O +moderate O +- O +dose O +, O +24 O +. O +1 O +; O +high O +- O +dose O +, O +23 O +. O +6 O +; O +controls O +18 O +. O +7 O +; O +p O +< O +0 O +. O +01 O +) O +and O +striatum O +( O +moderate O +- O +dose O +25 O +. O +6 O +; O +high O +- O +dose O +26 O +. O +3 O +; O +controls O +18 O +. O +9 O +; O +p O +< O +0 O +. O +01 O +) O +, O +but O +not O +in O +hippocampus O +. O + +The O +number O +of O +stained O +microglia O +cells O +was O +significantly O +higher O +in O +the O +PDN O +treated O +groups O +in O +the O +prefrontal O +cortex O +than O +in O +controls O +( O +moderate O +- O +dose O +, O +29 O +. O +1 O +; O +high O +- O +dose O +, O +28 O +. O +4 O +; O +control O +, O +17 O +. O +7 O +cells O +per O +field O +; O +p O +< O +0 O +. O +01 O +) O +. O + +Stained O +microglia O +cells O +were O +significantly O +more O +numerous O +striatum O +and O +hippocampus O +in O +the O +high O +- O +dose O +group O +compared O +to O +controls O +. O + +CONCLUSION O +: O +Subacute O +exposure O +to O +PDN O +induced O +anxiety B +and O +reactivity O +of O +microglia O +. O + +The O +relevance O +of O +these O +features O +for O +patients O +using O +PDN O +remains O +to O +be O +elucidated O +. O + +Phase O +II O +study O +of O +carboplatin O +and O +liposomal O +doxorubicin O +in O +patients O +with O +recurrent O +squamous B +cell I +carcinoma I +of I +the I +cervix I +. O + +BACKGROUND O +: O +The O +activity O +of O +the O +combination O +of O +carboplatin O +and O +liposomal O +doxorubicin O +was O +tested O +in O +a O +Phase O +II O +study O +of O +patients O +with O +recurrent O +cervical B +carcinoma I +. O + +METHODS O +: O +The O +combination O +of O +carboplatin O +( O +area O +under O +the O +concentration O +curve O +[ O +AUC O +] O +, O +5 O +) O +and O +liposomal O +doxorubicin O +( O +Doxil O +; O +starting O +dose O +, O +40 O +mg O +/ O +m O +( O +2 O +) O +) O +was O +administered O +intravenously O +every O +28 O +days O +to O +37 O +patients O +with O +recurrent O +squamous B +cell I +cervical I +carcinoma I +to O +determine O +antitumor O +activity O +and O +toxicity B +profile O +. O + +RESULTS O +: O +Twenty O +- O +nine O +patients O +were O +assessable O +for O +response O +, O +and O +35 O +patients O +were O +assessable O +for O +toxicity B +. O + +The O +overall O +response O +rate O +was O +38 O +% O +, O +the O +median O +time O +to O +response O +was O +10 O +weeks O +, O +the O +median O +duration O +of O +response O +was O +26 O +weeks O +, O +and O +the O +median O +survival O +was O +37 O +weeks O +. O + +The O +main O +toxic B +effect O +was O +myelosuppression B +, O +with O +Grade O +3 O +and O +4 O +neutropenia B +in O +16 O +patients O +, O +anemia B +in O +12 O +patients O +, O +thrombocytopenia B +in O +11 O +patients O +, O +and O +neutropenic B +fever I +in O +3 O +patients O +. O + +Four O +patients O +had O +five O +infusion O +- O +related O +reactions O +during O +the O +infusion O +of O +liposomal O +doxorubicin O +, O +leading O +to O +treatment O +discontinuation O +in O +three O +patients O +. O + +Grade O +> O +or O += O +2 O +nonhematologic O +toxicity B +included O +nausea B +in O +17 O +patients O +, O +emesis B +in O +14 O +patients O +, O +fatigue B +in O +9 O +patients O +, O +mucositis B +and O +/ O +or O +stomatitis B +in O +8 O +patients O +, O +constipation B +in O +6 O +patients O +, O +weight B +loss I +in O +5 O +patients O +, O +hand B +- I +foot I +syndrome I +in O +2 O +patients O +, O +and O +skin O +reactions I +in O +3 O +patients O +. O + +CONCLUSIONS O +: O +The O +combination O +of O +carboplatin O +and O +liposomal O +doxorubicin O +has O +modest O +activity O +in O +patients O +with O +recurrent O +cervical B +carcinoma I +. O + +Antimicrobial O +- O +induced O +mania B +( O +antibiomania O +) O +: O +a O +review O +of O +spontaneous O +reports O +. O + +The O +authors O +reviewed O +reported O +cases O +of O +antibiotic O +- O +induced O +manic B +episodes O +by O +means O +of O +a O +MEDLINE O +and O +PsychLit O +search O +for O +reports O +of O +antibiotic O +- O +induced O +mania B +. O + +Unpublished O +reports O +were O +requested O +from O +the O +World O +Health O +Organization O +( O +WHO O +) O +and O +the O +Food O +and O +Drug O +Administration O +( O +FDA O +) O +. O + +Twenty O +- O +one O +reports O +of O +antimicrobial O +- O +induced O +mania B +were O +found O +in O +the O +literature O +. O + +There O +were O +6 O +cases O +implicating O +clarithromycin O +, O +13 O +implicating O +isoniazid O +, O +and O +1 O +case O +each O +implicating O +erythromycin O +and O +amoxicillin O +. O + +The O +WHO O +reported O +82 O +cases O +. O + +Of O +these O +, O +clarithromycin O +was O +implicated O +in O +23 O +( O +27 O +. O +6 O +% O +) O +cases O +, O +ciprofloxacin O +in O +12 O +( O +14 O +. O +4 O +% O +) O +cases O +, O +and O +ofloxacin O +in O +10 O +( O +12 O +% O +) O +cases O +. O + +Cotrimoxazole O +, O +metronidazole O +, O +and O +erythromycin O +were O +involved O +in O +15 O +reported O +manic B +episodes O +. O + +Cases O +reported O +by O +the O +FDA O +showed O +clarithromycin O +and O +ciprofloxacin O +to O +be O +the O +most O +frequently O +associated O +with O +the O +development O +of O +mania B +. O + +Statistical O +analysis O +of O +the O +data O +would O +not O +have O +demonstrated O +a O +significant O +statistical O +correlative O +risk O +and O +was O +therefore O +not O +undertaken O +. O + +Patients O +have O +an O +increased O +risk O +of O +developing O +mania B +while O +being O +treated O +with O +antimicrobials O +. O + +Although O +this O +is O +not O +a O +statistically O +significant O +risk O +, O +physicians O +must O +be O +aware O +of O +the O +effect O +and O +reversibility O +. O + +Further O +research O +clearly O +is O +required O +to O +determine O +the O +incidence O +of O +antimicrobial O +- O +induced O +mania B +, O +the O +relative O +risk O +factors O +of O +developing O +an O +antimicrobial O +- O +induced O +manic B +episode O +among O +various O +demographic O +populations O +, O +and O +the O +incidence O +of O +patients O +who O +continue O +to O +have O +persistent O +affective B +disorders I +once O +the O +initial O +episode O +, O +which O +occurs O +while O +the O +patient O +is O +taking O +antibiotics O +, O +subsides O +. O + +The O +authors O +elected O +to O +name O +this O +syndrome O +" O +antibiomania B +. O +" O + +Levodopa O +- O +induced O +ocular B +dyskinesias I +in O +Parkinson B +' I +s I +disease I +. O + +Levodopa O +- O +induced O +ocular B +dyskinesias I +are O +very O +uncommon O +. O + +Usually O +they O +occur O +simultaneously O +with O +limb O +peak O +- O +dose O +choreatic B +dyskinesias I +. O + +We O +report O +on O +a O +patient O +with O +leftward B +and I +upward I +deviations I +of I +gaze I +during O +the O +peak O +effect O +of O +levodopa O +, O +and O +hypothesize O +that O +a O +severe O +dopaminergic O +denervation O +in O +the O +caudate O +nucleus O +is O +needed O +for O +the O +appearance O +of O +these O +levodopa O +- O +induce O +ocular B +dyskinesias I +. O + +A O +comparison O +of O +glyceryl O +trinitrate O +with O +diclofenac O +for O +the O +treatment O +of O +primary O +dysmenorrhea I +: O +an O +open O +, O +randomized O +, O +cross O +- O +over O +trial O +. O + +Primary B +dysmenorrhea I +is O +a O +syndrome O +characterized O +by O +painful B +uterine O +contractility I +caused O +by O +a O +hypersecretion O +of O +endometrial O +prostaglandins O +; O +non O +- O +steroidal O +anti O +- O +inflammatory O +drugs O +are O +the O +first O +choice O +for O +its O +treatment O +. O + +However O +, O +in O +vivo O +and O +in O +vitro O +studies O +have O +demonstrated O +that O +myometrial O +cells O +are O +also O +targets O +of O +the O +relaxant O +effects O +of O +nitric O +oxide O +( O +NO O +) O +. O + +The O +aim O +of O +the O +present O +study O +was O +to O +determine O +the O +efficacy O +of O +glyceryl O +trinitrate O +( O +GTN O +) O +, O +an O +NO O +donor O +, O +in O +the O +resolution O +of O +primary O +dysmenorrhea B +in O +comparison O +with O +diclofenac O +( O +DCF O +) O +. O + +A O +total O +of O +24 O +patients O +with O +the O +diagnosis O +of O +severe O +primary O +dysmenorrhea I +were O +studied O +during O +two O +consecutive O +menstrual O +cycles O +. O + +In O +an O +open O +, O +cross O +- O +over O +, O +controlled O +design O +, O +patients O +were O +randomized O +to O +receive O +either O +DCF O +per O +os O +or O +GTN O +patches O +the O +first O +days O +of O +menses O +, O +when O +menstrual B +cramps I +became O +unendurable O +. O + +In O +the O +subsequent O +cycle O +the O +other O +treatment O +was O +used O +. O + +Patients O +received O +up O +to O +3 O +doses O +/ O +day O +of O +50 O +mg O +DCF O +or O +2 O +. O +5 O +mg O +/ O +24 O +h O +transdermal O +GTN O +for O +the O +first O +3 O +days O +of O +the O +cycle O +, O +according O +to O +their O +needs O +. O + +The O +participants O +recorded O +menstrual O +symptoms O +and O +possible O +side O +- O +effects O +at O +different O +times O +( O +0 O +, O +30 O +, O +60 O +, O +120 O +minutes O +) O +after O +the O +first O +dose O +of O +medication O +on O +the O +first O +day O +of O +the O +cycle O +, O +with O +both O +drugs O +. O + +The O +difference O +in O +pain B +intensity O +score O +( O +DPI O +) O +was O +the O +main O +outcome O +variable O +. O + +Both O +treatments O +significantly O +reduced O +DPI O +by O +the O +30th O +minute O +( O +GTN O +, O +- O +12 O +. O +8 O ++ O +/ O +- O +17 O +. O +9 O +; O +DCF O +, O +- O +18 O +. O +9 O ++ O +/ O +- O +16 O +. O +6 O +) O +. O + +However O +, O +DCF O +continued O +to O +be O +effective O +in O +reducing O +pelvic B +pain I +for O +two O +hours O +, O +whereas O +GTN O +scores O +remained O +more O +or O +less O +stable O +after O +30 O +min O +and O +significantly O +higher O +than O +those O +for O +DFC O +( O +after O +one O +hour O +: O +GTN O +, O +- O +12 O +. O +8 O ++ O +/ O +- O +17 O +. O +9 O +; O +DFC O +, O +- O +18 O +. O +9 O ++ O +/ O +- O +16 O +. O +6 O +and O +after O +two O +hours O +: O +GTN O +, O +- O +23 O +. O +7 O ++ O +/ O +- O +20 O +. O +5 O +; O +DFC O +, O +- O +59 O +. O +7 O ++ O +/ O +- O +17 O +. O +9 O +, O +p O += O +0 O +. O +0001 O +) O +. O + +Low B +back I +pain I +was O +also O +relieved O +by O +both O +drugs O +. O + +Headache B +was O +significantly O +increased O +by O +GTN O +but O +not O +by O +DCF O +. O + +Eight O +patients O +stopped O +using O +GTN O +because O +headache B +- O +- O +attributed O +to O +its O +use O +- O +- O +became O +intolerable O +. O + +These O +findings O +indicate O +that O +GTN O +has O +a O +reduced O +efficacy O +and O +tolerability O +by O +comparison O +with O +DCF O +in O +the O +treatment O +of O +primary O +dysmenorrhea I +. O + +Temocapril O +, O +a O +long O +- O +acting O +non O +- O +SH O +group O +angiotensin O +converting O +enzyme O +inhibitor O +, O +modulates O +glomerular B +injury I +in O +chronic O +puromycin O +aminonucleoside O +nephrosis B +. O + +The O +purpose O +of O +the O +present O +study O +was O +to O +determine O +whether O +chronic O +administration O +of O +temocapril O +, O +a O +long O +- O +acting O +non O +- O +SH O +group O +angiotensin O +converting O +enzyme O +( O +ACE O +) O +inhibitor O +, O +reduced O +proteinuria B +, O +inhibited O +glomerular B +hypertrophy I +and O +prevented O +glomerulosclerosis B +in O +chronic O +puromycin O +aminonucleoside O +( O +PAN O +) O +- O +induced O +nephrotic B +rats O +. O + +Nephrosis B +was O +induced O +by O +injection O +of O +PAN O +( O +15mg O +/ O +100g O +body O +weight O +) O +in O +male O +Sprague O +- O +Dawley O +( O +SD O +) O +rats O +. O + +Four O +groups O +were O +used O +, O +i O +) O +the O +PAN O +group O +( O +14 O +) O +, O +ii O +) O +PAN O +/ O +temocapril O +( O +13 O +) O +, O +iii O +) O +temocapril O +( O +14 O +) O +and O +iv O +) O +untreated O +controls O +( O +15 O +) O +. O + +Temocapril O +( O +8 O +mg O +/ O +kg O +/ O +day O +) O +was O +administered O +to O +the O +rats O +which O +were O +killed O +at O +weeks O +4 O +, O +14 O +or O +20 O +. O + +At O +each O +time O +point O +, O +systolic O +blood O +pressure O +( O +BP O +) O +, O +urinary O +protein O +excretion O +and O +renal O +histopathological O +findings O +were O +evaluated O +, O +and O +morphometric O +image O +analysis O +was O +done O +. O + +Systolic O +BP O +in O +the O +PAN O +group O +was O +significantly O +high O +at O +4 O +, O +14 O +and O +20 O +weeks O +, O +but O +was O +normal O +in O +the O +PAN O +/ O +temocapril O +group O +. O + +Urinary O +protein O +excretion O +in O +the O +PAN O +group O +increased O +significantly O +, O +peaking O +at O +8 O +days O +, O +then O +decreased O +at O +4 O +weeks O +, O +but O +rose O +again O +significantly O +at O +14 O +and O +20 O +weeks O +. O + +Temocapril O +did O +not O +attenuate O +proteinuria B +at O +8 O +days O +, O +but O +it O +did O +markedly O +lower O +it O +from O +weeks O +4 O +to O +20 O +. O + +The O +glomerulosclerosis B +index O +( O +GSI O +) O +was O +6 O +. O +21 O +% O +at O +4 O +weeks O +and O +respectively O +25 O +. O +35 O +% O +and O +30 O +. O +49 O +% O +at O +14 O +and O +20 O +weeks O +in O +the O +PAN O +group O +. O + +There O +was O +a O +significant O +correlation O +between O +urinary O +protein O +excretion O +and O +GSI O +( O +r O += O +0 O +. O +808 O +, O +p O +< O +0 O +. O +0001 O +) O +. O + +The O +ratio O +of O +glomerular O +tuft O +area O +to O +the O +area O +of O +Bowman O +' O +s O +capsules O +( O +GT O +/ O +BC O +) O +in O +the O +PAN O +group O +was O +significantly O +increased O +, O +but O +it O +was O +significantly O +lower O +in O +the O +PAN O +/ O +temocapril O +group O +. O + +It O +appears O +that O +temocapril O +was O +effective O +in O +retarding O +renal O +progression O +and O +protected O +renal O +function O +in O +PAN O +neprotic B +rats O +. O + +Pulmonary B +hypertension I +after O +ibuprofen O +prophylaxis O +in O +very O +preterm O +infants O +. O + +We O +report O +three O +cases O +of O +severe O +hypoxaemia B +after O +ibuprofen O +administration O +during O +a O +randomised O +controlled O +trial O +of O +prophylactic O +treatment O +of O +patent B +ductus I +arteriosus I +with O +ibuprofen O +in O +premature O +infants O +born O +at O +less O +than O +28 O +weeks O +of O +gestation O +. O + +Echocardiography O +showed O +severely O +decreased O +pulmonary O +blood O +flow O +. O + +Hypoxaemia B +resolved O +quickly O +on O +inhaled O +nitric O +oxide O +therapy O +. O + +We O +suggest O +that O +investigators O +involved O +in O +similar O +trials O +pay O +close O +attention O +to O +pulmonary O +pressure O +if O +hypoxaemia B +occurs O +after O +prophylactic O +administration O +of O +ibuprofen O +. O + +Hyponatremia B +and O +syndrome B +of I +inappropriate I +anti I +- I +diuretic I +hormone I +reported O +with O +the O +use O +of O +Vincristine O +: O +an O +over O +- O +representation O +of O +Asians O +? O + +PURPOSE O +: O +This O +retrospective O +study O +used O +a O +pharmaceutical O +company O +' O +s O +global O +safety O +database O +to O +determine O +the O +reporting O +rate O +of O +hyponatremia B +and O +/ O +or O +syndrome B +of I +inappropriate I +secretion I +of I +anti I +- I +diuretic I +hormone I +( O +SIADH O +) O +among O +vincristine O +- O +treated O +patients O +and O +to O +explore O +the O +possibility O +of O +at O +- O +risk O +population O +subgroups O +. O + +METHOD O +: O +We O +searched O +the O +Eli O +Lilly O +and O +Company O +' O +s O +computerized O +adverse O +event O +database O +for O +all O +reported O +cases O +of O +hyponatremia B +and O +/ O +or O +SIADH B +as O +of O +1 O +November O +1999 O +that O +had O +been O +reported O +during O +the O +use O +of O +vincristine O +. O + +RESULTS O +: O +A O +total O +of O +76 O +cases O +of O +hyponatremia B +and O +/ O +or O +SIADH B +associated O +with O +vincristine O +use O +were O +identified O +. O + +The O +overall O +reporting O +rate O +was O +estimated O +to O +be O +1 O +. O +3 O +/ O +100 O +, O +000 O +treated O +patients O +. O + +The O +average O +age O +of O +patients O +was O +35 O +. O +6 O ++ O +/ O +- O +28 O +. O +3 O +years O +, O +and O +62 O +% O +were O +males O +. O + +Approximately O +75 O +% O +of O +the O +patients O +were O +receiving O +treatment O +for O +leukemia B +or O +lymphoma B +. O + +Among O +the O +39 O +reports O +that O +included O +information O +on O +race O +, O +the O +racial O +distribution O +was O +: O +1 O +Black O +, O +3 O +Caucasian O +, O +and O +35 O +Asian O +. O + +CONCLUSION O +: O +Our O +data O +suggest O +that O +Asian O +patients O +may O +be O +at O +increased O +risk O +of O +hyponatremia B +and O +/ O +or O +SIADH B +associated O +with O +vincristine O +use O +. O + +Although O +the O +overall O +reported O +rate O +of O +SIADH B +associated O +with O +vincristine O +is O +very O +low O +, O +physicians O +caring O +for O +Asian O +oncology O +patients O +should O +be O +aware O +of O +this O +potential O +serious O +but O +reversible O +adverse O +event O +. O + +Delayed O +toxicity B +of O +cyclophosphamide O +on O +the O +bladder O +of O +DBA O +/ O +2 O +and O +C57BL O +/ O +6 O +female O +mouse O +. O + +The O +present O +study O +describes O +the O +delayed O +development O +of O +a O +severe O +bladder B +pathology I +in O +a O +susceptible O +strain O +of O +mice O +( O +DBA O +/ O +2 O +) O +but O +not O +in O +a O +resistant O +strain O +( O +C57BL O +/ O +6 O +) O +when O +both O +were O +treated O +with O +a O +single O +300 O +mg O +/ O +kg O +dose O +of O +cyclophosphamide O +( O +CY O +) O +. O + +Inbred O +DBA O +/ O +2 O +and O +C57BL O +/ O +6 O +female O +mice O +were O +injected O +with O +CY O +, O +and O +the O +effect O +of O +the O +drug O +on O +the O +bladder O +was O +assessed O +during O +100 O +days O +by O +light O +microscopy O +using O +different O +staining O +procedures O +, O +and O +after O +30 O +days O +by O +conventional O +electron O +microscopy O +. O + +Early O +CY O +toxicity O +caused O +a O +typical O +haemorrhagic B +cystitis I +in O +both O +strains O +that O +was O +completely O +repaired O +in O +about O +7 O +- O +10 O +days O +. O + +After O +30 O +days O +of O +CY O +injection O +ulcerous O +and O +non O +- O +ulcerous O +forms O +of O +chronic O +cystitis B +appeared O +in O +86 O +% O +of O +DBA O +/ O +2 O +mice O +but O +only O +in O +4 O +% O +of O +C57BL O +/ O +6 O +mice O +. O + +Delayed O +cystitis B +was O +characterized O +by O +infiltration O +and O +transepithelial O +passage O +into O +the O +lumen O +of O +inflammatory O +cells O +and O +by O +frequent O +exfoliation O +of O +the O +urothelium O +. O + +Mast O +cells O +appeared O +in O +the O +connective O +and O +muscular O +layers O +of O +the O +bladder O +at O +a O +much O +higher O +number O +in O +DBA O +/ O +2 O +mice O +than O +in O +C57BL O +/ O +6 O +mice O +or O +untreated O +controls O +. O + +Electron O +microscopy O +disclosed O +the O +absence O +of O +the O +typical O +discoidal O +vesicles O +normally O +present O +in O +the O +cytoplasm O +of O +surface O +cells O +. O + +Instead O +, O +numerous O +abnormal O +vesicles O +containing O +one O +or O +several O +dark O +granules O +were O +observed O +in O +the O +cytoplasm O +of O +cells O +from O +all O +the O +epithelial O +layers O +. O + +Delayed O +cystitis B +still O +persisted O +in O +DBA O +/ O +2 O +mice O +100 O +days O +after O +treatment O +. O + +These O +results O +indicate O +that O +delayed O +toxicity B +of O +CY O +in O +female O +DBA O +/ O +2 O +mice O +causes O +a O +bladder B +pathology I +that O +is O +not O +observed O +in O +C57BL O +/ O +6 O +mice O +. O + +This O +pathology O +resembles O +interstitial B +cystitis I +in O +humans O +and O +could O +perhaps O +be O +used O +as O +an O +animal O +model O +for O +studies O +on O +the O +disease O +. O + +High O +- O +dose O +5 O +- O +fluorouracil O +/ O +folinic O +acid O +in O +combination O +with O +three O +- O +weekly O +mitomycin O +C O +in O +the O +treatment O +of O +advanced O +gastric B +cancer I +. O + +A O +phase O +II O +study O +. O + +BACKGROUND O +: O +The O +24 O +- O +hour O +continuous O +infusion O +of O +5 O +- O +fluorouracil O +( O +5 O +- O +FU O +) O +and O +folinic O +acid O +( O +FA O +) O +as O +part O +of O +several O +new O +multidrug O +chemotherapy O +regimens O +in O +advanced B +gastric B +cancer I +( O +AGC B +) O +has O +shown O +to O +be O +effective O +, O +with O +low O +toxicity B +. O + +In O +a O +previous O +phase O +II O +study O +with O +3 O +- O +weekly O +bolus O +5 O +- O +FU O +, O +FA O +and O +mitomycin O +C O +( O +MMC O +) O +we O +found O +a O +low O +toxicity B +rate O +and O +response O +rates O +comparable O +to O +those O +of O +regimens O +such O +as O +ELF O +, O +FAM O +or O +FAMTX O +, O +and O +a O +promising O +median O +overall O +survival O +. O + +In O +order O +to O +improve O +this O +MMC O +- O +dependent O +schedule O +we O +initiated O +a O +phase O +II O +study O +with O +high O +- O +dose O +5 O +- O +FU O +/ O +FA O +and O +3 O +- O +weekly O +bolus O +MMC O +. O + +PATIENTS O +AND O +METHODS O +: O +From O +February O +, O +1998 O +to O +September O +, O +2000 O +we O +recruited O +33 O +patients O +with O +AGC B +to O +receive O +weekly O +24 O +- O +hour O +5 O +- O +FU O +2 O +, O +600 O +mg O +/ O +m O +( O +2 O +) O +preceded O +by O +2 O +- O +hour O +FA O +500 O +mg O +/ O +m O +( O +2 O +) O +for O +6 O +weeks O +, O +followed O +by O +a O +2 O +- O +week O +rest O +period O +. O + +Bolus O +MMC O +10 O +mg O +/ O +m O +( O +2 O +) O +was O +added O +in O +3 O +- O +weekly O +intervals O +. O + +Treatment O +given O +on O +an O +outpatient O +basis O +, O +using O +portable O +pump O +systems O +, O +was O +repeated O +on O +day O +57 O +. O + +Patients O +' O +characteristics O +were O +: O +male O +/ O +female O +ratio O +20 O +/ O +13 O +; O +median O +age O +57 O +( O +27 O +- O +75 O +) O +years O +; O +median O +WHO O +status O +1 O +( O +0 O +- O +2 O +) O +. O + +18 O +patients O +had O +a O +primary O +AGC B +, O +and O +15 O +showed O +a O +relapsed O +AGC B +. O + +Median O +follow O +- O +up O +was O +11 O +. O +8 O +months O +( O +range O +of O +those O +surviving O +: O +2 O +. O +7 O +- O +11 O +. O +8 O +months O +) O +. O + +RESULTS O +: O +32 O +patients O +were O +evaluable O +for O +response O +- O +complete O +remission O +9 O +. O +1 O +% O +( O +n O += O +3 O +) O +, O +partial O +remission O +45 O +. O +5 O +% O +( O +n O += O +15 O +) O +, O +no O +change O +27 O +. O +3 O +% O +( O +n O += O +9 O +) O +, O +progressive O +disease O +15 O +. O +1 O +% O +( O +n O += O +5 O +) O +. O + +Median O +overall O +survival O +time O +was O +10 O +. O +2 O +months O +[ O +95 O +% O +confidence O +interval O +( O +CI O +) O +: O +8 O +. O +7 O +- O +11 O +. O +6 O +] O +, O +and O +median O +progression O +- O +free O +survival O +time O +was O +7 O +. O +6 O +months O +( O +95 O +% O +CI O +: O +4 O +. O +4 O +- O +10 O +. O +9 O +) O +. O + +The O +worst O +toxicities B +( O +% O +) O +observed O +were O +( O +CTC O +- O +NCI O +1 O +/ O +2 O +/ O +3 O +) O +: O +leukopenia B +45 O +. O +5 O +/ O +18 O +. O +2 O +/ O +6 O +. O +1 O +, O +thrombocytopenia B +33 O +. O +3 O +/ O +9 O +. O +1 O +/ O +6 O +. O +1 O +, O +vomitus B +24 O +. O +2 O +/ O +9 O +. O +1 O +/ O +0 O +, O +diarrhea B +36 O +. O +4 O +/ O +6 O +. O +1 O +/ O +3 O +. O +0 O +, O +stomatitis B +18 O +. O +2 O +/ O +9 O +. O +1 O +/ O +0 O +, O +hand B +- I +foot I +syndrome I +12 O +. O +1 O +/ O +0 O +/ O +0 O +. O + +Two O +patients O +developed O +hemolytic B +- I +uremic I +syndrome I +( O +HUS B +) O +. O + +CONCLUSIONS O +: O +High O +- O +dose O +5 O +- O +FU O +/ O +FA O +/ O +MMC O +is O +an O +effective O +and O +well O +- O +tolerated O +outpatient O +regimen O +for O +AGC B +( O +objective O +response O +rate O +54 O +. O +6 O +% O +) O +. O + +It O +may O +serve O +as O +an O +alternative O +to O +cisplatin O +- O +containing O +regimens O +; O +however O +, O +it O +has O +to O +be O +considered O +that O +possibly O +HUS B +may O +occur O +. O + +Persistent O +sterile O +leukocyturia B +is O +associated O +with O +impaired B +renal I +function I +in O +human B +immunodeficiency I +virus I +type I +1 I +- I +infected I +children O +treated O +with O +indinavir O +. O + +BACKGROUND O +: O +Prolonged O +administration O +of O +indinavir O +is O +associated O +with O +the O +occurrence O +of O +a O +variety O +of O +renal B +complications I +in O +adults O +. O + +These O +well O +- O +documented O +side O +effects O +have O +restricted O +the O +use O +of O +this O +potent O +protease O +inhibitor O +in O +children O +. O + +DESIGN O +: O +A O +prospective O +study O +to O +monitor O +indinavir O +- O +related O +nephrotoxicity B +in O +a O +cohort O +of O +30 O +human B +immunodeficiency I +virus I +type I +1 I +- I +infected I +children O +treated O +with O +indinavir O +. O + +METHODS O +: O +Urinary O +pH O +, O +albumin O +, O +creatinine O +, O +the O +presence O +of O +erythrocytes O +, O +leukocytes O +, O +bacteria O +and O +crystals O +, O +and O +culture O +were O +analyzed O +every O +3 O +months O +for O +96 O +weeks O +. O + +Serum O +creatinine O +levels O +were O +routinely O +determined O +at O +the O +same O +time O +points O +. O + +Steady O +- O +state O +pharmacokinetics O +of O +indinavir O +were O +done O +at O +week O +4 O +after O +the O +initiation O +of O +indinavir O +. O + +RESULTS O +: O +The O +cumulative O +incidence O +of O +persistent O +sterile O +leukocyturia B +( O +> O +or O += O +75 O +cells O +/ O +micro O +L O +in O +at O +least O +2 O +consecutive O +visits O +) O +after O +96 O +weeks O +was O +53 O +% O +. O + +Persistent O +sterile O +leukocyturia B +was O +frequently O +associated O +with O +a O +mild O +increase O +in O +the O +urine O +albumin O +/ O +creatinine O +ratio O +and O +by O +microscopic O +hematuria B +. O + +The O +cumulative O +incidence O +of O +serum O +creatinine O +levels O +> O +50 O +% O +above O +normal O +was O +33 O +% O +after O +96 O +weeks O +. O + +Children O +with O +persistent O +sterile O +leukocyturia B +more O +frequently O +had O +serum O +creatinine O +levels O +of O +50 O +% O +above O +normal O +than O +those O +children O +without O +persistent O +sterile O +leukocyturia B +. O + +In O +children O +younger O +than O +5 O +. O +6 O +years O +, O +persistent O +sterile O +leukocyturia B +was O +significantly O +more O +frequent O +than O +in O +older O +children O +. O + +A O +higher O +cumulative O +incidence O +of O +persistent O +leukocyturia B +was O +found O +in O +children O +with O +an O +area O +under O +the O +curve O +> O +19 O +mg O +/ O +L O +x O +h O +or O +a O +peak O +serum O +level O +of O +indinavir O +> O +12 O +mg O +/ O +L O +. O + +In O +4 O +children O +, O +indinavir O +was O +discontinued O +because O +of O +nephrotoxicity B +. O + +Subsequently O +, O +the O +serum O +creatinine O +levels O +decreased O +, O +the O +urine O +albumin O +/ O +creatinine O +ratios O +returned O +to O +zero O +, O +and O +the O +leukocyturia B +disappeared O +within O +3 O +months O +. O + +CONCLUSIONS O +: O +Children O +treated O +with O +indinavir O +have O +a O +high O +cumulative O +incidence O +of O +persistent O +sterile O +leukocyturia B +. O + +Children O +with O +persistent O +sterile O +leukocyturia B +more O +frequently O +had O +an O +increase O +in O +serum O +creatinine O +levels O +of O +> O +50 O +% O +above O +normal O +. O + +Younger O +children O +have O +an O +additional O +risk O +for O +renal B +complications I +. O + +The O +impairment B +of I +the I +renal I +function I +in O +these O +children O +occurred O +in O +the O +absence O +of O +clinical O +symptoms O +of O +nephrolithiasis B +. O + +Indinavir O +- O +associated O +nephrotoxicity B +must O +be O +monitored O +closely O +, O +especially O +in O +children O +with O +risk O +factors O +such O +as O +persistent O +sterile O +leukocyturia B +, O +age O +< O +5 O +. O +6 O +years O +, O +an O +area O +under O +the O +curve O +of O +indinavir O +> O +19 O +mg O +/ O +L O +x O +h O +, O +and O +a O +C O +( O +max O +) O +> O +12 O +mg O +/ O +L O +. O + +Utility O +of O +troponin O +I O +in O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +. O + +Baseline O +electrocardiogram O +abnormalities O +and O +market O +elevations O +not O +associated O +with O +myocardial B +necrosis I +make O +accurate O +diagnosis O +of O +myocardial B +infarction I +( O +MI B +) O +difficult O +in O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +. O + +Troponin O +sampling O +may O +offer O +greater O +diagnostic O +utility O +in O +these O +patients O +. O + +OBJECTIVE O +: O +To O +assess O +outcomes O +based O +on O +troponin O +positivity O +in O +patients O +with O +cocaine O +chest B +pain I +admitted O +for O +exclusion O +of O +MI B +. O + +METHODS O +: O +Outcomes O +were O +examined O +in O +patients O +admitted O +for O +possible O +MI B +after O +cocaine O +use O +. O + +All O +patients O +underwent O +a O +rapid O +rule O +- O +in O +protocol O +that O +included O +serial O +sampling O +of O +creatine O +kinase O +( O +CK O +) O +, O +CK O +- O +MB O +, O +and O +cardiac O +troponin O +I O +( O +cTnI O +) O +over O +eight O +hours O +. O + +Outcomes O +included O +CK O +- O +MB O +MI O +( O +CK O +- O +MB O +> O +or O += O +8 O +ng O +/ O +mL O +with O +a O +relative O +index O +[ O +( O +CK O +- O +MB O +x O +100 O +) O +/ O +total O +CK O +] O +> O +or O += O +4 O +, O +cardiac B +death I +, O +and O +significant O +coronary B +disease I +( O +> O +or O += O +50 O +% O +) O +. O + +RESULTS O +: O +Of O +the O +246 O +admitted O +patients O +, O +34 O +( O +14 O +% O +) O +met O +CK O +- O +MB O +criteria O +for O +MI B +and O +38 O +( O +16 O +% O +) O +had O +cTnI O +elevations O +. O + +Angiography O +was O +performed O +in O +29 O +of O +38 O +patients O +who O +were O +cTnI O +- O +positive O +, O +with O +significant O +disease O +present O +in O +25 O +( O +86 O +% O +) O +. O + +Three O +of O +the O +four O +patients O +without O +significant O +disease O +who O +had O +cTnI O +elevations O +met O +CK O +- O +MB O +criteria O +for O +MI B +, O +and O +the O +other O +had O +a O +peak O +CK O +- O +MB O +level O +of O +13 O +ng O +/ O +mL O +. O + +Sensitivities O +, O +specificities O +, O +and O +positive O +and O +negative O +likelihood O +ratios O +for O +predicting O +cardiac B +death I +or O +significant O +disease O +were O +high O +for O +both O +CK O +- O +MB O +MI O +and O +cTnI O +and O +were O +not O +significantly O +different O +. O + +CONCLUSIONS O +: O +Most O +patients O +with O +cTnI O +elevations O +meet O +CK O +- O +MB O +criteria O +for O +MI B +, O +as O +well O +as O +have O +a O +high O +incidence O +of O +underlying O +significant O +disease O +. O + +Troponin O +appears O +to O +have O +an O +equivalent O +diagnostic O +accuracy O +compared O +with O +CK O +- O +MB O +for O +diagnosing O +necrosis B +in O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +and O +suspected O +MI B +. O + +Acute O +interstitial B +nephritis I +due O +to O +nicergoline O +( O +Sermion O +) O +. O + +We O +report O +a O +case O +of O +acute O +interstitial B +nephritis I +( O +AIN B +) O +due O +to O +nicergoline O +( O +Sermion O +) O +. O + +A O +50 O +- O +year O +- O +old O +patient O +admitted O +to O +our O +hospital O +for O +fever B +and O +acute B +renal I +failure I +. O + +Before O +admission O +, O +he O +had O +been O +taking O +nicergoline O +and O +bendazac O +lysine O +due O +to O +retinal B +vein I +occlusion I +at O +ophthalmologic O +department O +. O + +Thereafter O +, O +he O +experienced O +intermittent B +fever I +and O +skin B +rash I +. O + +On O +admission O +, O +clinical O +symptoms O +( O +i O +. O +e O +. O +arthralgia B +and O +fever B +) O +and O +laboratory O +findings O +( O +i O +. O +e O +. O +eosinophilia B +and O +renal B +failure I +) O +suggested O +AIN B +, O +and O +which O +was O +confirmed O +by O +pathologic O +findings O +on O +renal O +biopsy O +. O + +A O +lymphocyte O +transformation O +test O +demonstrated O +a O +positive O +result O +against O +nicergoline O +. O + +Treatment O +was O +consisted O +of O +withdrawal O +of O +nicergoline O +and O +intravenous O +methylprednisolone O +, O +and O +his O +renal O +function O +was O +completely O +recovered O +. O + +To O +our O +knowledge O +, O +this O +is O +the O +first O +report O +of O +nicergoline O +- O +associated O +AIN B +. O + +Neuroleptic B +malignant I +syndrome I +complicated O +by O +massive O +intestinal B +bleeding I +in O +a O +patient O +with O +chronic B +renal I +failure I +. O + +A O +patient O +with O +chronic B +renal I +failure I +( O +CRF B +) O +developed O +neuroleptic B +malignant I +syndrome I +( O +NMS B +) O +after O +administration O +of O +risperidone O +and O +levomepromazine O +. O + +In O +addition O +to O +the O +typical O +symptoms O +of O +NMS B +, O +massive O +intestinal B +bleeding I +was O +observed O +during O +the O +episode O +. O + +This O +report O +suggests O +that O +NMS B +in O +a O +patient O +with O +CRF B +may O +be O +complicated O +by O +intestinal B +bleeding I +and O +needs O +special O +caution O +for O +this O +complication O +. O + +Blood O +brain O +barrier O +in O +right O +- O +and O +left O +- O +pawed O +female O +rats O +assessed O +by O +a O +new O +staining O +method O +. O + +The O +asymmetrical O +breakdown O +of O +the O +blood O +- O +brain O +barrier O +( O +BBB O +) O +was O +studied O +in O +female O +rats O +. O + +Paw O +preference O +was O +assessed O +by O +a O +food O +reaching O +test O +. O + +Adrenaline O +- O +induced O +hypertension B +was O +used O +to O +destroy O +the O +BBB O +, O +which O +was O +evaluated O +using O +triphenyltetrazolium O +( O +TTC O +) O +staining O +of O +the O +brain O +slices O +just O +after O +giving O +adrenaline O +for O +30 O +s O +. O + +In O +normal O +rats O +, O +the O +whole O +brain O +sections O +exhibited O +complete O +staining O +with O +TTC O +. O + +After O +adrenaline O +infusion O +for O +30 O +s O +, O +there O +were O +large O +unstained O +areas O +in O +the O +left O +brain O +in O +right O +- O +pawed O +animals O +, O +and O +vice O +versa O +in O +left O +- O +pawed O +animals O +. O + +Similar O +results O +were O +obtained O +in O +seizure B +- O +induced O +breakdown O +of O +BBB O +. O + +These O +results O +were O +explained O +by O +an O +asymmetric O +cerebral O +blood O +flow O +depending O +upon O +the O +paw O +preference O +in O +rats O +. O + +It O +was O +suggested O +that O +this O +new O +method O +and O +the O +results O +are O +consistent O +with O +contralateral O +motor O +control O +that O +may O +be O +important O +in O +determining O +the O +dominant O +cerebral O +hemisphere O +in O +animals O +. O + +Carvedilol O +protects O +against O +doxorubicin O +- O +induced O +mitochondrial B +cardiomyopathy I +. O + +Several O +cytopathic O +mechanisms O +have O +been O +suggested O +to O +mediate O +the O +dose O +- O +limiting O +cumulative O +and O +irreversible O +cardiomyopathy B +caused O +by O +doxorubicin O +. O + +Recent O +evidence O +indicates O +that O +oxidative O +stress O +and O +mitochondrial B +dysfunction I +are O +key O +factors O +in O +the O +pathogenic O +process O +. O + +The O +objective O +of O +this O +investigation O +was O +to O +test O +the O +hypothesis O +that O +carvedilol O +, O +a O +nonselective O +beta O +- O +adrenergic O +receptor O +antagonist O +with O +potent O +antioxidant O +properties O +, O +protects O +against O +the O +cardiac O +and O +hepatic O +mitochondrial O +bioenergetic I +dysfunction I +associated O +with O +subchronic O +doxorubicin O +toxicity B +. O + +Heart O +and O +liver O +mitochondria O +were O +isolated O +from O +rats O +treated O +for O +7 O +weeks O +with O +doxorubicin O +( O +2 O +mg O +/ O +kg O +sc O +/ O +week O +) O +, O +carvedilol O +( O +1 O +mg O +/ O +kg O +ip O +/ O +week O +) O +, O +or O +the O +combination O +of O +the O +two O +drugs O +. O + +Heart O +mitochondria O +isolated O +from O +doxorubicin O +- O +treated O +rats O +exhibited O +depressed O +rates O +for O +state O +3 O +respiration O +( O +336 O ++ O +/ O +- O +26 O +versus O +425 O ++ O +/ O +- O +53 O +natom O +O O +/ O +min O +/ O +mg O +protein O +) O +and O +a O +lower O +respiratory O +control O +ratio O +( O +RCR O +) O +( O +4 O +. O +3 O ++ O +/ O +- O +0 O +. O +6 O +versus O +5 O +. O +8 O ++ O +/ O +- O +0 O +. O +4 O +) O +compared O +with O +cardiac O +mitochondria O +isolated O +from O +saline O +- O +treated O +rats O +. O + +Mitochondrial O +calcium O +- O +loading O +capacity O +and O +the O +activity O +of O +NADH O +- O +dehydrogenase O +were O +also O +suppressed O +in O +cardiac O +mitochondria O +from O +doxorubicin O +- O +treated O +rats O +. O + +Doxorubicin O +treatment O +also O +caused O +a O +decrease O +in O +RCR O +for O +liver O +mitochondria O +( O +3 O +. O +9 O ++ O +/ O +- O +0 O +. O +9 O +versus O +5 O +. O +6 O ++ O +/ O +- O +0 O +. O +7 O +for O +control O +rats O +) O +and O +inhibition O +of O +hepatic O +cytochrome O +oxidase O +activity O +. O + +Coadministration O +of O +carvedilol O +decreased O +the O +extent O +of O +cellular O +vacuolization O +in O +cardiac O +myocytes O +and O +prevented O +the O +inhibitory O +effect O +of O +doxorubicin O +on O +mitochondrial O +respiration O +in O +both O +heart O +and O +liver O +. O + +Carvedilol O +also O +prevented O +the O +decrease O +in O +mitochondrial O +Ca O +( O +2 O ++ O +) O +loading O +capacity O +and O +the O +inhibition O +of O +the O +respiratory O +complexes O +of O +heart O +mitochondria O +caused O +by O +doxorubicin O +. O + +Carvedilol O +by O +itself O +did O +not O +affect O +any O +of O +the O +parameters O +measured O +for O +heart O +or O +liver O +mitochondria O +. O + +It O +is O +concluded O +that O +this O +protection O +by O +carvedilol O +against O +both O +the O +structural O +and O +functional O +cardiac O +tissue I +damage I +may O +afford O +significant O +clinical O +advantage O +in O +minimizing O +the O +dose O +- O +limiting O +mitochondrial B +dysfunction I +and O +cardiomyopathy B +that O +accompanies O +long O +- O +term O +doxorubicin O +therapy O +in O +cancer B +patients O +. O + +Cocaine O +- O +induced O +hyperactivity B +is O +more O +influenced O +by O +adenosine O +receptor O +agonists O +than O +amphetamine O +- O +induced O +hyperactivity B +. O + +The O +influence O +of O +adenosine O +receptor O +agonists O +and O +antagonists O +on O +cocaine O +- O +and O +amphetamine O +- O +induced O +hyperactivity B +was O +examined O +in O +mice O +. O + +All O +adenosine O +receptor O +agonists O +significantly O +decreased O +the O +locomotor O +activity O +in O +mice O +, O +and O +the O +effects O +were O +dose O +- O +dependent O +. O + +It O +seems O +that O +adenosine O +A1 O +and O +A2 O +receptors O +might O +be O +involved O +in O +this O +reaction O +. O + +Moreover O +, O +all O +adenosine O +receptor O +agonists O +: O +2 O +- O +p O +- O +( O +2 O +- O +carboxyethyl O +) O +phenethylamino O +- O +5 O +' O +- O +N O +- O +ethylcarboxamidoadenosine O +( O +CGS O +21680 O +) O +, O +A2A O +receptor O +agonist O +, O +N6 O +- O +cyclopentyladenosine O +( O +CPA O +) O +, O +A1 O +receptor O +agonist O +, O +and O +5 O +' O +- O +N O +- O +ethylcarboxamidoadenosine O +( O +NECA O +) O +, O +A2 O +/ O +A1 O +receptor O +agonist O +significantly O +and O +dose O +- O +dependently O +decreased O +cocaine O +- O +induced O +locomotor O + +CPA O +reduced O +cocaine O +action O +at O +the O +doses O +which O +, O +given O +alone O +, O +did O +not O +influence O +motility O +, O +while O +CGS O +21680 O +and O +NECA O +decreased O +the O +action O +of O +cocaine O +at O +the O +doses O +which O +, O +given O +alone O +, O +decreased O +locomotor O +activity O +in O +animals O +. O + +These O +results O +suggest O +the O +involvement O +of O +both O +adenosine O +receptors O +in O +the O +action O +of O +cocaine O +although O +agonists O +of O +A1 O +receptors O +seem O +to O +have O +stronger O +influence O +on O +it O +. O + +The O +selective O +blockade O +of O +A2 O +adenosine O +receptor O +by O +DMPX O +( O +3 O +, O +7 O +- O +dimethyl O +- O +1 O +- O +propargylxanthine O +) O +significantly O +enhanced O +cocaine O +- O +induced O +locomotor O +activity O +of O +animals O +. O + +Caffeine O +had O +similar O +action O +but O +the O +effect O +was O +not O +significant O +. O + +CPT O +( O +8 O +- O +cyclopentyltheophylline O +) O +- O +- O +A1 O +receptor O +antagonist O +, O +did O +not O +show O +any O +influence O +in O +this O +test O +. O + +Similarly O +, O +all O +adenosine O +receptor O +agonists O +decreased O +amphetamine O +- O +induced O +hyperactivity B +, O +but O +at O +the O +higher O +doses O +than O +those O +which O +were O +active O +in O +cocaine O +- O +induced O +hyperactivity B +. O + +The O +selective O +blockade O +of O +A2 O +adenosine O +receptors O +( O +DMPX O +) O +and O +non O +- O +selective O +blockade O +of O +adenosine O +receptors O +( O +caffeine O +) O +significantly O +increased O +the O +action O +of O +amphetamine O +in O +the O +locomotor O +activity O +test O +. O + +Our O +results O +have O +shown O +that O +all O +adenosine O +receptor O +agonists O +( O +A1 O +and O +A2 O +) O +reduce O +cocaine O +- O +and O +amphetamine O +- O +induced O +locomotor O +activity O +and O +indicate O +that O +cocaine O +- O +induced O +hyperactivity B +is O +more O +influenced O +by O +adenosine O +receptor O +agonists O +( O +particularly O +A1 O +receptors O +) O +than O +amphetamine O +- O +induced O +hyperactivity B +. O + +Amiodarone O +and O +the O +risk O +of O +bradyarrhythmia B +requiring O +permanent O +pacemaker O +in O +elderly O +patients O +with O +atrial B +fibrillation I +and O +prior O +myocardial B +infarction I +. O + +OBJECTIVES O +: O +The O +aim O +of O +this O +study O +was O +to O +determine O +whether O +the O +use O +of O +amiodarone O +in O +patients O +with O +atrial B +fibrillation I +( O +AF B +) O +increases O +the O +risk O +of O +bradyarrhythmia B +requiring O +a O +permanent O +pacemaker O +. O + +BACKGROUND O +: O +Reports O +of O +severe O +bradyarrhythmia B +during O +amiodarone O +therapy O +are O +infrequent O +and O +limited O +to O +studies O +assessing O +the O +therapy O +' O +s O +use O +in O +the O +management O +of O +patients O +with O +ventricular B +arrhythmias I +. O + +METHODS O +: O +A O +study O +cohort O +of O +8 O +, O +770 O +patients O +age O +> O +or O += O +65 O +years O +with O +a O +new O +diagnosis O +of O +AF B +was O +identified O +from O +a O +provincewide O +database O +of O +Quebec O +residents O +with O +a O +myocardial B +infarction I +( O +MI B +) O +between O +1991 O +and O +1999 O +. O + +Using O +a O +nested O +case O +- O +control O +design O +, O +477 O +cases O +of O +bradyarrhythmia B +requiring O +a O +permanent O +pacemaker O +were O +matched O +( O +1 O +: O +4 O +) O +to O +1 O +, O +908 O +controls O +. O + +Multivariable O +logistic O +regression O +was O +used O +to O +estimate O +the O +odds O +ratio O +( O +OR O +) O +of O +pacemaker O +insertion O +associated O +with O +amiodarone O +use O +, O +controlling O +for O +baseline O +risk O +factors O +and O +exposure O +to O +sotalol O +, O +Class O +I O +antiarrhythmic O +agents O +, O +beta O +- O +blockers O +, O +calcium O +channel O +blockers O +, O +and O +digoxin O +. O + +RESULTS O +: O +amiodarone O +use O +was O +associated O +with O +an O +increased O +risk O +of O +pacemaker O +insertion O +( O +OR O +: O +2 O +. O +14 O +, O +95 O +% O +confidence O +interval O +[ O +CI O +] O +: O +1 O +. O +30 O +to O +3 O +. O +54 O +) O +. O + +This O +effect O +was O +modified O +by O +gender O +, O +with O +a O +greater O +risk O +in O +women O +versus O +men O +( O +OR O +: O +3 O +. O +86 O +, O +95 O +% O +CI O +: O +1 O +. O +70 O +to O +8 O +. O +75 O +vs O +. O +OR O +: O +1 O +. O +52 O +, O +95 O +% O +CI O +: O +0 O +. O +80 O +to O +2 O +. O +89 O +) O +. O + +Digoxin O +was O +the O +only O +other O +medication O +associated O +with O +an O +increased O +risk O +of O +pacemaker O +insertion O +( O +OR O +: O +1 O +. O +78 O +, O +95 O +% O +CI O +: O +1 O +. O +37 O +to O +2 O +. O +31 O +) O +. O + +CONCLUSIONS O +: O +This O +study O +suggests O +that O +the O +use O +of O +amiodarone O +in O +elderly O +patients O +with O +AF B +and O +a O +previous O +MI O +increases O +the O +risk O +of O +bradyarrhythmia B +requiring O +a O +permanent O +pacemaker O +. O + +The O +finding O +of O +an O +augmented O +risk O +of O +pacemaker O +insertion O +in O +elderly O +women O +receiving O +amiodarone O +requires O +further O +investigation O +. O + +Indomethacin O +- O +induced O +morphologic O +changes O +in O +the O +rat O +urinary O +bladder O +epithelium O +. O + +OBJECTIVES O +: O +To O +evaluate O +the O +morphologic O +changes O +in O +rat O +urothelium O +induced O +by O +indomethacin O +. O + +Nonsteroidal O +anti O +- O +inflammatory O +drug O +- O +induced O +cystitis B +is O +a O +poorly O +recognized O +and O +under O +- O +reported O +condition O +. O + +In O +addition O +to O +tiaprofenic O +acid O +, O +indomethacin O +has O +been O +reported O +to O +be O +associated O +with O +this O +condition O +. O + +METHODS O +: O +Three O +groups O +were O +established O +: O +a O +control O +group O +( O +n O += O +10 O +) O +, O +a O +high O +- O +dose O +group O +( O +n O += O +10 O +) O +, O +treated O +with O +one O +intraperitoneal O +injection O +of O +indomethacin O +20 O +mg O +/ O +kg O +, O +and O +a O +therapeutic O +dose O +group O +( O +n O += O +10 O +) O +in O +which O +oral O +indomethacin O +was O +administered O +3 O +. O +25 O +mg O +/ O +kg O +body O +weight O +daily O +for O +3 O +weeks O +. O + +The O +animals O +were O +then O +killed O +and O +the O +bladders O +removed O +for O +light O +and O +electron O +microscopic O +studies O +. O + +RESULTS O +: O +The O +light O +microscopic O +findings O +showed O +some O +focal O +epithelial B +degeneration I +that O +was O +more O +prominent O +in O +the O +high O +- O +dose O +group O +. O + +When O +compared O +with O +the O +control O +group O +, O +both O +indomethacin O +groups O +revealed O +statistically O +increased O +numbers O +of O +mast O +cells O +in O +the O +mucosa O +( O +P O +< O +0 O +. O +0001 O +) O +and O +penetration O +of O +lanthanum O +nitrate O +through O +intercellular O +areas O +of O +the O +epithelium O +. O + +Furthermore O +, O +the O +difference O +in O +mast O +cell O +counts O +between O +the O +high O +and O +therapeutic O +dose O +groups O +was O +also O +statistically O +significant O +( O +P O +< O +0 O +. O +0001 O +) O +. O + +CONCLUSIONS O +: O +Indomethacin O +resulted O +in O +histopathologic O +findings O +typical O +of O +interstitial B +cystitis I +, O +such O +as O +leaky B +bladder O +epithelium O +and O +mucosal B +mastocytosis B +. O + +The O +true O +incidence O +of O +nonsteroidal O +anti O +- O +inflammatory O +drug O +- O +induced O +cystitis B +in O +humans O +must O +be O +clarified O +by O +prospective O +clinical O +trials O +. O + +An O +open O +- O +label O +phase O +II O +study O +of O +low O +- O +dose O +thalidomide O +in O +androgen O +- O +independent O +prostate B +cancer I +. O + +The O +antiangiogenic O +effects O +of O +thalidomide O +have O +been O +assessed O +in O +clinical O +trials O +in O +patients O +with O +various O +solid B +and I +haematological I +malignancies I +. O + +Thalidomide O +blocks O +the O +activity O +of O +angiogenic O +agents O +including O +bFGF O +, O +VEGF O +and O +IL O +- O +6 O +. O + +We O +undertook O +an O +open O +- O +label O +study O +using O +thalidomide O +100 O +mg O +once O +daily O +for O +up O +to O +6 O +months O +in O +20 O +men O +with O +androgen O +- O +independent O +prostate B +cancer I +. O + +The O +mean O +time O +of O +study O +was O +109 O +days O +( O +median O +107 O +, O +range O +4 O +- O +184 O +days O +) O +. O + +Patients O +underwent O +regular O +measurement O +of O +prostate O +- O +specific O +antigen O +( O +PSA O +) O +, O +urea O +and O +electrolytes O +, O +serum O +bFGF O +and O +VEGF O +. O + +Three O +men O +( O +15 O +% O +) O +showed O +a O +decline O +in O +serum O +PSA O +of O +at O +least O +50 O +% O +, O +sustained O +throughout O +treatment O +. O + +Of O +16 O +men O +treated O +for O +at O +least O +2 O +months O +, O +six O +( O +37 O +. O +5 O +% O +) O +showed O +a O +fall O +in O +absolute O +PSA O +by O +a O +median O +of O +48 O +% O +. O + +Increasing O +levels O +of O +serum O +bFGF O +and O +VEGF O +were O +associated O +with O +progressive O +disease O +; O +five O +of O +six O +men O +who O +demonstrated O +a O +fall O +in O +PSA O +also O +showed O +a O +decline O +in O +bFGF O +and O +VEGF O +levels O +, O +and O +three O +of O +four O +men O +with O +a O +rising O +PSA O +showed O +an O +increase O +in O +both O +growth O +factors O +. O + +Adverse O +effects O +included O +constipation B +, O +morning O +drowsiness I +, O +dizziness B +and O +rash B +, O +and O +resulted O +in O +withdrawal O +from O +the O +study O +by O +three O +men O +. O + +Evidence O +of O +peripheral B +sensory I +neuropathy I +was O +found O +in O +nine O +of O +13 O +men O +before O +treatment O +. O + +In O +the O +seven O +men O +who O +completed O +six O +months O +on O +thalidomide O +, O +subclinical O +evidence O +of O +peripheral B +neuropathy I +was O +found O +in O +four O +before O +treatment O +, O +but O +in O +all O +seven O +at O +repeat O +testing O +. O + +The O +findings O +indicate O +that O +thalidomide O +may O +be O +an O +option O +for O +patients O +who O +have O +failed O +other O +forms O +of O +therapy O +, O +provided O +close O +follow O +- O +up O +is O +maintained O +for O +development O +of O +peripheral B +neuropathy I +. O + +Central B +nervous I +system I +toxicity I +following O +the O +administration O +of O +levobupivacaine O +for O +lumbar O +plexus O +block O +: O +A O +report O +of O +two O +cases O +. O + +BACKGROUND O +AND O +OBJECTIVES O +: O +Central B +nervous I +system I +and I +cardiac I +toxicity I +following O +the O +administration O +of O +local O +anesthetics O +is O +a O +recognized O +complication O +of O +regional O +anesthesia O +. O + +Levobupivacaine O +, O +the O +pure O +S O +( O +- O +) O +enantiomer O +of O +bupivacaine O +, O +was O +developed O +to O +improve O +the O +cardiac O +safety O +profile O +of O +bupivacaine O +. O + +We O +describe O +2 O +cases O +of O +grand B +mal I +seizures I +following O +accidental O +intravascular O +injection O +of O +levobupivacaine O +. O + +CASE O +REPORT O +: O +Two O +patients O +presenting O +for O +elective O +orthopedic O +surgery O +of O +the O +lower O +limb O +underwent O +blockade O +of O +the O +lumbar O +plexus O +via O +the O +posterior O +approach O +. O + +Immediately O +after O +the O +administration O +of O +levobupivacaine O +0 O +. O +5 O +% O +with O +epinephrine O +2 O +. O +5 O +microgram O +/ O +mL O +, O +the O +patients O +developed O +grand B +mal I +seizures B +, O +despite O +negative O +aspiration O +for O +blood O +and O +no O +clinical O +signs O +of O +intravenous O +epinephrine O +administration O +. O + +The O +seizures B +were O +successfully O +treated O +with O +sodium O +thiopental O +in O +addition O +to O +succinylcholine O +in O +1 O +patient O +. O + +Neither O +patient O +developed O +signs O +of O +cardiovascular B +toxicity I +. O + +Both O +patients O +were O +treated O +preoperatively O +with O +beta O +- O +adrenergic O +antagonist O +medications O +, O +which O +may O +have O +masked O +the O +cardiovascular O +signs O +of O +the O +unintentional O +intravascular O +administration O +of O +levobupivacaine O +with O +epinephrine O +. O + +CONCLUSIONS O +: O +Although O +levobupivacaine O +may O +have O +a O +safer O +cardiac B +toxicity I +profile O +than O +racemic O +bupivacaine O +, O +if O +adequate O +amounts O +of O +levobupivacaine O +reach O +the O +circulation O +, O +it O +will O +result O +in O +convulsions B +. O + +Plasma O +concentrations O +sufficient O +to O +result O +in O +central O +nervous O +system I +toxicity B +did O +not O +produce O +manifestations O +of O +cardiac B +toxicity I +in O +these O +2 O +patients O +. O + +Amiodarone O +- O +induced O +torsade B +de I +pointes I +during O +bladder O +irrigation O +: O +an O +unusual O +presentation O +- O +- O +a O +case O +report O +. O + +The O +authors O +present O +a O +case O +of O +early O +( O +within O +4 O +days O +) O +development O +of O +torsade B +de I +pointes I +( O +TdP B +) O +associated O +with O +oral O +amiodarone O +therapy O +. O + +Consistent O +with O +other O +reports O +this O +case O +of O +TdP B +occurred O +in O +the O +context O +of O +multiple O +exacerbating O +factors O +including O +hypokalemia B +and O +digoxin O +excess O +. O + +Transient O +prolongation B +of I +the I +QT I +during O +bladder O +irrigation O +prompted O +the O +episode O +of O +TdP B +. O + +It O +is O +well O +known O +that O +bradycardia B +exacerbates O +acquired O +TdP B +. O + +The O +authors O +speculate O +that O +the O +increased O +vagal O +tone O +during O +bladder O +irrigation O +, O +a O +vagal O +maneuver O +, O +in O +the O +context O +of O +amiodarone O +therapy O +resulted O +in O +amiodarone O +- O +induced O +proarrhythmia B +. O + +In O +the O +absence O +of O +amiodarone O +therapy O +, O +a O +second O +bladder O +irrigation O +did O +not O +induce O +TdP B +despite O +hypokalemia B +and O +hypomagnesemia B +. O + +Anaesthetic O +complications O +associated O +with O +myotonia B +congenita I +: O +case O +study O +and O +comparison O +with O +other O +myotonic B +disorders I +. O + +Myotonia B +congenita I +( O +MC B +) O +is O +caused O +by O +a O +defect O +in O +the O +skeletal O +muscle O +chloride O +channel O +function O +, O +which O +may O +cause O +sustained O +membrane O +depolarisation O +. O + +We O +describe O +a O +previously O +healthy O +32 O +- O +year O +- O +old O +woman O +who O +developed O +a O +life O +- O +threatening O +muscle B +spasm I +and O +secondary O +ventilation O +difficulties O +following O +a O +preoperative O +injection O +of O +suxamethonium O +. O + +The O +muscle B +spasms I +disappeared O +spontaneously O +and O +the O +surgery O +proceeded O +without O +further O +problems O +. O + +When O +subsequently O +questioned O +, O +she O +reported O +minor O +symptoms O +suggesting O +a O +myotonic B +condition O +. O + +Myotonia B +was O +found O +on O +clinical O +examination O +and O +EMG O +. O + +The O +diagnosis O +MC B +was O +confirmed O +genetically O +. O + +Neither O +the O +patient O +nor O +the O +anaesthetist O +were O +aware O +of O +the O +diagnosis O +before O +this O +potentially O +lethal O +complication O +occurred O +. O + +We O +give O +a O +brief O +overview O +of O +ion B +channel I +disorders I +including O +malignant B +hyperthermia I +and O +their O +anaesthetic O +considerations O +. O + +Respiratory O +pattern O +in O +a O +rat O +model O +of O +epilepsy B +. O + +PURPOSE O +: O +Apnea B +is O +known O +to O +occur O +during O +seizures B +, O +but O +systematic O +studies O +of O +ictal O +respiratory O +changes O +in O +adults O +are O +few O +. O + +Data O +regarding O +respiratory O +pattern O +defects O +during O +interictal O +periods O +also O +are O +scarce O +. O + +Here O +we O +sought O +to O +generate O +information O +with O +regard O +to O +the O +interictal O +period O +in O +animals O +with O +pilocarpine O +- O +induced O +epilepsy B +. O + +METHODS O +: O +Twelve O +rats O +( O +six O +chronically O +epileptic B +animals O +and O +six O +controls O +) O +were O +anesthetized O +, O +given O +tracheotomies O +, O +and O +subjected O +to O +hyperventilation O +or O +hypoventilation B +conditions O +. O + +Breathing O +movements O +caused O +changes O +in O +thoracic O +volume O +and O +forced O +air O +to O +flow O +tidally O +through O +a O +pneumotachograph O +. O + +This O +flow O +was O +measured O +by O +using O +a O +differential O +pressure O +transducer O +, O +passed O +through O +a O +polygraph O +, O +and O +from O +this O +to O +a O +computer O +with O +custom O +software O +that O +derived O +ventilation O +( O +VE O +) O +, O +tidal O +volume O +( O +VT O +) O +, O +inspiratory O +time O +( O +TI O +) O +, O +expiratory O +time O +( O +TE O +) O +, O +breathing O +frequency O +( O +f O +) O +, O +and O +mean O +inspiratory O +flow O +( O +VT O +/ O +TI O +) O +on O +a O +breath O +- O +by O +- O +breath O +basis O +. O + +RESULTS O +: O +The O +hyperventilation O +maneuver O +caused O +a O +decrease O +in O +spontaneous O +ventilation O +in O +pilocarpine O +- O +treated O +and O +control O +rats O +. O + +Although O +VE O +had O +a O +similar O +decrease O +in O +both O +groups O +, O +in O +the O +epileptic B +group O +, O +the O +decrease O +in O +VE O +was O +due O +to O +a O +significant O +( O +p O +< O +0 O +. O +05 O +) O +increase O +in O +TE O +peak O +in O +relation O +to O +that O +of O +the O +control O +animals O +. O + +The O +hypoventilation B +maneuver O +led O +to O +an O +increase O +in O +the O +arterial O +Paco2 O +, O +followed O +by O +an O +increase O +in O +VE O +. O + +In O +the O +epileptic B +group O +, O +the O +increase O +in O +VE O +was O +mediated O +by O +a O +significant O +( O +p O +< O +0 O +. O +05 O +) O +decrease O +in O +TE O +peak O +compared O +with O +the O +control O +group O +. O + +Systemic O +application O +of O +KCN O +, O +to O +evaluate O +the O +effects O +of O +peripheral O +chemoreception O +activation O +on O +ventilation O +, O +led O +to O +a O +similar O +increase O +in O +VE O +for O +both O +groups O +. O + +CONCLUSIONS O +: O +The O +data O +indicate O +that O +pilocarpine O +- O +treated O +animals O +have O +an O +altered O +ability O +to O +react O +to O +( O +or O +compensate O +for O +) O +blood O +gas O +changes O +with O +changes O +in O +ventilation O +and O +suggest O +that O +it O +is O +centrally O +determined O +. O + +We O +speculate O +on O +the O +possible O +relation O +of O +the O +current O +findings O +on O +treating O +different O +epilepsy B +- O +associated O +conditions O +. O + +Fatal O +myeloencephalopathy B +due O +to O +intrathecal O +vincristine O +administration O +. O + +Vincristine O +was O +accidentally O +given O +intrathecally O +to O +a O +child O +with O +leukaemia B +, O +producing O +sensory B +and I +motor I +dysfunction I +followed O +by O +encephalopathy B +and O +death B +. O + +Separate O +times O +for O +administering O +vincristine O +and O +intrathecal O +therapy O +is O +recommended O +. O + +Progesterone O +potentiation O +of O +bupivacaine O +arrhythmogenicity B +in O +pentobarbital O +- O +anesthetized O +rats O +and O +beating O +rat O +heart O +cell O +cultures O +. O + +The O +effects O +of O +progesterone O +treatment O +on O +bupivacaine O +arrhythmogenicity O +in O +beating O +rat O +heart O +myocyte O +cultures O +and O +on O +anesthetized O +rats O +were O +determined O +. O + +After O +determining O +the O +bupivacaine O +AD50 O +( O +the O +concentration O +of O +bupivacaine O +that O +caused O +50 O +% O +of O +all O +beating O +rat O +heart O +myocyte O +cultures O +to O +become O +arrhythmic B +) O +, O +we O +determined O +the O +effect O +of O +1 O +- O +hour O +progesterone O +HCl O +exposure O +on O +myocyte O +contractile O +rhythm O +. O + +Each O +concentration O +of O +progesterone O +( O +6 O +. O +25 O +, O +12 O +. O +5 O +, O +25 O +, O +and O +50 O +micrograms O +/ O +ml O +) O +caused O +a O +significant O +and O +concentration O +- O +dependent O +reduction O +in O +the O +AD50 O +for O +bupivacaine O +. O + +Estradiol O +treatment O +also O +increased O +the O +arrhythmogenicity O +of O +bupivacaine O +in O +myocyte O +cultures O +, O +but O +was O +only O +one O +fourth O +as O +potent O +as O +progesterone O +. O + +Neither O +progesterone O +nor O +estradiol O +effects O +on O +bupivacaine O +arrhythmogenicity O +were O +potentiated O +by O +epinephrine O +. O + +Chronic O +progesterone O +pretreatment O +( O +5 O +mg O +/ O +kg O +/ O +day O +for O +21 O +days O +) O +caused O +a O +significant O +increase O +in O +bupivacaine O +arrhythmogenicity O +in O +intact O +pentobarbital O +- O +anesthetized O +rats O +. O + +There O +was O +a O +significant O +decrease O +in O +the O +time O +to O +onset O +of O +arrhythmia B +as O +compared O +with O +control O +nonprogesterone O +- O +treated O +rats O +( O +6 O +. O +2 O ++ O +/ O +- O +1 O +. O +3 O +vs O +. O +30 O +. O +8 O ++ O +/ O +- O +2 O +. O +5 O +min O +, O +mean O ++ O +/ O +- O +SE O +) O +. O + +The O +results O +of O +this O +study O +indicate O +that O +progesterone O +can O +potentiate O +bupivacaine O +arrhythmogenicity O +both O +in O +vivo O +and O +in O +vitro O +. O + +Potentiation O +of O +bupivacaine O +arrhythmia B +in O +myocyte O +cultures O +suggests O +that O +this O +effect O +is O +at O +least O +partly O +mediated O +at O +the O +myocyte O +level O +. O + +Increased O +serum O +soluble O +Fas O +in O +patients O +with O +acute B +liver I +failure I +due O +to O +paracetamol O +overdose B +. O + +BACKGROUND O +/ O +AIMS O +: O +Experimental O +studies O +have O +suggested O +that O +apoptosis O +via O +the O +Fas O +/ O +Fas O +Ligand O +signaling O +system O +may O +play O +an O +important O +role O +in O +the O +development O +of O +acute B +liver I +failure I +. O + +The O +aim O +of O +the O +study O +was O +to O +investigate O +the O +soluble O +form O +of O +Fas O +in O +patients O +with O +acute B +liver I +failure I +. O + +METHODOLOGY O +: O +Serum O +levels O +of O +sFas O +( O +soluble O +Fas O +) O +were O +measured O +by O +ELISA O +in O +24 O +patients O +with O +acute B +liver I +failure I +and O +10 O +normal O +control O +subjects O +. O + +Serum O +levels O +of O +tumor B +necrosis O +factor O +- O +alpha O +and O +interferon O +- O +gamma O +were O +also O +determined O +by O +ELISA O +. O + +RESULTS O +: O +Serum O +sFas O +was O +significantly O +increased O +in O +patients O +with O +acute B +liver I +failure I +( O +median O +, O +26 O +. O +8 O +U O +/ O +mL O +; O +range O +, O +6 O +. O +9 O +- O +52 O +. O +7 O +U O +/ O +mL O +) O +compared O +to O +the O +normal O +controls O +( O +median O +, O +8 O +. O +6 O +U O +/ O +mL O +; O +range O +, O +6 O +. O +5 O +- O +12 O +. O +0 O +U O +/ O +mL O +, O +P O +< O +0 O +. O +0001 O +) O +. O + +Levels O +were O +significantly O +greater O +in O +patients O +with O +acute B +liver I +failure I +due O +to O +paracetamol O +overdose B +( O +median O +, O +28 O +. O +7 O +U O +/ O +mL O +; O +range O +, O +12 O +. O +8 O +- O +52 O +. O +7 O +U O +/ O +mL O +, O +n O += O +17 O +) O +than O +those O +due O +to O +non B +- I +A I +to I +E I +hepatitis B +( O +median O +, O +12 O +. O +5 O +U O +/ O +mL O +; O +range O +, O +6 O +. O +9 O +- O +46 O +. O +0 O +U O +/ O +mL O +, O +n O += O +7 O +, O +P O +< O +0 O +. O +01 O +) O +. O + +There O +was O +no O +relationship O +of O +sFas O +to O +eventual O +outcome O +in O +the O +patients O +. O + +A O +significant O +correlation O +was O +observed O +between O +serum O +sFas O +levels O +and O +aspartate O +aminotransferase O +( O +r O += O +0 O +. O +613 O +, O +P O +< O +0 O +. O +01 O +) O +. O + +CONCLUSIONS O +: O +The O +increased O +concentration O +of O +sFas O +in O +serum O +of O +patients O +with O +acute B +liver I +failure I +may O +reflect O +activation O +of O +Fas O +- O +mediated O +apoptosis O +in O +the O +liver O +and O +this O +together O +with O +increased O +tumor B +necrosis O +factor O +- O +alpha O +may O +be O +an O +important O +factor O +in O +liver O +cell O +loss O +. O + +Bilateral O +subthalamic O +nucleus O +stimulation O +for O +Parkinson B +' I +s I +disease I +. O + +High O +frequency O +stimulation O +of O +the O +subthalamic O +nucleus O +( O +STN O +) O +is O +known O +to O +ameliorate O +the O +signs O +and O +symptoms O +of O +advanced O +Parkinson B +' I +s I +disease I +. O + +AIM O +: O +We O +studied O +the O +effect O +of O +high O +frequency O +STN O +stimulation O +in O +23 O +patients O +. O + +METHOD O +: O +Twenty O +- O +three O +patients O +suffering O +from O +severe O +Parkinson B +' I +s I +disease I +( O +Stages O +III O +- O +V O +on O +Hoehn O +and O +Yahr O +scale O +) O +and O +, O +particularly O +bradykinesia B +, O +rigidity B +, O +and O +levodopa O +- O +induced O +dyskinesias B +underwent O +bilateral O +implantation O +of O +electrodes O +in O +the O +STN O +. O + +Preoperative O +and O +postoperative O +assessments O +of O +these O +patients O +at O +1 O +, O +3 O +, O +6 O +and O +12 O +months O +follow O +- O +up O +, O +in O +" O +on O +" O +and O +" O +off O +" O +drug O +conditions O +, O +was O +carried O +out O +using O +Unified O +Parkinson B +' I +s I +Disease I +Rating O +Scale O +, O +Hoehn O +and O +Yahr O +staging O +, O +England O +activities O +of O +daily O +living O +score O +and O +video O +recordings O +. O + +RESULTS O +: O +After O +one O +year O +of O +electrical O +stimulation O +of O +the O +STN O +, O +the O +patients O +' O +scores O +for O +activities O +of O +daily O +living O +and O +motor O +examination O +scores O +( O +Unified O +Parkinson B +' I +s I +Disease I +Rating O +Scale O +parts O +II O +and O +III O +) O +off O +medication O +improved O +by O +62 O +% O +and O +61 O +% O +respectively O +( O +p O +< O +0 O +. O +0005 O +) O +. O + +The O +subscores O +for O +the O +akinesia B +, O +rigidity B +, O +tremor B +and O +gait O +also O +improved O +. O + +( O +p O +< O +0 O +. O +0005 O +) O +. O + +The O +average O +levodopa O +dose O +decreased O +from O +813 O +mg O +to O +359 O +mg O +. O + +The O +cognitive O +functions O +remained O +unchanged O +. O + +Two O +patients O +developed O +device O +- O +related O +complications O +and O +two O +patients O +experienced O +abnormal O +weight O +gain I +. O + +CONCLUSION O +: O +Bilateral O +subthalamic O +nucleus O +stimulation O +is O +an O +effective O +treatment O +for O +advanced O +Parkinson B +' I +s I +disease I +. O + +It O +reduces O +the O +severity O +of O +" O +off O +" O +phase O +symptoms O +, O +improves O +the O +axial O +symptoms O +and O +reduces O +levodopa O +requirements O +. O + +The O +reduction O +in O +the O +levodopa O +dose O +is O +useful O +in O +controlling O +drug O +- O +induced O +dyskinesias B +. O + +Acute B +renal I +failure I +occurring O +during O +intravenous O +desferrioxamine O +therapy O +: O +recovery O +after O +haemodialysis O +. O + +A O +patient O +with O +transfusion O +- O +dependent O +thalassemia B +was O +undergoing O +home O +intravenous O +desferrioxamine O +( O +DFX O +) O +treatment O +by O +means O +of O +a O +totally O +implanted O +system O +because O +of O +his O +poor O +compliance O +with O +the O +nightly O +subcutaneous O +therapy O +. O + +Due O +to O +an O +accidental O +malfunctioning O +of O +the O +infusion O +pump O +, O +the O +patient O +was O +inadvertently O +administered O +a O +toxic O +dosage O +of O +the O +drug O +which O +caused O +renal B +insufficiency I +. O + +Given O +the O +progressive O +deterioration O +of O +the O +symptoms O +and O +of O +the O +laboratory O +values O +, O +despite O +adequate O +medical O +treatment O +, O +a O +decision O +was O +made O +to O +introduce O +haemodialytical O +therapy O +in O +order O +to O +remove O +the O +drug O +and O +therapy O +reduce O +the O +nephrotoxicity B +. O + +From O +the O +results O +obtained O +, O +haemodialysis O +can O +therefore O +be O +suggested O +as O +a O +useful O +therapy O +in O +rare O +cases O +of O +progressive O +acute B +renal I +failure I +caused O +by O +desferrioxamine O +. O + +Ocular O +motility O +changes O +after O +subtenon O +carboplatin O +chemotherapy O +for O +retinoblastoma B +. O + +BACKGROUND O +: O +Focal O +subtenon O +carboplatin O +injections O +have O +recently O +been O +used O +as O +a O +presumably O +toxicity B +- O +free O +adjunct O +to O +systemic O +chemotherapy O +for O +intraocular B +retinoblastoma I +. O + +OBJECTIVE O +: O +To O +report O +our O +clinical O +experience O +with O +abnormal B +ocular I +motility I +in O +patients O +treated O +with O +subtenon O +carboplatin O +chemotherapy O +. O + +METHODS O +: O +We O +noted O +abnormal O +ocular O +motility O +in O +10 O +consecutive O +patients O +with O +retinoblastoma B +who O +had O +received O +subtenon O +carboplatin O +. O + +During O +ocular O +manipulation O +under O +general O +anesthesia O +, O +we O +assessed O +their O +eyes O +by O +forced O +duction O +testing O +, O +comparing O +ocular O +motility O +after O +tumor B +control O +with O +ocular O +motility O +at O +diagnosis O +. O + +Eyes O +subsequently O +enucleated O +because O +of O +treatment O +failure O +( O +n O += O +4 O +) O +were O +examined O +histologically O +. O + +RESULTS O +: O +Limitation B +of I +ocular I +motility I +was O +detected O +in O +all O +12 O +eyes O +of O +10 O +patients O +treated O +for O +intraocular B +retinoblastoma I +with O +1 O +to O +6 O +injections O +of O +subtenon O +carboplatin O +as O +part O +of O +multimodality O +therapy O +. O + +Histopathological O +examination O +revealed O +many O +lipophages O +in O +the O +periorbital O +fat O +surrounding O +the O +optic O +nerve O +in O +1 O +eye O +, O +indicative O +of O +phagocytosis O +of O +previously O +existing O +fat O +cells O +and O +suggesting O +prior O +fat B +necrosis I +. O + +The O +enucleations O +were O +technically O +difficult O +and O +hazardous O +for O +globe B +rupture I +because O +of O +extensive O +orbital O +soft O +tissue O +adhesions O +. O + +CONCLUSIONS O +: O +Subtenon O +carboplatin O +chemotherapy O +is O +associated O +with O +significant O +fibrosis B +of O +orbital O +soft O +tissues O +, O +leading O +to O +mechanical O +restriction B +of I +eye O +movements O +and O +making O +subsequent O +enucleation O +difficult O +. O + +Subtenon O +carboplatin O +is O +not O +free O +of O +toxicity B +, O +and O +its O +use O +is O +best O +restricted O +to O +specific O +indications O +. O + +Ethambutol O +and O +optic B +neuropathy I +. O + +PURPOSE O +: O +To O +demonstrate O +the O +association O +between O +ethambutol O +and O +optic B +neuropathy I +. O + +METHOD O +: O +Thirteen O +patients O +who O +developed O +optic B +neuropathy I +after O +being O +treated O +with O +ethambutol O +for O +tuberculosis B +of O +the O +lung O +or O +lymph O +node O +at O +Siriraj O +Hospital O +between O +1997 O +and O +2001 O +were O +retrospectively O +reviewed O +. O + +The O +clinical O +characteristics O +and O +initial O +and O +final O +visual O +acuity O +were O +analyzed O +to O +determine O +visual O +outcome O +. O + +RESULTS O +: O +All O +patients O +had O +optic B +neuropathy I +between O +1 O +to O +6 O +months O +( O +mean O += O +2 O +. O +9 O +months O +) O +after O +starting O +ethambutol O +therapy O +at O +a O +dosage O +ranging O +from O +13 O +to O +20 O +mg O +/ O +kg O +/ O +day O +( O +mean O += O +17 O +mg O +/ O +kg O +/ O +day O +) O +. O + +Seven O +( O +54 O +% O +) O +of O +the O +13 O +patients O +experienced O +visual O +recovery O +after O +stopping O +the O +drug O +. O + +Of O +6 O +patients O +with O +irreversible O +visual B +impairment I +, O +4 O +patients O +had O +diabetes B +mellitus I +, O +glaucoma B +and O +a O +history O +of O +heavy O +smoking O +. O + +CONCLUSION O +: O +Early O +recognition O +of O +optic B +neuropathy I +should O +be O +considered O +in O +patients O +with O +ethambutol O +therapy O +. O + +A O +low O +dose O +and O +prompt O +discontinuation O +of O +the O +drug O +is O +recommended O +particularly O +in O +individuals O +with O +diabetes B +mellitus I +, O +glaucoma B +or O +who O +are O +heavy O +smokers O +. O + +Treatment O +of O +compensatory O +gustatory O +hyperhidrosis I +with O +topical O +glycopyrrolate O +. O + +Gustatory B +hyperhidrosis I +is O +facial B +sweating I +usually O +associated O +with O +the O +eating O +of O +hot O +spicy O +food O +or O +even O +smelling O +this O +food O +. O + +Current O +options O +of O +treatment O +include O +oral O +anticholinergic O +drugs O +, O +the O +topical O +application O +of O +anticholinergics O +or O +aluminum O +chloride O +, O +and O +the O +injection O +of O +botulinum O +toxin O +. O + +Thirteen O +patients O +have O +been O +treated O +to O +date O +with O +1 O +. O +5 O +% O +or O +2 O +% O +topical O +glycopyrrolate O +. O + +All O +patients O +had O +gustatory B +hyperhidrosis I +, O +which O +interfered O +with O +their O +social O +activities O +, O +after O +transthroacic O +endoscopic O +sympathectomy O +, O +and O +which O +was O +associated O +with O +compensatory O +focal O +hyperhidrosis B +. O + +After O +applying O +topical O +glycopyrrolate O +, O +the O +subjective O +effect O +was O +excellent O +( O +no O +sweating O +after O +eating O +hot O +spicy O +food O +) O +in O +10 O +patients O +( O +77 O +% O +) O +, O +and O +fair O +( O +clearly O +reduced O +sweating O +) O +in O +3 O +patients O +( O +23 O +% O +) O +. O + +All O +had O +reported O +incidents O +of O +being O +very O +embarrassed O +whilst O +eating O +hot O +spicy O +foods O +. O + +Adverse O +effects O +included O +a O +mildly O +dry B +mouth I +and O +a O +sore B +throat I +in O +2 O +patients O +( O +2 O +% O +glycopyrrolate O +) O +, O +a O +light O +headache B +in O +1 O +patient O +( O +1 O +. O +5 O +% O +glycopyrrolate O +) O +. O + +The O +topical O +application O +of O +a O +glycopyrrolate O +pad O +appeared O +to O +be O +safe O +, O +efficacious O +, O +well O +tolerated O +, O +and O +a O +convenient O +method O +of O +treatment O +for O +moderate O +to O +severe O +symptoms O +of O +gustatory B +hyperhidrosis I +in O +post O +transthoracic O +endoscopic O +sympathectomy O +or O +sympathicotomy O +patients O +, O +with O +few O +side O +effects O +. O + +Neuroleptic O +- O +associated O +hyperprolactinemia B +. O + +Can O +it O +be O +treated O +with O +bromocriptine O +? O + +Six O +stable O +psychiatric B +outpatients O +with O +hyperprolactinemia B +and O +amenorrhea B +/ O +oligomenorrhea B +associated O +with O +their O +neuroleptic O +medications O +were O +treated O +with O +bromocriptine O +. O + +Daily O +dosages O +of O +5 O +- O +10 O +mg O +corrected O +the O +hyperprolactinemia B +and O +restored O +menstruation O +in O +four O +of O +the O +six O +patients O +. O + +One O +woman O +, O +however O +, O +developed O +worsened O +psychiatric B +symptoms I +while O +taking O +bromocriptine O +, O +and O +it O +was O +discontinued O +. O + +Thus O +, O +three O +of O +six O +patients O +had O +their O +menstrual B +irregularity I +successfully O +corrected O +with O +bromocriptine O +. O + +This O +suggests O +that O +bromocriptine O +should O +be O +further O +evaluated O +as O +potential O +therapy O +for O +neuroleptic O +- O +associated O +hyperprolactinemia B +and O +amenorrhea B +/ O +galactorrhea B +. O + +Ethacrynic O +acid O +- O +induced O +convulsions B +and O +brain O +neurotransmitters O +in O +mice O +. O + +Intracerebroventricular O +injection O +of O +ethacrynic O +acid O +( O +50 O +% O +convulsive B +dose O +; O +50 O +micrograms O +/ O +mouse O +) O +accelerated O +the O +synthesis O +/ O +turnover O +of O +5 O +- O +hydroxytryptamine O +( O +5 O +- O +HT O +) O +but O +suppressed O +the O +synthesis O +of O +gamma O +- O +aminobutyric O +acid O +and O +acetylcholine O +in O +mouse O +brain O +. O + +These O +effects O +were O +completely O +antagonized O +by O +pretreatment O +with O +a O +glutamate O +/ O +N O +- O +methyl O +- O +D O +- O +aspartate O +antagonist O +, O +aminophosphonovaleric O +acid O +. O + +In O +ethacrynic O +acid O +- O +induced O +convulsions B +, O +these O +neurotransmitter O +systems O +may O +be O +differentially O +modulated O +, O +probably O +through O +activation O +of O +glutaminergic O +neurons O +in O +the O +brain O +. O + +Pharmacology O +of O +gamma O +- O +aminobutyric O +acidA O +receptor O +complex O +after O +the O +in O +vivo O +administration O +of O +the O +anxioselective O +and O +anticonvulsant O +beta O +- O +carboline O +derivative O +abecarnil O +. O + +In O +rodents O +, O +the O +effect O +of O +the O +beta O +- O +carboline O +derivative O +isopropyl O +- O +6 O +- O +benzyloxy O +- O +4 O +- O +methoxymethyl O +- O +beta O +- O +carboline O +- O +3 O +- O +carboxylate O +( O +abecarrnil O +) O +, O +a O +new O +ligand O +for O +benzodiazepine O +receptors O +possessing O +anxiolytic O +and O +anticonvulsant O +properties O +, O +was O +evaluated O +on O +the O +function O +of O +central O +gamma O +- O +aminobutyric O +acid O +( O +GABA O +) O +A O +receptor O +complex O +, O +both O +in O +vitro O +and O +in O +vivo O +. O + +Added O +in O +vitro O +to O +rat O +cortical O +membrane O +preparation O +, O +abecarnil O +increased O +[ O +3H O +] O +GABA O +binding O +, O +enhanced O +muscimol O +- O +stimulated O +36Cl O +- O +uptake O +and O +reduced O +the O +binding O +of O +t O +- O +[ O +35S O +] O +butylbicyclophosphorothionate O +( O +[ O +35S O +] O +TBPS O +) O +. O + +These O +effects O +were O +similar O +to O +those O +induced O +by O +diazepam O +, O +whereas O +the O +partial O +agonist O +Ro O +16 O +- O +6028 O +( O +tert O +- O +butyl O +- O +( O +S O +) O +- O +8 O +- O +bromo O +- O +11 O +, O +12 O +, O +13 O +, O +13a O +- O +tetrahydro O +- O +9 O +- O +oxo O +- O +9H O +- O +imidazo O +[ O +1 O +, O +5 O +- O +a O +] O +- O +pyrrolo O +- O +[ O +2 O +, O +1 O +- O +c O +] O +[ O +1 O +, O +4 O +] O +benzodiazepine O +- O +1 O +- O +carboxylate O +) O +showed O +very O +weak O +efficacy O +in O +these O +biochemical O +tests O +. O + +After O +i O +. O +p O +. O +injection O +to O +rats O +, O +abecarnil O +and O +diazepam O +decreased O +in O +a O +time O +- O +dependent O +and O +dose O +- O +related O +( O +0 O +. O +25 O +- O +20 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +manner O +[ O +35S O +] O +TBPS O +binding O +measured O +ex O +vivo O +in O +the O +cerebral O +cortex O +. O + +Moreover O +, O +both O +drugs O +at O +the O +dose O +of O +0 O +. O +5 O +mg O +/ O +kg O +antagonized O +completely O +the O +convulsant O +activity O +and O +the O +increase O +of O +[ O +35S O +] O +TBPS O +binding O +induced O +by O +isoniazide O +( O +350 O +mg O +/ O +kg O +s O +. O +c O +. O +) O +as O +well O +as O +the O +increase O +of O +[ O +35S O +] O +TBPS O +binding O +induced O +by O +foot O +- O +shock O +stress O +. O + +To O +better O +correlate O +the O +biochemical O +and O +the O +pharmacological O +effects O +, O +we O +studied O +the O +action O +of O +abecarnil O +on O +[ O +35S O +] O +TBPS O +binding O +, O +exploratory O +motility O +and O +on O +isoniazid O +- O +induced O +biochemical O +and O +pharmacological O +effects O +in O +mice O +. O + +In O +these O +animals O +, O +abecarnil O +produced O +a O +paralleled O +dose O +- O +dependent O +( O +0 O +. O +05 O +- O +1 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +reduction O +of O +both O +motor O +behavior O +and O +cortical O +[ O +35S O +] O +TBPS O +binding O +. O + +Moreover O +, O +0 O +. O +05 O +mg O +/ O +kg O +of O +this O +beta O +- O +carboline O +reduced O +markedly O +the O +increase O +of O +[ O +35S O +] O +TBPS O +binding O +and O +the O +convulsions B +induced O +by O +isoniazid O +( O +200 O +mg O +/ O +kg O +s O +. O +c O +. O +) O +. O +( O +ABSTRACT O +TRUNCATED O +AT O +250 O +WORDS O +) O + +Recurrent O +myocardial B +infarction I +in O +a O +postpartum O +patient O +receiving O +bromocriptine O +. O + +Myocardial B +infarction I +in O +puerperium O +is O +infrequently O +reported O +. O + +Spasm B +, O +coronary B +dissection I +, O +or O +atheromatous B +etiology O +has O +been O +described O +. O + +Bromocriptine O +has O +been O +implicated O +in O +several O +previous O +case O +reports O +of O +myocardial B +infarction I +in O +the O +puerperium O +. O + +Our O +case O +( O +including O +an O +inadvertent O +rechallenge O +) O +suggests O +such O +a O +relationship O +. O + +Although O +generally O +regarded O +as O +" O +safe O +, O +" O +possible O +serious O +cardiac O +effects O +of O +bromocriptine O +should O +be O +acknowledged O +. O + +Asterixis B +induced O +by O +carbamazepine O +therapy O +. O + +There O +are O +very O +few O +reports O +about O +asterixis B +as O +a O +side O +effect O +of O +treatment O +with O +psychopharmacologic O +agents O +. O + +In O +this O +report O +we O +present O +four O +patients O +treated O +with O +a O +combination O +of O +different O +psychotropic O +drugs O +, O +in O +whom O +asterixis B +was O +triggered O +either O +by O +adding O +carbamazepine O +( O +CBZ O +) O +to O +a O +treatment O +regimen O +, O +or O +by O +increasing O +its O +dosage O +. O + +Neither O +dosage O +nor O +serum O +levels O +of O +CBZ O +were O +in O +a O +higher O +range O +. O + +We O +consider O +asterixis B +to O +be O +an O +easily O +overlooked O +sign O +of O +neurotoxicity B +, O +which O +may O +occur O +even O +at O +low O +or O +moderate O +dosage O +levels O +, O +if O +certain O +drugs O +as O +lithium O +or O +clozapine O +are O +used O +in O +combination O +with O +CBZ O +. O + +Pharmacodynamics O +of O +the O +hypotensive B +effect O +of O +levodopa O +in O +parkinsonian B +patients O +. O + +Blood O +pressure O +effects O +of O +i O +. O +v O +. O +levodopa O +were O +examined O +in O +parkinsonian B +patients O +with O +stable O +and O +fluctuating O +responses O +to O +levodopa O +. O + +The O +magnitude O +of O +the O +hypotensive B +effect O +of O +levodopa O +was O +concentration O +dependent O +and O +was O +fit O +to O +an O +Emax O +model O +in O +fluctuating O +responders O +. O + +Stable O +responders O +demonstrated O +a O +small O +hypotensive B +response O +. O + +Baseline O +blood O +pressures O +were O +higher O +in O +fluctuating O +patients O +; O +a O +higher O +baseline O +blood O +pressure O +correlated O +with O +greater O +hypotensive B +effects O +. O + +Antiparkinsonian O +effects O +of O +levodopa O +temporally O +correlated O +with O +blood O +pressure O +changes O +. O + +Phenylalanine O +, O +a O +large O +neutral O +amino O +acid O +( O +LNAA O +) O +competing O +with O +levodopa O +for O +transport O +across O +the O +blood O +- O +brain O +barrier O +, O +reduced O +the O +hypotensive B +and O +antiparkinsonian O +effects O +of O +levodopa O +. O + +We O +conclude O +that O +levodopa O +has O +a O +central O +hypotensive B +action O +that O +parallels O +the O +motor O +effects O +in O +fluctuating O +patients O +. O + +The O +hypotensive B +effect O +appears O +to O +be O +related O +to O +the O +higher O +baseline O +blood O +pressure O +we O +observed O +in O +fluctuating O +patients O +relative O +to O +stable O +patients O +. O + +Syndrome B +of I +inappropriate I +secretion I +of I +antidiuretic I +hormone I +after O +infusional O +vincristine O +. O + +A O +77 O +- O +year O +- O +old O +woman O +with O +refractory O +multiple B +myeloma I +was O +treated O +with O +a O +4 O +- O +day O +continuous O +intravenous O +infusion O +of O +vincristine O +and O +doxorubicin O +and O +4 O +days O +of O +oral O +dexamethasone O +. O + +Nine O +days O +after O +her O +second O +cycle O +she O +presented O +with O +lethargy B +and O +weakness B +associated O +with O +hyponatremia B +. O + +Evaluation O +revealed O +the O +syndrome B +of I +inappropriate I +secretion I +of I +antidiuretic I +hormone I +, O +which O +was O +attributed O +to O +the O +vincristine O +infusion O +. O + +After O +normal O +serum O +sodium O +levels O +returned O +, O +further O +doxorubicin O +and O +dexamethasone O +chemotherapy O +without O +vincristine O +did O +not O +produce O +this O +complication O +. O + +Heart B +failure I +: O +to O +digitalise O +or O +not O +? O + +The O +view O +against O +. O + +Despite O +extensive O +clinical O +experience O +the O +role O +of O +digoxin O +is O +still O +not O +well O +defined O +. O + +In O +patients O +with O +atrial B +fibrillation I +digoxin O +is O +beneficial O +for O +ventricular O +rate O +control O +. O + +For O +patients O +in O +sinus O +rhythm O +and O +heart B +failure I +the O +situation O +is O +less O +clear O +. O + +Digoxin O +has O +a O +narrow O +therapeutic O +: O +toxic O +ratio O +and O +concentrations O +are O +affected O +by O +a O +number O +of O +drugs O +. O + +Also O +, O +digoxin O +has O +undesirable O +effects O +such O +as O +increasing O +peripheral O +resistance O +and O +myocardial O +demands O +, O +and O +causing O +arrhythmias B +. O + +There O +is O +a O +paucity O +of O +data O +from O +well O +- O +designed O +trials O +. O + +The O +trials O +that O +are O +available O +are O +generally O +small O +with O +limitations O +in O +design O +and O +these O +show O +variation O +in O +patient O +benefit O +. O + +More O +convincing O +evidence O +is O +required O +showing O +that O +digoxin O +improves O +symptoms O +or O +exercise O +capacity O +. O + +Furthermore O +, O +no O +trial O +has O +had O +sufficient O +power O +to O +evaluate O +mortality O +. O + +Pooled O +analysis O +of O +the O +effects O +of O +other O +inotropic O +drugs O +shows O +an O +excess O +mortality O +and O +there O +is O +a O +possibility O +that O +digoxin O +may O +increase O +mortality O +after O +myocardial B +infarction I +( O +MI B +) O +. O + +Angiotensin O +- O +converting O +enzyme O +( O +ACE O +) O +inhibitors O +should O +be O +used O +first O +as O +they O +are O +safer O +, O +do O +not O +require O +blood O +level O +monitoring O +, O +modify O +progression O +of O +disease O +, O +relieve O +symptoms O +, O +improve O +exercise O +tolerance O +and O +reduce O +mortality O +. O + +Caution O +should O +be O +exercised O +in O +using O +digoxin O +until O +large O +mortality O +trials O +are O +completed O +showing O +either O +benefit O +or O +harm O +. O + +Until O +then O +digoxin O +should O +be O +considered O +a O +third O +- O +line O +therapy O +. O + +Isradipine O +treatment O +for O +hypertension B +in O +general O +practice O +in O +Hong O +Kong O +. O + +A O +6 O +- O +week O +open O +study O +of O +the O +introduction O +of O +isradipine O +treatment O +was O +conducted O +in O +general O +practice O +in O +Hong O +Kong O +. O + +303 O +Chinese O +patients O +with O +mild O +to O +moderate O +hypertension B +entered O +the O +study O +. O + +Side O +effects O +were O +reported O +in O +21 O +% O +of O +patients O +and O +caused O +withdrawal O +from O +the O +study O +in O +3 O +patients O +. O + +The O +main O +side O +- O +effects O +were O +headache B +, O +dizziness B +, O +palpitation B +and O +flushing B +and O +these O +were O +not O +more O +frequent O +than O +reported O +in O +other O +studies O +with O +isradipine O +or O +with O +placebo O +. O + +Supine O +blood O +pressure O +was O +reduced O +( O +P O +less O +than O +0 O +. O +01 O +) O +from O +170 O ++ O +/ O +- O +20 O +/ O +102 O ++ O +/ O +- O +6 O +mmHg O +to O +153 O ++ O +/ O +- O +19 O +/ O +92 O ++ O +/ O +- O +8 O +, O +147 O ++ O +/ O +- O +18 O +/ O +88 O ++ O +/ O +- O +7 O +and O +144 O ++ O +/ O +- O +14 O +/ O +87 O ++ O +/ O +- O +6 O +mmHg O +at O +2 O +, O +4 O +and O +6 O +weeks O +respectively O +in O +evaluable O +patients O +. O + +Similar O +reductions O +occurred O +in O +standing O +blood O +pressure O +and O +there O +was O +no O +evidence O +of O +postural B +hypotension B +. O + +Normalization O +and O +responder O +rates O +at O +6 O +weeks O +were O +86 O +% O +and O +69 O +% O +respectively O +. O + +Dosage O +was O +increased O +from O +2 O +. O +5 O +mg O +b O +. O +d O +. O +to O +5 O +mg O +b O +. O +d O +. O +at O +4 O +weeks O +in O +patients O +with O +diastolic O +blood O +pressure O +greater O +than O +90 O +mmHg O +and O +their O +further O +response O +was O +greater O +than O +those O +remaining O +on O +2 O +. O +5 O +mg O +b O +. O +d O +. O + +Pharmacological O +characteristics O +and O +side O +effects O +of O +a O +new O +galenic O +formulation O +of O +propofol O +without O +soyabean O +oil O +. O + +We O +compared O +the O +pharmacokinetics O +, O +pharmacodynamics O +and O +safety O +profile O +of O +a O +new O +galenic O +formulation O +of O +propofol O +( O +AM149 O +1 O +% O +) O +, O +which O +does O +not O +contain O +soyabean O +oil O +, O +with O +a O +standard O +formulation O +of O +propofol O +( O +Disoprivan O +1 O +% O +) O +. O + +In O +a O +randomised O +, O +double O +- O +blind O +, O +cross O +- O +over O +study O +, O +30 O +healthy O +volunteers O +received O +a O +single O +intravenous O +bolus O +injection O +of O +2 O +. O +5 O +mg O +. O +kg O +- O +1 O +propofol O +. O + +Plasma O +propofol O +levels O +were O +measured O +for O +48 O +h O +following O +drug O +administration O +and O +evaluated O +according O +to O +a O +three O +- O +compartment O +model O +. O + +The O +pharmacodynamic O +parameters O +assessed O +included O +induction O +and O +emergence O +times O +, O +respiratory O +and O +cardiovascular O +effects O +, O +and O +pain B +on O +injection O +. O + +Patients O +were O +monitored O +for O +side O +effects O +over O +48 O +h O +. O + +Owing O +to O +a O +high O +incidence O +of O +thrombophlebitis B +, O +the O +study O +was O +terminated O +prematurely O +and O +only O +the O +data O +of O +the O +two O +parallel O +treatment O +groups O +( O +15 O +patients O +in O +each O +group O +) O +were O +analysed O +. O + +Plasma O +concentrations O +did O +not O +differ O +significantly O +between O +the O +two O +formulations O +. O + +Anaesthesia O +induction O +and O +emergence O +times O +, O +respiratory O +and O +cardiovascular O +variables O +showed O +no O +significant O +differences O +between O +the O +two O +treatment O +groups O +. O + +Pain B +on O +injection O +( O +80 O +vs O +. O +20 O +% O +, O +p O +< O +0 O +. O +01 O +) O +and O +thrombophlebitis B +( O +93 O +. O +3 O +vs O +. O +6 O +. O +6 O +% O +, O +p O +< O +0 O +. O +001 O +) O +occurred O +more O +frequently O +with O +AM149 O +than O +with O +Disoprivan O +. O + +Although O +both O +formulations O +had O +similar O +pharmacokinetic O +and O +pharmacodynamic O +profiles O +the O +new O +formulation O +is O +not O +suitable O +for O +clinical O +use O +due O +to O +the O +high O +incidence O +of O +thrombophlebitis B +produced O +. O + +Pure B +red I +cell I +aplasia I +, O +toxic B +dermatitis I +and O +lymphadenopathy B +in O +a O +patient O +taking O +diphenylhydantoin O +. O + +A O +patient O +taking O +diphenylhydantoin O +for O +3 O +weeks O +developed O +a O +generalized O +skin B +rash I +, O +lymphadenopathy B +and O +pure B +red B +cell I +aplasia I +. O + +After O +withdrawal O +of O +the O +pharmacon O +all O +symptoms O +disappeared O +spontaneously O +. O + +Skin B +rash I +is O +a O +well O +- O +known O +complication O +of O +diphenylhydantoin O +treatment O +as O +is O +benign B +and I +malignant I +lymphadenopathy I +. O + +Pure B +red I +cell I +aplasia I +associated O +with O +diphenylhydantoin O +medication O +has O +been O +reported O +in O +3 O +patients O +. O + +The O +exact O +mechanism O +by O +which O +diphenylhydantoin O +exerts O +its O +toxic O +effects O +is O +not O +known O +. O + +In O +this O +patient O +the O +time O +relation O +between O +the O +ingestion O +of O +diphenylhydantoin O +and O +the O +occurrence O +of O +the O +skin B +rash I +, O +lymphadenopathy B +and O +pure B +red I +cell I +aplasia I +is O +very O +suggestive O +of O +a O +direct O +connection O +. O + +Vinorelbine O +- O +related O +cardiac O +events O +: O +a O +meta O +- O +analysis O +of O +randomized O +clinical O +trials O +. O + +Several O +cases O +of O +cardiac B +adverse O +reactions O +related O +to O +vinorelbine O +( O +VNR O +) O +have O +been O +reported O +in O +the O +literature O +. O + +In O +order O +to O +quantify O +the O +incidence O +of O +these O +cardiac O +events O +, O +we O +performed O +a O +meta O +- O +analysis O +of O +clinical O +trials O +comparing O +VNR O +with O +other O +chemotherapeutic O +agents O +in O +the O +treatment O +of O +various O +malignancies B +. O + +Randomized O +clinical O +trials O +comparing O +VNR O +with O +other O +drugs O +in O +the O +treatment O +of O +cancer B +were O +searched O +in O +Medline O +, O +Embase O +, O +Evidence O +- O +based O +Medicine O +Reviews O +databases O +and O +the O +Cochrane O +library O +from O +1987 O +to O +2002 O +. O + +Outcomes O +of O +interest O +were O +severe O +cardiac O +events O +, O +toxic O +deaths O +and O +cardiac O +event O +- O +related O +deaths B +reported O +in O +each O +publication O +. O + +We O +found O +19 O +trials O +, O +involving O +2441 O +patients O +treated O +by O +VNR O +and O +2050 O +control O +patients O +. O + +The O +incidence O +of O +cardiac O +events O +with O +VNR O +was O +1 O +. O +19 O +% O +[ O +95 O +% O +confidence O +interval O +( O +CI O +) O +( O +0 O +. O +75 O +; O +1 O +. O +67 O +) O +] O +. O + +There O +was O +no O +difference O +in O +the O +risk O +of O +cardiac O +events O +between O +VNR O +and O +other O +drugs O +[ O +odds O +ratio O +: O +0 O +. O +92 O +, O +95 O +% O +CI O +( O +0 O +. O +54 O +; O +1 O +. O +55 O +) O +] O +. O + +The O +risk O +of O +VNR O +cardiac O +events O +was O +similar O +to O +vindesine O +( O +VDS O +) O +and O +other O +cardiotoxic B +drugs O +[ O +fluorouracil O +, O +anthracyclines O +, O +gemcitabine O +( O +GEM O +) O +em O +leader O +] O +. O + +Even O +if O +it O +did O +not O +reach O +statistical O +significance O +because O +of O +a O +few O +number O +of O +cases O +, O +the O +risk O +was O +lower O +in O +trials O +excluding O +patients O +with O +cardiac O +history O +, O +and O +seemed O +to O +be O +higher O +in O +trials O +including O +patients O +with O +pre O +- O +existing O +cardiac B +diseases I +. O + +Vinorelbine O +- O +related O +cardiac B +events O +concern O +about O +1 O +% O +of O +treated O +patients O +in O +clinical O +trials O +. O + +However O +, O +the O +risk O +associated O +with O +VNR O +seems O +to O +be O +similar O +to O +that O +of O +other O +chemotherapeutic O +agents O +in O +the O +same O +indications O +. O + +MRI O +findings O +of O +hypoxic B +cortical O +laminar I +necrosis I +in O +a O +child O +with O +hemolytic B +anemia I +crisis O +. O + +We O +present O +magnetic O +resonance O +imaging O +findings O +of O +a O +5 O +- O +year O +- O +old O +girl O +who O +had O +a O +rapidly O +installing O +hemolytic B +anemia I +crisis O +induced O +by O +trimethoprim O +- O +sulfomethoxazole O +, O +resulting O +in O +cerebral B +anoxia I +leading O +to O +permanent O +damage O +. O + +Magnetic O +Resonance O +imaging O +revealed O +cortical O +laminar O +necrosis B +in O +arterial O +border O +zones O +in O +both O +cerebral O +hemispheres O +, O +ischemic B +changes O +in O +subcortical O +white O +matter O +of O +left O +cerebral O +hemisphere O +, O +and O +in O +the O +left O +putamen O +. O + +Although O +cortical B +laminar I +necrosis I +is O +a O +classic O +entity O +in O +adulthood O +related O +to O +conditions O +of O +energy O +depletions O +, O +there O +are O +few O +reports O +available O +in O +children O +. O + +A O +wide O +review O +of O +the O +literature O +is O +also O +presented O +. O + +The O +natural O +history O +of O +Vigabatrin O +associated O +visual B +field I +defects I +in O +patients O +electing O +to O +continue O +their O +medication O +. O + +PURPOSE O +: O +To O +determine O +the O +natural O +history O +of O +visual B +field I +defects I +in O +a O +group O +of O +patients O +known O +to O +have O +Vigabatrin O +- O +associated O +changes O +who O +elected O +to O +continue O +the O +medication O +because O +of O +good O +seizure B +control O +. O + +METHODS O +: O +All O +patients O +taking O +Vigabatrin O +alone O +or O +in O +combination O +with O +other O +antiepileptic O +drugs O +for O +at O +least O +5 O +years O +( O +range O +5 O +- O +12 O +years O +) O +were O +entered O +into O +a O +visual O +surveillance O +programme O +. O + +Patients O +were O +followed O +up O +at O +6 O +- O +monthly O +intervals O +for O +not O +less O +than O +18 O +months O +( O +range O +18 O +- O +43 O +months O +) O +. O + +In O +all O +, O +16 O +patients O +with O +unequivocal O +defects O +continued O +the O +medication O +. O + +Following O +already O +published O +methodology O +( O +Eye O +2002 O +; O +16 O +; O +567 O +- O +571 O +) O +monocular O +mean O +radial O +degrees O +( O +MRDs O +) O +to O +the O +I O +/ O +4e O +isopter O +on O +Goldmann O +perimetry O +was O +calculated O +for O +the O +right O +eye O +at O +the O +time O +of O +discovery O +of O +a O +visual B +field I +defect I +and O +again O +after O +not O +less O +than O +18 O +months O +follow O +- O +up O +. O + +RESULTS O +: O +Mean O +right O +eye O +MRD O +at O +presentation O +was O +36 O +. O +98 O +degrees O +( O +range O +22 O +. O +25 O +- O +51 O +. O +0 O +) O +, O +compared O +to O +38 O +. O +40 O +degrees O +( O +range O +22 O +. O +5 O +- O +49 O +. O +75 O +) O +after O +follow O +- O +up O +; O +P O += O +0 O +. O +338 O +unpaired O +t O +- O +test O +. O + +Only O +one O +patient O +demonstrated O +a O +deterioration O +in I +visual I +field I +during O +the O +study O +period O +and O +discontinued O +treatment O +. O + +CONCLUSION O +: O +Established O +visual B +field I +defects I +presumed O +to O +be O +due O +to O +Vigabatrin O +therapy O +did O +not O +usually O +progress O +in O +spite O +of O +continuing O +use O +of O +the O +medication O +. O + +These O +data O +give O +support O +to O +the O +hypothesis O +that O +the O +pathogenesis O +of O +Vigabatrin O +- O +associated O +visual B +field I +defects I +may O +be O +an O +idiosyncratic O +adverse O +drug O +reaction O +rather O +than O +dose O +- O +dependent O +toxicity B +. O + +Induction O +of O +rosaceiform O +dermatitis B +during O +treatment O +of O +facial O +inflammatory I +dermatoses I +with O +tacrolimus O +ointment O +. O + +BACKGROUND O +: O +Tacrolimus O +ointment O +is O +increasingly O +used O +for O +anti O +- O +inflammatory O +treatment O +of O +sensitive O +areas O +such O +as O +the O +face O +, O +and O +recent O +observations O +indicate O +that O +the O +treatment O +is O +effective O +in O +steroid O +- O +aggravated O +rosacea B +and O +perioral B +dermatitis I +. O + +We O +report O +on O +rosaceiform O +dermatitis B +as O +a O +complication O +of O +treatment O +with O +tacrolimus O +ointment O +. O + +OBSERVATIONS O +: O +Six O +adult O +patients O +with O +inflammatory O +facial I +dermatoses I +were O +treated O +with O +tacrolimus O +ointment O +because O +of O +the O +ineffectiveness O +of O +standard O +treatments O +. O + +Within O +2 O +to O +3 O +weeks O +of O +initially O +effective O +and O +well O +- O +tolerated O +treatment O +, O +3 O +patients O +with O +a O +history O +of O +rosacea B +and O +1 O +with O +a O +history O +of O +acne B +experienced O +sudden O +worsening O +with O +pustular B +rosaceiform I +lesions I +. O + +Biopsy O +revealed O +an O +abundance O +of O +Demodex O +mites O +in O +2 O +of O +these O +patients O +. O + +In O +1 O +patient O +with O +eyelid B +eczema I +, O +rosaceiform O +periocular O +dermatitis I +gradually O +appeared O +after O +3 O +weeks O +of O +treatment O +. O + +In O +1 O +patient O +with O +atopic B +dermatitis I +, O +telangiectatic B +and I +papular I +rosacea I +insidiously O +appeared O +after O +5 O +months O +of O +treatment O +. O + +CONCLUSIONS O +: O +Our O +observations O +suggest O +that O +the O +spectrum O +of O +rosaceiform O +dermatitis B +as O +a O +complication O +of O +treatment O +with O +tacrolimus O +ointment O +is O +heterogeneous O +. O + +A O +variety O +of O +factors O +, O +such O +as O +vasoactive O +properties O +of O +tacrolimus O +, O +proliferation O +of O +Demodex O +due O +to O +local O +immunosuppression O +, O +and O +the O +occlusive O +properties O +of O +the O +ointment O +, O +may O +be O +involved O +in O +the O +observed O +phenomena O +. O + +Future O +studies O +are O +needed O +to O +identify O +individual O +risk O +factors O +. O + +Intravascular B +hemolysis B +and O +acute B +renal I +failure I +following O +intermittent O +rifampin O +therapy O +. O + +Renal B +failure I +is O +a O +rare O +complication O +associated O +with O +the O +use O +of O +rifampin O +. O + +Intravascular B +hemolysis B +leading O +to O +acute B +renal I +failure I +following O +rifampin O +therapy O +is O +extremely O +rare O +. O + +Two O +patients O +with O +leprosy B +who O +developed O +hemolysis B +and O +acute B +renal I +failure I +following O +rifampin O +are O +reported O +. O + +Structural B +abnormalities I +in O +the O +brains O +of O +human O +subjects O +who O +use O +methamphetamine O +. O + +We O +visualize O +, O +for O +the O +first O +time O +, O +the O +profile O +of O +structural O +deficits I +in O +the O +human O +brain O +associated O +with O +chronic O +methamphetamine O +( O +MA O +) O +abuse O +. O + +Studies O +of O +human O +subjects O +who O +have O +used O +MA O +chronically O +have O +revealed O +deficits B +in I +dopaminergic I +and O +serotonergic I +systems I +and O +cerebral B +metabolic I +abnormalities I +. O + +Using O +magnetic O +resonance O +imaging O +( O +MRI O +) O +and O +new O +computational O +brain O +- O +mapping O +techniques O +, O +we O +determined O +the O +pattern O +of O +structural O +brain O +alterations O +associated O +with O +chronic O +MA B +abuse I +in O +human O +subjects O +and O +related O +these O +deficits O +to O +cognitive B +impairment I +. O + +We O +used O +high O +- O +resolution O +MRI O +and O +surface O +- O +based O +computational O +image O +analyses O +to O +map O +regional O +abnormalities O +in O +the O +cortex O +, O +hippocampus O +, O +white O +matter O +, O +and O +ventricles O +in O +22 O +human O +subjects O +who O +used O +MA O +and O +21 O +age O +- O +matched O +, O +healthy O +controls O +. O + +Cortical O +maps O +revealed O +severe O +gray B +- I +matter I +deficits I +in O +the O +cingulate O +, O +limbic O +, O +and O +paralimbic O +cortices O +of O +MA B +abusers O +( O +averaging O +11 O +. O +3 O +% O +below O +control O +; O +p O +< O +0 O +. O +05 O +) O +. O + +On O +average O +, O +MA O +abusers O +had O +7 O +. O +8 O +% O +smaller O +hippocampal O +volumes O +than O +control O +subjects O +( O +p O +< O +0 O +. O +01 O +; O +left O +, O +p O += O +0 O +. O +01 O +; O +right O +, O +p O +< O +0 O +. O +05 O +) O +and O +significant O +white B +- I +matter I +hypertrophy I +( O +7 O +. O +0 O +% O +; O +p O +< O +0 O +. O +01 O +) O +. O + +Hippocampal B +deficits I +were O +mapped O +and O +correlated O +with O +memory O +performance O +on O +a O +word O +- O +recall O +test O +( O +p O +< O +0 O +. O +05 O +) O +. O + +MRI O +- O +based O +maps O +suggest O +that O +chronic O +methamphetamine O +abuse O +causes O +a O +selective O +pattern O +of O +cerebral B +deterioration I +that O +contributes O +to O +impaired B +memory I +performance I +. O + +MA O +may O +selectively O +damage O +the O +medial O +temporal O +lobe O +and O +, O +consistent O +with O +metabolic O +studies O +, O +the O +cingulate O +- O +limbic O +cortex O +, O +inducing O +neuroadaptation O +, O +neuropil O +reduction O +, O +or O +cell O +death O +. O + +Prominent O +white B +- I +matter I +hypertrophy I +may O +result O +from O +altered O +myelination O +and O +adaptive O +glial O +changes O +, O +including O +gliosis B +secondary O +to O +neuronal B +damage I +. O + +These O +brain O +substrates O +may O +help O +account O +for O +the O +symptoms O +of O +MA B +abuse I +, O +providing O +therapeutic O +targets O +for O +drug O +- O +induced O +brain B +injury I +. O + +Disruption O +of O +hepatic O +lipid O +homeostasis O +in O +mice O +after O +amiodarone O +treatment O +is O +associated O +with O +peroxisome O +proliferator O +- O +activated O +receptor O +- O +alpha O +target O +gene O +activation O +. O + +Amiodarone O +, O +an O +efficacious O +and O +widely O +used O +antiarrhythmic O +agent O +, O +has O +been O +reported O +to O +cause O +hepatotoxicity B +in O +some O +patients O +. O + +To O +gain O +insight O +into O +the O +mechanism O +of O +this O +unwanted O +effect O +, O +mice O +were O +administered O +various O +doses O +of O +amiodarone O +and O +examined O +for O +changes O +in O +hepatic O +histology O +and O +gene O +regulation O +. O + +Amiodarone O +induced O +hepatomegaly B +, O +hepatocyte O +microvesicular O +lipid O +accumulation O +, O +and O +a O +significant O +decrease O +in O +serum O +triglycerides O +and O +glucose O +. O + +Northern O +blot O +analysis O +of O +hepatic O +RNA O +revealed O +a O +dose O +- O +dependent O +increase O +in O +the O +expression O +of O +a O +number O +of O +genes O +critical O +for O +fatty O +acid O +oxidation O +, O +lipoprotein O +assembly O +, O +and O +lipid O +transport O +. O + +Many O +of O +these O +genes O +are O +regulated O +by O +the O +peroxisome O +proliferator O +- O +activated O +receptor O +- O +alpha O +( O +PPARalpha O +) O +, O +a O +ligand O +- O +activated O +nuclear O +hormone O +receptor O +transcription O +factor O +. O + +The O +absence O +of O +induction O +of O +these O +genes O +as O +well O +as O +hepatomegaly B +in O +PPARalpha O +knockout O +[ O +PPARalpha O +- O +/ O +- O +] O +mice O +indicated O +that O +the O +effects O +of O +amiodarone O +were O +dependent O +upon O +the O +presence O +of O +a O +functional O +PPARalpha O +gene O +. O + +Compared O +to O +wild O +- O +type O +mice O +, O +treatment O +of O +PPARalpha O +- O +/ O +- O +mice O +with O +amiodarone O +resulted O +in O +an O +increased O +rate O +and O +extent O +of O +total O +body O +weight B +loss I +. O + +The O +inability O +of O +amiodarone O +to O +directly O +activate O +either O +human O +or O +mouse O +PPARalpha O +transiently O +expressed O +in O +human O +HepG2 O +hepatoma B +cells O +indicates O +that O +the O +effects O +of O +amiodarone O +on O +the O +function O +of O +this O +receptor O +were O +indirect O +. O + +Based O +upon O +these O +results O +, O +we O +conclude O +that O +amiodarone O +disrupts O +hepatic O +lipid O +homeostasis O +and O +that O +the O +increased O +expression O +of O +PPARalpha O +target O +genes O +is O +secondary O +to O +this O +toxic O +effect O +. O + +These O +results O +provide O +important O +new O +mechanistic O +information O +regarding O +the O +hepatotoxic B +effects O +of O +amiodarone O +and O +indicate O +that O +PPARalpha O +protects O +against O +amiodarone O +- O +induced O +hepatotoxicity B +. O + +Safety O +and O +compliance O +with O +once O +- O +daily O +niacin O +extended O +- O +release O +/ O +lovastatin O +as O +initial O +therapy O +in O +the O +Impact O +of O +Medical O +Subspecialty O +on O +Patient O +Compliance O +to O +Treatment O +( O +IMPACT O +) O +study O +. O + +Niacin O +extended O +- O +release O +/ O +lovastatin O +is O +a O +new O +combination O +product O +approved O +for O +treatment O +of O +primary O +hypercholesterolemia B +and O +mixed O +dyslipidemia B +. O + +This O +open O +- O +labeled O +, O +multicenter O +study O +evaluated O +the O +safety O +of O +bedtime O +niacin O +extended O +- O +release O +/ O +lovastatin O +when O +dosed O +as O +initial O +therapy O +and O +patient O +compliance O +to O +treatment O +in O +various O +clinical O +practice O +settings O +. O + +A O +total O +of O +4 O +, O +499 O +patients O +with O +dyslipidemia B +requiring O +drug O +intervention O +was O +enrolled O +at O +1 O +, O +081 O +sites O +. O + +Patients O +were O +treated O +with O +1 O +tablet O +( O +500 O +mg O +of O +niacin O +extended O +- O +release O +/ O +20 O +mg O +of O +lovastatin O +) O +once O +nightly O +for O +4 O +weeks O +and O +then O +2 O +tablets O +for O +8 O +weeks O +. O + +Patients O +also O +received O +dietary O +counseling O +, O +educational O +materials O +, O +and O +reminders O +to O +call O +a O +toll O +- O +free O +number O +that O +provided O +further O +education O +about O +dyslipidemia B +and O +niacin O +extended O +- O +release O +/ O +lovastatin O +. O + +Primary O +end O +points O +were O +study O +compliance O +, O +increases O +in O +liver O +transaminases O +to O +> O +3 O +times O +the O +upper O +limit O +of O +normal O +, O +and O +clinical O +myopathy B +. O + +Final O +study O +status O +was O +available O +for O +4 O +, O +217 O +patients O +( O +94 O +% O +) O +. O + +Compliance O +to O +niacin O +extended O +- O +release O +/ O +lovastatin O +was O +77 O +% O +, O +with O +3 O +, O +245 O +patients O +completing O +the O +study O +. O + +Patients O +in O +the O +southeast O +and O +those O +enrolled O +by O +endocrinologists O +had O +the O +lowest O +compliance O +and O +highest O +adverse O +event O +rates O +. O + +Flushing B +was O +the O +most O +common O +adverse O +event O +, O +reported O +by O +18 O +% O +of O +patients O +and O +leading O +to O +discontinuation O +by O +6 O +% O +. O + +Incidence O +of O +increased O +aspartate O +aminotransferase O +and O +/ O +or O +alanine O +aminotransferase O +> O +3 O +times O +the O +upper O +limit O +of O +normal O +was O +< O +0 O +. O +3 O +% O +. O + +An O +increase O +of O +creatine O +phosphokinase O +to O +> O +5 O +times O +the O +upper O +limit O +of O +normal O +occurred O +in O +0 O +. O +24 O +% O +of O +patients O +, O +and O +no O +cases O +of O +drug O +- O +induced O +myopathy B +were O +observed O +. O + +Niacin O +extended O +- O +release O +/ O +lovastatin O +1 O +, O +000 O +/ O +40 O +mg O +, O +dosed O +as O +initial O +therapy O +, O +was O +associated O +with O +good O +compliance O +and O +safety O +and O +had O +very O +low O +incidences O +of O +increased O +liver O +and O +muscle O +enzymes O +. O + +Protective O +effect O +of O +Terminalia O +chebula O +against O +experimental O +myocardial B +injury I +induced O +by O +isoproterenol O +. O + +Cardioprotective O +effect O +of O +ethanolic O +extract O +of O +Terminalia O +chebula O +fruits O +( O +500 O +mg O +/ O +kg O +body O +wt O +) O +was O +examined O +in O +isoproterenol O +( O +200 O +mg O +/ O +kg O +body O +wt O +) O +induced O +myocardial B +damage I +in O +rats O +. O + +In O +isoproterenol O +administered O +rats O +, O +the O +level O +of O +lipid O +peroxides O +increased O +significantly O +in O +the O +serum O +and O +heart O +. O + +A O +significant O +decrease O +was O +observed O +in O +the O +activity O +of O +the O +myocardial O +marker O +enzymes O +with O +a O +concomitant O +increase O +in O +their O +activity O +in O +serum O +. O + +Histopathological O +examination O +was O +carried O +out O +to O +confirm O +the O +myocardial B +necrosis I +. O + +T O +. O +chebula O +extract O +pretreatment O +was O +found O +to O +ameliorate O +the O +effect O +of O +isoproterenol O +on O +lipid O +peroxide O +formation O +and O +retained O +the O +activities O +of O +the O +diagnostic O +marker O +enzymes O +. O + +A O +case O +of O +postoperative B +anxiety I +due O +to O +low O +dose O +droperidol O +used O +with O +patient O +- O +controlled O +analgesia O +. O + +A O +multiparous O +woman O +in O +good O +psychological O +health O +underwent O +urgent O +caesarean O +section O +in O +labour O +. O + +Postoperatively O +, O +she O +was O +given O +a O +patient O +- O +controlled O +analgesia O +device O +delivering O +boluses O +of O +diamorphine O +0 O +. O +5 O +mg O +and O +droperidol O +0 O +. O +025 O +mg O +. O + +Whilst O +using O +the O +device O +she O +gradually O +became O +anxious B +, O +the O +feeling O +worsening O +after O +each O +bolus O +. O + +The O +diagnosis O +of O +droperidol O +- O +induced O +psychological B +disturbance I +was O +not O +made O +straight O +away O +although O +on O +subsequent O +close O +questioning O +the O +patient O +gave O +a O +very O +clear O +history O +. O + +After O +she O +had O +received O +a O +total O +of O +only O +0 O +. O +9 O +mg O +droperidol O +, O +a O +syringe O +containing O +diamorphine O +only O +was O +substituted O +and O +her O +unease B +resolved O +completely O +. O + +We O +feel O +that O +, O +although O +the O +dramatic O +extrapyramidal O +side O +effects O +of O +dopaminergic O +antiemetics O +are O +well O +known O +, O +more O +subtle O +manifestations O +may O +easily O +be O +overlooked O +. O + +Accurate O +patient O +history O +contributes O +to O +differentiating O +diabetes B +insipidus I +: O +a O +case O +study O +. O + +This O +case O +study O +highlights O +the O +important O +contribution O +of O +nursing O +in O +obtaining O +an O +accurate O +health O +history O +. O + +The O +case O +discussed O +herein O +initially O +appeared O +to O +be O +neurogenic B +diabetes I +insipidus I +( O +DI B +) O +secondary O +to O +a O +traumatic B +brain I +injury I +. O + +The O +nursing O +staff O +, O +by O +reviewing O +the O +patient O +' O +s O +health O +history O +with O +his O +family O +, O +discovered O +a O +history O +of O +polydipsia B +and O +long O +- O +standing O +lithium O +use O +. O + +Lithium O +is O +implicated O +in O +drug O +- O +induced O +nephrogenic B +DI I +, O +and O +because O +the O +patient O +had O +not O +received O +lithium O +since O +being O +admitted O +to O +the O +hospital O +, O +his O +treatment O +changed O +to O +focus O +on O +nephrogenic B +DI I +. O + +By O +combining O +information O +from O +the O +patient O +history O +, O +the O +physical O +examination O +, O +and O +radiologic O +and O +laboratory O +studies O +, O +the O +critical O +care O +team O +demonstrated O +that O +the O +patient O +had O +been O +self O +- O +treating O +his O +lithium O +- O +induced O +nephrogenic B +DI I +and O +developed O +neurogenic B +DI I +secondary O +to O +brain B +trauma I +. O + +Thus O +successful O +treatment O +required O +that O +nephrogenic B +and I +neurogenic I +DI I +be O +treated O +concomitantly O +. O + +Factors O +contributing O +to O +ribavirin O +- O +induced O +anemia B +. O + +BACKGROUND O +AND O +AIM O +: O +Interferon O +and O +ribavirin O +combination O +therapy O +for O +chronic B +hepatitis I +C I +produces O +hemolytic B +anemia I +. O + +This O +study O +was O +conducted O +to O +identify O +the O +factors O +contributing O +to O +ribavirin O +- O +induced O +anemia B +. O + +METHODS O +: O +Eighty O +- O +eight O +patients O +with O +chronic B +hepatitis I +C I +who O +received O +interferon O +- O +alpha O +- O +2b O +at O +a O +dose O +of O +6 O +MU O +administered O +intramuscularly O +for O +24 O +weeks O +in O +combination O +with O +ribavirin O +administered O +orally O +at O +a O +dose O +of O +600 O +mg O +or O +800 O +mg O +participated O +in O +the O +study O +. O + +A O +hemoglobin O +concentration O +of O +< O +10 O +g O +/ O +dL O +was O +defined O +as O +ribavirin O +- O +induced O +anemia B +. O + +RESULTS O +: O +Ribavirin O +- O +induced O +anemia B +occurred O +in O +18 O +( O +20 O +. O +5 O +% O +) O +patients O +during O +treatment O +. O + +A O +2 O +g O +/ O +dL O +decrease O +in O +hemoglobin O +concentrations O +in O +patients O +with O +anemia B +was O +observed O +at O +week O +2 O +after O +the O +start O +of O +treatment O +. O + +The O +hemoglobin O +concentration O +in O +patients O +with O +> O +or O += O +2 O +g O +/ O +dL O +decrease O +at O +week O +2 O +was O +observed O +to O +be O +significantly O +lower O +even O +after O +week O +2 O +than O +in O +patients O +with O +< O +2 O +g O +/ O +dL O +decrease O +( O +P O +< O +0 O +. O +01 O +) O +. O + +A O +significant O +relationship O +was O +observed O +between O +the O +rate O +of O +reduction O +of O +hemoglobin O +concentrations O +at O +week O +2 O +and O +the O +severity O +of O +anemia B +( O +P O +< O +0 O +. O +01 O +) O +. O + +Such O +factors O +as O +sex O +( O +female O +) O +, O +age O +( O +> O +or O += O +60 O +years O +old O +) O +, O +and O +the O +ribavirin O +dose O +by O +body O +weight O +( O +12 O +mg O +/ O +kg O +or O +more O +) O +were O +significant O +by O +univariate O +analysis O +. O + +CONCLUSIONS O +: O +Careful O +administration O +is O +necessary O +in O +patients O +> O +or O += O +60 O +years O +old O +, O +in O +female O +patients O +, O +and O +in O +patients O +receiving O +a O +ribavirin O +dose O +of O +12 O +mg O +/ O +kg O +or O +more O +. O + +Patients O +who O +experience O +a O +fall O +in O +hemoglobin O +concentrations O +of O +2 O +g O +/ O +dL O +or O +more O +at O +week O +2 O +after O +the O +start O +of O +treatment O +should O +be O +monitored O +with O +particular O +care O +. O + +Zidovudine O +- O +induced O +hepatitis B +. O + +A O +case O +of O +acute O +hepatitis B +induced O +by O +zidovudine O +in O +a O +38 O +- O +year O +- O +old O +patient O +with O +AIDS B +is O +presented O +. O + +The O +mechanism O +whereby O +the O +hepatitis B +was O +induced O +is O +not O +known O +. O + +However O +, O +the O +patient O +tolerated O +well O +an O +alternative O +reverse O +transcriptase O +inhibitor O +, O +2 O +' O +3 O +' O +dideoxyinosine O +. O + +Physicians O +caring O +for O +patients O +with O +AIDS B +should O +be O +aware O +of O +this O +hitherto O +rarely O +reported O +complication O +. O + +Oxidative O +damage O +precedes O +nitrative O +damage O +in O +adriamycin O +- O +induced O +cardiac B +mitochondrial B +injury I +. O + +The O +purpose O +of O +the O +present O +study O +was O +to O +determine O +if O +elevated O +reactive O +oxygen O +( O +ROS O +) O +/ O +nitrogen O +species O +( O +RNS O +) O +reported O +to O +be O +present O +in O +adriamycin O +( O +ADR O +) O +- O +induced O +cardiotoxicity B +actually O +resulted O +in O +cardiomyocyte O +oxidative O +/ O +nitrative O +damage O +, O +and O +to O +quantitatively O +determine O +the O +time O +course O +and O +subcellular O +localization O +of O +these O +postulated O +damage O +products O +using O +an O +in O +vivo O +approach O +. O + +B6C3 O +mice O +were O +treated O +with O +a O +single O +dose O +of O +20 O +mg O +/ O +kg O +ADR O +. O + +Ultrastructural O +damage O +and O +levels O +of O +4 O +- O +hydroxy O +- O +2 O +- O +nonenal O +( O +4HNE O +) O +- O +protein O +adducts O +and O +3 O +- O +nitrotyrosine O +( O +3NT O +) O +were O +analyzed O +. O + +Quantitative O +ultrastructural O +damage O +using O +computerized O +image O +techniques O +showed O +cardiomyocyte O +injury O +as O +early O +as O +3 O +hours O +, O +with O +mitochondria O +being O +the O +most O +extensively O +and O +progressively O +injured O +subcellular O +organelle O +. O + +Analysis O +of O +4HNE O +protein O +adducts O +by O +immunogold O +electron O +microscopy O +showed O +appearance O +of O +4HNE O +protein O +adducts O +in O +mitochondria O +as O +early O +as O +3 O +hours O +, O +with O +a O +peak O +at O +6 O +hours O +and O +subsequent O +decline O +at O +24 O +hours O +. O + +3NT O +levels O +were O +significantly O +increased O +in O +all O +subcellular O +compartments O +at O +6 O +hours O +and O +subsequently O +declined O +at O +24 O +hours O +. O + +Our O +data O +showed O +ADR O +induced O +4HNE O +- O +protein O +adducts O +in O +mitochondria O +at O +the O +same O +time O +point O +as O +when O +mitochondrial B +injury I +initially O +appeared O +. O + +These O +results O +document O +for O +the O +first O +time O +in O +vivo O +that O +mitochondrial O +oxidative O +damage O +precedes O +nitrative O +damage O +. O + +The O +progressive O +nature O +of O +mitochondrial B +injury I +suggests O +that O +mitochondria O +, O +not O +other O +subcellular O +organelles O +, O +are O +the O +major O +site O +of O +intracellular O +injury O +. O + +Sotalol O +- O +induced O +coronary B +spasm I +in O +a O +patient O +with O +dilated B +cardiomyopathy I +associated O +with O +sustained O +ventricular B +tachycardia I +. O + +A O +54 O +- O +year O +- O +old O +man O +with O +severe O +left B +ventricular I +dysfunction I +due O +to O +dilated B +cardiomyopathy I +was O +referred O +to O +our O +hospital O +for O +symptomatic O +incessant O +sustained O +ventricular B +tachycardia I +( O +VT B +) O +. O + +After O +the O +administration O +of O +nifekalant O +hydrochloride O +, O +sustained O +VT O +was O +terminated O +. O + +An O +alternate O +class O +III O +agent O +, O +sotalol O +, O +was O +also O +effective O +for O +the O +prevention O +of O +VT B +. O + +However O +, O +one O +month O +after O +switching O +over O +nifekalant O +to O +sotalol O +, O +a O +short O +duration O +of O +ST O +elevation O +was O +documented O +in O +ECG O +monitoring O +at O +almost O +the O +same O +time O +for O +three O +consecutive O +days O +. O + +ST O +elevation I +with O +chest B +discomfort I +disappeared O +since O +he O +began O +taking O +long O +- O +acting O +diltiazem O +. O + +Coronary B +vasospasm I +may O +be O +induced O +by O +the O +non O +- O +selective O +beta O +- O +blocking O +properties O +of O +sotalol O +. O + +Effects O +of O +the O +antidepressant O +trazodone O +, O +a O +5 O +- O +HT O +2A O +/ O +2C O +receptor O +antagonist O +, O +on O +dopamine O +- O +dependent O +behaviors O +in O +rats O +. O + +RATIONALE O +: O +5 O +- O +Hydroxytryptamine O +, O +via O +stimulation O +of O +5 O +- O +HT O +2C O +receptors O +, O +exerts O +a O +tonic O +inhibitory O +influence O +on O +dopaminergic O +neurotransmission O +, O +whereas O +activation O +of O +5 O +- O +HT O +2A O +receptors O +enhances O +stimulated O +DAergic O +neurotransmission O +. O + +The O +antidepressant O +trazodone O +is O +a O +5 O +- O +HT O +2A O +/ O +2C O +receptor O +antagonist O +. O + +OBJECTIVES O +: O +To O +evaluate O +the O +effect O +of O +trazodone O +treatment O +on O +behaviors O +dependent O +on O +the O +functional O +status O +of O +the O +nigrostriatal O +DAergic O +system O +. O + +METHODS O +: O +The O +effect O +of O +pretreatment O +with O +trazodone O +on O +dexamphetamine O +- O +and O +apomorphine O +- O +induced O +oral O +stereotypies O +, O +on O +catalepsy B +induced O +by O +haloperidol O +and O +apomorphine O +( O +0 O +. O +05 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +, O +on O +ergometrine O +- O +induced O +wet O +dog O +shake O +( O +WDS O +) O +behavior O +and O +fluoxetine O +- O +induced O +penile O +erections O +was O +studied O +in O +rats O +. O + +We O +also O +investigated O +whether O +trazodone O +induces O +catalepsy B +in O +rats O +. O + +RESULTS O +: O +Trazodone O +at O +2 O +. O +5 O +- O +20 O +mg O +/ O +kg O +i O +. O +p O +. O +did O +not O +induce O +catalepsy B +, O +and O +did O +not O +antagonize O +apomorphine O +( O +1 O +. O +5 O +and O +3 O +mg O +/ O +kg O +) O +stereotypy O +and O +apomorphine O +( O +0 O +. O +05 O +mg O +/ O +kg O +) O +- O +induced O +catalepsy B +. O + +However O +, O +pretreatment O +with O +5 O +, O +10 O +and O +20 O +mg O +/ O +kg O +i O +. O +p O +. O +trazodone O +enhanced O +dexamphetamine O +stereotypy O +, O +and O +antagonized O +haloperidol O +catalepsy B +, O +ergometrine O +- O +induced O +WDS B +behavior O +and O +fluoxetine O +- O +induced O +penile O +erections O +. O + +Trazodone O +at O +30 O +, O +40 O +and O +50 O +mg O +/ O +kg O +i O +. O +p O +. O +induced O +catalepsy B +and O +antagonized O +apomorphine O +and O +dexamphetamine O +stereotypies O +. O + +CONCLUSIONS O +: O +Our O +results O +indicate O +that O +trazodone O +at O +2 O +. O +5 O +- O +20 O +mg O +/ O +kg O +does O +not O +block O +pre O +- O +and O +postsynaptic O +striatal O +D2 O +DA O +receptors O +, O +while O +at O +30 O +, O +40 O +and O +50 O +mg O +/ O +kg O +it O +blocks O +postsynaptic O +striatal O +D2 O +DA O +receptors O +. O + +Furthermore O +, O +at O +5 O +, O +10 O +and O +20 O +mg O +/ O +kg O +, O +trazodone O +blocks O +5 O +- O +HT O +2A O +and O +5 O +- O +HT O +2C O +receptors O +. O + +We O +suggest O +that O +trazodone O +( O +5 O +, O +10 O +and O +20 O +mg O +/ O +kg O +) O +, O +by O +blocking O +the O +5 O +- O +HT O +2C O +receptors O +, O +releases O +the O +nigrostriatal O +DAergic O +neurons O +from O +tonic O +inhibition O +caused O +by O +5 O +- O +HT O +, O +and O +thereby O +potentiates O +dexamphetamine O +stereotypy O +and O +antagonizes O +haloperidol O +catalepsy B +. O + +Swallowing B +abnormalities I +and O +dyskinesia B +in O +Parkinson B +' I +s I +disease I +. O + +Gastrointestinal B +abnormalities I +in O +Parkinson B +' I +s I +disease I +( O +PD B +) O +have O +been O +known O +for O +almost O +two O +centuries O +, O +but O +many O +aspects O +concerning O +their O +pathophysiology O +have O +not O +been O +completely O +clarified O +. O + +The O +aim O +of O +this O +study O +was O +to O +characterize O +the O +oropharyngeal O +dynamics O +in O +PD B +patients O +with O +and O +without O +levodopa O +- O +induced O +dyskinesia B +. O + +Fifteen O +dyskinetic B +, O +12 O +nondyskinetic O +patients O +, O +and O +a O +control O +group O +were O +included O +. O + +Patients O +were O +asked O +about O +dysphagia B +and O +evaluated O +with O +the O +Unified O +Parkinson B +' I +s I +Disease I +Rating O +Scale O +Parts O +II O +and O +III O +and O +the O +Hoehn O +and O +Yahr O +scale O +. O + +Deglutition O +was O +assessed O +using O +modified O +barium O +swallow O +with O +videofluoroscopy O +. O + +Nondyskinetic O +patients O +, O +but O +not O +the O +dyskinetic B +ones O +, O +showed O +less O +oropharyngeal O +swallowing O +efficiency O +( O +OPSE O +) O +for O +liquid O +food O +than O +controls O +( O +Dunnett O +, O +P O += O +0 O +. O +02 O +) O +. O + +Dyskinetic B +patients O +tended O +to O +have O +a O +greater O +OPSE O +than O +nondyskinetic O +( O +Dunnett O +, O +P O += O +0 O +. O +06 O +) O +. O + +Patients O +who O +were O +using O +a O +higher O +dose O +of O +levodopa O +had O +a O +greater O +OPSE O +and O +a O +trend O +toward O +a O +smaller O +oral O +transit O +time O +( O +Pearson O +' O +s O +correlation O +, O +P O += O +0 O +. O +01 O +and O +0 O +. O +08 O +, O +respectively O +) O +. O + +Neither O +the O +report O +of O +dysphagia B +nor O +any O +of O +the O +PD B +severity O +parameters O +correlated O +to O +the O +videofluoroscopic O +variables O +. O + +In O +the O +current O +study O +, O +dyskinetic B +patients O +performed O +better O +in O +swallowing O +function O +, O +which O +could O +be O +explained O +on O +the O +basis O +of O +a O +greater O +levodopa O +dose O +. O + +Our O +results O +suggest O +a O +role O +for O +levodopa O +in O +the O +oral O +phase O +of O +deglutition O +and O +confirm O +that O +dysphagia B +is O +not O +a O +good O +predictor O +of O +deglutition O +alterations O +in O +PD B +. O + +Inhibition O +of O +nuclear O +factor O +- O +kappaB O +activation O +attenuates O +tubulointerstitial B +nephritis I +induced O +by O +gentamicin O +. O + +BACKGROUND O +: O +Animals O +treated O +with O +gentamicin O +can O +show O +residual O +areas O +of O +interstitial B +fibrosis B +in O +the O +renal O +cortex O +. O + +This O +study O +investigated O +the O +expression O +of O +nuclear O +factor O +- O +kappaB O +( O +NF O +- O +kappaB O +) O +, O +mitogen O +- O +activated O +protein O +( O +MAP O +) O +kinases O +and O +macrophages O +in O +the O +renal O +cortex O +and O +structural O +and O +functional O +renal O +changes O +of O +rats O +treated O +with O +gentamicin O +or O +gentamicin O ++ O +pyrrolidine O +dithiocarbamate O +( O +PDTC O +) O +, O +an O +NF O +- O +kappaB O +inhibitor O +. O + +METHODS O +: O +38 O +female O +Wistar O +rats O +were O +injected O +with O +gentamicin O +, O +40 O +mg O +/ O +kg O +, O +twice O +a O +day O +for O +9 O +days O +, O +38 O +with O +gentamicin O ++ O +PDTC O +, O +and O +28 O +with O +0 O +. O +15 O +M O +NaCl O +solution O +. O + +The O +animals O +were O +killed O +5 O +and O +30 O +days O +after O +these O +injections O +and O +the O +kidneys O +were O +removed O +for O +histological O +and O +immunohistochemical O +studies O +. O + +The O +results O +of O +the O +immunohistochemical O +studies O +were O +scored O +according O +to O +the O +extent O +of O +staining O +. O + +The O +fractional O +interstitial O +area O +was O +determined O +by O +morphometry O +. O + +RESULTS O +: O +Gentamicin O +- O +treated O +rats O +presented O +a O +transitory O +increase O +in O +plasma O +creatinine O +levels O +. O + +Increased O +ED O +- O +1 O +, O +MAP O +kinases O +and O +NF O +- O +kappaB O +staining O +were O +also O +observed O +in O +the O +renal O +cortex O +from O +all O +gentamicin O +- O +treated O +rats O +compared O +to O +control O +( O +p O +< O +0 O +. O +05 O +) O +. O + +The O +animals O +killed O +on O +day O +30 O +also O +presented O +fibrosis B +in O +the O +renal O +cortex O +despite O +the O +recovery O +of O +renal O +function O +. O + +Treatment O +with O +PDTC O +reduced O +the O +functional O +and O +structural O +changes O +induced O +by O +gentamicin O +. O + +CONCLUSIONS O +: O +These O +data O +show O +that O +inhibition O +of O +NF O +- O +kappaB O +activation O +attenuates O +tubulointerstitial B +nephritis I +induced O +by O +gentamicin O +. O + +Glucose O +metabolism O +in O +patients O +with O +schizophrenia B +treated O +with O +atypical O +antipsychotic O +agents O +: O +a O +frequently O +sampled O +intravenous O +glucose O +tolerance O +test O +and O +minimal O +model O +analysis O +. O + +BACKGROUND O +: O +While O +the O +incidence O +of O +new O +- O +onset O +diabetes B +mellitus I +may O +be O +increasing O +in O +patients O +with O +schizophrenia B +treated O +with O +certain O +atypical O +antipsychotic O +agents O +, O +it O +remains O +unclear O +whether O +atypical O +agents O +are O +directly O +affecting O +glucose O +metabolism O +or O +simply O +increasing O +known O +risk O +factors O +for O +diabetes B +. O + +OBJECTIVE O +: O +To O +study O +the O +2 O +drugs O +most O +clearly O +implicated O +( O +clozapine O +and O +olanzapine O +) O +and O +risperidone O +using O +a O +frequently O +sampled O +intravenous O +glucose O +tolerance O +test O +. O + +DESIGN O +: O +A O +cross O +- O +sectional O +design O +in O +stable O +, O +treated O +patients O +with O +schizophrenia B +evaluated O +using O +a O +frequently O +sampled O +intravenous O +glucose O +tolerance O +test O +and O +the O +Bergman O +minimal O +model O +analysis O +. O + +SETTING O +: O +Subjects O +were O +recruited O +from O +an O +urban O +community O +mental O +health O +clinic O +and O +were O +studied O +at O +a O +general O +clinical O +research O +center O +. O + +Patients O +Fifty O +subjects O +signed O +informed O +consent O +and O +41 O +underwent O +the O +frequently O +sampled O +intravenous O +glucose O +tolerance O +test O +. O + +Thirty O +- O +six O +nonobese O +subjects O +with O +schizophrenia B +or O +schizoaffective B +disorder I +, O +matched O +by O +body O +mass O +index O +and O +treated O +with O +either O +clozapine O +, O +olanzapine O +, O +or O +risperidone O +, O +were O +included O +in O +the O +analysis O +. O + +MAIN O +OUTCOME O +MEASURES O +: O +Fasting O +plasma O +glucose O +and O +fasting O +serum O +insulin O +levels O +, O +insulin O +sensitivity O +index O +, O +homeostasis O +model O +assessment O +of O +insulin B +resistance I +, O +and O +glucose O +effectiveness O +. O + +RESULTS O +: O +The O +mean O ++ O +/ O +- O +SD O +duration O +of O +treatment O +with O +the O +identified O +atypical O +antipsychotic O +agent O +was O +68 O +. O +3 O ++ O +/ O +- O +28 O +. O +9 O +months O +( O +clozapine O +) O +, O +29 O +. O +5 O ++ O +/ O +- O +17 O +. O +5 O +months O +( O +olanzapine O +) O +, O +and O +40 O +. O +9 O ++ O +/ O +- O +33 O +. O +7 O +( O +risperidone O +) O +. O + +Fasting O +serum O +insulin O +concentrations O +differed O +among O +groups O +( O +F O +( O +33 O +) O += O +3 O +. O +35 O +; O +P O += O +. O +047 O +) O +( O +clozapine O +> O +olanzapine O +> O +risperidone O +) O +with O +significant O +differences O +between O +clozapine O +and O +risperidone O +( O +t O +( O +33 O +) O += O +2 O +. O +32 O +; O +P O += O +. O +03 O +) O +and O +olanzapine O +and O +risperidone O +( O +t O +( O +33 O +) O += O +2 O +. O +15 O +; O +P O += O +. O +04 O +) O +. O + +There O +was O +a O +significant O +difference O +in O +insulin O +sensitivity O +index O +among O +groups O +( O +F O +( O +33 O +) O += O +10 O +. O +66 O +; O +P O +< O +. O +001 O +) O +( O +clozapine O +< O +olanzapine O +< O +risperidone O +) O +, O +with O +subjects O +who O +received O +clozapine O +and O +olanzapine O +exhibiting O +significant O +insulin B +resistance I +compared O +with O +subjects O +who O +were O +treated O +with O +risperidone O +( O +clozapine O +vs O +risperidone O +, O +t O +( O +33 O +) O += O +- O +4 O +. O +29 O +; O +P O +< O +. O +001 O +; O +olanzapine O +vs O +risperidone O +, O +t O +( O +33 O +) O += O +- O +3 O +. O +62 O +; O +P O += O +. O + +001 O +[ O +P O +< O +. O +001 O +] O +) O +. O + +The O +homeostasis O +model O +assessment O +of O +insulin B +resistance I +also O +differed O +significantly O +among O +groups O +( O +F O +( O +33 O +) O += O +4 O +. O +92 O +; O +P O += O +. O +01 O +) O +( O +clozapine O +> O +olanzapine O +> O +risperidone O +) O +( O +clozapine O +vs O +risperidone O +, O +t O +( O +33 O +) O += O +2 O +. O +94 O +; O +P O += O +. O +006 O +; O +olanzapine O +vs O +risperidone O +, O +t O +( O +33 O +) O += O +2 O +. O +42 O +; O +P O += O +. O +02 O +) O +. O + +There O +was O +a O +significant O +difference O +among O +groups O +in O +glucose O +effectiveness O +( O +F O +( O +30 O +) O += O +4 O +. O +18 O +; O +P O += O +. O +02 O +) O +( O +clozapine O +< O +olanzapine O +< O +risperidone O +) O +with O +significant O +differences O +between O +clozapine O +and O +risperidone O +( O +t O +( O +30 O +) O += O +- O +2 O +. O +59 O +; O +P O += O +. O +02 O +) O +and O +olanzapine O +and O +risperidone O +( O +t O +( O +30 O +) O += O +- O +2 O +. O +34 O +, O +P O += O +. O +03 O +) O +. O + +CONCLUSIONS O +: O +Both O +nonobese O +clozapine O +- O +and O +olanzapine O +- O +treated O +groups O +displayed O +significant O +insulin B +resistance I +and O +impairment O +of O +glucose O +effectiveness O +compared O +with O +risperidone O +- O +treated O +subjects O +. O + +Patients O +taking O +clozapine O +and O +olanzapine O +must O +be O +examined O +for O +insulin B +resistance I +and O +its O +consequences O +. O + +Thoracic O +hematomyelia B +secondary O +to O +coumadin O +anticoagulant O +therapy O +: O +a O +case O +report O +. O + +A O +case O +of O +thoracic O +hematomyelia B +secondary O +to O +anticoagulant O +therapy O +is O +presented O +. O + +Clinical O +features O +, O +similar O +to O +2 O +other O +previously O +reported O +cases O +, O +are O +discussed O +. O + +A O +high O +index O +of O +suspicion O +may O +lead O +to O +a O +quick O +diagnostic O +procedure O +and O +successful O +decompressive O +surgery O +. O + +Mania B +associated O +with O +fluoxetine O +treatment O +in O +adolescents O +. O + +Fluoxetine O +, O +a O +selective O +serotonin O +reuptake O +inhibitor O +, O +is O +gaining O +increased O +acceptance O +in O +the O +treatment O +of O +adolescent O +depression B +. O + +Generally O +safe O +and O +well O +tolerated O +by O +adults O +, O +fluoxetine O +has O +been O +reported O +to O +induce O +mania B +. O + +The O +cases O +of O +five O +depressed B +adolescents O +, O +14 O +- O +16 O +years O +of O +age O +, O +who O +developed O +mania B +during O +pharmacotherapy O +with O +fluoxetine O +, O +are O +reported O +here O +. O + +Apparent O +risk O +factors O +for O +the O +development O +of O +mania B +or O +hypomania B +during O +fluoxetine O +pharmacotherapy O +in O +this O +population O +were O +the O +combination O +of O +attention B +- I +deficit I +hyperactivity I +disorder I +and O +affective B +instability I +; O +major B +depression I +with O +psychotic B +features O +; O +a O +family O +history O +of O +affective B +disorder I +, O +especially O +bipolar B +disorder I +; O +and O +a O +diagnosis O +of O +bipolar B +disorder I +. O + +Further O +study O +is O +needed O +to O +determine O +the O +optimal O +dosage O +and O +to O +identify O +risk O +factors O +that O +increase O +individual O +vulnerability O +to O +fluoxetine O +induced O +mania B +in O +adolescents O +. O + +Acute B +renal I +insufficiency I +after O +high O +- O +dose O +melphalan O +in O +patients O +with O +primary O +systemic I +amyloidosis I +during O +stem O +cell O +transplantation O +. O + +BACKGROUND O +: O +Patients O +with O +primary B +systemic I +amyloidosis I +( O +AL B +) O +have O +a O +poor O +prognosis O +. O + +Median O +survival O +time O +from O +standard O +treatments O +is O +only O +17 O +months O +. O + +High O +- O +dose O +intravenous O +melphalan O +followed O +by O +peripheral O +blood O +stem O +cell O +transplant O +( O +PBSCT O +) O +appears O +to O +be O +the O +most O +promising O +therapy O +, O +but O +treatment O +mortality O +can O +be O +high O +. O + +The O +authors O +have O +noted O +the O +development O +of O +acute B +renal I +insufficiency I +immediately O +after O +melphalan O +conditioning O +. O + +This O +study O +was O +undertaken O +to O +further O +examine O +its O +risk O +factors O +and O +impact O +on O +posttransplant O +mortality O +. O + +METHODS O +: O +Consecutive O +AL B +patients O +who O +underwent O +PBSCT O +were O +studied O +retrospectively O +. O + +Acute B +renal I +insufficiency I +( O +ARI B +) O +after O +high O +- O +dose O +melphalan O +was O +defined O +by O +a O +minimum O +increase O +of O +0 O +. O +5 O +mg O +/ O +dL O +( O +44 O +micromol O +/ O +L O +) O +in O +the O +serum O +creatinine O +level O +that O +is O +greater O +than O +50 O +% O +of O +baseline O +immediately O +after O +conditioning O +. O + +Urine O +sediment O +score O +was O +the O +sum O +of O +the O +individual O +types O +of O +sediment O +identified O +on O +urine O +microscopy O +. O + +RESULTS O +: O +Of O +the O +80 O +patients O +studied O +, O +ARI B +developed O +in O +18 O +. O +8 O +% O +of O +the O +patients O +after O +high O +- O +dose O +melphalan O +. O + +Univariate O +analysis O +identified O +age O +, O +hypoalbuminemia B +, O +heavy O +proteinuria B +, O +diuretic O +use O +, O +and O +urine O +sediment O +score O +( O +> O +3 O +) O +as O +risk O +factors O +. O + +Age O +and O +urine O +sediment O +score O +remained O +independently O +significant O +risk O +factors O +in O +the O +multivariate O +analysis O +. O + +Patients O +who O +had O +ARI O +after O +high O +- O +dose O +melphalan O +underwent O +dialysis O +more O +often O +( O +P O += O +0 O +. O +007 O +) O +, O +and O +had O +a O +worse O +1 O +- O +year O +survival O +( O +P O += O +0 O +. O +03 O +) O +. O + +CONCLUSION O +: O +The O +timing O +of O +renal B +injury I +strongly O +suggests O +melphalan O +as O +the O +causative O +agent O +. O + +Ongoing O +tubular B +injury I +may O +be O +a O +prerequisite O +for O +renal B +injury I +by O +melphalan O +as O +evidenced O +by O +the O +active O +urinary O +sediment O +. O + +Development O +of O +ARI O +adversely O +affected O +the O +outcome O +after O +PBSCT O +. O + +Effective O +preventive O +measures O +may O +help O +decrease O +the O +treatment O +mortality O +of O +PBSCT B +in O +AL B +patients O +. O + +Focal O +cerebral B +ischemia I +in O +rats O +: O +effect O +of O +phenylephrine O +- O +induced O +hypertension B +during O +reperfusion O +. O + +After O +180 O +min O +of O +temporary O +middle B +cerebral I +artery I +occlusion I +in O +spontaneously O +hypertensive B +rats O +, O +the O +effect O +of O +phenylephrine O +- O +induced O +hypertension B +on O +ischemic B +brain I +injury I +and O +blood O +- O +brain O +barrier O +permeability O +was O +determined O +. O + +Blood O +pressure O +was O +manipulated O +by O +one O +of O +the O +following O +schedules O +during O +120 O +min O +of O +reperfusion O +: O +Control O +, O +normotensive O +reperfusion O +; O +90 O +/ O +hypertension B +( O +90 O +/ O +HTN O +) O +, O +blood O +pressure O +was O +increased O +by O +35 O +mm O +Hg O +during O +the O +initial O +90 O +min O +of O +reperfusion O +only O +; O +15 O +/ O +hypertension B +( O +15 O +/ O +HTN O +) O +, O +normotensive O +reperfusion O +for O +30 O +min O +followed O +by O +15 O +min O +of O +hypertension B +and O +75 O +min O +of O +normotension O +. O + +Part O +A O +, O +for O +eight O +rats O +in O +each O +group O +brain B +injury I +was O +evaluated O +by O +staining O +tissue O +using O +2 O +, O +3 O +, O +5 O +- O +triphenyltetrazolium O +chloride O +and O +edema B +was O +evaluated O +by O +microgravimetry O +. O + +Part O +B O +, O +for O +eight O +different O +rats O +in O +each O +group O +blood O +- O +brain O +barrier O +permeability O +was O +evaluated O +by O +measuring O +the O +amount O +and O +extent O +of O +extravasation O +of O +Evans O +Blue O +dye O +. O + +Brain B +injury I +( O +percentage O +of O +the O +ischemic O +hemisphere O +) O +was O +less O +in O +the O +15 O +/ O +HTN O +group O +( O +16 O ++ O +/ O +- O +6 O +, O +mean O ++ O +/ O +- O +SD O +) O +versus O +the O +90 O +/ O +HTN O +group O +( O +30 O ++ O +/ O +- O +6 O +) O +, O +which O +was O +in O +turn O +less O +than O +the O +control O +group O +( O +42 O ++ O +/ O +- O +5 O +) O +. O + +Specific O +gravity O +was O +greater O +in O +the O +15 O +/ O +HTN O +group O +( O +1 O +. O +043 O ++ O +/ O +- O +0 O +. O +002 O +) O +versus O +the O +90 O +/ O +HTN O +( O +1 O +. O +036 O ++ O +/ O +- O +0 O +. O +003 O +) O +and O +control O +( O +1 O +. O +037 O ++ O +/ O +- O +0 O +. O +003 O +) O +groups O +. O + +Evans O +Blue O +( O +mug O +g O +- O +1 O +of O +brain O +tissue O +) O +was O +greater O +in O +the O +90 O +/ O +HTN O +group O +( O +24 O +. O +4 O ++ O +/ O +- O +6 O +. O +0 O +) O +versus O +the O +control O +group O +( O +12 O +. O +3 O ++ O +/ O +- O +4 O +. O +1 O +) O +, O +which O +was O +in O +turn O +greater O +than O +the O +15 O +/ O +HTN O +group O +( O +7 O +. O +3 O ++ O +/ O +- O +3 O +. O +2 O +) O +. O + +This O +study O +supports O +a O +hypothesis O +that O +during O +reperfusion O +, O +a O +short O +interval O +of O +hypertension B +decreases O +brain B +injury I +and O +edema B +; O +and O +that O +sustained O +hypertension B +increases O +the O +risk O +of O +vasogenic O +edema B +. O + +People O +aged O +over O +75 O +in O +atrial B +fibrillation I +on O +warfarin O +: O +the O +rate O +of O +major O +hemorrhage B +and O +stroke B +in O +more O +than O +500 O +patient O +- O +years O +of O +follow O +- O +up O +. O + +OBJECTIVES O +: O +To O +determine O +the O +incidence O +of O +major O +hemorrhage B +and O +stroke B +in O +people O +aged O +76 O +and O +older O +with O +atrial B +fibrillation I +on O +adjusted O +- O +dose O +warfarin O +who O +had O +been O +recently O +been O +admitted O +to O +hospital O +. O + +DESIGN O +: O +A O +retrospective O +observational O +cohort O +study O +. O + +SETTING O +: O +A O +major O +healthcare O +network O +involving O +four O +tertiary O +hospitals O +. O + +PARTICIPANTS O +: O +Two O +hundred O +thirty O +- O +five O +patients O +aged O +76 O +and O +older O +admitted O +to O +a O +major O +healthcare O +network O +between O +July O +1 O +, O +2001 O +, O +and O +June O +30 O +, O +2002 O +, O +with O +atrial B +fibrillation I +on O +warfarin O +were O +enrolled O +. O + +MEASUREMENTS O +: O +Information O +regarding O +major O +bleeding B +episodes O +, O +strokes B +, O +and O +warfarin O +use O +was O +obtained O +from O +patients O +, O +relatives O +, O +primary O +physicians O +, O +and O +medical O +records O +. O + +RESULTS O +: O +Two O +hundred O +twenty O +- O +eight O +patients O +( O +42 O +% O +men O +) O +with O +a O +mean O +age O +of O +81 O +. O +1 O +( O +range O +76 O +- O +94 O +) O +were O +included O +in O +the O +analysis O +. O + +Total O +follow O +- O +up O +on O +warfarin O +was O +530 O +years O +( O +mean O +28 O +months O +) O +. O + +There O +were O +53 O +major O +hemorrhages B +, O +for O +an O +annual O +rate O +of O +10 O +. O +0 O +% O +, O +including O +24 O +( O +45 O +. O +3 O +% O +) O +life O +- O +threatening O +and O +five O +( O +9 O +. O +4 O +% O +) O +fatal O +bleeds B +. O + +The O +annual O +stroke B +rate O +after O +initiation O +of O +warfarin O +was O +2 O +. O +6 O +% O +. O + +CONCLUSION O +: O +The O +rate O +of O +major O +hemorrhage B +was O +high O +in O +this O +old O +, O +frail O +group O +, O +but O +excluding O +fatalities O +, O +resulted O +in O +no O +long O +- O +term O +sequelae O +, O +and O +the O +stroke B +rate O +on O +warfarin O +was O +low O +, O +demonstrating O +how O +effective O +warfarin O +treatment O +is O +. O + +Safety O +of O +celecoxib O +in O +patients O +with O +adverse O +skin O +reactions I +to O +acetaminophen O +( O +paracetamol O +) O +and O +nimesulide O +associated O +or O +not O +with O +common O +non O +- O +steroidal O +anti O +- O +inflammatory O +drugs O +. O + +BACKGROUND O +: O +Acetaminophen O +( O +paracetamol O +- O +- O +P O +) O +and O +Nimesulide O +( O +N O +) O +are O +widely O +used O +analgesic O +- O +antipyretic O +/ O +anti O +- O +inflammatory O +drugs O +. O + +The O +rate O +of O +adverse O +hypersensitivity B +reactions O +to O +these O +agents O +is O +generally O +low O +. O + +On O +the O +contrary O +non O +- O +steroidal O +anti O +- O +inflammatory O +drugs O +( O +NSAIDs O +) O +are O +commonly O +involved O +in O +such O +reactions O +. O + +Celecoxib O +( O +CE O +) O +is O +a O +novel O +drug O +, O +with O +high O +selectivity O +and O +affinity O +for O +COX O +- O +2 O +enzyme O +. O + +OBJECTIVE O +: O +We O +evaluated O +the O +tolerability O +of O +CE O +in O +a O +group O +of O +patients O +with O +documented O +history O +of O +adverse O +cutaneous O +reactions O +to O +P O +and O +N O +associated O +or O +not O +to O +classic O +NSAIDs O +. O + +METHODS O +: O +We O +studied O +9 O +patients O +with O +hypersensitivity B +to I +P O +and O +N O +with O +or O +without O +associated O +reactions O +to O +classic O +NSAIDs O +. O + +The O +diagnosis O +of O +P O +and O +N O +- O +induced O +skin O +reactions O +was O +based O +in O +vivo O +challenge O +. O + +The O +placebo O +was O +blindly O +administered O +at O +the O +beginning O +of O +each O +challenge O +. O + +After O +three O +days O +, O +a O +cumulative O +dosage O +of O +200 O +mg O +of O +CE O +in O +refracted O +doses O +were O +given O +. O + +After O +2 O +- O +3 O +days O +, O +a O +single O +dose O +of O +200 O +mg O +was O +administered O +. O + +All O +patients O +were O +observed O +for O +6 O +hours O +after O +each O +challenge O +, O +and O +controlled O +again O +after O +24 O +hours O +to O +exclude O +delayed O +reactions O +. O + +The O +challenge O +was O +considered O +positive O +if O +one O +or O +more O +of O +the O +following O +appeared O +: O +erythema B +, O +rush O +or O +urticaria B +- O +angioedema B +. O + +RESULTS O +: O +No O +reaction O +was O +observed O +with O +placebo O +and O +eight O +patients O +( O +88 O +. O +8 O +% O +) O +tolerated O +CE O +. O + +Only O +one O +patient O +developed O +a O +moderate O +angioedema B +of I +the I +lips I +. O + +CONCLUSION O +: O +Only O +one O +hypersensitivity B +reaction O +to O +CE O +was O +documented O +among O +9 O +P O +and O +N O +- O +highly O +NSAIDs O +intolerant O +patients O +. O + +Thus O +, O +we O +conclude O +that O +CE O +is O +a O +reasonably O +safe O +alternative O +to O +be O +used O +in O +subjects O +who O +do O +not O +tolerate O +P O +and O +N O +. O + +Case O +- O +control O +study O +of O +regular O +analgesic O +and O +nonsteroidal O +anti O +- O +inflammatory O +use O +and O +end B +- I +stage I +renal I +disease I +. O + +BACKGROUND O +: O +Studies O +on O +the O +association O +between O +the O +long O +- O +term O +use O +of O +aspirin O +and O +other O +analgesic O +and O +nonsteroidal O +anti O +- O +inflammatory O +drugs O +( O +NSAIDs O +) O +and O +end B +- I +stage I +renal I +disease I +( O +ESRD B +) O +have O +given O +conflicting O +results O +. O + +In O +order O +to O +examine O +this O +association O +, O +a O +case O +- O +control O +study O +with O +incident O +cases O +of O +ESRD B +was O +carried O +out O +. O + +METHODS O +: O +The O +cases O +were O +all O +patients O +entering O +the O +local O +dialysis O +program O +because O +of O +ESRD B +in O +the O +study O +area O +between O +June O +1 O +, O +1995 O +and O +November O +30 O +, O +1997 O +. O + +They O +were O +classified O +according O +to O +the O +underlying O +disease O +, O +which O +had O +presumably O +led O +them O +to O +ESRD B +. O + +Controls O +were O +patients O +admitted O +to O +the O +same O +hospitals O +from O +where O +the O +cases O +arose O +, O +also O +matched O +by O +age O +and O +sex O +. O + +Odds O +ratios O +were O +calculated O +using O +a O +conditional O +logistic O +model O +, O +including O +potential O +confounding O +factors O +, O +both O +for O +the O +whole O +study O +population O +and O +for O +the O +various O +underlying O +diseases O +. O + +RESULTS O +: O +Five O +hundred O +and O +eighty O +- O +three O +cases O +and O +1190 O +controls O +were O +included O +in O +the O +analysis O +. O + +Long O +- O +term O +use O +of O +any O +analgesic O +was O +associated O +with O +an O +overall O +odds O +ratio O +of O +1 O +. O +22 O +( O +95 O +% O +CI O +, O +0 O +. O +89 O +- O +1 O +. O +66 O +) O +. O + +For O +specific O +groups O +of O +drugs O +, O +the O +risks O +were O +1 O +. O +56 O +( O +1 O +. O +05 O +- O +2 O +. O +30 O +) O +for O +aspirin O +, O +1 O +. O +03 O +( O +0 O +. O +60 O +- O +1 O +. O +76 O +) O +for O +pyrazolones O +, O +0 O +. O +80 O +( O +0 O +. O +39 O +- O +1 O +. O +63 O +) O +for O +paracetamol O +, O +and O +0 O +. O +94 O +( O +0 O +. O +57 O +- O +1 O +. O +56 O +) O +for O +nonaspirin O +NSAIDs O +. O + +The O +risk O +of O +ESRD B +associated O +with O +aspirin O +was O +related O +to O +the O +cumulated O +dose O +and O +duration O +of O +use O +, O +and O +it O +was O +particularly O +high O +among O +the O +subset O +of O +patients O +with O +vascular B +nephropathy I +as O +underlying O +disease O +[ O +2 O +. O +35 O +( O +1 O +. O +17 O +- O +4 O +. O +72 O +) O +] O +. O + +CONCLUSION O +: O +Our O +data O +indicate O +that O +long O +- O +term O +use O +of O +nonaspirin O +analgesic O +drugs O +and O +NSAIDs O +is O +not O +associated O +with O +an O +increased O +risk O +of O +ESRD B +. O + +However O +, O +the O +chronic O +use O +of O +aspirin O +may O +increase O +the O +risk O +of O +ESRD B +. O + +Two O +cases O +of O +amisulpride O +overdose B +: O +a O +cause O +for O +prolonged B +QT I +syndrome I +. O + +Two O +cases O +of O +deliberate O +self O +- O +poisoning B +with O +5 O +g O +and O +3 O +. O +6 O +g O +of O +amisulpride O +, O +respectively O +, O +are O +reported O +. O + +In O +both O +cases O +, O +QT B +prolongation I +and O +hypocalcaemia B +were O +noted O +. O + +The O +QT B +prolongation I +appeared O +to O +respond O +to O +administration O +of O +i O +. O +v O +. O +calcium O +gluconate 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 B +rats O +treated O +with O +cycloheximide O +. 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 B +. 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 B +epilepticus I +induced O +by O +pilocarpine O +( O +Pilo O +) O +, O +previously O +injected O +or O +not O +with O +cycloheximide O +( O +CHX O +) 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 +03 O +) O +as O +compared O +with O +that O +in O +the O +Pilo O +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 O +- 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 + +Nicotine O +antagonizes O +caffeine O +- O +but O +not O +pentylenetetrazole O +- O +induced O +anxiogenic O +effect O +in O +mice O +. O + +RATIONALE O +: O +Nicotine O +and O +caffeine O +are O +widely O +consumed O +licit O +psychoactive O +drugs O +worldwide O +. O + +Epidemiological O +studies O +showed O +that O +they O +were O +generally O +used O +concurrently O +. O + +Although O +some O +studies O +in O +experimental O +animals O +indicate O +clear O +pharmacological O +interactions O +between O +them O +, O +no O +studies O +have O +shown O +a O +specific O +interaction O +on O +anxiety B +responses O +. O + +OBJECTIVES O +: O +The O +present O +study O +investigates O +the O +effects O +of O +nicotine O +on O +anxiety B +induced O +by O +caffeine O +and O +another O +anxiogenic O +drug O +, O +pentylenetetrazole O +, O +in O +mice O +. O + +The O +elevated O +plus O +- O +maze O +( O +EPM O +) O +test O +was O +used O +to O +evaluate O +the O +effects O +of O +drugs O +on O +anxiety B +. O + +METHODS O +: O +Adult O +male O +Swiss O +Webster O +mice O +( O +25 O +- O +32 O +g O +) O +were O +given O +nicotine O +( O +0 O +. O +05 O +- O +0 O +. O +25 O +mg O +/ O +kg O +s O +. O +c O +. O +) O +or O +saline O +10 O +min O +before O +caffeine O +( O +70 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +or O +pentylenetetrazole O +( O +15 O +and O +30 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +injections O +. O + +After O +15 O +min O +, O +mice O +were O +evaluated O +for O +their O +open O +- O +and O +closed O +- O +arm O +time O +and O +entries O +on O +the O +EPM O +for O +a O +10 O +- O +min O +session O +. O + +Locomotor O +activity O +was O +recorded O +for O +individual O +groups O +by O +using O +the O +same O +treatment O +protocol O +with O +the O +EPM O +test O +. O + +RESULTS O +: O +Nicotine O +( O +0 O +. O +05 O +- O +0 O +. O +25 O +mg O +/ O +kg O +) O +itself O +did O +not O +produce O +any O +significant O +effect O +in O +the O +EPM O +test O +, O +whereas O +caffeine O +( O +70 O +mg O +/ O +kg O +) O +and O +pentylenetetrazole O +( O +30 O +mg O +/ O +kg O +) O +produced O +an O +anxiogenic O +effect O +, O +apparent O +with O +decreases O +in O +open O +- O +arm O +time O +and O +entry O +. O + +Nicotine O +( O +0 O +. O +25 O +mg O +/ O +kg O +) O +pretreatment O +blocked O +the O +caffeine O +- O +but O +not O +pentylenetetrazole O +- O +induced O +anxiety B +. O + +Administration O +of O +each O +drug O +and O +their O +combinations O +did O +not O +produce O +any O +effect O +on O +locomotor O +activity O +. O + +CONCLUSIONS O +: O +Our O +results O +suggest O +that O +the O +antagonistic O +effect O +of O +nicotine O +on O +caffeine O +- O +induced O +anxiety B +is O +specific O +to O +caffeine O +, O +instead O +of O +a O +non O +- O +specific O +anxiolytic O +effect O +. O + +Thus O +, O +it O +may O +extend O +the O +current O +findings O +on O +the O +interaction O +between O +nicotine O +and O +caffeine O +. O + +Long O +term O +hormone O +therapy O +for O +perimenopausal O +and O +postmenopausal O +women O +. O + +BACKGROUND O +: O +Hormone O +therapy O +( O +HT O +) O +is O +widely O +used O +for O +controlling O +menopausal O +symptoms O +. O + +It O +has O +also O +been O +used O +for O +the O +management O +and O +prevention O +of O +cardiovascular B +disease I +, O +osteoporosis B +and O +dementia B +in O +older O +women O +but O +the O +evidence O +supporting O +its O +use O +for O +these O +indications O +is O +largely O +observational O +. O + +OBJECTIVES O +: O +To O +assess O +the O +effect O +of O +long O +- O +term O +HT O +on O +mortality O +, O +heart B +disease I +, O +venous B +thromboembolism I +, O +stroke B +, O +transient B +ischaemic I +attacks I +, O +breast B +cancer I +, O +colorectal B +cancer I +, O +ovarian B +cancer I +, O +endometrial B +cancer I +, O +gallbladder B +disease I +, O +cognitive O +function O +, O +dementia B +, O +fractures B +and O +quality O +of O +life O +. O + +SEARCH O +STRATEGY O +: O +We O +searched O +the O +following O +databases O +up O +to O +November O +2004 O +: O +the O +Cochrane O +Menstrual B +Disorders I +and O +Subfertility O +Group O +Trials O +Register O +, O +Cochrane O +Central O +Register O +of O +Controlled O +Trials O +( O +CENTRAL O +) O +, O +MEDLINE O +, O +EMBASE O +, O +Biological O +Abstracts O +. O + +Relevant O +non O +- O +indexed O +journals O +and O +conference O +abstracts O +were O +also O +searched O +. O + +SELECTION O +CRITERIA O +: O +Randomised O +double O +- O +blind O +trials O +of O +HT O +( O +oestrogens O +with O +or O +without O +progestogens O +) O +versus O +placebo O +, O +taken O +for O +at O +least O +one O +year O +by O +perimenopausal O +or O +postmenopausal O +women O +. O + +DATA O +COLLECTION O +AND O +ANALYSIS O +: O +Fifteen O +RCTs O +were O +included O +. O + +Trials O +were O +assessed O +for O +quality O +and O +two O +review O +authors O +extracted O +data O +independently O +. O + +They O +calculated O +risk O +ratios O +for O +dichotomous O +outcomes O +and O +weighted O +mean O +differences O +for O +continuous O +outcomes O +. O + +Clinical O +heterogeneity O +precluded O +meta O +- O +analysis O +for O +most O +outcomes O +. O + +MAIN O +RESULTS O +: O +All O +the O +statistically O +significant O +results O +were O +derived O +from O +the O +two O +biggest O +trials O +. O + +In O +relatively O +healthy O +women O +, O +combined O +continuous O +HT O +significantly O +increased O +the O +risk O +of O +venous B +thromboembolism I +or O +coronary O +event O +( O +after O +one O +year O +' O +s O +use O +) O +, O +stroke B +( O +after O +3 O +years O +) O +, O +breast B +cancer I +( O +after O +5 O +years O +) O +and O +gallbladder B +disease I +. O + +Long O +- O +term O +oestrogen O +- O +only O +HT O +also O +significantly O +increased O +the O +risk O +of O +stroke B +and O +gallbladder B +disease I +. O + +Overall O +, O +the O +only O +statistically O +significant O +benefits O +of O +HT O +were O +a O +decreased O +incidence O +of O +fractures B +and O +colon B +cancer I +with O +long O +- O +term O +use O +. O + +Among O +relatively O +healthy O +women O +over O +65 O +years O +taking O +continuous O +combined O +HT O +, O +there O +was O +a O +statistically O +significant O +increase O +in O +the O +incidence O +of O +dementia B +. O + +Among O +women O +with O +cardiovascular B +disease I +, O +long O +- O +term O +use O +of O +combined O +continuous O +HT O +significantly O +increased O +the O +risk O +of O +venous B +thromboembolism I +. O + +No O +trials O +focussed O +specifically O +on O +younger O +women O +. O + +However O +, O +one O +trial O +analysed O +subgroups O +of O +2839 O +relatively O +healthy O +50 O +to O +59 O +year O +- O +old O +women O +taking O +combined O +continuous O +HT O +and O +1637 O +taking O +oestrogen O +- O +only O +HT O +, O +versus O +similar O +- O +sized O +placebo O +groups O +. O + +The O +only O +significantly O +increased O +risk O +reported O +was O +for O +venous B +thromboembolism I +in O +women O +taking O +combined O +continuous O +HT O +; O +their O +absolute O +risk O +remained O +very O +low O +. O + +AUTHORS O +' O +CONCLUSIONS O +: O +HT O +is O +not O +indicated O +for O +the O +routine O +management O +of O +chronic O +disease O +. O + +We O +need O +more O +evidence O +on O +the O +safety O +of O +HT O +for O +menopausal O +symptom O +control O +, O +though O +short O +- O +term O +use O +appears O +to O +be O +relatively O +safe O +for O +healthy O +younger O +women O +. O + +Drug O +- O +induced O +liver B +injury I +: O +an O +analysis O +of O +461 O +incidences O +submitted O +to O +the O +Spanish O +registry O +over O +a O +10 O +- O +year O +period O +. O + +BACKGROUND O +& O +AIMS O +: O +Progress O +in O +the O +understanding O +of O +susceptibility O +factors O +to O +drug O +- O +induced I +liver B +injury I +( O +DILI B +) O +and O +outcome O +predictability O +are O +hampered O +by O +the O +lack O +of O +systematic O +programs O +to O +detect O +bona O +fide O +cases O +. O + +METHODS O +: O +A O +cooperative O +network O +was O +created O +in O +1994 O +in O +Spain O +to O +identify O +all O +suspicions O +of O +DILI B +following O +a O +prospective O +structured O +report O +form O +. O + +The O +liver B +damage I +was O +characterized O +according O +to O +hepatocellular O +, O +cholestatic O +, O +and O +mixed O +laboratory O +criteria O +and O +to O +histologic O +criteria O +when O +available O +. O + +Further O +evaluation O +of O +causality O +assessment O +was O +centrally O +performed O +. O + +RESULTS O +: O +Since O +April O +1994 O +to O +August O +2004 O +, O +461 O +out O +of O +570 O +submitted O +cases O +, O +involving O +505 O +drugs O +, O +were O +deemed O +to O +be O +related O +to O +DILI O +. O + +The O +antiinfective O +group O +of O +drugs O +was O +the O +more O +frequently O +incriminated O +, O +amoxicillin O +- O +clavulanate O +accounting O +for O +the O +12 O +. O +8 O +% O +of O +the O +whole O +series O +. O + +The O +hepatocellular O +pattern O +of O +damage O +was O +the O +most O +common O +( O +58 O +% O +) O +, O +was O +inversely O +correlated O +with O +age O +( O +P O +< O +. O +0001 O +) O +, O +and O +had O +the O +worst O +outcome O +( O +Cox O +regression O +, O +P O +< O +. O +034 O +) O +. O + +Indeed O +, O +the O +incidence O +of O +liver O +transplantation O +and O +death B +in O +this O +group O +was O +11 O +. O +7 O +% O +if O +patients O +had O +jaundice B +at O +presentation O +, O +whereas O +the O +corresponding O +figure O +was O +3 O +. O +8 O +% O +in O +nonjaundiced O +patients O +( O +P O +< O +. O +04 O +) O +. O + +Factors O +associated O +with O +the O +development O +of O +fulminant B +hepatic I +failure I +were O +female O +sex O +( O +OR O += O +25 O +; O +95 O +% O +CI O +: O +4 O +. O +1 O +- O +151 O +; O +P O +< O +. O +0001 O +) O +, O +hepatocellular B +damage I +( O +OR O += O +7 O +. O +9 O +; O +95 O +% O +CI O +: O +1 O +. O +6 O +- O +37 O +; O +P O +< O +. O +009 O +) O +, O +and O +higher O +baseline O +plasma O +bilirubin O +value O +( O +OR O += O +1 O +. O +15 O +; O +95 O +% O +CI O +: O +1 O +. O +09 O +- O +1 O +. O +22 O +; O +P O +< O +. O +0001 O +) O +. O + +CONCLUSIONS O +: O +Patients O +with O +drug O +- O +induced O +hepatocellular B +jaundice I +have O +11 O +. O +7 O +% O +chance O +of O +progressing O +to O +death O +or O +transplantation O +. O + +Amoxicillin O +- O +clavulanate O +stands O +out O +as O +the O +most O +common O +drug O +related O +to O +DILI O +. O + +Morphological O +evaluation O +of O +the O +effect O +of O +d O +- O +ribose O +on O +adriamycin O +- O +evoked O +cardiotoxicity B +in O +rats O +. O + +The O +influence O +of O +d O +- O +ribose O +on O +adriamycin O +- O +induced O +myocardiopathy B +in O +rats O +was O +studied O +. O + +Adriamycin O +in O +the O +cumulative O +dose O +of O +25 O +mg O +/ O +kg O +evoked O +fully O +developed O +cardiac B +toxicity I +. O + +D O +- O +ribose O +in O +the O +multiple O +doses O +of O +200 O +mg O +/ O +kg O +did O +not O +influence O +ADR O +cardiotoxicity B +. 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 O +- O +induced O +nephrotoxicity B +: 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 O +( O +VCM O +) O +- O +induced O +oxidative O +stress O +that O +promotes O +production O +of O +reactive O +oxygen O +species O +( O +ROS O +) 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 B +impairment I +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 +) O +with O +200mgkg O +( 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 O +( O +MDA O +) O +and O +urinary O +N O +- O +acetyl O +- O +beta O +- O +d O +- O +glucosaminidase O +( O +NAG O +, O +a O +marker O +of O +renal B +tubular I +injury I +) 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 O +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 B +. 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 B +, O +and O +necrosis B +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 B +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 B +damage I +both O +at O +the O +biochemical O +and O +histological O +levels O +. O + +Gemfibrozil O +- O +lovastatin O +therapy O +for O +primary O +hyperlipoproteinemias B +. O + +The O +specific O +aim O +of O +this O +retrospective O +, O +observational O +study O +was O +to O +assess O +safety O +and O +efficacy O +of O +long O +- O +term O +( O +21 O +months O +/ O +patient O +) O +, O +open O +- O +label O +, O +gemfibrozil O +- O +lovastatin O +treatment O +in O +80 O +patients O +with O +primary O +mixed O +hyperlipidemia B +( O +68 O +% O +of O +whom O +had O +atherosclerotic B +vascular I +disease I +) O +. O + +Because O +ideal O +lipid O +targets O +were O +not O +reached O +( O +low O +- O +density O +lipoprotein O +( O +LDL O +) O +cholesterol O +less O +than O +130 O +mg O +/ O +dl O +, O +high O +- O +density O +lipoprotein O +( O +HDL O +) O +cholesterol O +greater O +than O +35 O +mg O +/ O +dl O +, O +or O +total O +cholesterol O +/ O +HDL O +cholesterol O +less O +than O +4 O +. O +5 O +mg O +/ O +dl O +) O +with O +diet O +plus O +a O +single O +drug O +, O +gemfibrozil O +( O +1 O +. O +2 O +g O +/ O +day O +) O +- O +lovastatin O +( O +primarily O +20 O +or O +40 O +mg O +) O +treatment O +was O +given O +. O + +Follow O +- O +up O +visits O +were O +scheduled O +with O +2 O +- O +drug O +therapy O +every O +6 O +to O +8 O +weeks O +, O +an O +average O +of O +10 O +. O +3 O +visits O +per O +patient O +, O +with O +741 O +batteries O +of O +6 O +liver O +function O +tests O +and O +714 O +creatine O +phosphokinase O +levels O +measured O +. O + +Only O +1 O +of O +the O +4 O +, O +446 O +liver O +function O +tests O +( O +0 O +. O +02 O +% O +) O +, O +a O +gamma O +glutamyl O +transferase O +, O +was O +greater O +than O +or O +equal O +to O +3 O +times O +the O +upper O +normal O +limit O +. O + +Of O +the O +714 O +creatine O +phosphokinase O +levels O +, O +9 O +% O +were O +high O +; O +only O +1 O +( O +0 O +. O +1 O +% O +) O +was O +greater O +than O +or O +equal O +to O +3 O +times O +the O +upper O +normal O +limit O +. O + +With O +2 O +- O +drug O +therapy O +, O +mean O +total O +cholesterol O +decreased O +22 O +% O +from O +255 O +to O +200 O +mg O +/ O +dl O +, O +triglyceride O +levels O +decreased O +35 O +% O +from O +236 O +to O +154 O +mg O +/ O +dl O +, O +LDL O +cholesterol O +decreased O +26 O +% O +from O +176 O +to O +131 O +mg O +/ O +dl O +, O +and O +the O +total O +cholesterol O +/ O +HDL O +cholesterol O +ratio O +decreased O +24 O +% O +from O +7 O +. O +1 O +to O +5 O +. O +4 O +, O +all O +p O +less O +than O +or O +equal O +to O +0 O +. O +0001 O +. O + +Myositis B +, O +attributable O +to O +the O +drug O +combination O +and O +symptomatic O +enough O +to O +discontinue O +it O +, O +occurred O +in O +3 O +% O +of O +patients O +, O +and O +in O +1 O +% O +with O +concurrent O +high O +creatine O +phosphokinase O +( O +769 O +U O +/ O +liter O +) O +; O +no O +patients O +had O +rhabdomyolysis B +or O +myoglobinuria B +. O +( O +ABSTRACT O +TRUNCATED O +AT O +250 O +WORDS O +) O + +Does O +domperidone O +potentiate O +mirtazapine O +- O +associated O +restless B +legs I +syndrome I +? O + +There O +is O +now O +evidence O +to O +suggest O +a O +central O +role O +for O +the O +dopaminergic O +system O +in O +restless B +legs I +syndrome I +( O +RLS B +) O +. O + +For O +example O +, O +the O +symptoms O +of O +RLS B +can O +be O +dramatically O +improved O +by O +levodopa O +and O +dopamine O +agonists O +, O +whereas O +central O +dopamine O +D2 O +receptor O +antagonists O +can O +induce O +or O +aggravate O +RLS B +symptoms O +. O + +To O +our O +knowledge O +, O +there O +is O +no O +previous O +report O +regarding O +whether O +domperidone O +, O +a O +peripheral O +dopamine O +D2 O +receptor O +antagonist O +, O +can O +also O +induce O +or O +aggravate O +symptoms O +of O +RLS B +. O + +Mirtazapine O +, O +the O +first O +noradrenergic O +and O +specific O +serotonergic O +antidepressant O +( O +NaSSA O +) O +, O +has O +been O +associated O +with O +RLS B +in O +several O +recent O +publications O +. O + +The O +authors O +report O +here O +a O +depressed B +patient O +comorbid O +with O +postprandial B +dyspepsia I +who O +developed O +RLS B +after O +mirtazapine O +had O +been O +added O +to O +his O +domperidone O +therapy O +. O + +Our O +patient O +started O +to O +have O +symptoms O +of O +RLS B +only O +after O +he O +had O +been O +treated O +with O +mirtazapine O +, O +and O +his O +RLS B +symptoms O +resolved O +completely O +upon O +discontinuation O +of O +his O +mirtazapine O +. O + +Such O +a O +temporal O +relationship O +between O +the O +use O +of O +mirtazapine O +and O +the O +symptoms O +of O +RLS B +in O +our O +patient O +did O +not O +support O +a O +potentiating O +effect O +of O +domperione O +on O +mirtazapine O +- O +associated O +RLS B +. O + +However O +, O +physicians O +should O +be O +aware O +of O +the O +possibility O +that O +mirtazapine O +can O +be O +associated O +with O +RLS B +in O +some O +individuals O +, O +especially O +those O +receiving O +concomitant O +dopamine O +D2 O +receptor O +antagonists O +. O + +Antiandrogenic O +therapy O +can O +cause O +coronary B +arterial I +disease I +. O + +AIM O +: O +To O +study O +the O +change O +of O +lipid O +metabolism O +by O +antiandrogen O +therapy O +in O +patients O +with O +prostate B +cancer I +. O + +MATERIALS O +AND O +METHODS O +: O +We O +studied O +with O +a O +2 O +. O +5 O +years O +follow O +- O +up O +the O +changes O +in O +plasma O +cholesterols O +( O +C O +) O +, O +triglycerides O +( O +TG O +) O +, O +lipoproteins O +( O +LP O +) O +, O +and O +apolipoproteins O +( O +Apo O +) O +B O +- O +100 O +, O +A O +- O +I O +, O +and O +A O +- O +II O +pro O +fi O +les O +in O +24 O +patients O +of O +mean O +age O +60 O +years O +with O +low O +risk O +prostate B +cancer I +( O +stage O +: O +T1cN0M0 O +, O +Gleason O +score O +: O +2 O +- O +5 O +) O +during O +treatment O +with O +cyproterone O +acetate O +( O +CPA O +) O +without O + +surgical O +management O +or O +radiation O +therapy O +. O + +RESULTS O +: O +Significant O +decreases O +of O +HDL O +- O +C O +, O +Apo O +A O +- O +I O +and O +Apo O +A O +- O +II O +and O +an O +increase O +of O +triglyceride O +levels O +in O +VLDL O +were O +induced O +by O +CPA O +. O + +After O +a O +period O +of O +2 O +. O +5 O +years O +on O +CPA O +treatment O +, O +four O +patients O +out O +of O +twenty O +- O +four O +were O +found O +to O +be O +affected O +by O +coronary B +heart I +disease I +. O + +CONCLUSIONS O +: O +Ischaemic B +coronary I +arteriosclerosis I +with O +an O +incidence O +rate O +of O +16 O +. O +6 O +% O +as O +caused O +by O +prolonged O +CPA O +therapy O +is O +mediated O +through O +changes O +in O +HDL O +cholesterol O +, O +Apo O +A O +- O +I O +and O +Apo O +A O +- O +II O +pro O +fi O +les O +, O +other O +than O +the O +well O +- O +known O +hyperglyceridemic B +effect O +caused O +by O +estrogen O +. O + +5 O +- O +Fluorouracil O +cardiotoxicity B +induced O +by O +alpha O +- O +fluoro O +- O +beta O +- O +alanine O +. O + +Cardiotoxicity B +is O +a O +rare O +complication O +occurring O +during O +5 O +- O +fluorouracil O +( O +5 O +- O +FU O +) O +treatment O +for O +malignancies B +. O + +We O +herein O +report O +the O +case O +of O +a O +70 O +- O +year O +- O +old O +man O +with O +5 O +- O +FU O +- O +induced O +cardiotoxicity B +, O +in O +whom O +a O +high O +serum O +level O +of O +alpha O +- O +fluoro O +- O +beta O +- O +alanine O +( O +FBAL O +) O +was O +observed O +. O + +The O +patient O +, O +who O +had O +unresectable O +colon B +cancer I +metastases O +to O +the O +liver O +and O +lung O +, O +was O +referred O +to O +us O +for O +chemotherapy O +from O +an O +affiliated O +hospital O +; O +he O +had O +no O +cardiac O +history O +. O + +After O +admission O +, O +the O +patient O +received O +a O +continuous O +intravenous O +infusion O +of O +5 O +- O +FU O +( O +1000 O +mg O +/ O +day O +) O +, O +during O +which O +precordial B +pain B +with O +right B +bundle I +branch I +block I +occurred O +concomitantly O +with O +a O +high O +serum O +FBAL O +concentration O +of O +1955 O +ng O +/ O +ml O +. O + +Both O +the O +precordial O +pain B +and O +the O +electrocardiographic O +changes O +disappeared O +spontaneously O +after O +the O +discontinuation O +of O +5 O +- O +FU O +. O + +As O +the O +precordial B +pain B +in O +this O +patient O +was O +considered O +to O +have O +been O +due O +to O +5 O +- O +FU O +- O +induced O +cardiotoxicity B +, O +the O +administration O +of O +5 O +- O +FU O +was O +abandoned O +. O + +Instead O +, O +oral O +administration O +of O +S O +- O +1 O +( O +a O +derivative O +of O +5 O +- O +FU O +) O +, O +at O +200 O +mg O +/ O +day O +twice O +a O +week O +, O +was O +instituted O +, O +because O +S O +- O +1 O +has O +a O +strong O +inhibitory O +effect O +on O +dihydropyrimidine O +dehydrogenase O +, O +which O +catalyzes O +the O +degradative O +of O +5 O +- O +FU O +into O +FBAL O +. O + +The O +serum O +FBAL O +concentration O +subsequently O +decreased O +to O +352 O +ng O +/ O +ml O +, O +the O +same O +as O +the O +value O +measured O +on O +the O +first O +day O +of O +S O +- O +1 O +administration O +. O + +Thereafter O +, O +no O +cardiac O +symptoms O +were O +observed O +. O + +The O +patient O +achieved O +a O +partial O +response O +6 O +months O +after O +the O +initiation O +of O +the O +S O +- O +1 O +treatment O +. O + +The O +experience O +of O +this O +case O +, O +together O +with O +a O +review O +of O +the O +literature O +, O +suggests O +that O +FBAL O +is O +related O +to O +5 O +- O +FU O +- O +induced O +cardiotoxicity B +. O + +S O +- O +1 O +may O +be O +administered O +safely O +to O +patients O +with O +5 O +- O +FU O +- O +induced O +cardiotoxicity B +. O + +Hepatocellular B +carcinoma I +in O +Fanconi B +' I +s I +anemia I +treated O +with O +androgen O +and O +corticosteroid O +. O + +The O +case O +of O +an O +11 O +- O +year O +- O +old O +boy O +is O +reported O +who O +was O +known O +to O +have O +Fanconi B +' I +s I +anemia I +for O +3 O +years O +and O +was O +treated O +with O +androgens O +, O +corticosteroids O +and O +transfusions O +. O + +Two O +weeks O +before O +his O +death O +he O +was O +readmitted O +because O +of O +aplastic B +crisis I +with O +septicemia B +and O +marked O +abnormalities B +in I +liver I +function I +and O +died O +of O +hemorrhagic B +bronchopneumonia I +. O + +At O +autopsy O +peliosis B +and O +multiple O +hepatic B +tumors I +were O +found O +which O +histologically O +proved O +to O +be O +well O +- O +differentiated O +hepatocellular B +carcinoma I +. O + +This O +case O +contributes O +to O +the O +previous O +observations O +that O +non O +- O +metastasizing O +hepatic B +neoplasms I +and O +peliosis B +can O +develop O +in O +patients O +with O +androgen O +- O +and O +corticosteroid O +- O +treated O +Fanconi B +' I +s I +anemia I +. O + +The O +influence O +of O +the O +time O +interval O +between O +monoHER O +and O +doxorubicin O +administration O +on O +the O +protection O +against O +doxorubicin O +- O +induced O +cardiotoxicity B +in O +mice O +. O + +PURPOSE O +: O +Despite O +its O +well O +- O +known O +cardiotoxicity B +, O +the O +anthracyclin O +doxorubicin O +( O +DOX O +) O +continues O +to O +be O +an O +effective O +and O +widely O +used O +chemotherapeutic O +agent O +. O + +DOX O +- O +induced O +cardiac B +damage I +presumably O +results O +from O +the O +formation O +of O +free O +radicals O +by O +DOX O +. O + +Reactive O +oxygen O +species O +particularly O +affect O +the O +cardiac O +myocytes O +because O +these O +cells O +seem O +to O +have O +a O +relatively O +poor O +antioxidant O +defense O +system O +. O + +The O +semisynthetic O +flavonoid O +monohydroxyethylrutoside O +( O +monoHER O +) O +showed O +cardioprotection O +against O +DOX O +- O +induced O +cardiotoxicity B +through O +its O +radical O +scavenging O +and O +iron O +chelating O +properties O +. O + +Because O +of O +the O +relatively O +short O +final O +half O +- O +life O +of O +monoHER O +( O +about O +30 O +min O +) O +, O +it O +is O +expected O +that O +the O +time O +interval O +between O +monoHER O +and O +DOX O +might O +be O +of O +influence O +on O +the O +cardioprotective O +effect O +of O +monoHER O +. O + +Therefore O +, O +the O +aim O +of O +the O +present O +study O +was O +to O +investigate O +this O +possible O +effect O +. O + +METHODS O +: O +Six O +groups O +of O +6 O +BALB O +/ O +c O +mice O +were O +treated O +with O +saline O +, O +DOX O +alone O +or O +DOX O +( O +4 O +mg O +/ O +kg O +i O +. O +v O +. O +) O +preceded O +by O +monoHER O +( O +500 O +mg O +/ O +kg O +i O +. O +p O +. O +) O +with O +an O +interval O +of O +10 O +, O +30 O +, O +60 O +or O +120 O +min O +. O + +After O +a O +6 O +- O +week O +treatment O +period O +and O +additional O +observation O +for O +2 O +weeks O +, O +the O +mice O +were O +sacrificed O +. O + +Their O +cardiac O +tissues O +were O +processed O +for O +light O +microscopy O +, O +after O +which O +cardiomyocyte O +damage O +was O +evaluated O +according O +to O +Billingham O +( O +in O +Cancer B +Treat O +Rep O +62 O +( O +6 O +) O +: O +865 O +- O +872 O +, O +1978 O +) O +. O + +Microscopic O +evaluation O +revealed O +that O +treatment O +with O +DOX O +alone O +induced O +significant O +cardiac B +damage I +in O +comparison O +to O +the O +saline O +control O +group O +( O +P O +< O +0 O +. O +001 O +) O +. O + +RESULTS O +: O +The O +number O +of O +damaged O +cardiomyocytes O +was O +9 O +. O +6 O +- O +fold O +( O +95 O +% O +CI O +4 O +. O +4 O +- O +21 O +. O +0 O +) O +higher O +in O +mice O +treated O +with O +DOX O +alone O +than O +that O +in O +animals O +of O +the O +control O +group O +. O + +The O +ratio O +of O +aberrant O +cardiomyocytes O +in O +mice O +treated O +with O +DOX O +preceded O +by O +monoHER O +and O +those O +in O +mice O +treated O +with O +saline O +ranged O +from O +1 O +. O +6 O +to O +2 O +. O +8 O +( O +mean O +2 O +. O +2 O +, O +95 O +% O +CI O +1 O +. O +2 O +- O +4 O +. O +1 O +, O +P O += O +0 O +. O +019 O +) O +. O + +The O +mean O +protective O +effect O +by O +adding O +monoHER O +before O +DOX O +led O +to O +a O +significant O +4 O +. O +4 O +- O +fold O +reduction O +( O +P O +< O +0 O +. O +001 O +, O +95 O +% O +CI O +2 O +. O +3 O +- O +8 O +. O +2 O +) O +of O +abnormal O +cardiomyocytes O +. O + +This O +protective O +effect O +did O +not O +depend O +on O +the O +time O +interval O +between O +monoHER O +and O +DOX O +administration O +( O +P O += O +0 O +. O +345 O +) O +. O + +CONCLUSION O +: O +The O +results O +indicate O +that O +in O +an O +outpatient O +clinical O +setting O +monoHER O +may O +be O +administered O +shortly O +before O +DOX O +. O + +Clinical O +evaluation O +of O +adverse O +effects O +during O +bepridil O +administration O +for O +atrial B +fibrillation I +and I +flutter I +. O + +BACKGROUND O +: O +Bepridil O +hydrochloride O +( O +Bpd O +) O +has O +attracted O +attention O +as O +an O +effective O +drug O +for O +atrial B +fibrillation I +( O +AF B +) O +and O +atrial B +flutter I +( O +AFL B +) O +. O + +However O +, O +serious O +adverse O +effects O +, O +including O +torsade B +de I +pointes I +( O +Tdp B +) O +, O +have O +been O +reported O +. O + +METHODS O +AND O +RESULTS O +: O +Adverse O +effects O +of O +Bpd O +requiring O +discontinuation O +of O +treatment O +were O +evaluated O +. O + +Bpd O +was O +administered O +to O +459 O +patients O +( O +361 O +males O +, O +63 O ++ O +/ O +- O +12 O +years O +old O +) O +comprising O +378 O +AF B +and O +81 O +AFL B +cases O +. O + +Mean O +left O +ventricular O +ejection O +fraction O +and O +atrial O +dimension O +( O +LAD O +) O +were O +66 O ++ O +/ O +- O +11 O +% O +and O +40 O ++ O +/ O +- O +6 O +mm O +, O +respectively O +. O + +Adverse O +effects O +were O +observed O +in O +19 O +patients O +( O +4 O +% O +) O +during O +an O +average O +follow O +- O +up O +of O +20 O +months O +. O + +There O +was O +marked O +QT B +prolongation I +greater O +than O +0 O +. O +55 O +s O +in O +13 O +patients O +, O +bradycardia B +less O +than O +40 O +beats O +/ O +min O +in O +6 O +patients O +, O +dizziness B +and O +general O +fatigue B +in O +1 O +patient O +each O +. O + +In O +4 O +of O +13 O +patients O +with O +QT B +prolongation I +, O +Tdp B +occurred O +. O + +The O +major O +triggering O +factors O +of O +Tdp B +were O +hypokalemia B +and O +sudden O +decrease O +in O +heart O +rate O +. O + +There O +were O +no O +differences O +in O +the O +clinical O +backgrounds O +of O +the O +patients O +with O +and O +without O +Tdp B +other O +than O +LAD O +and O +age O +, O +which O +were O +larger O +and O +older O +in O +the O +patients O +with O +Tdp B +. O + +CONCLUSION O +: O +Careful O +observation O +of O +serum O +potassium O +concentration O +and O +the O +ECG O +should O +always O +be O +done O +during O +Bpd O +administration O +, O +particularly O +in O +elderly O +patients O +. O + +Enhanced O +isoproterenol O +- O +induced O +cardiac B +hypertrophy I +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 O +( O +Iso O +) O +. 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 O +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 ++ O +dP O +/ O +dt O +( O +max O +) 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 O +hypertrophy B +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 +/ O +- O +0 O +. O +004 O +vs O +. O +0 O +. O +24 O ++ O +/ O +- O +0 O +. O +004 O +, O +respectively O +) O +. O + +The O +greater O +LV O +hypertrophy B +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 O +- O +AR O +antagonist O +metoprolol O +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 +- O +9 O +. O +9 O ++ O +/ O +- O +1 O +. O +7 O +% O +vs O +. O +- O +18 O +. O +1 O ++ O +/ O +- O +1 O +. O +5 O +% O +) O +, O +whereas O +the O +effect O +of O +parasympathetic O +blockade O +by O +atropine O +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 B +, O +possibly O +due O +to O +chronically O +low O +sympathetic O +outflow O +directed O +to O +the O +heart O +. O + +Drug O +- O +induced O +long B +QT I +syndrome I +in O +injection O +drug O +users O +receiving O +methadone O +: O +high O +frequency O +in O +hospitalized O +patients O +and O +risk O +factors O +. O + +BACKGROUND O +: O +Drug O +- O +induced O +long B +QT I +syndrome I +is O +a O +serious O +adverse O +drug O +reaction O +. O + +Methadone O +prolongs O +the O +QT O +interval O +in O +vitro O +in O +a O +dose O +- O +dependent O +manner O +. O + +In O +the O +inpatient O +setting O +, O +the O +frequency O +of O +QT B +interval I +prolongation I +with O +methadone O +treatment O +, O +its O +dose O +dependence O +, O +and O +the O +importance O +of O +cofactors O +such O +as O +drug O +- O +drug O +interactions O +remain O +unknown O +. O + +METHODS O +: O +We O +performed O +a O +systematic O +, O +retrospective O +study O +comparing O +active O +or O +former O +intravenous O +drug O +users O +receiving O +methadone O +and O +those O +not O +receiving O +methadone O +among O +all O +patients O +hospitalized O +over O +a O +5 O +- O +year O +period O +in O +a O +tertiary O +care O +hospital O +. O + +A O +total O +of O +167 O +patients O +receiving O +methadone O +fulfilled O +the O +inclusion O +criteria O +and O +were O +compared O +with O +a O +control O +group O +of O +80 O +injection O +drug O +users O +not O +receiving O +methadone O +. O + +In O +addition O +to O +methadone O +dose O +, O +15 O +demographic O +, O +biological O +, O +and O +pharmacological O +variables O +were O +considered O +as O +potential O +risk O +factors O +for O +QT B +prolongation I +. O + +RESULTS O +: O +Among O +167 O +methadone O +maintenance O +patients O +, O +the O +prevalence O +of O +QTc B +prolongation I +to O +0 O +. O +50 O +second O +( O +( O +1 O +/ O +2 O +) O +) O +or O +longer O +was O +16 O +. O +2 O +% O +compared O +with O +0 O +% O +in O +80 O +control O +subjects O +. O + +Six O +patients O +( O +3 O +. O +6 O +% O +) O +in O +the O +methadone O +group O +presented O +torsades B +de I +pointes I +. O + +QTc O +length O +was O +weakly O +but O +significantly O +associated O +with O +methadone O +daily O +dose O +( O +Spearman O +rank O +correlation O +coefficient O +, O +0 O +. O +20 O +; O +P O +< O +. O +01 O +) O +. O + +Multivariate O +regression O +analysis O +allowed O +attribution O +of O +31 O +. O +8 O +% O +of O +QTc O +variability O +to O +methadone O +dose O +, O +cytochrome O +P O +- O +450 O +3A4 O +drug O +- O +drug O +interactions O +, O +hypokalemia B +, O +and O +altered B +liver I +function I +. O + +CONCLUSIONS O +: O +QT B +interval I +prolongation I +in O +methadone O +maintenance O +patients O +hospitalized O +in O +a O +tertiary O +care O +center O +is O +a O +frequent O +finding O +. O + +Methadone O +dose O +, O +presence O +of O +cytochrome O +P O +- O +450 O +3A4 O +inhibitors O +, O +potassium O +level O +, O +and O +liver O +function O +contribute O +to O +QT B +prolongation I +. O + +Long B +QT I +syndrome I +can O +occur O +with O +low O +doses O +of O +methadone O +. O + +Mechanisms O +of O +hypertension B +induced O +by O +nitric O +oxide O +( O +NO O +) O +deficiency O +: O +focus O +on O +venous O +function O +. O + +Loss O +of O +endothelial O +cell O +- O +derived O +nitric O +oxide O +( O +NO O +) O +in O +hypertension B +is O +a O +hallmark O +of O +arterial B +dysfunction I +. O + +Experimental O +hypertension B +created O +by O +the O +removal O +of O +NO O +, O +however O +, O +involves O +mechanisms O +in O +addition O +to O +decreased O +arterial O +vasodilator O +activity O +. O + +These O +include O +augmented O +endothelin O +- O +1 O +( O +ET O +- O +1 O +) O +release O +, O +increased O +sympathetic O +nervous O +system O +activity O +, O +and O +elevated O +tissue O +oxidative O +stress O +. O + +We O +hypothesized O +that O +increased O +venous O +smooth O +muscle O +( O +venomotor O +) O +tone O +plays O +a O +role O +in O +Nomega O +- O +nitro O +- O +L O +- O +arginine O +( O +LNNA O +) O +hypertension B +through O +these O +mechanisms O +. O + +Rats O +were O +treated O +with O +the O +NO O +synthase O +inhibitor O +LNNA O +( O +0 O +. O +5 O +g O +/ O +L O +in O +drinking O +water O +) O +for O +2 O +weeks O +. O + +Mean O +arterial O +pressure O +of O +conscious O +rats O +was O +119 O ++ O +/ O +- O +2 O +mm O +Hg O +in O +control O +and O +194 O ++ O +/ O +- O +5 O +mm O +Hg O +in O +LNNA O +rats O +( O +P O +< O +0 O +. O +05 O +) O +. O + +Carotid O +arteries O +and O +vena O +cava O +were O +removed O +for O +measurement O +of O +isometric O +contraction O +. O + +Maximal O +contraction O +to O +norepinephrine O +was O +modestly O +reduced O +in O +arteries O +from O +LNNA O +compared O +with O +control O +rats O +whereas O +the O +maximum O +contraction O +to O +ET O +- O +1 O +was O +significantly O +reduced O +( O +54 O +% O +control O +) O +. O + +Maximum O +contraction O +of O +vena O +cava O +to O +norepinephrine O +( O +37 O +% O +control O +) O +also O +was O +reduced O +but O +no O +change O +in O +response O +to O +ET O +- O +1 O +was O +observed O +. O + +Mean O +circulatory O +filling O +pressure O +, O +an O +in O +vivo O +measure O +of O +venomotor O +tone O +, O +was O +not O +elevated O +in O +LNNA O +hypertension B +at O +1 O +or O +2 O +weeks O +after O +LNNA O +. O + +The O +superoxide O +scavenger O +tempol O +( O +30 O +, O +100 O +, O +and O +300 O +micromol O +kg O +( O +- O +1 O +) O +, O +IV O +) O +did O +not O +change O +arterial O +pressure O +in O +control O +rats O +but O +caused O +a O +dose O +- O +dependent O +decrease O +in O +LNNA O +rats O +( O +- O +18 O ++ O +/ O +- O +8 O +, O +- O +26 O ++ O +/ O +- O +15 O +, O +and O +- O +54 O ++ O +/ O +- O +11 O +mm O +Hg O +) O +. O + +Similarly O +, O +ganglionic O +blockade O +with O +hexamethonium O +caused O +a O +significantly O +greater O +fall O +in O +LNNA O +hypertensive B +rats O +( O +76 O ++ O +/ O +- O +9 O +mm O +Hg O +) O +compared O +with O +control O +rats O +( O +35 O ++ O +/ O +- O +10 O +mm O +Hg O +) O +. O + +Carotid O +arteries O +, O +vena O +cava O +, O +and O +sympathetic O +ganglia O +from O +LNNA O +rats O +had O +higher O +basal O +levels O +of O +superoxide O +compared O +with O +those O +from O +control O +rats O +. O + +These O +data O +suggest O +that O +while O +NO O +deficiency O +increases O +oxidative O +stress O +and O +sympathetic O +activity O +in O +both O +arterial O +and O +venous O +vessels O +, O +the O +impact O +on O +veins O +does O +not O +make O +a O +major O +contribution O +to O +this O +form O +of O +hypertension B +. O + +Association O +of O +DRD2 O +polymorphisms O +and O +chlorpromazine O +- O +induced O +extrapyramidal B +syndrome I +in O +Chinese O +schizophrenic B +patients O +. O + +AIM O +: O +Extrapyramidal B +syndrome I +( O +EPS B +) O +is O +most O +commonly O +affected O +by O +typical O +antipsychotic O +drugs O +that O +have O +a O +high O +affinity O +with O +the O +D2 O +receptor O +. O + +Recently O +, O +many O +research O +groups O +have O +reported O +on O +the O +positive O +relationship O +between O +the O +genetic O +variations O +in O +the O +DRD2 O +gene O +and O +the O +therapeutic O +response O +in O +schizophrenia B +patients O +as O +a O +result O +of O +the O +role O +of O +variations O +in O +the O +receptor O +in O +modulating O +receptor O +expression O +. O + +In O +this O +study O +, O +we O +evaluate O +the O +role O +DRD2 O +plays O +in O +chlorpromazine O +- O +induced O +EPS B +in O +schizophrenic B +patients O +. O + +METHODS O +: O +We O +identified O +seven O +SNP O +( O +single O +nucleotide O +polymorphism O +) O +( O +- O +141Cins O +> O +del O +, O +TaqIB O +, O +TaqID O +, O +Ser311Cys O +, O +rs6275 O +, O +rs6277 O +and O +TaqIA O +) O +in O +the O +DRD2 O +gene O +in O +146 O +schizophrenic B +inpatients O +( O +59 O +with O +EPS B +and O +87 O +without O +EPS B +according O +to O +the O +Simpson O +- O +Angus O +Scale O +) O +treated O +with O +chlorpromazine O +after O +8 O +weeks O +. O + +The O +alleles O +of O +all O +loci O +were O +determined O +by O +PCR O +( O +polymerase O +chain O +reaction O +) O +. O + +RESULTS O +: O +Polymorphisms O +TaqID O +, O +Ser311Cys O +and O +rs6277 O +were O +not O +polymorphic O +in O +the O +population O +recruited O +in O +the O +present O +study O +. O + +No O +statistical O +significance O +was O +found O +in O +the O +allele O +distribution O +of O +- O +141Cins O +> O +del O +, O +TaqIB O +, O +rs6275 O +and O +TaqIA O +or O +in O +the O +estimated O +haplotypes O +( O +constituted O +by O +TaqIB O +, O +rs6275 O +and O +TaqIA O +) O +in O +linkage O +disequilibrium O +between O +the O +two O +groups O +. O + +CONCLUSION O +: O +Our O +results O +did O +not O +lend O +strong O +support O +to O +the O +view O +that O +the O +genetic O +variation O +of O +the O +DRD2 O +gene O +plays O +a O +major O +role O +in O +the O +individually O +variable O +adverse O +effect O +induced O +by O +chlorpromazine O +, O +at O +least O +in O +Chinese O +patients O +with O +schizophrenia B +. O + +Our O +results O +confirmed O +a O +previous O +study O +on O +the O +relationship O +between O +DRD2 O +and O +EPS B +in O +Caucasians O +. O + +Physical O +training O +decreases O +susceptibility O +to O +subsequent O +pilocarpine O +- O +induced O +seizures B +in O +the O +rat O +. O + +Regular O +motor O +activity O +has O +many O +benefits O +for O +mental O +and O +physical O +condition O +but O +its O +implications O +for O +epilepsy B +are O +still O +controversial O +. O + +In O +order O +to O +elucidate O +this O +problem O +, O +we O +have O +studied O +the O +effect O +of O +long O +- O +term O +physical O +activity O +on O +susceptibility O +to O +subsequent O +seizures B +. O + +Male O +Wistar O +rats O +were O +subjected O +to O +repeated O +training O +sessions O +in O +a O +treadmill O +and O +swimming O +pool O +. O + +Thereafter O +, O +seizures B +were O +induced O +by O +pilocarpine O +injections O +in O +trained O +and O +non O +- O +trained O +control O +groups O +. O + +During O +the O +acute O +period O +of O +status B +epilepticus I +, O +we O +measured O +: O +( O +1 O +) O +the O +latency O +of O +the O +first O +motor O +sign O +, O +( O +2 O +) O +the O +intensity O +of O +seizures B +, O +( O +3 O +) O +the O +time O +when O +it O +occurred O +within O +the O +6 O +- O +h O +observation O +period O +, O +and O +( O +4 O +) O +the O +time O +when O +the O +acute O +period O +ended O +. O + +All O +these O +behavioral O +parameters O +showed O +statistically O +significant O +changes O +suggesting O +that O +regular O +physical O +exercises O +decrease O +susceptibility O +to O +subsequently O +induced O +seizures B +and O +ameliorate O +the O +course O +of O +experimentally O +induced O +status B +epilepticus I +. O + +Tonic O +dopaminergic O +stimulation O +impairs O +associative O +learning O +in O +healthy O +subjects O +. O + +Endogenous O +dopamine O +plays O +a O +central O +role O +in O +salience O +coding O +during O +associative O +learning O +. O + +Administration O +of O +the O +dopamine O +precursor O +levodopa O +enhances O +learning O +in O +healthy O +subjects O +and O +stroke B +patients O +. O + +Because O +levodopa O +increases O +both O +phasic O +and O +tonic O +dopaminergic O +neurotransmission O +, O +the O +critical O +mechanism O +mediating O +the O +enhancement O +of O +learning O +is O +unresolved O +. O + +We O +here O +probed O +how O +selective O +tonic O +dopaminergic O +stimulation O +affects O +associative O +learning O +. O + +Forty O +healthy O +subjects O +were O +trained O +in O +a O +novel O +vocabulary O +of O +45 O +concrete O +nouns O +over O +the O +course O +of O +5 O +consecutive O +training O +days O +in O +a O +prospective O +, O +randomized O +, O +double O +- O +blind O +, O +placebo O +- O +controlled O +design O +. O + +Subjects O +received O +the O +tonically O +stimulating O +dopamine O +- O +receptor O +agonist O +pergolide O +( O +0 O +. O +1 O +mg O +) O +vs O +placebo O +120 O +min O +before O +training O +on O +each O +training O +day O +. O + +The O +dopamine O +agonist O +significantly O +impaired O +novel O +word O +learning O +compared O +to O +placebo O +. O + +This O +learning O +decrement O +persisted O +up O +to O +the O +last O +follow O +- O +up O +4 O +weeks O +post O +- O +training O +. O + +Subjects O +treated O +with O +pergolide O +also O +showed O +restricted O +emotional O +responses O +compared O +to O +the O +PLACEBO O +group O +. O + +The O +extent O +of O +' O +flattened O +' O +affect O +with O +pergolide O +was O +related O +to O +the O +degree O +of O +learning O +inhibition O +. O + +These O +findings O +suggest O +that O +tonic O +occupation O +of O +dopamine O +receptors O +impairs O +learning O +by O +competition O +with O +phasic O +dopamine O +signals O +. O + +Thus O +, O +phasic O +signaling O +seems O +to O +be O +the O +critical O +mechanism O +by O +which O +dopamine O +enhances O +associative O +learning O +in O +healthy O +subjects O +and O +stroke B +patients O +. O + +Minocycline O +- O +induced O +vasculitis B +fulfilling O +the O +criteria O +of O +polyarteritis B +nodosa I +. O + +A O +47 O +- O +year O +- O +old O +man O +who O +had O +been O +taking O +minocycline O +for O +palmoplantar B +pustulosis I +developed O +fever B +, O +myalgias B +, O +polyneuropathy B +, O +and O +testicular B +pain I +, O +with O +elevated O +C O +- O +reactive O +protein O +( O +CRP O +) O +. O + +Neither O +myeloperoxidase O +- O +nor O +proteinase O +- O +3 O +- O +antineutrophil O +cytoplasmic O +antibody O +was O +positive O +. O + +These O +manifestations O +met O +the O +American O +College O +of O +Rheumatology O +1990 O +criteria O +for O +the O +classification O +of O +polyarteritis B +nodosa I +. O + +Stopping O +minocycline O +led O +to O +amelioration O +of O +symptoms O +and O +normalization O +of O +CRP O +level O +. O + +To O +our O +knowledge O +, O +this O +is O +the O +second O +case O +of O +minocycline O +- O +induced O +vasculitis B +satisfying O +the O +criteria O +. O + +Differential O +diagnosis O +for O +drug B +- I +induced I +disease I +is O +invaluable O +even O +for O +patients O +with O +classical O +polyarteritis B +nodosa I +. O + +Intramuscular O +hepatitis B +B I +immune O +globulin O +combined O +with O +lamivudine O +in O +prevention O +of O +hepatitis B +B I +recurrence O +after O +liver O +transplantation O +. O + +BACKGROUND O +: O +Combined O +hepatitis B +B I +immune O +globulin O +( O +HBIg O +) O +and O +lamivudine O +in O +prophylaxis O +of O +the O +recurrence O +of O +hepatitis B +B I +after O +liver O +transplantation O +has O +significantly O +improved O +the O +survival O +of O +HBsAg O +positive O +patients O +. O + +This O +study O +was O +undertaken O +to O +evaluate O +the O +outcomes O +of O +liver O +transplantation O +for O +patients O +with O +hepatitis B +B I +virus I +( O +HBV B +) O +. O + +METHODS O +: O +A O +retrospective O +chart O +analysis O +and O +a O +review O +of O +the O +organ O +transplant O +database O +identified O +51 O +patients O +( O +43 O +men O +and O +8 O +women O +) O +transplanted O +for O +benign O +HBV O +- O +related O +cirrhotic B +diseases I +between O +June O +2002 O +and O +December O +2004 O +who O +had O +survived O +more O +than O +3 O +months O +. O + +HBIg O +was O +administered O +intravenously O +during O +the O +first O +week O +and O +intramuscularly O +thereafter O +. O + +RESULTS O +: O +At O +a O +median O +follow O +- O +up O +of O +14 O +. O +1 O +months O +, O +the O +overall O +recurrence O +rate O +in O +the O +51 O +patients O +was O +3 O +. O +9 O +% O +( O +2 O +/ O +51 O +) O +. O + +The O +overall O +patient O +survival O +was O +88 O +. O +3 O +% O +, O +and O +82 O +. O +4 O +% O +after O +1 O +and O +2 O +years O +, O +respectively O +. O + +A O +daily O +oral O +dose O +of O +100 O +mg O +lamivudine O +for O +2 O +weeks O +before O +transplantation O +for O +10 O +patients O +enabled O +57 O +. O +1 O +% O +( O +4 O +/ O +7 O +) O +and O +62 O +. O +5 O +% O +( O +5 O +/ O +8 O +) O +of O +HBV O +- O +DNA O +and O +HBeAg O +positive O +patients O +respectively O +to O +convert O +to O +be O +negative O +. O + +Intramuscular O +HBIg O +was O +well O +tolerated O +in O +all O +patients O +. O + +CONCLUSION O +: O +Lamivudine O +combined O +with O +intramuscular O +HBIg O +can O +effectively O +prevent O +allograft O +from O +the O +recurrence O +of O +HBV B +after O +liver O +transplantation O +. O + +Anticonvulsant O +effect O +of O +eslicarbazepine O +acetate O +( O +BIA O +2 O +- O +093 O +) O +on O +seizures B +induced O +by O +microperfusion O +of O +picrotoxin O +in O +the O +hippocampus O +of O +freely O +moving O +rats O +. O + +Eslicarbazepine O +acetate O +( O +BIA O +2 O +- O +093 O +, O +S O +- O +( O +- O +) O +- O +10 O +- O +acetoxy O +- O +10 O +, O +11 O +- O +dihydro O +- O +5H O +- O +dibenzo O +/ O +b O +, O +f O +/ O +azepine O +- O +5 O +- O +carboxamide O +) O +is O +a O +novel O +antiepileptic O +drug O +, O +now O +in O +Phase O +III O +clinical O +trials O +, O +designed O +with O +the O +aim O +of O +improving O +efficacy O +and O +safety O +in O +comparison O +with O +the O +structurally O +related O +drugs O +carbamazepine O +( O +CBZ O +) O +and O +oxcarbazepine O +( O +OXC O +) O +. O + +We O +have O +studied O +the O +effects O +of O +oral O +treatment O +with O +eslicarbazepine O +acetate O +on O +a O +whole O +- O +animal O +model O +in O +which O +partial O +seizures B +can O +be O +elicited O +repeatedly O +on O +different O +days O +without O +changes O +in O +threshold O +or O +seizure B +patterns O +. O + +In O +the O +animals O +treated O +with O +threshold O +doses O +of O +picrotoxin O +, O +the O +average O +number O +of O +seizures B +was O +2 O +. O +3 O ++ O +/ O +- O +1 O +. O +2 O +, O +and O +average O +seizure B +duration O +was O +39 O +. O +5 O ++ O +/ O +- O +8 O +. O +4s O +. O + +Pre O +- O +treatment O +with O +a O +dose O +of O +30 O +mg O +/ O +kg O +2h O +before O +picrotoxin O +microperfusion O +prevented O +seizures B +in O +the O +75 O +% O +of O +the O +rats O +. O + +Lower O +doses O +( O +3 O +and O +10mg O +/ O +kg O +) O +did O +not O +suppress O +seizures B +, O +however O +, O +after O +administration O +of O +10mg O +/ O +kg O +, O +significant O +reductions O +in O +seizures B +duration O +( O +24 O +. O +3 O ++ O +/ O +- O +6 O +. O +8s O +) O +and O +seizure B +number O +( O +1 O +. O +6 O ++ O +/ O +- O +0 O +. O +34 O +) O +were O +found O +. O + +No O +adverse O +effects O +of O +eslicarbazepine O +acetate O +were O +observed O +in O +the O +behavioral O +/ O +EEG O +patterns O +studied O +, O +including O +sleep O +/ O +wakefulness O +cycle O +, O +at O +the O +doses O +studied O +. O + +Acute B +renal I +failure I +associated O +with O +prolonged O +intake O +of O +slimming O +pills O +containing O +anthraquinones O +. O + +Chinese O +herbal O +medicine O +preparations O +are O +widely O +available O +and O +often O +regarded O +by O +the O +public O +as O +natural O +and O +safe O +remedies O +for O +a O +variety O +of O +medical O +conditions O +. O + +Nephropathy B +caused O +by O +Chinese O +herbs O +has O +previously O +been O +reported O +, O +usually O +involving O +the O +use O +of O +aristolochic O +acids O +. O + +We O +report O +a O +23 O +- O +year O +- O +old O +woman O +who O +developed O +acute B +renal I +failure I +following O +prolonged O +use O +of O +a O +proprietary O +Chinese O +herbal O +slimming O +pill O +that O +contained O +anthraquinone O +derivatives O +, O +extracted O +from O +Rhizoma O +Rhei O +( O +rhubarb O +) O +. O + +The O +renal B +injury I +was O +probably O +aggravated O +by O +the O +concomitant O +intake O +of O +a O +non O +- O +steroidal O +anti O +- O +inflammatory O +drug O +, O +diclofenac O +. O + +Renal O +pathology O +was O +that O +of O +hypocellular O +interstitial B +fibrosis B +. O + +Spontaneous O +renal O +recovery O +occurred O +upon O +cessation O +of O +the O +slimming O +pills O +, O +but O +mild O +interstitial B +fibrosis B +and O +tubular B +atrophy I +was O +still O +evident O +histologically O +4 O +months O +later O +. O + +Although O +a O +causal O +relationship O +between O +the O +use O +of O +an O +anthraquinone O +- O +containing O +herbal O +agent O +and O +renal B +injury I +remains O +to O +be O +proven O +, O +phytotherapy O +- O +associated O +interstitial B +nephropathy I +should O +be O +considered O +in O +patients O +who O +present O +with O +unexplained O +renal B +failure I +. O + +Chloroacetaldehyde O +as O +a O +sulfhydryl O +reagent O +: O +the O +role O +of O +critical O +thiol O +groups O +in O +ifosfamide O +nephropathy B +. O + +Chloroacetaldehyde O +( O +CAA O +) O +is O +a O +metabolite O +of O +the O +alkylating O +agent O +ifosfamide O +( O +IFO O +) O +and O +putatively O +responsible O +for O +renal B +damage I +following O +anti O +- O +tumor B +therapy O +with O +IFO O +. O + +Depletion O +of O +sulfhydryl O +( O +SH O +) O +groups O +has O +been O +reported O +from O +cell O +culture O +, O +animal O +and O +clinical O +studies O +. O + +In O +this O +work O +the O +effect O +of O +CAA O +on O +human O +proximal O +tubule O +cells O +in O +primary O +culture O +( O +hRPTEC O +) O +was O +investigated O +. O + +Toxicity B +of O +CAA O +was O +determined O +by O +protein O +content O +, O +cell O +number O +, O +LDH O +release O +, O +trypan O +blue O +exclusion O +assay O +and O +caspase O +- O +3 O +activity O +. O + +Free O +thiols O +were O +measured O +by O +the O +method O +of O +Ellman O +. O + +CAA O +reduced O +hRPTEC O +cell O +number O +and O +protein O +, O +induced O +a O +loss O +in O +free O +intracellular O +thiols O +and O +an O +increase O +in O +necrosis B +markers O +. O + +CAA O +but O +not O +acrolein O +inhibited O +the O +cysteine O +proteases O +caspase O +- O +3 O +, O +caspase O +- O +8 O +and O +cathepsin O +B O +. O + +Caspase O +activation O +by O +cisplatin O +was O +inhibited O +by O +CAA O +. O + +In O +cells O +stained O +with O +fluorescent O +dyes O +targeting O +lysosomes O +, O +CAA O +induced O +an O +increase O +in O +lysosomal O +size O +and O +lysosomal O +leakage O +. O + +The O +effects O +of O +CAA O +on O +cysteine O +protease O +activities O +and O +thiols O +could O +be O +reproduced O +in O +cell O +lysate O +. O + +Acidification O +, O +which O +slowed O +the O +reaction O +of O +CAA O +with O +thiol O +donors O +, O +could O +also O +attenuate O +effects O +of O +CAA O +on O +necrosis B +markers O +, O +thiol O +depletion O +and O +cysteine O +protease O +inhibition O +in O +living O +cells O +. O + +Thus O +, O +CAA O +directly O +reacts O +with O +cellular O +protein O +and O +non O +- O +protein O +thiols O +, O +mediating O +its O +toxicity B +on O +hRPTEC O +. O + +This O +effect O +can O +be O +reduced O +by O +acidification O +. O + +Therefore O +, O +urinary O +acidification O +could O +be O +an O +option O +to O +prevent O +IFO O +nephropathy B +in O +patients O +. O + +Stereological O +methods O +reveal O +the O +robust O +size O +and O +stability O +of O +ectopic O +hilar O +granule O +cells O +after O +pilocarpine O +- O +induced O +status B +epilepticus I +in O +the O +adult O +rat O +. O + +Following O +status B +epilepticus I +in O +the O +rat O +, O +dentate O +granule O +cell O +neurogenesis O +increases O +greatly O +, O +and O +many O +of O +the O +new O +neurons O +appear O +to O +develop O +ectopically O +, O +in O +the O +hilar O +region O +of O +the O +hippocampal O +formation O +. O + +It O +has O +been O +suggested O +that O +the O +ectopic O +hilar O +granule O +cells O +could O +contribute O +to O +the O +spontaneous O +seizures B +that O +ultimately O +develop O +after O +status B +epilepticus I +. O + +However O +, O +the O +population O +has O +never O +been O +quantified O +, O +so O +it O +is O +unclear O +whether O +it O +is O +substantial O +enough O +to O +have O +a O +strong O +influence O +on O +epileptogenesis O +. O + +To O +quantify O +this O +population O +, O +the O +total O +number O +of O +ectopic O +hilar O +granule O +cells O +was O +estimated O +using O +unbiased O +stereology O +at O +different O +times O +after O +pilocarpine O +- O +induced O +status B +epilepticus I +. O + +The O +number O +of O +hilar O +neurons O +immunoreactive O +for O +Prox O +- O +1 O +, O +a O +granule O +- O +cell O +- O +specific O +marker O +, O +was O +estimated O +using O +the O +optical O +fractionator O +method O +. O + +The O +results O +indicate O +that O +the O +size O +of O +the O +hilar O +ectopic O +granule O +cell O +population O +after O +status B +epilepticus I +is O +substantial O +, O +and O +stable O +over O +time O +. O + +Interestingly O +, O +the O +size O +of O +the O +population O +appears O +to O +be O +correlated O +with O +the O +frequency O +of O +behavioral O +seizures B +, O +because O +animals O +with O +more O +ectopic O +granule O +cells O +in O +the O +hilus O +have O +more O +frequent O +behavioral O +seizures B +. O + +The O +hilar O +ectopic O +granule O +cell O +population O +does O +not O +appear O +to O +vary O +systematically O +across O +the O +septotemporal O +axis O +, O +although O +it O +is O +associated O +with O +an O +increase O +in O +volume O +of O +the O +hilus O +. O + +The O +results O +provide O +new O +insight O +into O +the O +potential O +role O +of O +ectopic O +hilar O +granule O +cells O +in O +the O +pilocarpine O +model O +of O +temporal B +lobe I +epilepsy I +. O + +A O +prospective O +, O +open O +- O +label O +trial O +of O +galantamine O +in O +autistic B +disorder I +. O + +OBJECTIVE O +: O +Post O +- O +mortem O +studies O +have O +reported O +abnormalities O +of O +the O +cholinergic O +system O +in O +autism B +. O + +The O +purpose O +of O +this O +study O +was O +to O +assess O +the O +use O +of O +galantamine O +, O +an O +acetylcholinesterase O +inhibitor O +and O +nicotinic O +receptor O +modulator O +, O +in O +the O +treatment O +of O +interfering O +behaviors O +in O +children O +with O +autism B +. O + +METHODS O +: O +Thirteen O +medication O +- O +free O +children O +with O +autism B +( O +mean O +age O +, O +8 O +. O +8 O ++ O +/ O +- O +3 O +. O +5 O +years O +) O +participated O +in O +a O +12 O +- O +week O +, O +open O +- O +label O +trial O +of O +galantamine O +. O + +Patients O +were O +rated O +monthly O +by O +parents O +on O +the O +Aberrant O +Behavior O +Checklist O +( O +ABC O +) O +and O +the O +Conners O +' O +Parent O +Rating O +Scale O +- O +Revised O +, O +and O +by O +a O +physician O +using O +the O +Children O +' O +s O +Psychiatric B +Rating O +Scale O +and O +the O +Clinical O +Global O +Impressions O +scale O +. O + +RESULTS O +: O +Patients O +showed O +a O +significant O +reduction O +in O +parent O +- O +rated O +irritability B +and O +social O +withdrawal I +on O +the O +ABC O +as O +well O +as O +significant O +improvements O +in O +emotional B +lability I +and O +inattention B +on O +the O +Conners O +' O +Parent O +Rating O +Scale O +- O +- O +Revised O +. O + +Similarly O +, O +clinician O +ratings O +showed O +reductions O +in O +the O +anger B +subscale O +of O +the O +Children O +' O +s O +Psychiatric B +Rating O +Scale O +. O + +Eight O +of O +13 O +participants O +were O +rated O +as O +responders O +on O +the O +basis O +of O +their O +improvement O +scores O +on O +the O +Clinical O +Global O +Impressions O +scale O +. O + +Overall O +, O +galantamine O +was O +well O +- O +tolerated O +, O +with O +no O +significant O +adverse O +effects O +apart O +from O +headaches B +in O +one O +patient O +. O + +CONCLUSION O +: O +In O +this O +open O +trial O +, O +galantamine O +was O +well O +- O +tolerated O +and O +appeared O +to O +be O +beneficial O +for O +the O +treatment O +of O +interfering O +behaviors O +in O +children O +with O +autism B +, O +particularly O +aggression B +, O +behavioral B +dyscontrol I +, O +and O +inattention B +. O + +Further O +controlled O +trials O +are O +warranted O +. O + +Randomized O +comparison O +of O +olanzapine O +versus O +risperidone O +for O +the O +treatment O +of O +first O +- O +episode O +schizophrenia B +: O +4 O +- O +month O +outcomes O +. O + +OBJECTIVE O +: O +The O +authors O +compared O +4 O +- O +month O +treatment O +outcomes O +for O +olanzapine O +versus O +risperidone O +in O +patients O +with O +first O +- O +episode O +schizophrenia B +spectrum I +disorders I +. O + +METHOD O +: O +One O +hundred O +twelve O +subjects O +( O +70 O +% O +male O +; O +mean O +age O += O +23 O +. O +3 O +years O +[ O +SD O += O +5 O +. O +1 O +] O +) O +with O +first O +- O +episode O +schizophrenia B +( O +75 O +% O +) O +, O +schizophreniform B +disorder I +( O +17 O +% O +) O +, O +or O +schizoaffective B +disorder I +( O +8 O +% O +) O +were O +randomly O +assigned O +to O +treatment O +with O +olanzapine O +( O +2 O +. O +5 O +- O +20 O +mg O +/ O +day O +) O +or O +risperidone O +( O +1 O +- O +6 O +mg O +/ O +day O +) O +. O + +RESULTS O +: O +Response O +rates O +did O +not O +significantly O +differ O +between O +olanzapine O +( O +43 O +. O +7 O +% O +, O +95 O +% O +CI O += O +28 O +. O +8 O +% O +- O +58 O +. O +6 O +% O +) O +and O +risperidone O +( O +54 O +. O +3 O +% O +, O +95 O +% O +CI O += O +39 O +. O +9 O +% O +- O +68 O +. O +7 O +% O +) O +. O + +Among O +those O +responding O +to O +treatment O +, O +more O +subjects O +in O +the O +olanzapine O +group O +( O +40 O +. O +9 O +% O +, O +95 O +% O +CI O += O +16 O +. O +8 O +% O +- O +65 O +. O +0 O +% O +) O +than O +in O +the O +risperidone O +group O +( O +18 O +. O +9 O +% O +, O +95 O +% O +CI O += O +0 O +% O +- O +39 O +. O +2 O +% O +) O +had O +subsequent O +ratings O +not O +meeting O +response O +criteria O +. O + +Negative O +symptom O +outcomes O +and O +measures O +of O +parkinsonism B +and O +akathisia B +did O +not O +differ O +between O +medications O +. O + +Extrapyramidal O +symptom O +severity O +scores O +were O +1 O +. O +4 O +( O +95 O +% O +CI O += O +1 O +. O +2 O +- O +1 O +. O +6 O +) O +with O +risperidone O +and O +1 O +. O +2 O +( O +95 O +% O +CI O += O +1 O +. O +0 O +- O +1 O +. O +4 O +) O +with O +olanzapine O +. O + +Significantly O +more O +weight B +gain I +occurred O +with O +olanzapine O +than O +with O +risperidone O +: O +the O +increase O +in O +weight O +at O +4 O +months O +relative O +to O +baseline O +weight O +was O +17 O +. O +3 O +% O +( O +95 O +% O +CI O += O +14 O +. O +2 O +% O +- O +20 O +. O +5 O +% O +) O +with O +olanzapine O +and O +11 O +. O +3 O +% O +( O +95 O +% O +CI O += O +8 O +. O +4 O +% O +- O +14 O +. O +3 O +% O +) O +with O +risperidone O +. O + +Body O +mass O +index O +at O +baseline O +and O +at O +4 O +months O +was O +24 O +. O +3 O +( O +95 O +% O +CI O += O +22 O +. O +8 O +- O +25 O +. O +7 O +) O +versus O +28 O +. O +2 O +( O +95 O +% O +CI O += O +26 O +. O +7 O +- O +29 O +. O +7 O +) O +with O +olanzapine O +and O +23 O +. O +9 O +( O +95 O +% O +CI O += O +22 O +. O +5 O +- O +25 O +. O +3 O +) O +versus O +26 O +. O +7 O +( O +95 O +% O +CI O += O +25 O +. O +2 O +- O +28 O +. O +2 O +) O +with O +risperidone O +. O + +CONCLUSIONS O +: O +Clinical O +outcomes O +with O +risperidone O +were O +equal O +to O +those O +with O +olanzapine O +, O +and O +response O +may O +be O +more O +stable O +. O + +Olanzapine O +may O +have O +an O +advantage O +for O +motor O +side O +effects O +. O + +Both O +medications O +caused O +substantial O +rapid O +weight B +gain I +, O +but O +weight B +gain I +was O +greater O +with O +olanzapine O +. O + +Early O +paracentral O +visual B +field I +loss I +in O +patients O +taking O +hydroxychloroquine O +. O + +OBJECTIVE O +: O +To O +review O +the O +natural O +history O +and O +ocular O +and O +systemic O +adverse O +effects O +of O +patients O +taking O +hydroxychloroquine O +sulfate O +who O +attended O +an O +ophthalmic O +screening O +program O +. O + +DESIGN O +: O +Retrospective O +study O +. O + +RESULTS O +: O +Records O +of O +262 O +patients O +who O +were O +taking O +hydroxychloroquine O +and O +screened O +in O +the O +Department O +of O +Ophthalmology O +were O +reviewed O +. O + +Of O +the O +262 O +patients O +, O +14 O +( O +18 O +% O +) O +of O +76 O +who O +had O +stopped O +treatment O +at O +the O +time O +of O +the O +study O +experienced O +documented O +adverse O +effects O +. O + +Systemic O +adverse O +effects O +occurred O +in O +8 O +patients O +( O +10 O +. O +5 O +% O +) O +and O +ocular O +adverse O +effects O +, O +in O +5 O +( O +6 O +. O +5 O +% O +) O +. O + +Thirty O +- O +five O +patients O +( O +13 O +. O +4 O +% O +) O +had O +visual B +field I +abnormalities I +, O +which O +were O +attributed O +to O +hydroxychloroquine O +treatment O +in O +4 O +patients O +( O +1 O +. O +5 O +% O +) O +. O + +Three O +of O +the O +4 O +patients O +were O +taking O +less O +than O +6 O +. O +5 O +mg O +/ O +kg O +per O +day O +and O +all O +patients O +had O +normal O +renal O +and O +liver O +function O +test O +results O +. O + +CONCLUSIONS O +: O +The O +current O +study O +used O +a O +protocol O +of O +visual O +acuity O +and O +color O +vision O +assessment O +, O +funduscopy O +, O +and O +Humphrey O +10 O +- O +2 O +visual O +field O +testing O +and O +shows O +that O +visual B +field I +defects I +appeared O +before O +any O +corresponding O +changes O +in O +any O +other O +tested O +clinical O +parameters O +; O +the O +defects O +were O +reproducible O +and O +the O +test O +parameters O +were O +reliable O +. O + +Patients O +taking O +hydroxychloroquine O +can O +demonstrate O +a O +toxic O +reaction O +in O +the O +retina O +despite O +the O +absence O +of O +known O +risk O +factors O +. O + +Screening O +, O +including O +Humphrey O +10 O +- O +2 O +visual O +field O +assessment O +, O +is O +recommended O +2 O +years O +after O +the O +initial O +baseline O +and O +yearly O +thereafter O +. O + +Peri O +- O +operative O +atrioventricular B +block I +as O +a O +result O +of O +chemotherapy O +with O +epirubicin O +and O +paclitaxel O +. O + +A O +47 O +- O +year O +- O +old O +woman O +presented O +for O +mastectomy O +and O +immediate O +latissimus O +dorsi O +flap O +reconstruction O +having O +been O +diagnosed O +with O +carcinoma B +of I +the I +breast I +6 O +months O +previously O +. O + +In O +the O +preceding O +months O +she O +had O +received O +neo O +- O +adjuvant O +chemotherapy O +with O +epirubicin O +, O +paclitaxel O +( O +Taxol O +) O +and O +cyclophosphamide O +. O + +This O +had O +been O +apparently O +uncomplicated O +and O +she O +had O +maintained O +a O +remarkably O +high O +level O +of O +physical O +activity O +. O + +She O +was O +found O +to O +be O +bradycardic B +at O +pre O +- O +operative O +assessment O +but O +had O +no O +cardiac O +symptoms O +. O + +Second O +degree O +Mobitz B +type O +II O +atrioventricular B +block I +was O +diagnosed O +on O +electrocardiogram O +, O +and O +temporary O +transvenous O +ventricular O +pacing O +instituted O +in O +the O +peri O +- O +operative O +period O +. O + +We O +discuss O +how O +evidence O +- O +based O +guidelines O +would O +not O +have O +been O +helpful O +in O +this O +case O +, O +and O +how O +chemotherapy O +can O +exhibit O +substantial O +cardiotoxicity B +that O +may O +develop O +over O +many O +years O +. O + +We O +suggest O +that O +patients O +who O +have O +received O +chemotherapy O +at O +any O +time O +should O +have O +a O +pre O +- O +operative O +electrocardiogram O +even O +if O +they O +are O +asymptomatic O +. O + +Risks O +and O +benefits O +of O +COX O +- O +2 O +inhibitors O +vs O +non O +- O +selective O +NSAIDs O +: O +does O +their O +cardiovascular O +risk O +exceed O +their O +gastrointestinal O +benefit O +? O + +A O +retrospective O +cohort O +study O +. O + +OBJECTIVES O +: O +The O +risk O +of O +acute B +myocardial I +infarction I +( O +AMI B +) O +with O +COX O +- O +2 O +inhibitors O +may O +offset O +their O +gastrointestinal O +( O +GI O +) O +benefit O +compared O +with O +non O +- O +selective O +( O +NS O +) O +non O +- O +steroidal O +anti O +- O +inflammatory O +drugs O +( O +NSAIDs O +) O +. O + +We O +aimed O +to O +compare O +the O +risks O +of O +hospitalization O +for O +AMI B +and I +GI I +bleeding I +among O +elderly O +patients O +using O +COX O +- O +2 O +inhibitors O +, O +NS O +- O +NSAIDs O +and O +acetaminophen O +. O + +METHODS O +: O +We O +conducted O +a O +retrospective O +cohort O +study O +using O +administrative O +data O +of O +patients O +> O +or O += O +65 O +years O +of O +age O +who O +filled O +a O +prescription O +for O +NSAID O +or O +acetaminophen O +during O +1999 O +- O +2002 O +. O + +Outcomes O +were O +compared O +using O +Cox O +regression O +models O +with O +time O +- O +dependent O +exposures O +. O + +RESULTS O +: O +Person O +- O +years O +of O +exposure O +among O +non O +- O +users O +of O +aspirin O +were O +: O +75 O +, O +761 O +to O +acetaminophen O +, O +42 O +, O +671 O +to O +rofecoxib O +65 O +, O +860 O +to O +celecoxib O +, O +and O +37 O +, O +495 O +to O +NS O +- O +NSAIDs O +. O + +Among O +users O +of O +aspirin O +, O +they O +were O +: O +14 O +, O +671 O +to O +rofecoxib O +, O +22 O +, O +875 O +to O +celecoxib O +, O +9 O +, O +832 O +to O +NS O +- O +NSAIDs O +and O +38 O +, O +048 O +to O +acetaminophen O +. O + +Among O +non O +- O +users O +of O +aspirin O +, O +the O +adjusted O +hazard O +ratios O +( O +95 O +% O +confidence O +interval O +) O +of O +hospitalization O +for O +AMI B +/ O +GI B +vs O +the O +acetaminophen O +( O +with O +no O +aspirin O +) O +group O +were O +: O +rofecoxib O +1 O +. O +27 O +( O +1 O +. O +13 O +, O +1 O +. O +42 O +) O +, O +celecoxib O +0 O +. O +93 O +( O +0 O +. O +83 O +, O +1 O +. O +03 O +) O +, O +naproxen O +1 O +. O +59 O +( O +1 O +. O +31 O +, O +1 O +. O +93 O +) O +, O +diclofenac O +1 O +. O +17 O +( O +0 O +. O +99 O +, O +1 O +. O +38 O +) O +and O +ibuprofen O +1 O +. O +05 O +( O +0 O +. O + +74 O +, O +1 O +. O +51 O +) O +. O + +Among O +users O +of O +aspirin O +, O +they O +were O +: O +rofecoxib O +1 O +. O +73 O +( O +1 O +. O +52 O +, O +1 O +. O +98 O +) O +, O +celecoxib O +1 O +. O +34 O +( O +1 O +. O +19 O +, O +1 O +. O +52 O +) O +, O +ibuprofen O +1 O +. O +51 O +( O +0 O +. O +95 O +, O +2 O +. O +41 O +) O +, O +diclofenac O +1 O +. O +69 O +( O +1 O +. O +35 O +, O +2 O +. O +10 O +) O +, O +naproxen O +1 O +. O +35 O +( O +0 O +. O +97 O +, O +1 O +. O +88 O +) O +and O +acetaminophen O +1 O +. O +29 O +( O +1 O +. O +17 O +, O +1 O +. O +42 O +) O +. O + +CONCLUSION O +: O +Among O +non O +- O +users O +of O +aspirin O +, O +naproxen O +seemed O +to O +carry O +the O +highest O +risk O +for O +AMI B +/ I +GI B +bleeding I +. O + +The O +AMI B +/ I +GI I +toxicity I +of O +celecoxib O +was O +similar O +to O +that O +of O +acetaminophen O +and O +seemed O +to O +be O +better O +than O +those O +of O +rofecoxib O +and O +NS O +- O +NSAIDs O +. O + +Among O +users O +of O +aspirin O +, O +both O +celecoxib O +and O +naproxen O +seemed O +to O +be O +the O +least O +toxic O +. O + +Quinine O +- O +induced O +arrhythmia B +in O +a O +patient O +with O +severe O +malaria B +. O + +It O +was O +reported O +that O +there O +was O +a O +case O +of O +severe O +malaria B +patient O +with O +jaundice B +who O +presented O +with O +arrhythmia B +( O +premature B +ventricular I +contraction I +) O +while O +getting O +quinine O +infusion O +was O +reported O +. O + +A O +man O +, O +25 O +years O +old O +, O +was O +admitted O +to O +hospital O +with O +high B +fever I +, O +chill B +, O +vomiting B +, O +jaundice B +. O + +The O +patient O +was O +fully O +conscious O +, O +blood O +pressure O +120 O +/ O +80 O +mmHg O +, O +pulse O +rate O +100 O +x O +/ O +minute O +, O +regular O +. O + +On O +admission O +, O +laboratory O +examination O +showed O +Plasmodium O +falciparum O +( O ++ O ++ O ++ O ++ O +) O +, O +total O +bilirubin O +8 O +. O +25 O +mg O +/ O +dL O +, O +conjugated O +bilirubin O +4 O +. O +36 O +mg O +/ O +dL O +, O +unconjugated O +bilirubin O +3 O +. O +89 O +mg O +/ O +dL O +, O +potassium O +3 O +. O +52 O +meq O +/ O +L O +Patient O +was O +diagnosed O +as O +severe O +malaria B +with O +jaundice B +and O +got O +quinine O +infusion O +in O +dextrose O +5 O +% O +500 O +mg O +/ O +8 O +hour O +. O + +On O +the O +second O +day O +the O +patient O +had O +vomitus B +, O +diarrhea B +, O +tinnitus B +, O +loss B +of I +hearing I +. O + +After O +30 O +hours O +of O +quinine O +infusion O +the O +patient O +felt O +palpitation B +and O +electrocardiography O +( O +ECG O +) O +recording O +showed O +premature B +ventricular I +contraction I +( O +PVC O +) O +> O +5 O +x O +/ O +minute O +, O +trigemini O +, O +constant O +type O +- O +- O +sinoatrial B +block I +, O +positive O +U O +wave O +. O + +He O +was O +treated O +with O +lidocaine O +50 O +mg O +intravenously O +followed O +by O +infusion O +1500 O +mg O +in O +dextrose O +5 O +% O +/ O +24 O +hour O +and O +potassium O +aspartate O +tablet O +. O + +Quinine O +infusion O +was O +discontinued O +and O +changed O +with O +sulfate O +quinine O +tablets O +. O + +Three O +hours O +later O +the O +patient O +felt O +better O +, O +the O +frequency O +of O +PVC O +reduced O +to O +4 O +- O +5 O +x O +/ O +minute O +and O +on O +the O +third O +day O +ECG O +was O +normal O +, O +potassium O +level O +was O +3 O +. O +34 O +meq O +/ O +L O +. O + +He O +was O +discharged O +on O +7th O +day O +in O +good O +condition O +. O + +Quinine O +, O +like O +quinidine O +, O +is O +a O +chincona O +alkaloid O +that O +has O +anti O +- O +arrhythmic O +property O +, O +although O +it O +also O +pro O +- O +arrhythmic O +that O +can O +cause O +various O +arrhythmias B +, O +including O +severe O +arrhythmia B +such O +as O +multiple O +PVC I +. O + +Administration O +of O +parenteral O +quinine O +must O +be O +done O +carefully O +and O +with O +good O +observation O +because O +of O +its O +pro O +- O +arrhythmic O +effect O +, O +especially O +in O +older O +patients O +who O +have O +heart B +diseases I +or O +patients O +with O +electrolyte B +disorder I +( O +hypokalemia B +) O +which O +frequently O +occurs O +due O +to O +vomiting B +and O +or O +diarrhea B +in O +malaria B +cases O +. O + +Penicillamine O +- O +related O +lichenoid B +dermatitis I +and O +utility O +of O +zinc O +acetate O +in O +a O +Wilson B +disease I +patient O +with O +hepatic O +presentation O +, O +anxiety B +and O +SPECT O +abnormalities I +. O + +Wilson B +' I +s I +disease I +is O +an O +autosomal B +recessive I +disorder I +of I +hepatic I +copper I +metabolism I +with O +consequent O +copper O +accumulation O +and O +toxicity B +in O +many O +tissues O +and O +consequent O +hepatic B +, I +neurologic I +and I +psychiatric I +disorders I +. O + +We O +report O +a O +case O +of O +Wilson B +' I +s I +disease I +with O +chronic B +liver I +disease I +; O +moreover O +, O +in O +our O +patient O +, O +presenting O +also O +with O +high O +levels O +of O +state O +anxiety B +without O +depression B +, O +99mTc O +- O +ECD O +- O +SPECT O +showed O +cortical O +hypoperfusion B +in O +frontal O +lobes O +, O +more O +marked O +on O +the O +left O +frontal O +lobe O +. O + +During O +the O +follow O +- O +up O +of O +our O +patient O +, O +penicillamine O +was O +interrupted O +after O +the O +appearance O +of O +a O +lichenoid B +dermatitis I +, O +and O +zinc O +acetate O +permitted O +to O +continue O +the O +successful O +treatment O +of O +the O +patient O +without O +side O +- O +effects O +. O + +In O +our O +case O +the O +therapy O +with O +zinc O +acetate O +represented O +an O +effective O +treatment O +for O +a O +Wilson B +' I +s I +disease I +patient O +in O +which O +penicillamine O +- O +related O +side O +effects O +appeared O +. O + +The O +safety O +of O +the O +zinc O +acetate O +allowed O +us O +to O +avoid O +other O +potentially O +toxic O +chelating O +drugs O +; O +this O +observation O +is O +in O +line O +with O +the O +growing O +evidence O +on O +the O +efficacy O +of O +the O +drug O +in O +the O +treatment O +of O +Wilson B +' I +s I +disease I +. O + +Since O +most O +of O +Wilson B +' I +s I +disease I +penicillamine O +- O +treated O +patients O +do O +not O +seem O +to O +develop O +this O +skin B +lesion I +, O +it O +could O +be O +conceivable O +that O +a O +specific O +genetic O +factor O +is O +involved O +in O +drug O +response O +. O + +Further O +studies O +are O +needed O +for O +a O +better O +clarification O +of O +Wilson B +' I +s I +disease I +therapy O +, O +and O +in O +particular O +to O +differentiate O +specific O +therapies O +for O +different O +Wilson B +' I +s I +disease I +phenotypes O +. O + +A O +dramatic O +drop B +in I +blood I +pressure I +following O +prehospital O +GTN O +administration O +. O + +A O +male O +in O +his O +sixties O +with O +no O +history O +of O +cardiac O +chest B +pain I +awoke O +with O +chest B +pain I +following O +an O +afternoon O +sleep O +. O + +The O +patient O +did O +not O +self O +medicate O +. O + +The O +patient O +' O +s O +observations O +were O +within O +normal O +limits O +, O +he O +was O +administered O +oxygen O +via O +a O +face O +mask O +and O +glyceryl O +trinitrate O +( O +GTN O +) O +. O + +Several O +minutes O +after O +the O +GTN O +the O +patient O +experienced O +a O +sudden O +drop O +in I +blood O +pressure O +and O +heart O +rate O +, O +this O +was O +rectified O +by O +atropine O +sulphate O +and O +a O +fluid O +challenge O +. O + +There O +was O +no O +further O +deterioration O +in O +the O +patient O +' O +s O +condition O +during O +transport O +to O +hospital O +. O + +There O +are O +very O +few O +documented O +case O +like O +this O +in O +the O +prehospital O +scientific O +literature O +. O + +The O +cause O +appears O +to O +be O +the O +Bezold O +- O +Jarish O +reflex O +, O +stimulation O +of O +the O +ventricular O +walls O +which O +in O +turn O +decreases O +sympathetic O +outflow O +from O +the O +vasomotor O +centre O +. O + +Prehospital O +care O +providers O +who O +are O +managing O +any O +patient O +with O +a O +syncopal B +episode I +that O +fails O +to O +recover O +within O +a O +reasonable O +time O +frame O +should O +consider O +the O +Bezold B +- I +Jarisch O +reflex O +as O +the O +cause O +and O +manage O +the O +patient O +accordingly O +. O + +Chronic O +lesion O +of O +rostral O +ventrolateral O +medulla O +in O +spontaneously O +hypertensive B +rats O +. O + +We O +studied O +the O +effects O +of O +chronic O +selective O +neuronal O +lesion O +of O +rostral O +ventrolateral O +medulla O +on O +mean O +arterial O +pressure O +, O +heart O +rate O +, O +and O +neurogenic O +tone O +in O +conscious O +, O +unrestrained O +spontaneously O +hypertensive B +rats O +. O + +The O +lesions O +were O +placed O +via O +bilateral O +microinjections O +of O +30 O +nmol O +/ O +200 O +nl O +N O +- O +methyl O +- O +D O +- O +aspartic O +acid O +. O + +The O +restimulation O +of O +this O +area O +with O +N O +- O +methyl O +- O +D O +- O +aspartic O +acid O +15 O +days O +postlesion O +failed O +to O +produce O +a O +pressor O +response O +. O + +One O +day O +postlesion O +, O +the O +resting O +mean O +arterial O +pressure O +was O +significantly O +decreased O +in O +lesioned O +rats O +when O +compared O +with O +sham O +rats O +( O +100 O ++ O +/ O +- O +7 O +versus O +173 O ++ O +/ O +- O +4 O +mm O +Hg O +, O +p O +less O +than O +0 O +. O +05 O +) O +. O + +Fifteen O +days O +later O +, O +the O +lesioned O +group O +still O +showed O +values O +significantly O +lower O +than O +the O +sham O +group O +( O +150 O ++ O +/ O +- O +6 O +versus O +167 O ++ O +/ O +- O +5 O +mm O +Hg O +, O +p O +less O +than O +0 O +. O +05 O +) O +. O + +No O +significant O +heart O +rate O +differences O +were O +observed O +between O +the O +sham O +and O +lesioned O +groups O +. O + +The O +ganglionic O +blocker O +trimethaphan O +( O +5 O +mg O +/ O +kg O +i O +. O +v O +. O +) O +caused O +similar O +reductions O +in O +mean O +arterial O +pressure O +in O +both O +lesioned O +and O +sham O +groups O +. O + +The O +trimethaphan O +- O +induced O +hypotension B +was O +accompanied O +by O +a O +significant O +bradycardia B +in O +lesioned O +rats O +( O +- O +32 O ++ O +/ O +- O +13 O +beats O +per O +minute O +) O +but O +a O +tachycardia B +in O +sham O +rats O +( O ++ O +33 O ++ O +/ O +- O +12 O +beats O +per O +minute O +) O +1 O +day O +postlesion O +. O + +Therefore O +, O +rostral O +ventrolateral O +medulla O +neurons O +appear O +to O +play O +a O +significant O +role O +in O +maintaining O +hypertension B +in O +conscious O +spontaneously O +hypertensive B +rats O +. O + +Spinal O +or O +suprabulbar O +structures O +could O +be O +responsible O +for O +the O +gradual O +recovery O +of O +the O +hypertension B +in O +the O +lesioned O +rats O +. O + +Acute O +encephalopathy B +and O +cerebral B +vasospasm I +after O +multiagent O +chemotherapy O +including O +PEG O +- O +asparaginase O +and O +intrathecal O +cytarabine O +for O +the O +treatment O +of O +acute B +lymphoblastic I +leukemia I +. O + +A O +7 O +- O +year O +- O +old O +girl O +with O +an O +unusual O +reaction O +to O +induction O +chemotherapy O +for O +precursor O +B O +- O +cell O +acute B +lymphoblastic I +leukemia I +( O +ALL B +) O +is O +described O +. O + +The O +patient O +developed O +acute O +encephalopathy B +evidenced O +by O +behavioral O +changes O +, O +aphasia B +, O +incontinence B +, O +visual B +hallucinations I +, O +and O +right B +- I +sided I +weakness I +with O +diffuse O +cerebral B +vasospasm I +on O +magnetic O +resonance O +angiography O +after O +the O +administration O +of O +intrathecal O +cytarabine O +. O + +Vincristine O +, O +dexamethasone O +, O +and O +polyethylene O +glycol O +- O +asparaginase O +were O +also O +administered O +before O +the O +episode O +as O +part O +of O +induction O +therapy O +. O + +Neurologic O +status O +returned O +to O +baseline O +within O +10 O +days O +of O +the O +acute O +event O +, O +and O +magnetic O +resonance O +angiography O +findings O +returned O +to O +normal O +4 O +months O +later O +. O + +Comparison O +of O +valsartan O +/ O +hydrochlorothiazide O +combination O +therapy O +at O +doses O +up O +to O +320 O +/ O +25 O +mg O +versus O +monotherapy O +: O +a O +double O +- O +blind O +, O +placebo O +- O +controlled O +study O +followed O +by O +long O +- O +term O +combination O +therapy O +in O +hypertensive B +adults O +. O + +BACKGROUND O +: O +One O +third O +of O +patients O +treated O +for O +hypertension B +attain O +adequate O +blood O +pressure O +( O +BP O +) O +control O +, O +and O +multidrug O +regimens O +are O +often O +required O +. O + +Given O +the O +lifelong O +nature O +of O +hypertension B +, O +there O +is O +a O +need O +to O +evaluate O +the O +long O +- O +term O +efficacy O +and O +tolerability O +of O +higher O +doses O +of O +combination O +anti O +- O +hypertensive B +therapies O +. O + +OBJECTIVE O +: O +This O +study O +investigated O +the O +efficacy O +and O +tolerability O +of O +valsartan O +( O +VAL O +) O +or O +hydrochlorothiazide O +( O +HCTZ O +) O +- O +monotherapy O +and O +higher O +- O +dose O +combinations O +in O +patients O +with O +essential O +hypertension B +. O + +METHODS O +: O +The O +first O +part O +of O +this O +study O +was O +an O +8 O +- O +week O +, O +multicenter O +, O +randomized O +, O +double O +- O +blind O +, O +placebo O +controlled O +, O +parallel O +- O +group O +trial O +. O + +Patients O +with O +essential O +hypertension B +( O +mean O +sitting O +diastolic O +BP O +[ O +MSDBP O +] O +, O +> O +or O += O +95 O +mm O +Hg O +and O +< O +110 O +mm O +Hg O +) O +were O +randomized O +to O +1 O +of O +8 O +treatment O +groups O +: O +VAL O +160 O +or O +320 O +mg O +; O +HCTZ O +12 O +. O +5 O +or O +25 O +mg O +; O +VAL O +/ O +HCTZ O +160 O +/ O +12 O +. O +5 O +, O +320 O +/ O +12 O +. O +5 O +, O +or O +320 O +/ O +25 O +mg O +; O +or O +placebo O +. O + +Mean O +changes O +in O +MSDBP O +and O +mean O +sitting O +systolic O +BP O +( O +MSSBP O +) O +were O +analyzed O +at O +the O +8 O +- O +week O +core O +study O +end O +point O +. O + +VAL O +/ O +HCTZ O +320 O +/ O +12 O +. O +5 O +and O +320 O +/ O +25 O +mg O +were O +further O +investigated O +in O +a O +54 O +- O +week O +, O +open O +- O +label O +extension O +. O + +Response O +was O +defined O +as O +MSDBP O +< O +90 O +mm O +Hg O +or O +a O +> O +or O += O +10 O +mm O +Hg O +decrease O +compared O +to O +baseline O +. O + +Control O +was O +defined O +as O +MSDBP O +< O +90 O +mm O +Hg O +compared O +with O +baseline O +. O + +Tolerability O +was O +assessed O +by O +monitoring O +adverse O +events O +at O +randomization O +and O +all O +subsequent O +study O +visits O +and O +regular O +evaluation O +of O +hematology O +and O +blood O +chemistry O +. O + +RESULTS O +: O +A O +total O +of O +1346 O +patients O +were O +randomized O +into O +the O +8 O +- O +week O +core O +study O +( O +734 O +men O +, O +612 O +women O +; O +924 O +white O +, O +291 O +black O +, O +23 O +Asian O +, O +108 O +other O +; O +mean O +age O +, O +52 O +. O +7 O +years O +; O +mean O +weight O +, O +92 O +. O +6 O +kg O +) O +. O + +All O +active O +treatments O +were O +associated O +with O +significantly O +reduced O +MSSBP O +and O +MSDBP O +during O +the O +core O +8 O +- O +week O +study O +, O +with O +each O +monotherapy O +significantly O +contributing O +to O +the O +overall O +effect O +of O +combination O +therapy O +( O +VAL O +and O +HCTZ O +, O +P O +< O +0 O +. O +001 O +) O +. O + +Each O +combination O +was O +associated O +with O +significantly O +greater O +reductions O +in O +MSSBP O +and O +MSDBP O +compared O +with O +the O +monotherapies O +and O +placebo O +( O +all O +, O +P O +< O +0 O +. O +001 O +) O +. O + +The O +mean O +reduction O +in O +MSSBP O +/ O +MSDBP O +with O +VAL O +/ O +HCTZ O +320 O +/ O +25 O +mg O +was O +24 O +. O +7 O +/ O +16 O +. O +6 O +mm O +Hg O +, O +compared O +with O +5 O +. O +9 O +/ O +7 O +. O +0 O +mm O +Hg O +with O +placebo O +. O + +The O +reduction O +in I +MSSBP I +was O +significantly O +greater O +with O +VAL O +/ O +HCTZ O +320 O +/ O +25 O +mg O +compared O +with O +VAL O +/ O +HCTZ O +160 O +/ O +12 O +. O +5 O +mg O +( O +P O +< O +0 O +. O +002 O +) O +. O + +Rates O +of O +response O +and O +BP O +control O +were O +significantly O +higher O +in O +the O +groups O +that O +received O +combination O +treatment O +compared O +with O +those O +that O +received O +monotherapy O +. O + +The O +incidence O +of O +hypokalemia B +was O +lower O +with O +VAL O +/ O +HCTZ O +combinations O +( O +1 O +. O +8 O +% O +- O +6 O +. O +1 O +% O +) O +than O +with O +HCTZ O +monotherapies O +( O +7 O +. O +1 O +% O +- O +13 O +. O +3 O +% O +) O +. O + +The O +majority O +of O +adverse O +events O +in O +the O +core O +study O +were O +of O +mild O +to O +moderate O +severity O +. O + +The O +efficacy O +and O +tolerability O +of O +VAL O +/ O +HCTZ O +combinations O +were O +maintained O +during O +the O +extension O +( O +797 O +patients O +) O +. O + +CONCLUSIONS O +: O +In O +this O +study O +population O +, O +combination O +therapies O +with O +VAL O +/ O +HCTZ O +were O +associated O +with O +significantly O +greater O +BP O +reductions O +compared O +with O +either O +monotherapy O +, O +were O +well O +tolerated O +, O +and O +were O +associated O +with O +less O +hypokalemia B +than O +HCTZ O +alone O +. O + +Succimer O +chelation O +improves O +learning O +, O +attention O +, O +and O +arousal O +regulation O +in O +lead O +- O +exposed O +rats O +but O +produces O +lasting O +cognitive B +impairment I +in O +the O +absence O +of O +lead O +exposure O +. O + +BACKGROUND O +: O +There O +is O +growing O +pressure O +for O +clinicians O +to O +prescribe O +chelation O +therapy O +at O +only O +slightly O +elevated O +blood O +lead O +levels O +. O + +However O +, O +very O +few O +studies O +have O +evaluated O +whether O +chelation O +improves O +cognitive O +outcomes O +in O +Pb O +- O +exposed O +children O +, O +or O +whether O +these O +agents O +have O +adverse O +effects O +that O +may O +affect O +brain O +development O +in O +the O +absence O +of O +Pb O +exposure O +. O + +OBJECTIVES O +: O +The O +present O +study O +was O +designed O +to O +answer O +these O +questions O +, O +using O +a O +rodent O +model O +of O +early O +childhood O +Pb O +exposure O +and O +treatment O +with O +succimer O +, O +a O +widely O +used O +chelating O +agent O +for O +the O +treatment O +of O +Pb O +poisoning B +. O + +RESULTS O +: O +Pb O +exposure O +produced O +lasting O +impairments O +in O +learning O +, O +attention O +, O +inhibitory O +control O +, O +and O +arousal O +regulation O +, O +paralleling O +the O +areas O +of O +dysfunction O +seen O +in O +Pb O +- O +exposed O +children O +. O + +Succimer O +treatment O +of O +the O +Pb O +- O +exposed O +rats O +significantly O +improved O +learning O +, O +attention O +, O +and O +arousal O +regulation O +, O +although O +the O +efficacy O +of O +the O +treatment O +varied O +as O +a O +function O +of O +the O +Pb O +exposure O +level O +and O +the O +specific O +functional O +deficit O +. O + +In O +contrast O +, O +succimer O +treatment O +of O +rats O +not O +previously O +exposed O +to O +Pb O +produced O +lasting O +and O +pervasive O +cognitive B +and I +affective I +dysfunction I +comparable O +in O +magnitude O +to O +that O +produced O +by O +the O +higher O +Pb O +exposure O +regimen O +. O + +CONCLUSIONS O +: O +These O +are O +the O +first O +data O +, O +to O +our O +knowledge O +, O +to O +show O +that O +treatment O +with O +any O +chelating O +agent O +can O +alleviate O +cognitive B +deficits I +due O +to O +Pb O +exposure O +. O + +These O +findings O +suggest O +that O +it O +may O +be O +possible O +to O +identify O +a O +succimer O +treatment O +protocol O +that O +improves O +cognitive O +outcomes O +in O +Pb O +- O +exposed O +children O +. O + +However O +, O +they O +also O +suggest O +that O +succimer O +treatment O +should O +be O +strongly O +discouraged O +for O +children O +who O +do O +not O +have O +elevated O +tissue O +levels O +of O +Pb O +or O +other O +heavy O +metals O +. O + +Caffeine O +challenge O +test O +in O +panic B +disorder I +and O +depression B +with O +panic B +attacks I +. O + +Our O +aim O +was O +to O +observe O +if O +patients O +with O +panic B +disorder I +( O +PD B +) O +and O +patients O +with O +major B +depression I +with O +panic B +attacks I +( O +MDP B +) O +( O +Diagnostic O +and O +Statistical O +Manual O +of O +Mental B +Disorders I +, O +Fourth O +Edition O +criteria O +) O +respond O +in O +a O +similar O +way O +to O +the O +induction O +of O +panic B +attacks I +by O +an O +oral O +caffeine O +challenge O +test O +. O + +We O +randomly O +selected O +29 O +patients O +with O +PD B +, O +27 O +with O +MDP B +, O +25 O +with O +major B +depression I +without O +panic B +attacks I +( O +MD B +) O +, O +and O +28 O +healthy O +volunteers O +. O + +The O +patients O +had O +no O +psychotropic O +drug O +for O +at O +least O +a O +4 O +- O +week O +period O +. O + +In O +a O +randomized O +double O +- O +blind O +experiment O +performed O +in O +2 O +occasions O +7 O +days O +apart O +, O +480 O +mg O +caffeine O +and O +a O +caffeine O +- O +free O +( O +placebo O +) O +solution O +were O +administered O +in O +a O +coffee O +form O +and O +anxiety B +scales O +were O +applied O +before O +and O +after O +each O +test O +. O + +A O +total O +of O +58 O +. O +6 O +% O +( O +n O += O +17 O +) O +of O +patients O +with O +PD B +, O +44 O +. O +4 O +% O +( O +n O += O +12 O +) O +of O +patients O +with O +MDP B +, O +12 O +. O +0 O +% O +( O +n O += O +3 O +) O +of O +patients O +with O +MD B +, O +and O +7 O +. O +1 O +% O +( O +n O += O +2 O +) O +of O +control O +subjects O +had O +a O +panic B +attack I +after O +the O +480 O +- O +mg O +caffeine O +challenge O +test O +( O +chi O +( O +2 O +) O +( O +3 O +) O += O +16 O +. O +22 O +, O +P O += O +. O +001 O +) O +. O + +The O +patients O +with O +PD B +and O +MDP B +were O +more O +sensitive O +to O +caffeine O +than O +were O +patients O +with O +MD B +and O +healthy O +volunteers O +. O + +No O +panic B +attack I +was O +observed O +after O +the O +caffeine O +- O +free O +solution O +intake O +. O + +The O +patients O +with O +MD B +had O +a O +lower O +heart O +rate O +response O +to O +the O +test O +than O +all O +the O +other O +groups O +( O +2 O +- O +way O +analysis O +of O +variance O +, O +group O +by O +time O +interaction O +with O +Greenhouse O +- O +Geisser O +correction O +: O +F O +( O +3 O +, O +762 O +) O += O +2 O +. O +85 O +, O +P O += O +. O +026 O +) O +. O + +Our O +data O +suggest O +that O +there O +is O +an O +association O +between O +panic B +attacks I +, O +no O +matter O +if O +associated O +with O +PD B +or O +MDP B +, O +and O +hyperreactivity B +to O +an O +oral O +caffeine O +challenge O +test O +. O + +Mitral O +annuloplasty O +as O +a O +ventricular O +restoration O +method O +for O +the O +failing O +left O +ventricle O +: O +a O +pilot O +study O +. O + +BACKGROUND O +AND O +AIM O +OF O +THE O +STUDY O +: O +Undersized O +mitral O +annuloplasty O +( O +MAP O +) O +is O +effective O +in O +patients O +with O +dilated B +cardiomyopathy I +and O +functional O +mitral B +regurgitation I +( O +MR B +) O +since O +, O +as O +well O +as O +addressing O +the O +MR B +, O +the O +MAP O +may O +also O +reshape O +the O +dilated O +left O +ventricular O +( O +LV O +) O +base O +. O + +However O +, O +the O +direct O +benefits O +of O +this O +possible O +reshaping O +on O +LV O +function O +in O +the O +absence O +of O +underlying O +MR B +remain O +incompletely O +understood O +. O + +The O +study O +aim O +was O +to O +identify O +these O +benefits O +in O +a O +canine O +model O +of O +acute B +heart I +failure I +. O + +METHODS O +: O +Six O +dogs O +underwent O +MAP O +with O +a O +prosthetic O +band O +on O +the O +posterior O +mitral O +annulus O +, O +using O +four O +mattress O +sutures O +. O + +The O +sutures O +were O +passed O +individually O +through O +four O +tourniquets O +and O +exteriorized O +untied O +via O +the O +left O +atriotomy O +. O + +Sonomicrometry O +crystals O +were O +implanted O +around O +the O +mitral O +annulus O +and O +left O +ventricle O +to O +measure O +geometry O +and O +regional O +function O +. O + +Acute B +heart I +failure I +was O +induced O +by O +propranolol O +and O +volume O +loading O +after O +weaning O +from O +cardiopulmonary O +bypass O +; O +an O +absence O +of O +MR B +was O +confirmed O +by O +echocardiography O +. O + +MAP O +was O +accomplished O +by O +cinching O +the O +tourniquets O +. O + +Data O +were O +acquired O +at O +baseline O +, O +after O +induction O +of O +acute B +heart I +failure I +, O +and O +after O +MAP O +. O + +RESULTS O +: O +MAP O +decreased O +mitral O +annular O +dimensions O +in O +both O +commissure O +- O +commissure O +and O +septal O +- O +lateral O +directions O +. O + +Concomitantly O +, O +the O +diastolic O +diameter O +of O +the O +LV O +base O +and O +LV O +sphericity O +decreased O +( O +i O +. O +e O +. O +, O +improved O +) O +from O +37 O +. O +4 O ++ O +/ O +- O +9 O +. O +3 O +to O +35 O +. O +9 O ++ O +/ O +- O +10 O +mm O +( O +p O += O +0 O +. O +063 O +) O +, O +and O +from O +67 O +. O +9 O ++ O +/ O +- O +18 O +. O +6 O +% O +to O +65 O +. O +3 O ++ O +/ O +- O +18 O +. O +9 O +% O +( O +p O += O +0 O +. O +016 O +) O +, O +respectively O +. O + +Decreases O +were O +evident O +in O +both O +LV O +end O +- O +diastolic O +pressure O +( O +from O +17 O ++ O +/ O +- O +7 O +to O +15 O ++ O +/ O +- O +6 O +mmHg O +, O +p O += O +0 O +. O +0480 O +and O +Tau O +( O +from O +48 O ++ O +/ O +- O +8 O +to O +45 O ++ O +/ O +- O +8 O +ms O +, O +p O +< O +0 O +. O +01 O +) O +, O +while O +fractional O +shortening O +at O +the O +LV O +base O +increased O +from O +7 O +. O +7 O ++ O +/ O +- O +4 O +. O +5 O +% O +to O +9 O +. O +4 O ++ O +/ O +- O +4 O +. O +5 O +% O +( O +p O += O +0 O +. O +045 O +) O +. O + +After O +MAP O +, O +increases O +were O +identified O +in O +both O +cardiac O +output O +( O +from O +1 O +. O +54 O ++ O +/ O +- O +0 O +. O +57 O +to O +1 O +. O +65 O ++ O +/ O +- O +0 O +. O +57 O +1 O +/ O +min O +) O +and O +Emax O +( O +from O +1 O +. O +86 O ++ O +/ O +- O +0 O +. O +9 O +to O +2 O +. O +41 O ++ O +/ O +- O +1 O +. O +31 O +mmHg O +/ O +ml O +) O +. O + +CONCLUSION O +: O +The O +data O +acquired O +suggest O +that O +isolated O +MAP O +may O +have O +certain O +benefits O +on O +LV O +dimension O +/ O +function O +in O +acute B +heart I +failure I +, O +even O +in O +the O +absence O +of O +MR O +. O + +However O +, O +further O +investigations O +are O +warranted O +in O +a O +model O +of O +chronic O +heart B +failure I +. O + +Piperacillin O +/ O +tazobactam O +- O +induced O +seizure B +rapidly O +reversed O +by O +high O +flux O +hemodialysis O +in O +a O +patient O +on O +peritoneal O +dialysis O +. O + +Despite O +popular O +use O +of O +piperacillin O +, O +the O +dire O +neurotoxicity B +associated O +with O +piperacillin O +still O +goes O +unrecognized O +, O +leading O +to O +a O +delay O +in O +appropriate O +management O +. O + +We O +report O +a O +57 O +- O +year O +- O +old O +woman O +with O +end B +- I +stage I +renal I +disease I +receiving O +continuous O +ambulatory O +peritoneal O +dialysis O +( O +CAPD O +) O +, O +who O +developed O +slurred O +speech O +, O +tremor B +, O +bizarre O +behavior O +, O +progressive O +mental O +confusion B +, O +and O +2 O +episodes O +of O +generalized O +tonic B +- I +clonic I +seizure I +( O +GTCS B +) O +after O +5 O +doses O +of O +piperacillin O +/ O +tazobactam O +( O +2 O +g O +/ O +250 O +mg O +) O +were O +given O +for O +bronchiectasis B +with O +secondary O +infection B +. O + +The O +laboratory O +data O +revealed O +normal O +plasma O +electrolyte O +and O +ammonia O +levels O +but O +leukocytosis B +. O + +Neurologic O +examinations O +showed O +dysarthria B +and O +bilateral O +Babinski O +sign O +. O + +Computed O +tomography O +of O +brain O +and O +electroencephalogram O +were O +unremarkable O +. O + +Despite O +the O +use O +of O +antiepileptic O +agents O +, O +another O +GTCS B +episode O +recurred O +after O +the O +sixth O +dose O +of O +piperacillin O +/ O +tazobactam O +. O + +Brain O +magnetic O +resonance O +imaging O +did O +not O +demonstrate O +acute B +infarction I +and O +organic B +brain I +lesions I +. O + +Initiation O +of O +high O +- O +flux O +hemodialysis O +rapidly O +reversed O +the O +neurologic O +symptoms O +within O +4 O +hours O +. O + +Piperacillin O +- O +induced O +encephalopathy B +should O +be O +considered O +in O +any O +uremic B +patients O +with O +unexplained O +neurological O +manifestations O +. O + +CAPD O +is O +inefficient O +in O +removing O +piperacillin O +, O +whereas O +hemodialysis O +can O +rapidly O +terminate O +the O +piperacillin O +- O +induced O +encephalopathy B +. O + +Frequency O +of O +transient O +ipsilateral O +vocal B +cord I +paralysis I +in O +patients O +undergoing O +carotid O +endarterectomy O +under O +local O +anesthesia O +. O + +BACKGROUND O +: O +Especially O +because O +of O +improvements O +in O +clinical O +neurologic O +monitoring O +, O +carotid O +endarterectomy O +done O +under O +local O +anesthesia O +has O +become O +the O +technique O +of O +choice O +in O +several O +centers O +. O + +Temporary O +ipsilateral O +vocal B +nerve I +palsies I +due O +to O +local O +anesthetics O +have O +been O +described O +, O +however O +. O + +Such O +complications O +are O +most O +important O +in O +situations O +where O +there O +is O +a O +pre O +- O +existing O +contralateral O +paralysis B +. O + +We O +therefore O +examined O +the O +effect O +of O +local O +anesthesia O +on O +vocal O +cord O +function O +to O +better O +understand O +its O +possible O +consequences O +. O + +METHODS O +: O +This O +prospective O +study O +included O +28 O +patients O +undergoing O +carotid O +endarterectomy O +under O +local O +anesthesia O +. O + +Vocal O +cord O +function O +was O +evaluated O +before O +, O +during O +, O +and O +after O +surgery O +( O +postoperative O +day O +1 O +) O +using O +flexible O +laryngoscopy O +. O + +Anesthesia O +was O +performed O +by O +injecting O +20 O +to O +40 O +mL O +of O +a O +mixture O +of O +long O +- O +acting O +( O +ropivacaine O +) O +and O +short O +- O +acting O +( O +prilocaine O +) O +anesthetic O +. O + +RESULTS O +: O +All O +patients O +had O +normal O +vocal O +cord O +function O +preoperatively O +. O + +Twelve O +patients O +( O +43 O +% O +) O +were O +found O +to O +have O +intraoperative O +ipsilateral O +vocal B +cord I +paralysis I +. O + +It O +resolved O +in O +all O +cases O +< O +or O += O +24 O +hours O +. O + +There O +were O +no O +significant O +differences O +in O +operating O +time O +or O +volume O +or O +frequency O +of O +anesthetic O +administration O +in O +patients O +with O +temporary O +vocal B +cord I +paralysis I +compared O +with O +those O +without O +. O + +CONCLUSION O +: O +Local O +anesthesia O +led O +to O +temporary O +ipsilateral O +vocal B +cord I +paralysis I +in O +almost O +half O +of O +these O +patients O +. O + +Because O +pre O +- O +existing O +paralysis B +is O +of O +a O +relevant O +frequency O +( O +up O +to O +3 O +% O +) O +, O +a O +preoperative O +evaluation O +of O +vocal O +cord O +function O +before O +carotid O +endarterectomy O +under O +local O +anesthesia O +is O +recommended O +to O +avoid O +intraoperative O +bilateral O +paralysis B +. O + +In O +patients O +with O +preoperative O +contralateral O +vocal B +cord I +paralysis I +, O +surgery O +under O +general O +anesthesia O +should O +be O +considered O +. O + +Impaired O +fear O +recognition O +in O +regular O +recreational O +cocaine O +users O +. O + +INTRODUCTION O +: O +The O +ability O +to O +read O +facial O +expressions O +is O +essential O +for O +normal O +human O +social O +interaction O +. O + +The O +aim O +of O +the O +present O +study O +was O +to O +conduct O +the O +first O +investigation O +of O +facial O +expression O +recognition O +performance O +in O +recreational O +cocaine O +users O +. O + +MATERIALS O +AND O +METHODS O +: O +Three O +groups O +, O +comprised O +of O +21 O +cocaine O +naive O +participants O +( O +CN O +) O +, O +30 O +occasional O +cocaine O +( O +OC O +) O +, O +and O +48 O +regular O +recreational O +cocaine O +( O +RC O +) O +users O +, O +were O +compared O +. O + +An O +emotional O +facial O +expression O +( O +EFE O +) O +task O +consisting O +of O +a O +male O +and O +female O +face O +expressing O +six O +basic O +emotions O +( O +happiness O +, O +surprise O +, O +sadness O +, O +anger O +, O +fear O +, O +and O +disgust O +) O +was O +administered O +. O + +Mean O +percent O +accuracy O +and O +latencies O +for O +correct O +responses O +across O +eight O +presentations O +of O +each O +basic O +emotion O +were O +derived O +. O + +Participants O +were O +also O +assessed O +with O +the O +" O +Eyes O +task O +" O +to O +investigate O +their O +ability O +to O +recognize O +more O +complex O +emotional O +states O +and O +the O +Symptom O +CheckList O +- O +90 O +- O +Revised O +to O +measure O +psychopathology O +. O + +RESULTS O +: O +There O +were O +no O +group O +differences O +in O +psychopathology O +or O +" O +eyes O +task O +" O +performance O +, O +but O +the O +RC O +group O +, O +who O +otherwise O +had O +similar O +illicit O +substance O +use O +histories O +to O +the O +OC O +group O +, O +exhibited O +impaired O +fear O +recognition O +accuracy O +compared O +to O +the O +OC O +and O +CN O +groups O +. O + +The O +RC O +group O +also O +correctly O +identified O +anger O +, O +fear O +, O +happiness O +, O +and O +surprise O +, O +more O +slowly O +than O +CN O +, O +but O +not O +OC O +participants O +. O + +The O +OC O +group O +was O +slower O +than O +CN O +when O +correctly O +identifying O +disgust O +. O + +The O +selective O +deficit O +in O +fear O +recognition O +accuracy O +manifested O +by O +the O +RC O +group O +cannot O +be O +explained O +by O +the O +subacute O +effects O +of O +cocaine O +, O +or O +ecstasy O +, O +because O +recent O +and O +less O +recent O +users O +of O +these O +drugs O +within O +this O +group O +were O +similarly O +impaired O +. O + +Possible O +parallels O +between O +RC O +users O +and O +psychopaths O +with O +respect O +to O +impaired B +fear I +recognition I +, O +amygdala B +dysfunction I +, O +and O +etiology O +are O +discussed O +. O + +Damage O +of O +substantia O +nigra I +pars I +reticulata I +during O +pilocarpine O +- O +induced O +status B +epilepticus I +in O +the O +rat O +: O +immunohistochemical O +study O +of O +neurons O +, O +astrocytes O +and O +serum O +- O +protein O +extravasation O +. O + +The O +substantia O +nigra O +has O +a O +gating O +function O +controlling O +the O +spread O +of O +epileptic B +seizure I +activity O +. O + +Additionally O +, O +in O +models O +of O +prolonged O +status B +epilepticus I +the O +pars O +reticulata O +of O +substantia O +nigra O +( O +SNR O +) O +suffers O +from O +a O +massive O +lesion O +which O +may O +arise O +from O +a O +massive O +metabolic O +derangement O +and O +hyperexcitation O +developing O +in O +the O +activated O +SNR O +. O + +In O +this O +study O +, O +status B +epilepticus I +was O +induced O +by O +systemic O +injection O +of O +pilocarpine O +in O +rats O +. O + +The O +neuropathology O +of O +SNR B +was O +investigated O +using O +immunohistochemical O +techniques O +with O +the O +major O +emphasis O +on O +the O +time O +- O +course O +of O +changes O +in O +neurons O +and O +astrocytes O +. O + +Animals O +surviving O +20 O +, O +30 O +, O +40 O +, O +60 O +min O +, O +2 O +, O +3 O +, O +6 O +hours O +, O +1 O +, O +2 O +, O +and O +3 O +days O +after O +induction O +of O +status B +epilepticus I +were O +perfusion O +- O +fixed O +, O +and O +brains O +processed O +for O +immunohistochemical O +staining O +of O +SNR O +. O + +Nissl O +- O +staining O +and O +antibodies O +against O +the O +neuron O +- O +specific O +calcium O +- O +binding O +protein O +, O +parvalbumin O +, O +served O +to O +detect O +neuronal B +damage I +in O +SNR B +. O + +Antibodies O +against O +the O +astroglia O +- O +specific O +cytoskeletal O +protein O +, O +glial O +fibrillary O +acidic O +protein O +( O +GFAP O +) O +, O +and O +against O +the O +glial O +calcium O +- O +binding O +protein O +, O +S O +- O +100 O +protein O +, O +were O +used O +to O +assess O +the O +status O +of O +astrocytes O +. O + +Immunohistochemical O +staining O +for O +serum O +- O +albumin O +and O +immunoglobulins O +in O +brain O +tissue O +was O +taken O +as O +indicator O +of O +blood O +- O +brain O +barrier O +disturbances O +and O +vasogenic O +edema B +formation O +. O + +Immunohistochemical O +staining O +indicated O +loss O +of O +GFAP O +- O +staining O +already O +at O +30 O +min O +after O +induction O +of O +seizures B +in O +an O +oval O +focus O +situated O +in O +the O +center O +of O +SNR O +while O +sparing O +medial O +and O +lateral O +aspects O +. O + +At O +1 O +h O +there O +was O +additional O +vacuolation O +in O +S O +- O +100 O +protein O +staining O +. O + +By O +2 O +hours O +, O +parvalbumin O +- O +staining O +changed O +in O +the O +central O +SNR O +indicating O +neuronal B +damage I +, O +and O +Nissl O +- O +staining O +visualized O +some O +neuronal O +distortion O +. O + +Staining O +for O +serum O +- O +proteins O +occurred O +in O +a O +patchy O +manner O +throughout O +the O +forebrain O +during O +the O +first O +hours O +. O + +By O +6 O +h O +, O +vasogenic O +edema B +covered O +the O +lesioned O +SNR O +. O + +By O +24 O +h O +, O +glial O +and O +neuronal O +markers O +indicated O +a O +massive O +lesion O +in O +the O +center O +of O +SNR B +. O + +By O +48 O +- O +72 O +h O +, O +astrocytes O +surrounding O +the O +lesion O +increased O +in O +size O +, O +and O +polymorphic O +phagocytotic O +cells O +invaded O +the O +damaged O +area O +. O + +In O +a O +further O +group O +of O +animals O +surviving O +1 O +to O +5 O +days O +, O +conventional O +paraffin O +- O +sections O +confirmed O +the O +neuronal B +and I +glial I +damage I +of O +SNR O +. O + +Additional O +pathology O +of O +similar O +quality O +was O +found O +in O +the O +globus O +pallidus O +. O + +Since O +astrocytes O +were O +always O +damaged O +in O +parallel O +with O +neurons O +in O +SNR B +it O +is O +proposed O +that O +the O +anatomical O +and O +functional O +interrelationship O +between O +neurons O +and O +astrocytes O +is O +particularly O +tight O +in O +SNR B +. O + +Both O +cell O +elements O +may O +suffer O +in O +common O +from O +metabolic O +disturbance O +and O +neurotransmitter O +dysfunction O +as O +occur O +during O +massive O +status B +epilepticus I +. O + +Neuroprotective O +effects O +of O +melatonin O +upon O +the O +offspring O +cerebellar O +cortex O +in O +the O +rat O +model O +of O +BCNU O +- O +induced O +cortical B +dysplasia I +. O + +Cortical B +dysplasia I +is O +a O +malformation B +characterized O +by O +defects O +in O +proliferation O +, O +migration O +and O +maturation O +. O + +This O +study O +was O +designed O +to O +evaluate O +the O +alterations O +in O +offspring O +rat O +cerebellum O +induced O +by O +maternal O +exposure O +to O +carmustine O +- O +[ O +1 O +, O +3 O +- O +bis O +( O +2 O +- O +chloroethyl O +) O +- O +1 O +- O +nitrosoure O +] O +( O +BCNU O +) O +and O +to O +investigate O +the O +effects O +of O +exogenous O +melatonin O +upon O +cerebellar O +BCNU O +- O +induced O +cortical B +dysplasia I +, O +using O +histological O +and O +biochemical O +analyses O +. O + +Pregnant O +Wistar O +rats O +were O +assigned O +to O +five O +groups O +: O +intact O +- O +control O +, O +saline O +- O +control O +, O +melatonin O +- O +treated O +, O +BCNU O +- O +exposed O +and O +BCNU O +- O +exposed O +plus O +melatonin O +. O + +Rats O +were O +exposed O +to O +BCNU O +on O +embryonic O +day O +15 O +and O +melatonin O +was O +given O +until O +delivery O +. O + +Immuno O +/ O +histochemistry O +and O +electron O +microscopy O +were O +carried O +out O +on O +the O +offspring O +cerebellum O +, O +and O +levels O +of O +malondialdehyde O +and O +superoxide O +dismutase O +were O +determined O +. O + +Histopathologically O +, O +typical O +findings O +were O +observed O +in O +the O +cerebella O +from O +the O +control O +groups O +, O +but O +the O +findings O +consistent O +with O +early O +embryonic O +development O +were O +noted O +in O +BCNU O +- O +exposed O +cortical B +dysplasia I +group O +. O + +There O +was O +a O +marked O +increase O +in O +the O +number O +of O +TUNEL O +positive O +cells O +and O +nestin O +positive O +cells O +in O +BCNU O +- O +exposed O +group O +, O +but O +a O +decreased O +immunoreactivity O +to O +glial O +fibrillary O +acidic O +protein O +, O +synaptophysin O +and O +transforming O +growth O +factor O +beta1 O +was O +observed O +, O +indicating O +a O +delayed O +maturation O +, O +and O +melatonin O +significantly O +reversed O +these O +changes O +. O + +Malondialdehyde O +level O +in O +BCNU O +- O +exposed O +group O +was O +higher O +than O +those O +in O +control O +groups O +and O +melatonin O +decreased O +malondialdehyde O +levels O +in O +BCNU O +group O +( O +P O +< O +0 O +. O +01 O +) O +, O +while O +there O +were O +no O +significant O +differences O +in O +the O +superoxide O +dismutase O +levels O +between O +these O +groups O +. O + +These O +data O +suggest O +that O +exposure O +of O +animals O +to O +BCNU O +during O +pregnancy O +leads O +to O +delayed O +maturation O +of O +offspring O +cerebellum O +and O +melatonin O +protects O +the O +cerebellum O +against O +the O +effects O +of O +BCNU O +. O + +Reduced O +cardiotoxicity B +of O +doxorubicin O +given O +in O +the O +form O +of O +N O +- O +( O +2 O +- O +hydroxypropyl O +) O +methacrylamide O +conjugates O +: O +and O +experimental O +study O +in O +the O +rat O +. O + +A O +rat O +model O +was O +used O +to O +evaluate O +the O +general O +acute O +toxicity B +and O +the O +late O +cardiotoxicity B +of O +4 O +mg O +/ O +kg O +doxorubicin O +( O +DOX O +) O +given O +either O +as O +free O +drug O +or O +in O +the O +form O +of O +three O +N O +- O +( O +2 O +- O +hydroxypropyl O +) O +methacrylamide O +( O +HPMA O +) O +copolymer O +conjugates O +. O + +In O +these O +HPMA O +copolymers O +, O +DOX O +was O +covalently O +bound O +via O +peptide O +linkages O +that O +were O +either O +non O +- O +biodegradable O +( O +Gly O +- O +Gly O +) O +or O +degradable O +by O +lysosomal O +proteinases O +( O +Gly O +- O +Phe O +- O +Leu O +- O +Gly O +) O +. O + +In O +addition O +, O +one O +biodegradable O +conjugate O +containing O +galactosamine O +was O +used O +; O +this O +residue O +was O +targeted O +to O +the O +liver O +. O + +Over O +the O +first O +3 O +weeks O +after O +the O +i O +. O +v O +. O +administration O +of O +free O +and O +polymer O +- O +bound O +DOX O +, O +all O +animals O +showed O +a O +transient O +reduction O +in O +body O +weight O +. O + +However O +, O +the O +maximal O +reduction O +in O +body O +weight O +seen O +in O +animals O +that O +received O +polymer O +- O +bound O +DOX O +( O +4 O +mg O +/ O +kg O +) O +was O +significantly O +lower O +than O +that O +observed O +in O +those O +that O +received O +free O +DOX O +( O +4 O +mg O +/ O +kg O +) O +or O +a O +mixture O +of O +the O +unmodified O +parent O +HPMA O +copolymer O +and O +free O +DOX O +( O +4 O +mg O +/ O +kg O +; O +P O +less O +than O +0 O +. O +01 O +) O +. O + +Throughout O +the O +study O +( O +20 O +weeks O +) O +, O +deaths O +related O +to O +cardiotoxicity B +were O +observed O +only O +in O +animals O +that O +received O +either O +free O +DOX O +or O +the O +mixture O +of O +HPMA O +copolymer O +and O +free O +DOX O +; O +in O +these O +cases O +, O +histological O +investigations O +revealed O +marked O +changes O +in O +the O +heart O +that O +were O +consistent O +with O +DOX O +- O +induced O +cardiotoxicity B +. O + +Sequential O +measurements O +of O +cardiac O +output O +in O +surviving O +animals O +that O +received O +either O +free O +DOX O +or O +the O +mixture O +of O +HPMA O +copolymer O +and O +free O +DOX O +showed O +a O +reduction O +of O +approximately O +30 O +% O +in O +function O +beginning O +at O +the O +4th O +week O +after O +drug O +administration O +. O + +The O +heart O +rate O +in O +these O +animals O +was O +approximately O +12 O +% O +lower O +than O +that O +measured O +in O +age O +- O +matched O +control O +rats O +( O +P O +less O +than O +0 O +. O +05 O +) O +. O + +Animals O +that O +were O +given O +the O +HPMA O +copolymer O +conjugates O +containing O +DOX O +exhibited O +no O +significant O +change O +in O +cardiac O +output O +throughout O +the O +study O +( O +P O +less O +than O +0 O +. O +05 O +) O +. O + +In O +addition O +, O +no O +significant O +histological O +change O +was O +observed O +in O +the O +heart O +of O +animals O +that O +received O +DOX O +in O +the O +form O +of O +HPMA O +copolymer O +conjugates O +and O +were O +killed O +at O +the O +end O +of O +the O +study O +. O + +However O +, O +these O +animals O +had O +shown O +a O +significant O +increase O +in O +heart O +rate O +beginning O +at O +8 O +weeks O +after O +drug O +administration O +( O +P O +less O +than O +0 O +. O +01 O +) O +. O +( O +ABSTRACT O +TRUNCATED O +AT O +400 O +WORDS O +) O + +Corneal B +ulcers I +associated O +with O +aerosolized O +crack O +cocaine O +use O +. O + +PURPOSE O +: O +We O +report O +4 O +cases O +of O +corneal B +ulcers I +associated O +with O +drug B +abuse I +. O + +The O +pathogenesis O +of O +these O +ulcers B +and O +management O +of O +these O +patients O +are O +also O +reviewed O +. O + +METHODS O +: O +Review O +of O +all O +cases O +of O +corneal B +ulcers I +associated O +with O +drug B +abuse I +seen O +at O +our O +institution O +from O +July O +2006 O +to O +December O +2006 O +. O + +RESULTS O +: O +Four O +patients O +with O +corneal B +ulcers I +associated O +with O +crack O +cocaine O +use O +were O +reviewed O +. O + +All O +corneal B +ulcers I +were O +cultured O +, O +and O +the O +patients O +were O +admitted O +to O +the O +hospital O +for O +intensive O +topical O +antibiotic O +treatment O +. O + +Each O +patient O +received O +comprehensive O +health O +care O +, O +including O +medical O +and O +substance O +abuse O +consultations O +. O + +Streptococcal O +organisms O +were O +found O +in O +3 O +cases O +and O +Capnocytophaga O +and O +Brevibacterium O +casei O +in O +1 O +patient O +. O + +The O +infections B +responded O +to O +antibiotic O +treatment O +. O + +Two O +patients O +needed O +a O +lateral O +tarsorrhaphy O +for O +persistent O +epithelial B +defects I +. O + +CONCLUSIONS O +: O +Aerosolized O +crack O +cocaine O +use O +can O +be O +associated O +with O +the O +development O +of O +corneal B +ulcers I +. O + +Drug B +abuse I +provides O +additional O +challenges O +for O +management O +. O + +Not O +only O +treatment O +of O +their O +infections B +but O +also O +the O +overall O +poor O +health O +of O +the O +patients O +and O +increased O +risk O +of O +noncompliance O +need O +to O +be O +addressed O +. O + +Comprehensive O +care O +may O +provide O +the O +patient O +the O +opportunity O +to O +discontinue O +their O +substance B +abuse I +, O +improve O +their O +overall O +health O +, O +and O +prevent O +future O +corneal B +complications I +. O + +Topical O +0 O +. O +025 O +% O +capsaicin O +in O +chronic O +post B +- I +herpetic I +neuralgia I +: O +efficacy O +, O +predictors O +of O +response O +and O +long O +- O +term O +course O +. O + +In O +order O +to O +evaluate O +the O +efficacy O +, O +time O +- O +course O +of O +action O +and O +predictors O +of O +response O +to O +topical O +capsaicin O +, O +39 O +patients O +with O +chronic O +post B +- I +herpetic I +neuralgia I +( O +PHN B +) O +, O +median O +duration O +24 O +months O +, O +were O +treated O +with O +0 O +. O +025 O +% O +capsaicin O +cream O +for O +8 O +weeks O +. O + +During O +therapy O +the O +patients O +rated O +their O +pain B +on O +a O +visual O +analogue O +scale O +( O +VAS O +) O +and O +a O +verbal O +outcome O +scale O +. O + +A O +follow O +- O +up O +investigation O +was O +performed O +10 O +- O +12 O +months O +after O +study O +onset O +on O +the O +patients O +who O +had O +improved O +. O + +Nineteen O +patients O +( O +48 O +. O +7 O +% O +) O +substantially O +improved O +after O +the O +8 O +- O +week O +trial O +; O +5 O +( O +12 O +. O +8 O +% O +) O +discontinued O +therapy O +due O +to O +side O +- O +effects O +such O +as O +intolerable O +capsaicin O +- O +induced O +burning B +sensations I +( O +4 O +) O +or O +mastitis B +( O +1 O +) O +; O +15 O +( O +38 O +. O +5 O +% O +) O +reported O +no O +benefit O +. O + +The O +decrease O +in O +VAS O +ratings O +was O +significant O +after O +2 O +weeks O +of O +continuous O +application O +. O + +Of O +the O +responders O +72 O +. O +2 O +% O +were O +still O +improved O +at O +the O +follow O +- O +up O +; O +only O +one O +- O +third O +of O +them O +had O +continued O +application O +irregularly O +. O + +Treatment O +effect O +was O +not O +dependent O +on O +patient O +' O +s O +age O +, O +duration O +or O +localization O +of O +PHN B +( O +trigeminal O +involvement O +was O +excluded O +) O +, O +sensory O +disturbance O +or O +pain B +character O +. O + +Treatment O +response O +was O +not O +correlated O +with O +the O +incidence O +, O +time O +- O +course O +or O +severity O +of O +capsaicin O +- O +induced O +burning B +. O + +If O +confirmed O +in O +controlled O +trials O +, O +the O +long O +- O +term O +results O +of O +this O +open O +, O +non O +- O +randomized O +study O +might O +indicate O +that O +the O +analgesic O +effect O +of O +capsaicin O +in O +PHN B +is O +mediated O +by O +both O +interference O +with O +neuropeptide O +metabolism O +and O +morphological O +changes O +( O +perhaps O +degeneration O +) O +of O +nociceptive O +afferents O +. O + +Myo O +- O +inositol O +- O +1 O +- O +phosphate O +( O +MIP O +) O +synthase O +inhibition O +: O +in O +- O +vivo O +study O +in O +rats O +. O + +Lithium O +and O +valproate O +are O +the O +prototypic O +mood O +stabilizers O +and O +have O +diverse O +structures O +and O +targets O +. O + +Both O +drugs O +influence O +inositol O +metabolism O +. O + +Lithium O +inhibits O +IMPase O +and O +valproate O +inhibits O +MIP O +synthase O +. O + +This O +study O +shows O +that O +MIP O +synthase O +inhibition O +does O +not O +replicate O +or O +augment O +the O +effects O +of O +lithium O +in O +the O +inositol O +sensitive O +pilocarpine O +- O +induced O +seizures B +model O +. O + +This O +lack O +of O +effects O +may O +stem O +from O +the O +low O +contribution O +of O +de O +- O +novo O +synthesis O +to O +cellular O +inositol O +supply O +or O +to O +the O +inhibition O +of O +the O +de O +- O +novo O +synthesis O +by O +lithium O +itself O +. O + +Non O +- O +steroidal O +anti O +- O +inflammatory O +drugs O +- O +associated O +acute O +interstitial B +nephritis I +with O +granular O +tubular O +basement O +membrane O +deposits O +. O + +Acute B +tubulo I +- I +interstitial I +nephritis I +( O +ATIN B +) O +is O +an O +important O +cause O +of O +acute B +renal I +failure I +resulting O +from O +a O +variety O +of O +insults O +, O +including O +immune O +complex O +- O +mediated O +tubulo B +- I +interstitial I +injury I +, O +but O +drugs O +such O +as O +non O +- O +steroidal O +anti O +- O +inflammatory O +drugs O +( O +NSAIDs O +) O +are O +a O +far O +more O +frequent O +cause O +. O + +Overall O +, O +as O +an O +entity O +, O +ATIN B +remains O +under O +- O +diagnosed O +, O +as O +symptoms O +resolve O +spontaneously O +if O +the O +medication O +is O +stopped O +. O + +We O +report O +on O +a O +14 O +- O +year O +- O +old O +boy O +who O +developed O +acute B +renal I +failure I +2 O +weeks O +after O +aortic O +valve O +surgery O +. O + +He O +was O +put O +on O +aspirin O +following O +surgery O +and O +took O +ibuprofen O +for O +fever B +for O +nearly O +a O +week O +prior O +to O +presentation O +. O + +He O +then O +presented O +to O +the O +emergency O +department O +feeling O +quite O +ill O +and O +was O +found O +to O +have O +a O +blood O +urea O +nitrogen O +( O +BUN O +) O +concentration O +of O +of O +147 O +mg O +/ O +dl O +, O +creatinine O +of O +15 O +. O +3 O +mg O +/ O +dl O +and O +serum O +potassium O +of O +8 O +. O +7 O +mEq O +/ O +l O +. O + +Dialysis O +was O +immediately O +initiated O +. O + +A O +kidney O +biopsy O +showed O +inflammatory O +infiltrate O +consistent O +with O +ATIN B +. O + +However O +, O +in O +the O +tubular O +basement O +membrane O +( O +TBM O +) O +, O +very O +intense O +granular O +deposits O +of O +polyclonal O +IgG O +and O +C3 O +were O +noted O +. O + +He O +needed O +dialysis O +for O +2 O +weeks O +and O +was O +treated O +successfully O +with O +steroids O +for O +6 O +months O +. O + +His O +renal O +recovery O +and O +disappearance O +of O +proteinuria B +took O +a O +year O +. O + +In O +conclusion O +, O +this O +is O +a O +first O +report O +of O +NSAIDs O +- O +associated O +ATIN O +, O +showing O +deposits O +of O +granular O +immune O +complex O +present O +only O +in O +the O +TBM O +and O +not O +in O +the O +glomeruli O +. O + +Rifampicin O +- O +associated O +segmental O +necrotizing O +glomerulonephritis B +in O +staphylococcal B +endocarditis I +. O + +Segmental O +necrotising B +glomerulonephritis B +has O +been O +reported O +as O +complication O +of O +rifampicin O +therapy O +in O +patients O +receiving O +treatment O +for O +tuberculosis B +. O + +Changing O +epidemiology O +of O +infections B +such O +as O +infective B +endocarditis I +( O +IE B +) O +has O +led O +to O +an O +increase O +in O +the O +use O +of O +rifampicin O +for O +Staphylococcal B +infections I +. O + +We O +describe O +a O +case O +of O +a O +patient O +with O +Staphylococcal B +IE I +who O +developed O +acute B +renal I +failure I +secondary O +to O +a O +segmental O +necrotising O +glomerulonephritis B +while O +being O +treated O +with O +rifampicin O +, O +and O +review O +the O +literature O +regarding O +this O +complication O +of O +rifampicin O +therapy O +. O + +Rate O +of O +YMDD O +motif O +mutants O +in O +lamivudine O +- O +untreated O +Iranian O +patients O +with O +chronic B +hepatitis I +B I +virus I +infection I +. O + +BACKGROUND O +: O +Lamivudine O +is O +used O +for O +the O +treatment O +of O +chronic B +hepatitis I +B I +patients O +. O + +Recent O +studies O +show O +that O +the O +YMDD O +motif O +mutants O +( O +resistant O +hepatitis O +B O +virus O +) O +occur O +as O +natural O +genome O +variability O +in O +lamivudine O +- O +untreated O +chronic B +hepatitis I +B I +patients O +. O + +In O +this O +study O +we O +aimed O +to O +determine O +the O +rate O +of O +YMDD O +motif O +mutants O +in O +lamivudine O +- O +untreated O +chronic B +hepatitis I +B I +patients O +in O +Iran O +. O + +PATIENTS O +AND O +METHODS O +: O +A O +total O +of O +77 O +chronic B +hepatitis I +B I +patients O +who O +had O +not O +been O +treated O +with O +lamivudine O +were O +included O +in O +the O +study O +. O + +Serum O +samples O +from O +patients O +were O +tested O +by O +polymerase O +chain O +reaction O +- O +restriction O +fragment O +length O +polymorphism O +( O +PCR O +- O +RFLP O +) O +for O +detection O +of O +YMDD O +motif O +mutants O +. O + +All O +patients O +were O +also O +tested O +for O +liver O +enzymes O +, O +anti O +- O +HCV O +, O +HBeAg O +, O +and O +anti O +- O +HBe O +. O + +RESULTS O +: O +Of O +the O +77 O +patients O +enrolled O +in O +the O +study O +, O +73 O +% O +were O +male O +and O +27 O +% O +were O +female O +. O + +Mean O +ALT O +and O +AST O +levels O +were O +124 O +. O +4 O ++ O +/ O +- O +73 O +. O +4 O +and O +103 O +. O +1 O ++ O +/ O +- O +81 O +IU O +/ O +l O +, O +respectively O +. O + +HBeAg O +was O +positive O +in O +40 O +% O +and O +anti O +- O +HBe O +in O +60 O +% O +of O +the O +patients O +. O + +Anti O +- O +HCV O +was O +negative O +in O +all O +of O +them O +. O + +YMDD O +motif O +mutants O +were O +not O +detected O +in O +any O +of O +the O +patients O +despite O +the O +liver O +enzyme O +levels O +and O +the O +presence O +of O +HBeAg O +or O +anti O +- O +HBe O +. O + +CONCLUSION O +: O +Although O +the O +natural O +occurrence O +of O +YMDD O +motif O +mutants O +in O +lamivudine O +- O +untreated O +patients O +with O +chronic B +hepatitis I +B I +has O +been O +reported O +, O +these O +mutants O +were O +not O +detected O +in O +Iranian O +lamivudine O +- O +untreated O +chronic B +hepatitis I +B I +patients O +. O + +Branch O +retinal B +vein I +occlusion I +and O +fluoxetine O +. O + +A O +case O +of O +branch O +retinal B +vein I +occlusion I +associated O +with O +fluoxetine O +- O +induced O +secondary O +hypertension B +is O +described O +. O + +Although O +an O +infrequent O +complication O +of O +selective O +serotonin O +reuptake O +inhibitor O +therapy O +, O +it O +is O +important O +that O +ophthalmologists O +are O +aware O +that O +these O +agents O +can O +cause O +hypertension B +because O +this O +class O +of O +drugs O +is O +widely O +prescribed O +. O + +The O +differential O +effects O +of O +bupivacaine O +and O +lidocaine O +on O +prostaglandin O +E2 O +release O +, O +cyclooxygenase O +gene O +expression O +and O +pain B +in O +a O +clinical O +pain B +model O +. O + +BACKGROUND O +: O +In O +addition O +to O +blocking O +nociceptive O +input O +from O +surgical O +sites O +, O +long O +- O +acting O +local O +anesthetics O +might O +directly O +modulate O +inflammation B +. O + +In O +the O +present O +study O +, O +we O +describe O +the O +proinflammatory O +effects O +of O +bupivacaine O +on O +local O +prostaglandin O +E2 O +( O +PGE2 O +) O +production O +and O +cyclooxygenase O +( O +COX O +) O +gene O +expression O +that O +increases O +postoperative B +pain I +in O +human O +subjects O +. O + +METHODS O +: O +Subjects O +( O +n O += O +114 O +) O +undergoing O +extraction O +of O +impacted O +third O +molars O +received O +either O +2 O +% O +lidocaine O +or O +0 O +. O +5 O +% O +bupivacaine O +before O +surgery O +and O +either O +rofecoxib O +50 O +mg O +or O +placebo O +orally O +90 O +min O +before O +surgery O +and O +for O +the O +following O +48 O +h O +. O + +Oral O +mucosal O +biopsies O +were O +taken O +before O +surgery O +and O +48 O +h O +after O +surgery O +. O + +After O +extraction O +, O +a O +microdialysis O +probe O +was O +placed O +at O +the O +surgical O +site O +for O +PGE2 O +and O +thromboxane O +B2 O +( O +TXB2 O +) O +measurements O +. O + +RESULTS O +: O +The O +bupivacaine O +/ O +rofecoxib O +group O +reported O +significantly O +less O +pain B +, O +as O +assessed O +by O +a O +visual O +analog O +scale O +, O +compared O +with O +the O +other O +three O +treatment O +groups O +over O +the O +first O +4 O +h O +. O + +However O +, O +the O +bupivacaine O +/ O +placebo O +group O +reported O +significantly O +more O +pain B +at O +24 O +h O +and O +PGE2 O +levels O +during O +the O +first O +4 O +h O +were O +significantly O +higher O +than O +the O +other O +three O +treatment O +groups O +. O + +Moreover O +, O +bupivacaine O +significantly O +increased O +COX O +- O +2 O +gene O +expression O +at O +48 O +h O +as O +compared O +with O +the O +lidocaine O +/ O +placebo O +group O +. O + +Thromboxane O +levels O +were O +not O +significantly O +affected O +by O +any O +of O +the O +treatments O +, O +indicating O +that O +the O +effects O +seen O +were O +attributable O +to O +inhibition O +of O +COX O +- O +2 O +, O +but O +not O +COX O +- O +1 O +. O + +CONCLUSIONS O +: O +These O +results O +suggest O +that O +bupivacaine O +stimulates O +COX O +- O +2 O +gene O +expression O +after O +tissue B +injury I +, O +which O +is O +associated O +with O +higher O +PGE2 O +production O +and O +pain B +after O +the O +local O +anesthetic O +effect O +dissipates O +. O + +p75NTR O +expression O +in O +rat O +urinary O +bladder O +sensory O +neurons O +and O +spinal O +cord O +with O +cyclophosphamide O +- O +induced O +cystitis B +. O + +A O +role O +for O +nerve O +growth O +factor O +( O +NGF O +) O +in O +contributing O +to O +increased O +voiding O +frequency O +and O +altered O +sensation O +from O +the O +urinary O +bladder O +has O +been O +suggested O +. O + +Previous O +studies O +have O +examined O +the O +expression O +and O +regulation O +of O +tyrosine O +kinase O +receptors O +( O +Trks O +) O +in O +micturition O +reflexes O +with O +urinary B +bladder I +inflammation I +. O + +The O +present O +studies O +examine O +the O +expression O +and O +regulation O +of O +another O +receptor O +known O +to O +bind O +NGF O +, O +p75 O +( O +NTR O +) O +, O +after O +various O +durations O +of O +bladder B +inflammation I +induced O +by O +cyclophosphamide O +( O +CYP O +) O +. O + +CYP O +- O +induced O +cystitis B +increased O +( O +P O +< O +or O += O +0 O +. O +001 O +) O +p75 O +( O +NTR O +) O +expression O +in O +the O +superficial O +lateral O +and O +medial O +dorsal O +horn O +in O +L1 O +- O +L2 O +and O +L6 O +- O +S1 O +spinal O +segments O +. O + +The O +number O +of O +p75 O +( O +NTR O +) O +- O +immunoreactive O +( O +- O +IR O +) O +cells O +in O +the O +lumbosacral O +dorsal O +root O +ganglia O +( O +DRG O +) O +also O +increased O +( O +P O +< O +or O += O +0 O +. O +05 O +) O +with O +CYP O +- O +induced O +cystitis B +( O +acute O +, O +intermediate O +, O +and O +chronic O +) O +. O + +Quantitative O +, O +real O +- O +time O +polymerase O +chain O +reaction O +also O +demonstrated O +significant O +increases O +( O +P O +< O +or O += O +0 O +. O +01 O +) O +in O +p75 O +( O +NTR O +) O +mRNA O +in O +DRG O +with O +intermediate O +and O +chronic O +CYP O +- O +induced O +cystitis B +. O + +Retrograde O +dye O +- O +tracing O +techniques O +with O +Fastblue O +were O +used O +to O +identify O +presumptive O +bladder O +afferent O +cells O +in O +the O +lumbosacral O +DRG O +. O + +In O +bladder O +afferent O +cells O +in O +DRG O +, O +p75 O +( O +NTR O +) O +- O +IR O +was O +also O +increased O +( O +P O +< O +or O += O +0 O +. O +01 O +) O +with O +cystitis B +. O + +In O +addition O +to O +increases O +in O +p75 O +( O +NTR O +) O +- O +IR O +in O +DRG O +cell O +bodies O +, O +increases O +( O +P O +< O +or O += O +0 O +. O +001 O +) O +in O +pericellular O +( O +encircling O +DRG O +cells O +) O +p75 O +( O +NTR O +) O +- O +IR O +in O +DRG O +also O +increased O +. O + +Confocal O +analyses O +demonstrated O +that O +pericellular O +p75 O +( O +NTR O +) O +- O +IR O +was O +not O +colocalized O +with O +the O +glial O +marker O +, O +glial O +fibrillary O +acidic O +protein O +( O +GFAP O +) O +. O + +These O +studies O +demonstrate O +that O +p75 O +( O +NTR O +) O +expression O +in O +micturition O +reflexes O +is O +present O +constitutively O +and O +modified O +by O +bladder B +inflammation I +. O + +The O +functional O +significance O +of O +p75 O +( O +NTR O +) O +expression O +in O +micturition O +reflexes O +remains O +to O +be O +determined O +. O + +Azathioprine O +- O +induced O +suicidal O +erythrocyte O +death O +. O + +BACKGROUND O +: O +Azathioprine O +is O +widely O +used O +as O +an O +immunosuppressive O +drug O +. O + +The O +side O +effects O +of O +azathioprine O +include O +anemia B +, O +which O +has O +been O +attributed O +to O +bone B +marrow I +suppression I +. O + +Alternatively O +, O +anemia B +could O +result O +from O +accelerated O +suicidal O +erythrocyte O +death O +or O +eryptosis B +, O +which O +is O +characterized O +by O +exposure O +of O +phosphatidylserine O +( O +PS O +) O +at O +the O +erythrocyte O +surface O +and O +by O +cell O +shrinkage O +. O + +METHODS O +: O +The O +present O +experiments O +explored O +whether O +azathioprine O +influences O +eryptosis B +. O + +According O +to O +annexin O +V O +binding O +, O +erythrocytes O +from O +patients O +indeed O +showed O +a O +significant O +increase O +of O +PS O +exposure O +within O +1 O +week O +of O +treatment O +with O +azathioprine O +. O + +In O +a O +second O +series O +, O +cytosolic O +Ca2 O ++ O +activity O +( O +Fluo3 O +fluorescence O +) O +, O +cell O +volume O +( O +forward O +scatter O +) O +, O +and O +PS O +- O +exposure O +( O +annexin O +V O +binding O +) O +were O +determined O +by O +FACS O +analysis O +in O +erythrocytes O +from O +healthy O +volunteers O +. O + +RESULTS O +: O +Exposure O +to O +azathioprine O +( O +> O +or O += O +2 O +microg O +/ O +mL O +) O +for O +48 O +hours O +increased O +cytosolic O +Ca2 O ++ O +activity O +and O +annexin O +V O +binding O +and O +decreased O +forward O +scatter O +. O + +The O +effect O +of O +azathioprine O +on O +both O +annexin O +V O +binding O +and O +forward O +scatter O +was O +significantly O +blunted O +in O +the O +nominal O +absence O +of O +extracellular O +Ca2 O ++ O +. O + +CONCLUSIONS O +: O +Azathioprine O +triggers O +suicidal O +erythrocyte O +death O +, O +an O +effect O +presumably O +contributing O +to O +azathioprine O +- O +induced O +anemia B +. O + +Levetiracetam O +as O +an O +adjunct O +to O +phenobarbital O +treatment O +in O +cats O +with O +suspected O +idiopathic B +epilepsy I +. O + +OBJECTIVE O +: O +To O +assess O +pharmacokinetics O +, O +efficacy O +, O +and O +tolerability O +of O +oral O +levetiracetam O +administered O +as O +an O +adjunct O +to O +phenobarbital O +treatment O +in O +cats O +with O +poorly O +controlled O +suspected O +idiopathic B +epilepsy I +. O + +DESIGN O +- O +Open O +- O +label O +, O +noncomparative O +clinical O +trial O +. O + +ANIMALS O +: O +12 O +cats O +suspected O +to O +have O +idiopathic B +epilepsy I +that O +was O +poorly O +controlled O +with O +phenobarbital O +or O +that O +had O +unacceptable O +adverse O +effects O +when O +treated O +with O +phenobarbital O +. O + +PROCEDURES O +: O +Cats O +were O +treated O +with O +levetiracetam O +( O +20 O +mg O +/ O +kg O +[ O +9 O +. O +1 O +mg O +/ O +lb O +] O +, O +PO O +, O +q O +8 O +h O +) O +. O + +After O +a O +minimum O +of O +1 O +week O +of O +treatment O +, O +serum O +levetiracetam O +concentrations O +were O +measured O +before O +and O +2 O +, O +4 O +, O +and O +6 O +hours O +after O +drug O +administration O +, O +and O +maximum O +and O +minimum O +serum O +concentrations O +and O +elimination O +half O +- O +life O +were O +calculated O +. O + +Seizure B +frequencies O +before O +and O +after O +initiation O +of O +levetiracetam O +treatment O +were O +compared O +, O +and O +adverse O +effects O +were O +recorded O +. O + +RESULTS O +: O +Median O +maximum O +serum O +levetiracetam O +concentration O +was O +25 O +. O +5 O +microg O +/ O +mL O +, O +median O +minimum O +serum O +levetiracetam O +concentration O +was O +8 O +. O +3 O +microg O +/ O +mL O +, O +and O +median O +elimination O +half O +- O +life O +was O +2 O +. O +9 O +hours O +. O + +Median O +seizure B +frequency O +prior O +to O +treatment O +with O +levetiracetam O +( O +2 O +. O +1 O +seizures B +/ O +mo O +) O +was O +significantly O +higher O +than O +median O +seizure B +frequency O +after O +initiation O +of O +levetiracetam O +treatment O +( O +0 O +. O +42 O +seizures B +/ O +mo O +) O +, O +and O +7 O +of O +10 O +cats O +were O +classified O +as O +having O +responded O +to O +levetiracetam O +treatment O +( O +ie O +, O +reduction O +in O +seizure B +frequency O +of O +> O +or O += O +50 O +% O +) O +. O + +Two O +cats O +had O +transient O +lethargy B +and O +inappetence B +. O + +CONCLUSIONS O +AND O +CLINICAL O +RELEVANCE O +: O +Results O +suggested O +that O +levetiracetam O +is O +well O +tolerated O +in O +cats O +and O +may O +be O +useful O +as O +an O +adjunct O +to O +phenobarbital O +treatment O +in O +cats O +with O +idiopathic B +epilepsy I +. O + +Serotonin O +reuptake O +inhibitors O +, O +paranoia B +, O +and O +the O +ventral O +basal O +ganglia O +. O + +Antidepressants O +have O +previously O +been O +associated O +with O +paranoid B +reactions O +in O +psychiatric B +patients O +. O + +Five O +cases O +of O +paranoid B +exacerbation O +with O +the O +serotonin O +reuptake O +inhibitors O +fluoxetine O +and O +amitriptyline O +are O +reported O +here O +. O + +Elements O +common O +to O +these O +cases O +included O +a O +history O +of O +paranoid B +symptomatology O +and O +the O +concomitant O +occurrence O +of O +depressive B +and I +psychotic I +symptoms I +. O + +Complicated O +depressive B +disorders I +( O +including O +atypicality O +of O +course O +and O +symptomatology O +, O +chronicity O +, O +psychosis B +, O +bipolarity O +, O +and O +secondary O +onset O +in O +the O +course O +of O +a O +primary O +psychosis B +) O +may O +present O +particular O +vulnerability O +to O +paranoid O +exacerbations O +associated O +with O +serotonin O +reuptake O +inhibitors O +. O + +Although O +the O +pharmacology O +and O +neurobiology O +of O +paranoia B +remain O +cryptic O +, O +several O +mechanisms O +, O +including O +5HT3 O +receptor O +- O +mediated O +dopamine O +release O +, O +beta O +- O +noradrenergic O +receptor O +downregulation O +, O +or O +GABAB O +receptor O +upregulation O +acting O +in O +the O +vicinity O +of O +the O +ventral O +basal O +ganglia O +( O +possibly O +in O +lateral O +orbitofrontal O +or O +anterior O +cingulate O +circuits O +) O +, O +might O +apply O +to O +this O +phenomenon O +. O + +These O +cases O +call O +attention O +to O +possible O +paranoid B +exacerbations O +with O +serotonin O +reuptake O +blockers O +in O +select O +patients O +and O +raise O +neurobiological O +considerations O +regarding O +paranoia B +. 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 B +. O + +Efforts O +must O +therefore O +continue O +to O +be O +made O +to O +obviate O +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 +, 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 O +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 O +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 +) O +in O +the O +unilateral O +group O +and O +5 O +( O +13 O +. O +5 O +% O +) O +in O +the O +conventional O +group O +developed O +hypotension B +, O +P O += O +0 O +. O +71 O +. O + +Four O +( O +10 O +. O +8 O +% O +) O +patients O +in O +the O +conventional O +group O +and O +1 O +( O +2 O +. O +7 O +% 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 B +. 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 I +blood I +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 +003 O +, O +0 O +. O +001 O +and O +0 O +. O +004 O +) 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 + +Spectrum O +of O +adverse O +events O +after O +generic O +HAART O +in O +southern O +Indian O +HIV B +- I +infected I +patients O +. O + +To O +determine O +the O +incidence O +of O +clinically O +significant O +adverse O +events O +after O +long O +- O +term O +, O +fixed O +- O +dose O +, O +generic O +highly O +active O +antiretroviral O +therapy O +( O +HAART O +) O +use O +among O +HIV B +- I +infected I +individuals O +in O +South O +India O +, O +we O +examined O +the O +experiences O +of O +3154 O +HIV B +- I +infected I +individuals O +who O +received O +a O +minimum O +of O +3 O +months O +of O +generic O +HAART O +between O +February O +1996 O +and O +December O +2006 O +at O +a O +tertiary O +HIV B +care O +referral O +center O +in O +South O +India O +. O + +The O +most O +common O +regimens O +were O +3TC O ++ O +d4T O ++ O +nevirapine O +( O +NVP O +) O +( O +54 O +. O +8 O +% O +) O +, O +zidovudine O +( O +AZT O +) O ++ O +3TC O ++ O +NVP O +( O +14 O +. O +5 O +% O +) O +, O +3TC O ++ O +d4T O ++ O +efavirenz O +( O +EFV O +) O +( O +20 O +. O +1 O +% O +) O +, O +and O +AZT O ++ O +3TC O ++ O +EFV O +( O +5 O +. O +4 O +% O +) O +. O + +The O +most O +common O +adverse O +events O +and O +median O +CD4 O +at O +time O +of O +event O +were O +rash B +( O +15 O +. O +2 O +% O +; O +CD4 O +, O +285 O +cells O +/ O +microL O +) O +and O +peripheral B +neuropathy I +( O +9 O +. O +0 O +% O +and O +348 O +cells O +/ O +microL O +) O +. O + +Clinically O +significant O +anemia B +( O +hemoglobin O +< O +7 O +g O +/ O +dL O +) O +was O +observed O +in O +5 O +. O +4 O +% O +of O +patients O +( O +CD4 O +, O +165 O +cells O +/ O +microL O +) O +and O +hepatitis B +( O +clinical O +jaundice B +with O +alanine O +aminotransferase O +> O +5 O +times O +upper O +limits O +of O +normal O +) O +in O +3 O +. O +5 O +% O +of O +patients O +( O +CD4 O +, O +260 O +cells O +/ O +microL O +) O +. O + +Women O +were O +significantly O +more O +likely O +to O +experience O +lactic B +acidosis I +, O +while O +men O +were O +significantly O +more O +likely O +to O +experience O +immune B +reconstitution I +syndrome I +( O +p O +< O +0 O +. O +05 O +) O +. O + +Among O +the O +patients O +with O +1 O +year O +of O +follow O +- O +up O +, O +NVP O +therapy O +was O +significantly O +associated O +with O +developing O +rash B +and O +d4T O +therapy O +with O +developing O +peripheral B +neuropathy I +( O +p O +< O +0 O +. O +05 O +) O +. O + +Anemia B +and O +hepatitis B +often O +occur O +within O +12 O +weeks O +of O +initiating O +generic O +HAART O +. O + +Frequent O +and O +early O +monitoring O +for O +these O +toxicities B +is O +warranted O +in O +developing O +countries O +where O +generic O +HAART O +is O +increasingly O +available O +. O + +Thalidomide O +and O +sensory B +neurotoxicity I +: O +a O +neurophysiological O +study O +. O + +BACKGROUND O +: O +Recent O +studies O +confirmed O +a O +high O +incidence O +of O +sensory O +axonal I +neuropathy I +in O +patients O +treated O +with O +different O +doses O +of O +thalidomide O +. O + +The O +study O +' O +s O +aims O +were O +to O +measure O +variations O +in O +sural O +nerve O +sensory O +action O +potential O +( O +SAP O +) O +amplitude O +in O +patients O +with O +refractory B +cutaneous I +lupus I +erythematosus I +( O +CLE B +) O +treated O +with O +thalidomide O +and O +use O +these O +findings O +to O +identify O +the O +neurotoxic B +potential O +of O +thalidomide O +and O +the O +recovery O +capacity O +of O +sensory O +fibres O +after O +discontinuation O +of O +treatment O +. O + +PATIENTS O +AND O +METHODS O +: O +Clinical O +and O +electrophysiological O +data O +in O +12 O +female O +patients O +with O +CLE B +during O +treatment O +with O +thalidomide O +and O +up O +to O +47 O +months O +after O +discontinuation O +of O +treatment O +were O +analysed O +. O + +Sural O +nerve O +SAP O +amplitude O +reduction O +> O +or O += O +40 O +% O +was O +the O +criteria O +for O +discontinuing O +therapy O +. O + +RESULTS O +: O +During O +treatment O +, O +11 O +patients O +showed O +a O +reduction O +in O +sural O +nerve O +SAP O +amplitude O +compared O +to O +baseline O +values O +( O +9 O +with O +a O +reduction O +> O +or O += O +50 O +% O +and O +2 O +< O +50 O +% O +) O +. O + +One O +patient O +showed O +no O +changes O +in O +SAP O +amplitude O +. O + +Five O +patients O +complained O +of O +paresthesias B +and O +leg B +cramps I +. O + +After O +thalidomide O +treatment O +, O +sural O +SAP O +amplitude O +recovered O +in O +3 O +patients O +. O + +At O +detection O +of O +reduction O +in O +sural O +nerve O +SAP O +amplitude O +, O +the O +median O +thalidomide O +cumulative O +dose O +was O +21 O +. O +4 O +g O +. O + +The O +threshold O +neurotoxic B +dosage O +is O +lower O +than O +previously O +reported O +. O + +CONCLUSIONS O +: O +Sural O +nerve O +SAP O +amplitude O +reduction O +is O +a O +reliable O +and O +sensitive O +marker O +of O +degeneration O +and O +recovery O +of O +sensory O +fibres O +. O + +This O +electrophysiological O +parameter O +provides O +information O +about O +subclinical O +neurotoxic B +potential O +of O +thalidomide O +but O +is O +not O +helpful O +in O +predicting O +the O +appearance O +of O +sensory O +symptoms O +. O + +Five O +cases O +of O +encephalitis B +during O +treatment O +of O +loiasis B +with O +diethylcarbamazine O +. O + +Five O +cases O +of O +encephalitis B +following O +treatment O +with O +diethylcarbamazine O +( O +DEC O +) O +were O +observed O +in O +Congolese O +patients O +with O +Loa B +loa I +filariasis I +. O + +Two O +cases O +had O +a O +fatal O +outcome O +and O +one O +resulted O +in O +severe O +sequelae O +. O + +The O +notable O +fact O +was O +that O +this O +complication O +occurred O +in O +three O +patients O +hospitalized O +before O +treatment O +began O +, O +with O +whom O +particularly O +strict O +therapeutic O +precautions O +were O +taken O +, O +i O +. O +e O +. O +, O +initial O +dose O +less O +than O +10 O +mg O +of O +DEC O +, O +very O +gradual O +dose O +increases O +, O +and O +associated O +anti O +- O +allergic O +treatment O +. O + +This O +type O +of O +drug O +- O +induced O +complication O +may O +not O +be O +that O +uncommon O +in O +highly O +endemic O +regions O +. O + +It O +occurs O +primarily O +, O +but O +not O +exclusively O +, O +in O +subjects O +presenting O +with O +a O +high O +microfilarial O +load O +. O + +The O +relationship O +between O +the O +occurrence O +of O +encephalitis B +and O +the O +decrease O +in O +microfilaremia B +is O +evident O +. O + +The O +pathophysiological O +mechanisms O +are O +discussed O +in O +the O +light O +of O +these O +observations O +and O +the O +few O +other O +comments O +on O +this O +subject O +published O +in O +the O +literature O +. O + +Amiodarone O +- O +related O +pulmonary O +mass O +and O +unique O +membranous O +glomerulonephritis B +in O +a O +patient O +with O +valvular B +heart I +disease I +: O +Diagnostic O +pitfall O +and O +new O +findings O +. O + +Amiodarone O +is O +an O +anti O +- O +arrhythmic O +drug O +for O +life O +- O +threatening O +tachycardia B +, O +but O +various O +adverse O +effects O +have O +been O +reported O +. O + +Reported O +herein O +is O +an O +autopsy O +case O +of O +valvular B +heart I +disease I +, O +in O +a O +patient O +who O +developed O +a O +lung B +mass O +( O +1 O +. O +5 O +cm O +in O +diameter O +) O +and O +proteinuria B +( O +2 O +. O +76 O +g O +/ O +day O +) O +after O +treatment O +with O +amiodarone O +for O +a O +long O +time O +. O + +The O +lung O +mass O +was O +highly O +suspected O +to O +be O +lung B +cancer I +on O +CT O +and O +positron O +emission O +tomography O +, O +but O +histologically O +the O +lesion O +was O +composed O +of O +lymphoplasmacytic O +infiltrates O +in O +alveolar O +walls O +and O +intra O +- O +alveolar O +accumulation O +of O +foamy O +macrophages O +containing O +characteristic O +myelinoid O +bodies O +, O +indicating O +that O +it O +was O +an O +amiodarone O +- O +related O +lesion O +. O + +In O +addition O +, O +the O +lung O +tissue O +had O +unevenly O +distributed O +hemosiderin O +deposition O +, O +and O +abnormally O +tortuous O +capillaries O +were O +seen O +in O +the O +mass O +and O +in O +heavily O +hemosiderotic O +lung O +portions O +outside O +the O +mass O +. O + +In O +the O +kidneys O +, O +glomeruli O +had O +membrane O +spikes O +, O +prominent O +swelling O +of O +podocytes O +and O +subepithelial O +deposits O +, O +which O +were O +sometimes O +large O +and O +hump O +- O +like O +. O + +Autoimmune B +diseases I +, O +viral B +hepatitis I +, O +malignant B +neoplasms I +or O +other O +diseases O +with O +a O +known O +relationship O +to O +membranous B +glomerulonephritis I +were O +not O +found O +. O + +The O +present O +case O +highlights O +the O +possibility O +that O +differential O +diagnosis O +between O +an O +amiodarone O +- O +related O +pulmonary B +lesion I +and O +a O +neoplasm B +can O +be O +very O +difficult O +radiologically O +, O +and O +suggests O +that O +membranous B +glomerulonephritis B +might O +be O +another O +possible O +complication O +of O +amiodarone O +treatment O +. O + +Risk O +of O +coronary B +artery I +disease I +associated O +with O +initial O +sulphonylurea O +treatment O +of O +patients O +with O +type B +2 I +diabetes I +: O +a O +matched O +case O +- O +control O +study O +. O + +AIMS O +: O +This O +study O +sought O +to O +assess O +the O +risk O +of O +developing O +coronary B +artery I +disease I +( O +CAD B +) O +associated O +with O +initial O +treatment O +of O +type B +2 I +diabetes I +with O +different O +sulphonylureas O +. O + +METHODS O +: O +In O +type B +2 I +diabetic I +patients O +, O +cases O +who O +developed O +CAD B +were O +compared O +retrospectively O +with O +controls O +that O +did O +not O +. O + +The O +20 O +- O +year O +risk O +of O +CAD B +at O +diagnosis O +of O +diabetes B +, O +using O +the O +UKPDS O +risk O +engine O +, O +was O +used O +to O +match O +cases O +with O +controls O +. O + +RESULTS O +: O +The O +76 O +cases O +of O +CAD B +were O +compared O +with O +152 O +controls O +. O + +The O +hazard O +of O +developing O +CAD B +( O +95 O +% O +CI O +) O +associated O +with O +initial O +treatment O +increased O +by O +2 O +. O +4 O +- O +fold O +( O +1 O +. O +3 O +- O +4 O +. O +3 O +, O +P O += O +0 O +. O +004 O +) O +with O +glibenclamide O +; O +2 O +- O +fold O +( O +0 O +. O +9 O +- O +4 O +. O +6 O +, O +P O += O +0 O +. O +099 O +) O +with O +glipizide O +; O +2 O +. O +9 O +- O +fold O +( O +1 O +. O +6 O +- O +5 O +. O +1 O +, O +P O += O +0 O +. O +000 O +) O +with O +either O +, O +and O +was O +unchanged O +with O +metformin O +. O + +The O +hazard O +decreased O +0 O +. O +3 O +- O +fold O +( O +0 O +. O +7 O +- O +1 O +. O +7 O +, O +P O += O +0 O +. O +385 O +) O +with O +glimepiride O +, O +0 O +. O +4 O +- O +fold O +( O +0 O +. O +7 O +- O +1 O +. O +3 O +, O +P O += O +0 O +. O +192 O +) O +with O +gliclazide O +, O +and O +0 O +. O +4 O +- O +fold O +( O +0 O +. O +7 O +- O +1 O +. O +1 O +, O +P O += O +0 O +. O +09 O +) O +with O +either O +. O + +CONCLUSIONS O +: O +Initiating O +treatment O +of O +type B +2 I +diabetes I +with O +glibenclamide O +or O +glipizide O +is O +associated O +with O +increased O +risk O +of O +CAD B +in O +comparison O +to O +gliclazide O +or O +glimepiride O +. O + +If O +confirmed O +, O +this O +may O +be O +important O +because O +most O +Indian O +patients O +receive O +the O +cheaper O +older O +sulphonylureas O +, O +and O +present O +guidelines O +do O +not O +distinguish O +between O +individual O +agents O +. O + +Reduced O +progression O +of O +adriamycin O +nephropathy B +in O +spontaneously O +hypertensive B +rats O +treated O +by O +losartan O +. O + +BACKGROUND O +: O +The O +aim O +of O +the O +study O +was O +to O +investigate O +the O +antihypertensive O +effects O +of O +angiotensin O +II O +type O +- O +1 O +receptor O +blocker O +, O +losartan O +, O +and O +its O +potential O +in O +slowing O +down O +renal B +disease I +progression O +in O +spontaneously O +hypertensive B +rats O +( O +SHR O +) O +with O +adriamycin O +( O +ADR O +) O +nephropathy B +. O + +METHODS O +: O +Six O +- O +month O +- O +old O +female O +SHR O +were O +randomly O +selected O +in O +six O +groups O +. O + +Two O +control O +groups O +( O +SH O +( O +6 O +) O +, O +SH O +( O +12 O +) O +) O +received O +vehicle O +. O + +Groups O +ADR O +( O +6 O +) O +, O +ADR O ++ O +LOS O +( O +6 O +) O +and O +ADR O +( O +12 O +) O +, O +and O +ADR O ++ O +LOS O +( O +12 O +) O +received O +ADR O +( O +2 O +mg O +/ O +kg O +/ O +b O +. O +w O +. O +i O +. O +v O +. O +) O +twice O +in O +a O +3 O +- O +week O +interval O +. O + +Group O +ADR O ++ O +LOS O +( O +6 O +) O +received O +losartan O +( O +10 O +mg O +/ O +kg O +/ O +b O +. O +w O +. O +/ O +day O +by O +gavages O +) O +for O +6 O +weeks O +and O +group O +ADR O ++ O +LOS O +( O +12 O +) O +for O +12 O +weeks O +after O +second O +injection O +of O +ADR O +. O + +Animals O +were O +killed O +after O +6 O +or O +12 O +weeks O +, O +respectively O +. O + +Haemodynamic O +measurements O +were O +performed O +on O +anaesthetized O +animals O +, O +blood O +and O +urine O +samples O +were O +taken O +for O +biochemical O +analysis O +and O +the O +left O +kidney O +was O +processed O +for O +morphological O +studies O +. O + +RESULTS O +: O +Short O +- O +term O +losartan O +treatment O +, O +besides O +antihypertensive O +effect O +, O +improved O +glomerular O +filtration O +rate O +and O +ameliorated O +glomerulosclerosis B +resulting O +in O +decreased O +proteinuria B +. O + +Prolonged O +treatment O +with O +losartan O +showed O +further O +reduction O +of O +glomerulosclerosis B +associated O +with O +reduced O +progression O +of O +tubular B +atrophy I +and O +interstitial B +fibrosis I +, O +thus O +preventing O +heavy O +proteinuria B +and O +chronic B +renal I +failure I +. O + +Losartan O +reduced O +uraemia B +and O +increased O +urea O +clearance O +in O +advanced O +ADR O +nephropathy B +in O +SHR O +. O + +Histological O +examination O +showed O +that O +losartan O +could O +prevent O +tubular B +atrophy I +, O +interstitial O +infiltration O +and O +fibrosis B +in O +ADR O +nephropathy B +. O + +CONCLUSION O +: O +Losartan O +reduces O +the O +rate O +of O +progression O +of O +ADR O +- O +induced O +focal B +segmental I +glomerulosclerosis I +to O +end B +- I +stage I +renal I +disease I +in O +SHR O +. O + +The O +risks O +of O +aprotinin O +and O +tranexamic O +acid O +in O +cardiac O +surgery O +: O +a O +one O +- O +year O +follow O +- O +up O +of O +1188 O +consecutive O +patients O +. O + +BACKGROUND O +: O +Our O +aim O +was O +to O +investigate O +postoperative O +complications I +and O +mortality O +after O +administration O +of O +aprotinin O +compared O +to O +tranexamic O +acid O +in O +an O +unselected O +, O +consecutive O +cohort O +. O + +METHODS O +: O +Perioperative O +data O +from O +consecutive O +cardiac O +surgery O +patients O +were O +prospectively O +collected O +between O +September O +2005 O +and O +June O +2006 O +in O +a O +university O +- O +affiliated O +clinic O +( O +n O += O +1188 O +) O +. O + +During O +the O +first O +5 O +mo O +, O +596 O +patients O +received O +aprotinin O +( O +Group O +A O +) O +; O +in O +the O +next O +5 O +mo O +, O +592 O +patients O +were O +treated O +with O +tranexamic O +acid O +( O +Group O +T O +) O +. O + +Except O +for O +antifibrinolytic O +therapy O +, O +the O +anesthetic O +and O +surgical O +protocols O +remained O +unchanged O +. O + +RESULTS O +: O +The O +pre O +- O +and O +intraoperative O +variables O +were O +comparable O +between O +the O +treatment O +groups O +. O + +Postoperatively O +, O +a O +significantly O +higher O +incidence O +of O +seizures B +was O +found O +in O +Group O +T O +( O +4 O +. O +6 O +% O +vs O +1 O +. O +2 O +% O +, O +P O +< O +0 O +. O +001 O +) O +. O + +This O +difference O +was O +also O +significant O +in O +the O +primary O +valve O +surgery O +and O +the O +high O +risk O +surgery O +subgroups O +( O +7 O +. O +9 O +% O +vs O +1 O +. O +2 O +% O +, O +P O += O +0 O +. O +003 O +; O +7 O +. O +3 O +% O +vs O +2 O +. O +4 O +% O +, O +P O += O +0 O +. O +035 O +, O +respectively O +) O +. O + +Persistent O +atrial B +fibrillation I +( O +7 O +. O +9 O +% O +vs O +2 O +. O +3 O +% O +, O +P O += O +0 O +. O +020 O +) O +and O +renal B +failure I +( O +9 O +. O +7 O +% O +vs O +1 O +. O +7 O +% O +, O +P O += O +0 O +. O +002 O +) O +were O +also O +more O +common O +in O +Group O +T O +, O +in O +the O +primary O +valve O +surgery O +subgroup O +. O + +On O +the O +contrary O +, O +among O +primary O +coronary O +artery O +bypass O +surgery O +patients O +, O +there O +were O +more O +acute B +myocardial B +infarctions I +and O +renal B +dysfunction I +in O +Group O +A O +( O +5 O +. O +8 O +% O +vs O +2 O +. O +0 O +% O +, O +P O += O +0 O +. O +027 O +; O +22 O +. O +5 O +% O +vs O +15 O +. O +2 O +% O +, O +P O += O +0 O +. O +036 O +, O +respectively O +) O +. O + +The O +1 O +- O +yr O +mortality O +was O +significantly O +higher O +after O +aprotinin O +treatment O +in O +the O +high O +risk O +surgery O +group O +( O +17 O +. O +7 O +% O +vs O +9 O +. O +8 O +% O +, O +P O += O +0 O +. O +034 O +) O +. O + +CONCLUSION O +: O +Both O +antifibrinolytic O +drugs O +bear O +the O +risk O +of O +adverse O +outcome O +depending O +on O +the O +type O +of O +cardiac O +surgery O +. O + +Administration O +of O +aprotinin O +should O +be O +avoided O +in O +coronary O +artery O +bypass O +graft O +and O +high O +risk O +patients O +, O +whereas O +administration O +of O +tranexamic O +acid O +is O +not O +recommended O +in O +valve O +surgery O +. O + +Delirium B +in O +an O +elderly O +woman O +possibly O +associated O +with O +administration O +of O +misoprostol O +. O + +Misoprostol O +has O +been O +associated O +with O +adverse O +reactions O +, O +including O +gastrointestinal B +symptoms I +, O +gynecologic O +problems O +, O +and O +headache B +. O + +Changes O +in O +mental O +status O +, O +however O +, O +have O +not O +been O +reported O +. O + +We O +present O +a O +case O +in O +which O +an O +89 O +- O +year O +- O +old O +woman O +in O +a O +long O +- O +term O +care O +facility O +became O +confused O +after O +the O +initiation O +of O +misoprostol O +therapy O +. O + +The O +patient O +' O +s O +change O +in O +mental O +status O +was O +first O +reported O +nine O +days O +after O +the O +initiation O +of O +therapy O +. O + +Her O +delirium B +significantly O +improved O +after O +misoprostol O +was O +discontinued O +and O +her O +mental O +status O +returned O +to O +normal O +within O +a O +week O +. O + +Because O +no O +other O +factors O +related O +to O +this O +patient O +changed O +significantly O +, O +the O +delirium B +experienced O +by O +this O +patient O +possibly O +resulted O +from O +misoprostol O +therapy O +. O + +The O +biological O +properties O +of O +the O +optical O +isomers O +of O +propranolol O +and O +their O +effects O +on O +cardiac B +arrhythmias I +. O + +1 O +. O + +The O +optical O +isomers O +of O +propranolol O +have O +been O +compared O +for O +their O +beta O +- O +blocking O +and O +antiarrhythmic O +activities O +. O +2 O +. O + +In O +blocking O +the O +positive O +inotropic O +and O +chronotropic O +responses O +to O +isoprenaline O +, O +( O ++ O +) O +- O +propranolol O +had O +less O +than O +one O +hundredth O +the O +potency O +of O +( O +- O +) O +- O +propranolol O +. O + +At O +dose O +levels O +of O +( O ++ O +) O +- O +propranolol O +which O +attenuated O +the O +responses O +to O +isoprenaline O +, O +there O +was O +a O +significant O +prolongation O +of O +the O +PR O +interval O +of O +the O +electrocardiogram O +. O +3 O +. O + +The O +metabolic O +responses O +to O +isoprenaline O +in O +dogs O +( O +an O +increase O +in O +circulating O +glucose O +, O +lactate O +and O +free O +fatty O +acids O +) O +were O +all O +blocked O +by O +( O +- O +) O +- O +propranolol O +. O + +( O ++ O +) O +- O +Propranolol O +had O +no O +effect O +on O +fatty O +acid O +mobilization O +but O +significantly O +reduced O +the O +increments O +in O +both O +lactate O +and O +glucose O +. O +4 O +. O + +Both O +isomers O +of O +propranolol O +possessed O +similar O +depressant O +potency O +on O +isolated O +atrial O +muscle O +taken O +from O +guinea O +- O +pigs O +. O +5 O +. O + +The O +isomers O +of O +propranolol O +exhibited O +similar O +local O +anaesthetic O +potencies O +on O +an O +isolated O +frog O +nerve O +preparation O +at O +a O +level O +approximately O +three O +times O +that O +of O +procaine O +. O + +The O +racemic O +compound O +was O +significantly O +less O +potent O +than O +either O +isomer O +. O +6 O +. O + +Both O +isomers O +of O +propranolol O +were O +capable O +of O +preventing O +adrenaline O +- O +induced O +cardiac B +arrhythmias I +in O +cats O +anaesthetized O +with O +halothane O +, O +but O +the O +mean O +dose O +of O +( O +- O +) O +- O +propranolol O +was O +0 O +. O +09 O ++ O +/ O +- O +0 O +. O +02 O +mg O +/ O +kg O +whereas O +that O +of O +( O ++ O +) O +- O +propranolol O +was O +4 O +. O +2 O ++ O +/ O +- O +1 O +. O +2 O +mg O +/ O +kg O +. O + +At O +the O +effective O +dose O +level O +of O +( O ++ O +) O +- O +propranolol O +there O +was O +a O +significant O +prolongation O +of O +the O +PR O +interval O +of O +the O +electrocardiogram O +. O + +Blockade O +of O +arrhythmias B +with O +both O +isomers O +was O +surmountable O +by O +increasing O +the O +dose O +of O +adrenaline O +. O +7 O +. O + +Both O +isomers O +of O +propranolol O +were O +also O +capable O +of O +reversing O +ventricular B +tachycardia I +caused O +by O +ouabain O +in O +anaesthetized O +cats O +and O +dogs O +. O + +The O +dose O +of O +( O +- O +) O +- O +propranolol O +was O +significantly O +smaller O +than O +that O +of O +( O ++ O +) O +- O +propranolol O +in O +both O +species O +but O +much O +higher O +than O +that O +required O +to O +produce O +evidence O +of O +beta O +- O +blockade O +. O +8 O +. O + +The O +implications O +of O +these O +results O +are O +discussed O +. O + +Topotecan O +in O +combination O +with O +radiotherapy O +in O +unresectable O +glioblastoma B +: O +a O +phase O +2 O +study O +. O + +Improving O +glioblastoma B +multiforme I +( O +GBM B +) O +treatment O +with O +radio O +- O +chemotherapy O +remains O +a O +challenge O +. O + +Topotecan O +is O +an O +attractive O +option O +as O +it O +exhibits O +growth O +inhibition O +of O +human O +glioma B +as O +well O +as O +brain O +penetration O +. O + +The O +present O +study O +assessed O +the O +combination O +of O +radiotherapy O +( O +60 O +Gy O +/ O +30 O +fractions O +/ O +40 O +days O +) O +and O +topotecan O +( O +0 O +. O +9 O +mg O +/ O +m O +( O +2 O +) O +/ O +day O +on O +days O +1 O +- O +5 O +on O +weeks O +1 O +, O +3 O +and O +5 O +) O +in O +50 O +adults O +with O +histologically O +proven O +and O +untreated O +GBM B +. O + +The O +incidence O +of O +non O +- O +hematological O +toxicities B +was O +low O +and O +grade O +3 O +- O +4 O +hematological B +toxicities B +were O +reported O +in O +20 O +patients O +( O +mainly O +lymphopenia B +and O +neutropenia B +) O +. O + +Partial O +response O +and O +stabilization O +rates O +were O +2 O +% O +and O +32 O +% O +, O +respectively O +, O +with O +an O +overall O +time O +to O +progression O +of O +12 O +weeks O +. O + +One O +- O +year O +overall O +survival O +( O +OS O +) O +rate O +was O +42 O +% O +, O +with O +a O +median O +OS O +of O +40 O +weeks O +. O + +Topotecan O +in O +combination O +with O +radiotherapy O +was O +well O +tolerated O +. O + +However O +, O +while O +response O +and O +stabilization O +concerned O +one O +- O +third O +of O +the O +patients O +, O +the O +study O +did O +not O +show O +increased O +benefits O +in O +terms O +of O +survival O +in O +patients O +with O +unresectable O +GBM B +. O + +Long O +- O +term O +lithium O +therapy O +leading O +to O +hyperparathyroidism B +: O +a O +case O +report O +. O + +PURPOSE O +: O +This O +paper O +reviews O +the O +effect O +of O +chronic O +lithium O +therapy O +on O +serum O +calcium O +level O +and O +parathyroid O +glands O +, O +its O +pathogenesis O +, O +and O +treatment O +options O +. O + +We O +examined O +the O +case O +of O +a O +lithium O +- O +treated O +patient O +who O +had O +recurrent O +hypercalcemia B +to O +better O +understand O +the O +disease O +process O +. O + +CONCLUSION O +: O +Primary B +hyperparathyroidism I +is O +a O +rare O +but O +potentially O +life O +- O +threatening O +side O +effect O +of O +long O +- O +term O +lithium O +therapy O +. O + +Careful O +patient O +selection O +and O +long O +- O +term O +follow O +- O +up O +can O +reduce O +morbidity O +. O + +PRACTICAL O +IMPLICATIONS O +: O +As O +much O +as O +15 O +% O +of O +lithium O +- O +treated O +patients O +become O +hypercalcemic B +. O + +By O +routinely O +monitoring O +serum O +calcium O +levels O +, O +healthcare O +providers O +can O +improve O +the O +quality O +of O +life O +of O +this O +patient O +group O +. O + +Comparison O +of O +laryngeal O +mask O +with O +endotracheal O +tube O +for O +anesthesia O +in O +endoscopic O +sinus O +surgery O +. O + +BACKGROUND O +: O +The O +purpose O +of O +this O +study O +was O +to O +compare O +surgical O +conditions O +, O +including O +the O +amount O +of O +intraoperative O +bleeding B +as O +well O +as O +intraoperative O +blood O +pressure O +, O +during O +functional O +endoscopic O +sinus O +surgery O +( O +FESS O +) O +using O +flexible O +reinforced O +laryngeal O +mask O +airway O +( O +FRLMA O +) O +versus O +endotracheal O +tube O +( O +ETT O +) O +in O +maintaining O +controlled O +hypotension B +anesthesia O +induced O +by O +propofol O +- O +remifentanil O +total O +i O +. O +v O +. O +anesthesia O +( O +TIVA O +) O +. O + +METHODS O +: O +Sixty O +normotensive O +American O +Society O +of O +Anesthesiologists O +I O +- O +II O +adult O +patients O +undergoing O +FESS O +under O +controlled O +hypotension B +anesthesia O +caused O +by O +propofol O +- O +remifentanil O +- O +TIVA O +were O +randomly O +assigned O +into O +two O +groups O +: O +group O +I O +, O +FRLMA O +; O +group O +II O +, O +ETT O +. O + +Hemorrhage B +was O +measured O +and O +the O +visibility O +of O +the O +operative O +field O +was O +evaluated O +according O +to O +a O +six O +- O +point O +scale O +. O + +RESULTS O +: O +Controlled O +hypotension B +was O +achieved O +within O +a O +shorter O +period O +using O +laryngeal O +mask O +using O +lower O +rates O +of O +remifentanil O +infusion O +and O +lower O +total O +dose O +of O +remifentanil O +. O + +CONCLUSION O +: O +In O +summary O +, O +our O +results O +indicate O +that O +airway O +management O +using O +FRLMA O +during O +controlled O +hypotension B +anesthesia O +provided O +better O +surgical O +conditions O +in O +terms O +of O +quality O +of O +operative O +field O +and O +blood O +loss O +and O +allowed O +for O +convenient O +induced O +hypotension B +with O +low O +doses O +of O +remifentanil O +during O +TIVA O +in O +patients O +undergoing O +FESS O +. O + +Nonalcoholic B +fatty I +liver I +disease I +during O +valproate O +therapy O +. O + +Valproic O +acid O +( O +VPA O +) O +is O +effective O +for O +the O +treatment O +of O +many O +types O +of O +epilepsy B +, O +but O +its O +use O +can O +be O +associated O +with O +an O +increase O +in O +body O +weight O +. O + +We O +report O +a O +case O +of O +nonalcoholic B +fatty I +liver I +disease I +( O +NAFLD B +) O +arising O +in O +a O +child O +who O +developed O +obesity B +during O +VPA O +treatment O +. O + +Laboratory O +data O +revealed O +hyperinsulinemia B +with O +insulin B +resistance I +. O + +After O +the O +withdrawal O +of O +VPA O +therapy O +, O +our O +patient O +showed O +a O +significant O +weight B +loss I +, O +a O +decrease O +of O +body O +mass O +index O +, O +and O +normalization O +of O +metabolic O +and O +endocrine O +parameters O +; O +moreover O +, O +ultrasound O +measurements O +showed O +a O +complete O +normalization O +. O + +The O +present O +case O +suggests O +that O +obesity B +, O +hyperinsulinemia B +, O +insulin B +resistance I +, O +and O +long O +- O +term O +treatment O +with O +VPA O +may O +be O +all O +associated O +with O +the O +development O +of O +NAFLD B +; O +this O +side O +effect O +is O +reversible O +after O +VPA O +withdrawal O +. O + +Carbimazole O +induced O +ANCA O +positive O +vasculitis B +. O + +Anti O +- O +thyroid O +drugs O +, O +like O +carbimazole O +and O +propylthiouracil O +( O +PTU O +) O +are O +commonly O +prescribed O +for O +the O +treatment O +of O +hyperthyroidism B +. O + +One O +should O +be O +aware O +of O +the O +side O +effects O +of O +antithyroid O +medications O +. O + +Antineutrophil O +cytoplasmic O +antibody O +( O +ANCA O +) O +- O +- O +associated O +vasculitis B +is O +a O +potentially O +life O +- O +threatening O +adverse O +effect O +of O +antithyroidmedications O +. O + +We O +report O +a O +patient O +with O +Graves B +' I +disease I +who O +developed O +ANCA O +positive O +carbimazole O +induced O +vasculitis B +. O + +The O +episode O +was O +characterized O +by O +a O +vasculitic B +skin I +rash I +associated O +with O +large B +joint I +arthritis I +, O +pyrexia B +and O +parotiditis B +but O +no O +renal B +or I +pulmonary I +involvement I +. O + +He O +was O +referred O +to O +us O +for O +neurological O +evaluation O +because O +he O +had O +difficulty O +in O +getting O +up O +from O +squatting O +position O +and O +was O +suspected O +to O +have O +myositis B +. O + +Carbimazole O +and O +methimazole O +have O +a O +lower O +incidence O +of O +reported O +ANCA O +positive O +side O +effects O +than O +PUT O +. O + +To O +the O +best O +of O +our O +knowledge O +this O +is O +the O +first O +ANCA O +positive O +carbimazole O +induced O +vasculitis B +case O +reported O +from O +India O +. O + +Aspirin O +for O +the O +primary O +prevention O +of O +cardiovascular O +events O +: O +an O +update O +of O +the O +evidence O +for O +the O +U O +. O +S O +. O + +Preventive O +Services O +Task O +Force O +. O + +BACKGROUND O +: O +Coronary B +heart I +disease I +and O +cerebrovascular B +disease I +are O +leading O +causes O +of O +death B +in O +the O +United O +States O +. O + +In O +2002 O +, O +the O +U O +. O +S O +. O + +Preventive O +Services O +Task O +Force O +( O +USPSTF O +) O +strongly O +recommended O +that O +clinicians O +discuss O +aspirin O +with O +adults O +who O +are O +at O +increased O +risk O +for O +coronary B +heart I +disease I +. O + +PURPOSE O +: O +To O +determine O +the O +benefits O +and O +harms O +of O +taking O +aspirin O +for O +the O +primary O +prevention O +of O +myocardial B +infarctions I +, O +strokes B +, O +and O +death B +. O + +DATA O +SOURCES O +: O +MEDLINE O +and O +Cochrane O +Library O +( O +search O +dates O +, O +1 O +January O +2001 O +to O +28 O +August O +2008 O +) O +, O +recent O +systematic O +reviews O +, O +reference O +lists O +of O +retrieved O +articles O +, O +and O +suggestions O +from O +experts O +. O + +STUDY O +SELECTION O +: O +English O +- O +language O +randomized O +, O +controlled O +trials O +( O +RCTs O +) O +; O +case O +- O +control O +studies O +; O +meta O +- O +analyses O +; O +and O +systematic O +reviews O +of O +aspirin O +versus O +control O +for O +the O +primary O +prevention O +of O +cardiovascular B +disease I +( O +CVD B +) O +were O +selected O +to O +answer O +the O +following O +questions O +: O +Does O +aspirin O +decrease O +coronary O +heart I +events I +, O +strokes B +, O +death B +from O +coronary B +heart I +events I +or O +stroke B +, O +or O +all O +- O +cause O +mortality O +in O +adults O +without O +known O +CVD B +? O + +Does O +aspirin O +increase O +gastrointestinal B +bleeding I +or O +hemorrhagic B +strokes I +? O + +DATA O +EXTRACTION O +: O +All O +studies O +were O +reviewed O +, O +abstracted O +, O +and O +rated O +for O +quality O +by O +using O +predefined O +USPSTF O +criteria O +. O + +DATA O +SYNTHESIS O +: O +New O +evidence O +from O +1 O +good O +- O +quality O +RCT O +, O +1 O +good O +- O +quality O +meta O +- O +analysis O +, O +and O +2 O +fair O +- O +quality O +subanalyses O +of O +RCTs O +demonstrates O +that O +aspirin O +use O +reduces O +the O +number O +of O +CVD B +events O +in O +patients O +without O +known O +CVD B +. O + +Men O +in O +these O +studies O +experienced O +fewer O +myocardial B +infarctions I +and O +women O +experienced O +fewer O +ischemic B +strokes I +. O + +Aspirin O +does O +not O +seem O +to O +affect O +CVD B +mortality O +or O +all O +- O +cause O +mortality O +in O +either O +men O +or O +women O +. O + +The O +use O +of O +aspirin O +for O +primary O +prevention O +increases O +the O +risk O +for O +major O +bleeding B +events O +, O +primarily O +gastrointestinal B +bleeding I +events O +, O +in O +both O +men O +and O +women O +. O + +Men O +have O +an O +increased O +risk O +for O +hemorrhagic B +strokes I +with O +aspirin O +use O +. O + +A O +new O +RCT O +and O +meta O +- O +analysis O +suggest O +that O +the O +risk O +for O +hemorrhagic B +strokes I +in O +women O +is O +not O +statistically O +significantly O +increased O +. O + +LIMITATIONS O +: O +New O +evidence O +on O +aspirin O +for O +the O +primary O +prevention O +of O +CVD B +is O +limited O +. O + +The O +dose O +of O +aspirin O +used O +in O +the O +RCTs B +varied O +, O +which O +prevented O +the O +estimation O +of O +the O +most O +appropriate O +dose O +for O +primary O +prevention O +. O + +Several O +of O +the O +RCTs O +were O +conducted O +within O +populations O +of O +health O +professionals O +, O +which O +potentially O +limits O +generalizability O +. O + +CONCLUSION O +: O +Aspirin O +reduces O +the O +risk O +for O +myocardial B +infarction I +in O +men O +and O +strokes B +in O +women O +. O + +Aspirin O +use O +increases O +the O +risk O +for O +serious O +bleeding B +events O +. O + +Reducing O +harm O +associated O +with O +anticoagulation O +: O +practical O +considerations O +of O +argatroban O +therapy O +in O +heparin O +- O +induced O +thrombocytopenia B +. O + +Argatroban O +is O +a O +hepatically O +metabolized O +, O +direct O +thrombin O +inhibitor O +used O +for O +prophylaxis O +or O +treatment O +of O +thrombosis B +in O +heparin O +- O +induced O +thrombocytopenia B +( O +HIT B +) O +and O +for O +patients O +with O +or O +at O +risk O +of O +HIT B +undergoing O +percutaneous O +coronary O +intervention O +( O +PCI O +) O +. O + +The O +objective O +of O +this O +review O +is O +to O +summarize O +practical O +considerations O +of O +argatroban O +therapy O +in O +HIT B +. O + +The O +US O +FDA O +- O +recommended O +argatroban O +dose O +in O +HIT B +is O +2 O +microg O +/ O +kg O +/ O +min O +( O +reduced O +in O +patients O +with O +hepatic B +impairment I +and O +in O +paediatric O +patients O +) O +, O +adjusted O +to O +achieve O +activated O +partial O +thromboplastin O +times O +( O +aPTTs O +) O +1 O +. O +5 O +- O +3 O +times O +baseline O +( O +not O +> O +100 O +seconds O +) O +. O + +Contemporary O +experiences O +indicate O +that O +reduced O +doses O +are O +also O +needed O +in O +patients O +with O +conditions O +associated O +with O +hepatic B +hypoperfusion I +, O +e O +. O +g O +. O +heart B +failure I +, O +yet O +are O +unnecessary O +for O +renal B +dysfunction I +, O +adult O +age O +, O +sex O +, O +race O +/ O +ethnicity O +or O +obesity B +. O + +Argatroban O +0 O +. O +5 O +- O +1 O +. O +2 O +microg O +/ O +kg O +/ O +min O +typically O +supports O +therapeutic O +aPTTs O +. O + +The O +FDA O +- O +recommended O +dose O +during O +PCI O +is O +25 O +microg O +/ O +kg O +/ O +min O +( O +350 O +microg O +/ O +kg O +initial O +bolus O +) O +, O +adjusted O +to O +achieve O +activated O +clotting O +times O +( O +ACTs O +) O +of O +300 O +- O +450 O +sec O +. O + +For O +PCI B +, O +argatroban O +has O +not O +been O +investigated O +in O +hepatically B +impaired I +patients O +; O +dose O +adjustment O +is O +unnecessary O +for O +adult O +age O +, O +sex O +, O +race O +/ O +ethnicity O +or O +obesity B +, O +and O +lesser O +doses O +may O +be O +adequate O +with O +concurrent O +glycoprotein O +IIb O +/ O +IIIa O +inhibition O +. O + +Argatroban O +prolongs O +the O +International O +Normalized O +Ratio O +, O +and O +published O +approaches O +for O +monitoring O +the O +argatroban O +- O +to O +- O +warfarin O +transition O +should O +be O +followed O +. O + +Major O +bleeding B +with O +argatroban O +is O +0 O +- O +10 O +% O +in O +the O +non O +- O +interventional O +setting O +and O +0 O +- O +5 O +. O +8 O +% O +periprocedurally O +. O + +Argatroban O +has O +no O +specific O +antidote O +, O +and O +if O +excessive O +anticoagulation O +occurs O +, O +argatroban O +infusion O +should O +be O +stopped O +or O +reduced O +. O + +Improved O +familiarity O +of O +healthcare O +professionals O +with O +argatroban O +therapy O +in O +HIT B +, O +including O +in O +special O +populations O +and O +during O +PCI B +, O +may O +facilitate O +reduction O +of O +harm O +associated O +with O +HIT B +( O +e O +. O +g O +. O +fewer O +thromboses B +) O +or O +its O +treatment O +( O +e O +. O +g O +. O +fewer O +argatroban O +medication O +errors O +) O +. O + +Rhabdomyolysis B +and O +brain B +ischemic I +stroke I +in O +a O +heroin O +- O +dependent O +male O +under O +methadone O +maintenance O +therapy O +. O + +OBJECTIVE O +: O +There O +are O +several O +complications O +associated O +with O +heroin B +abuse I +, O +some O +of O +which O +are O +life O +- O +threatening O +. O + +Methadone O +may O +aggravate O +this O +problem O +. O + +METHOD O +: O +A O +clinical O +case O +description O +. O + +RESULTS O +: O +A O +33 O +- O +year O +- O +old O +man O +presented O +with O +rhabdomyolysis B +and O +cerebral B +ischemic I +stroke I +after O +intravenous O +heroin O +. O + +He O +had O +used O +heroin O +since O +age O +20 O +, O +and O +had O +used O +150 O +mg O +methadone O +daily O +for O +6 O +months O +. O + +He O +was O +found O +unconsciousness B +at O +home O +and O +was O +sent O +to O +our O +hospital O +. O + +In O +the O +ER O +, O +his O +opiate O +level O +was O +4497 O +ng O +/ O +ml O +. O + +In O +the O +ICU O +, O +we O +found O +rhabdomyolysis B +, O +acute B +renal I +failure I +and O +acute B +respiratory I +failure I +. O + +After O +transfer O +to O +an O +internal O +ward O +, O +we O +noted O +aphasia B +and O +weakness B +of I +his O +left O +limbs O +. O + +After O +MRI O +, O +we O +found O +cerebral B +ischemic I +infarction I +. O + +CONCLUSION O +: O +Those O +using O +methadone O +and O +heroin O +simultaneously O +may O +increase O +risk O +of O +rhabdomyolysis B +and O +ischemic B +stroke I +. O + +Patients O +under O +methadone O +maintenance O +therapy O +should O +be O +warned O +regarding O +these O +serious O +adverse O +events O +. O + +Hypotheses O +of O +heroin O +- O +related O +rhabdomyolysis B +and O +stroke B +in O +heroin O +abusers O +are O +discussed O +. O + +Increased O +vulnerability O +to O +6 O +- O +hydroxydopamine O +lesion O +and O +reduced O +development O +of O +dyskinesias B +in O +mice O +lacking O +CB1 O +cannabinoid O +receptors O +. O + +Motor B +impairment I +, O +dopamine O +( O +DA O +) O +neuronal O +activity O +and O +proenkephalin O +( O +PENK O +) O +gene O +expression O +in O +the O +caudate O +- O +putamen O +( O +CPu O +) O +were O +measured O +in O +6 O +- O +OHDA O +- O +lesioned O +and O +treated O +( O +L O +- O +DOPA O ++ O +benserazide O +) O +CB1 O +KO O +and O +WT O +mice O +. O + +A O +lesion O +induced O +by O +6 O +- O +OHDA O +produced O +more O +severe O +motor B +deterioration I +in O +CB1 O +KO O +mice O +accompanied O +by O +more O +loss O +of O +DA O +neurons O +and O +increased O +PENK O +gene O +expression O +in O +the O +CPu O +. O + +Oxidative O +/ O +nitrosative O +and O +neuroinflammatory O +parameters O +were O +estimated O +in O +the O +CPu O +and O +cingulate O +cortex O +( O +Cg O +) O +. O + +CB1 O +KO O +mice O +exhibited O +higher O +MDA O +levels O +and O +iNOS O +protein O +expression O +in O +the O +CPu O +and O +Cg O +compared O +to O +WT O +mice O +. O + +Treatment O +with O +L O +- O +DOPA O ++ O +benserazide O +( O +12 O +weeks O +) O +resulted O +in O +less O +severe O +dyskinesias B +in O +CB1 O +KO O +than O +in O +WT O +mice O +. O + +The O +results O +revealed O +that O +the O +lack O +of O +cannabinoid O +CB1 O +receptors O +increased O +the O +severity O +of O +motor B +impairment I +and O +DA B +lesion I +, O +and O +reduced O +L O +- O +DOPA O +- O +induced O +dyskinesias B +. O + +These O +results O +suggest O +that O +activation O +of O +CB1 O +receptors O +offers O +neuroprotection O +against O +dopaminergic B +lesion I +and O +the O +development O +of O +L O +- O +DOPA O +- O +induced O +dyskinesias B +. O + +Hepatocellular O +oxidant O +stress O +following O +intestinal B +ischemia I +- I +reperfusion I +injury I +. O + +Reperfusion O +of O +ischemic B +intestine O +results O +in O +acute B +liver I +dysfunction I +characterized O +by O +hepatocellular O +enzyme O +release O +into O +plasma O +, O +reduction O +in O +bile O +flow O +rate O +, O +and O +neutrophil O +sequestration O +within O +the O +liver O +. O + +The O +pathophysiology O +underlying O +this O +acute B +hepatic I +injury I +is O +unknown O +. O + +This O +study O +was O +undertaken O +to O +determine O +whether O +oxidants O +are O +associated O +with O +the O +hepatic B +injury I +and O +to O +determine O +the O +relative O +value O +of O +several O +indirect O +methods O +of O +assessing O +oxidant O +exposure O +in O +vivo O +. O + +Rats O +were O +subjected O +to O +a O +standardized O +intestinal O +ischemia I +- I +reperfusion I +injury I +. O + +Hepatic O +tissue O +was O +assayed O +for O +lipid O +peroxidation O +products O +and O +oxidized O +and O +reduced O +glutathione O +. O + +There O +was O +no O +change O +in O +hepatic O +tissue O +total O +glutathione O +following O +intestinal B +ischemia I +- I +reperfusion I +injury I +. O + +Oxidized O +glutathione O +( O +GSSG O +) O +increased O +significantly O +following O +30 O +and O +60 O +min O +of O +reperfusion O +. O + +There O +was O +no O +increase O +in O +any O +of O +the O +products O +of O +lipid O +peroxidation O +associated O +with O +this O +injury O +. O + +An O +increase O +in O +GSSG O +within O +hepatic O +tissue O +during O +intestinal O +reperfusion O +suggests O +exposure O +of O +hepatocytes O +to O +an O +oxidant O +stress O +. O + +The O +lack O +of O +a O +significant O +increase O +in O +products O +of O +lipid O +peroxidation O +suggests O +that O +the O +oxidant O +stress O +is O +of O +insufficient O +magnitude O +to O +result O +in O +irreversible O +injury O +to O +hepatocyte O +cell O +membranes O +. O + +These O +data O +also O +suggest O +that O +the O +measurement O +of O +tissue O +GSSG O +may O +be O +a O +more O +sensitive O +indicator O +of O +oxidant O +stress O +than O +measurement O +of O +products O +of O +lipid O +peroxidation O +. O + +Animal O +model O +of O +mania B +induced O +by O +ouabain O +: O +Evidence O +of O +oxidative O +stress O +in O +submitochondrial O +particles O +of O +the O +rat O +brain O +. O + +The O +intracerebroventricular O +( O +ICV O +) O +administration O +of O +ouabain O +( O +a O +Na O +( O ++ O +) O +/ O +K O +( O ++ O +) O +- O +ATPase O +inhibitor O +) O +in O +rats O +has O +been O +suggested O +to O +mimic O +some O +symptoms O +of O +human O +bipolar B +mania I +. O + +Clinical O +studies O +have O +shown O +that O +bipolar B +disorder I +may O +be O +related O +to O +mitochondrial B +dysfunction I +. O + +Herein O +, O +we O +investigated O +the O +behavioral O +and O +biochemical O +effects O +induced O +by O +the O +ICV O +administration O +of O +ouabain O +in O +rats O +. O + +To O +achieve O +this O +aim O +, O +the O +effects O +of O +ouabain O +injection O +immediately O +after O +and O +7 O +days O +following O +a O +single O +ICV O +administration O +( O +at O +concentrations O +of O +10 O +( O +- O +2 O +) O +and O +10 O +( O +- O +3 O +) O +M O +) O +on O +locomotion O +was O +measured O +using O +the O +open O +- O +field O +test O +. O + +Additionally O +, O +thiobarbituric O +acid O +reactive O +substances O +( O +TBARSs O +) O +and O +superoxide O +production O +were O +measured O +in O +submitochondrial O +particles O +of O +the O +prefrontal O +cortex O +, O +hippocampus O +, O +striatum O +and O +amygdala O +. O + +Our O +findings O +demonstrated O +that O +ouabain O +at O +10 O +( O +- O +2 O +) O +and O +10 O +( O +- O +3 O +) O +M O +induced O +hyperlocomotion B +in O +rats O +, O +and O +this O +response O +remained O +up O +to O +7 O +days O +following O +a O +single O +ICV O +injection O +. O + +In O +addition O +, O +we O +observed O +that O +the O +persistent O +increase O +in O +the O +rat O +spontaneous O +locomotion O +is O +associated O +with O +increased O +TBARS O +levels O +and O +superoxide O +generation O +in O +submitochondrial O +particles O +in O +the O +prefrontal O +cortex O +, O +striatum O +and O +amygdala O +. O + +In O +conclusion O +, O +ouabain O +- O +induced O +mania B +- O +like O +behavior O +may O +provide O +a O +useful O +animal O +model O +to O +test O +the O +hypothesis O +of O +the O +involvement O +of O +oxidative O +stress O +in O +bipolar B +disorder I +. O + +Intraoperative O +dialysis O +during O +liver O +transplantation O +with O +citrate O +dialysate O +. O + +Liver O +transplantation O +for O +acutely O +ill O +patients O +with O +fulminant B +liver I +failure I +carries O +high O +intraoperative O +and O +immediate O +postoperative O +risks O +. O + +These O +are O +increased O +with O +the O +presence O +of O +concomitant O +acute B +kidney I +injury I +( O +AKI B +) O +and O +intraoperative O +dialysis O +is O +sometimes O +required O +to O +allow O +the O +transplant O +to O +proceed O +. O + +The O +derangements O +in O +the O +procoagulant O +and O +anticoagulant O +pathways O +during O +fulminant B +liver I +failure I +can O +lead O +to O +difficulties O +with O +anticoagulation O +during O +dialysis O +, O +especially O +when O +continued O +in O +the O +operating O +room O +. O + +Systemic O +anticoagulation O +is O +unsafe O +and O +regional O +citrate O +anticoagulation O +in O +the O +absence O +of O +a O +functional O +liver O +carries O +the O +risk O +of O +citrate O +toxicity B +. O + +Citrate O +dialysate O +, O +a O +new O +dialysate O +with O +citric O +acid O +can O +be O +used O +for O +anticoagulation O +in O +patients O +who O +cannot O +tolerate O +heparin O +or O +regional O +citrate O +. O + +We O +report O +a O +case O +of O +a O +40 O +- O +year O +- O +old O +female O +with O +acetaminophen O +- O +induced O +fulminant B +liver I +failure I +with O +associated O +AKI B +who O +underwent O +intraoperative O +dialytic O +support O +during O +liver O +transplantation O +anticoagulated O +with O +citrate O +dialysate O +during O +the O +entire O +procedure O +. O + +The O +patient O +tolerated O +the O +procedure O +well O +without O +any O +signs O +of O +citrate O +toxicity B +and O +maintained O +adequate O +anticoagulation O +for O +patency O +of O +the O +dialysis O +circuit O +. O + +Citrate O +dialysate O +is O +a O +safe O +alternative O +for O +intradialytic O +support O +of O +liver O +transplantation O +in O +fulminant B +liver I +failure I +. O + +Delirium B +in O +a O +patient O +with O +toxic O +flecainide O +plasma O +concentrations O +: O +the O +role O +of O +a O +pharmacokinetic O +drug O +interaction O +with O +paroxetine O +. O + +OBJECTIVE O +: O +To O +describe O +a O +case O +of O +flecainide O +- O +induced O +delirium B +associated O +with O +a O +pharmacokinetic O +drug O +interaction O +with O +paroxetine O +. 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 B +and O +paranoia B +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 O +2 O +mg O +/ O +day O +, O +folic O +acid O +1 O +mg O +/ O +day O +, O +levothyroxine O +100 O +microg O +/ O +day O +, O +pantoprazole O +40 O +mg O +/ O +day O +, O +paroxetine O +40 O +mg O +/ O +day O +, O +and O +flecainide O +100 O +mg O +twice O +daily O +. O + +Flecainide O +had O +been O +started O +2 O +weeks O +prior O +for O +atrial B +fibrillation I +. O + +Laboratory O +test O +findings O +on O +admission O +were O +notable O +only O +for O +a O +flecainide O +plasma O +concentration O +of O +1360 O +microg O +/ O +L O +( O +reference O +range O +200 O +- O +1000 O +) O +. O + +A O +metabolic O +drug O +interaction O +between O +flecainide O +and O +paroxetine O +, 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 O +was O +discontinued O +and O +the O +dose O +of O +flecainide O +was O +reduced O +to O +50 O +mg O +twice O +daily O +. O + +Her O +delirium B +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 O +channels O +may O +cause O +delirium B +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 O +, O +a O +CYP2D6 O +substrate O +, O +and O +paroxetine O +, O +a O +CYP2D6 O +inhibitor O +, O +as O +well O +as O +3 O +case O +reports O +of O +flecainide O +- O +induced O +delirium B +. O + +According O +to O +the O +Naranjo O +probability O +scale O +, O +flecainide O +was O +the O +probable O +cause O +of O +the O +patient O +' O +s O +delirium B +; 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 O +and O +paroxetine O +. O + +CONCLUSIONS O +: O +Supratherapeutic O +flecainide O +plasma O +concentrations O +may O +cause O +delirium B +. O + +Because O +toxicity B +may O +occur O +when O +flecainide O +is O +prescribed O +with O +paroxetine O +and O +other O +potent O +CYP2D6 O +inhibitors O +, O +flecainide O +plasma O +concentrations O +should O +be O +monitored O +closely O +with O +commencement O +of O +CYP2D6 O +inhibitors O +. O + +Efficacy O +of O +everolimus O +( O +RAD001 O +) O +in O +patients O +with O +advanced O +NSCLC B +previously O +treated O +with O +chemotherapy O +alone O +or O +with O +chemotherapy O +and O +EGFR O +inhibitors O +. O + +BACKGROUND O +: O +Treatment O +options O +are O +scarce O +in O +pretreated O +advanced O +non B +- I +small I +- I +cell I +lung I +cancer I +( O +NSCLC B +) O +patients O +. O + +RAD001 O +, O +an O +oral O +inhibitor O +of O +the O +mammalian O +target O +of O +rapamycin O +( O +mTOR O +) O +, O +has O +shown O +phase O +I O +efficacy O +in O +NSCLC B +. O + +METHODS O +: O +Stage O +IIIb O +or O +IV O +NSCLC B +patients O +, O +with O +two O +or O +fewer O +prior O +chemotherapy O +regimens O +, O +one O +platinum O +based O +( O +stratum O +1 O +) O +or O +both O +chemotherapy O +and O +epidermal O +growth O +factor O +receptor O +tyrosine O +kinase O +inhibitors O +( O +stratum O +2 O +) O +, O +received O +RAD001 O +10 O +mg O +/ O +day O +until O +progression O +or O +unacceptable O +toxicity B +. O + +Primary O +objective O +was O +overall O +response O +rate O +( O +ORR O +) O +. O + +Analyses O +of O +markers O +associated O +with O +the O +mTOR O +pathway O +were O +carried O +out O +on O +archival O +tumor B +from O +a O +subgroup O +using O +immunohistochemistry O +( O +IHC O +) O +and O +direct O +mutation O +sequencing O +. O + +RESULTS O +: O +Eighty O +- O +five O +patients O +were O +enrolled O +, O +42 O +in O +stratum O +1 O +and O +43 O +in O +stratum O +. O + +ORR O +was O +4 O +. O +7 O +% O +( O +7 O +. O +1 O +% O +stratum O +1 O +; O +2 O +. O +3 O +% O +stratum O +2 O +) O +. O + +Overall O +disease O +control O +rate O +was O +47 O +. O +1 O +% O +. O + +Median O +progression O +- O +free O +survivals O +( O +PFSs O +) O +were O +2 O +. O +6 O +( O +stratum O +1 O +) O +and O +2 O +. O +7 O +months O +( O +stratum O +2 O +) O +. O + +Common O +> O +or O += O +grade O +3 O +events O +were O +fatigue B +, O +dyspnea B +, O +stomatitis B +, O +anemia B +, O +and O +thrombocytopenia B +. O + +Pneumonitis B +, O +probably O +or O +possibly O +related O +, O +mainly O +grade O +1 O +/ O +2 O +, O +occurred O +in O +25 O +% O +. O + +Cox O +regression O +analysis O +of O +IHC O +scores O +found O +that O +only O +phospho O +AKT O +( O +pAKT O +) O +was O +a O +significant O +independent O +predictor O +of O +worse O +PFS O +. O + +CONCLUSIONS O +: O +RAD001 O +10 O +mg O +/ O +day O +was O +well O +tolerated O +, O +showing O +modest O +clinical O +activity O +in O +pretreated O +NSCLC B +. O + +Evaluation O +of O +RAD001 O +plus O +standard O +therapy O +for O +metastatic O +NSCLC B +continues O +. O + +Posttransplant O +anemia B +: O +the O +role O +of O +sirolimus O +. O + +Posttransplant O +anemia B +is O +a O +common O +problem O +that O +may O +hinder O +patients O +' O +quality O +of O +life O +. O + +It O +occurs O +in O +12 O +to O +76 O +% O +of O +patients O +, O +and O +is O +most O +common O +in O +the O +immediate O +posttransplant O +period O +. O + +A O +variety O +of O +factors O +have O +been O +identified O +that O +increase O +the O +risk O +of O +posttransplant O +anemia B +, O +of O +which O +the O +level O +of O +renal O +function O +is O +most O +important O +. O + +Sirolimus O +, O +a O +mammalian O +target O +of O +rapamycin O +inhibitor O +, O +has O +been O +implicated O +as O +playing O +a O +special O +role O +in O +posttransplant B +anemia I +. O + +This O +review O +considers O +anemia B +associated O +with O +sirolimus O +, O +including O +its O +presentation O +, O +mechanisms O +, O +and O +management O +. O + +Coronary O +computerized O +tomography O +angiography O +for O +rapid O +discharge O +of O +low O +- O +risk O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +. O + +BACKGROUND O +: O +Most O +patients O +presenting O +to O +emergency O +departments O +( O +EDs O +) O +with O +cocaine O +- O +associated O +chest B +pain I +are O +admitted O +for O +at O +least O +12 O +hours O +and O +receive O +a O +" O +rule O +out O +acute B +coronary I +syndrome I +" O +protocol O +, O +often O +with O +noninvasive O +testing O +prior O +to O +discharge O +. O + +In O +patients O +without O +cocaine O +use O +, O +coronary O +computerized O +tomography O +angiography O +( O +CTA O +) O +has O +been O +shown O +to O +be O +useful O +for O +identifying O +a O +group O +of O +patients O +at O +low O +risk O +for O +cardiac O +events O +who O +can O +be O +safely O +discharged O +. O + +It O +is O +unclear O +whether O +a O +coronary O +CTA O +strategy O +would O +be O +efficacious O +in O +cocaine O +- O +associated O +chest B +pain I +, O +as O +coronary B +vasospasm I +may O +account O +for O +some O +of O +the O +ischemia B +. O + +We O +studied O +whether O +a O +negative O +coronary O +CTA O +in O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +could O +identify O +a O +subset O +safe O +for O +discharge O +. O + +METHODS O +: O +We O +prospectively O +evaluated O +the O +safety O +of O +coronary O +CTA O +for O +low O +- O +risk O +patients O +who O +presented O +to O +the O +ED O +with O +cocaineassociated O +chest B +pain I +( O +self O +- O +reported O +or O +positive O +urine O +test O +) O +. O + +Consecutive O +patients O +received O +either O +immediate O +coronary O +CTA O +in O +the O +ED O +( O +without O +serial O +markers O +) O +or O +underwent O +coronary O +CTA O +after O +a O +brief O +observation O +period O +with O +serial O +cardiac O +marker O +measurements O +. O + +Patients O +with O +negative O +coronary O +CTA O +( O +maximal O +stenosis O +less O +than O +50 O +% O +) O +were O +discharged O +. O + +The O +main O +outcome O +was O +30 O +- O +day O +cardiovascular B +death I +or O +myocardial B +infarction I +. O + +RESULTS O +: O +A O +total O +of O +59 O +patients O +with O +cocaine O +- O +associated O +chest B +pain I +were O +evaluated O +. O + +Patients O +had O +a O +mean O +age O +of O +45 O +. O +6 O ++ O +/ O +- O +6 O +. O +6 O +yrs O +and O +were O +86 O +% O +black O +, O +66 O +% O +male O +. O + +Seventy O +- O +nine O +percent O +had O +a O +normal O +or O +nonspecific O +ECG O +and O +85 O +% O +had O +a O +TIMI O +score O +< O +2 O +. O + +Twenty O +patients O +received O +coronary O +CTA O +immediately O +in O +the O +ED O +, O +18 O +of O +whom O +were O +discharged O +following O +CTA O +( O +90 O +% O +) O +. O + +Thirty O +- O +nine O +received O +coronary O +CTA O +after O +a O +brief O +observation O +period O +, O +with O +37 O +discharged O +home O +following O +CTA O +( O +95 O +% O +) O +. O + +Six O +patients O +had O +coronary B +stenosis I +> O +or O += O +50 O +% O +. O + +During O +the O +30 O +- O +day O +follow O +- O +up O +period O +, O +no O +patients O +died O +of O +a O +cardiovascular O +event O +( O +0 O +% O +; O +95 O +% O +CI O +, O +0 O +- O +6 O +. O +1 O +% O +) O +and O +no O +patient O +sustained O +a O +nonfatal O +myocardial B +infarction I +( O +0 O +% O +; O +95 O +% O +CI O +, O +0 O +- O +6 O +. O +1 O +% O +) O +. O + +CONCLUSIONS O +: O +Although O +cocaine O +- O +associated O +myocardial B +ischemia I +can O +result O +from O +coronary O +vasoconstriction O +, O +patients O +with O +cocaine O +associated O +chest B +pain I +, O +a O +non O +- O +ischemic O +ECG O +, O +and O +a O +TIMI O +risk O +score O +< O +2 O +may O +be O +safely O +discharged O +from O +the O +ED O +after O +a O +negative O +coronary O +CTA O +with O +a O +low O +risk O +of O +30 O +- O +day O +adverse O +events O +. O + +Bilateral O +haemorrhagic B +infarction I +of I +the I +globus I +pallidus I +after O +cocaine O +and O +alcohol O +intoxication O +. O + +Cocaine O +is O +a O +risk O +factor O +for O +both O +ischemic B +and I +haemorrhagic I +stroke I +. 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 B +of I +the I +globus I +pallidus I +after O +excessive O +alcohol O +and O +intranasal O +cocaine O +use O +. O + +Drug O +- O +related O +globus B +pallidus I +infarctions I +are O +most O +often O +associated O +with O +heroin O +. O + +Bilateral O +basal B +ganglia I +infarcts I +after O +the O +use O +of O +cocaine O +, 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 B +arrhythmia I +or O +respiratory B +dysfunction I +related O +to O +cocaine O +and O +/ O +or O +ethanol O +use O +were O +the O +most O +likely O +causes O +of O +cerebral B +hypoperfusion I +. O + +Late O +fulminant O +posterior O +reversible O +encephalopathy B +syndrome I +after O +liver O +transplant O +. O + +OBJECTIVES O +: O +Posterior O +leukoencephalopathy B +due O +to O +calcineurin O +- O +inhibitor O +- O +related O +neurotoxicity B +is O +a O +rare O +but O +severe O +complication O +that O +results O +from O +treatment O +with O +immunosuppressive O +agents O +( O +primarily O +those O +administered O +after O +a O +liver O +or O +kidney O +transplant O +) O +. O + +The O +pathophysiologic O +mechanisms O +of O +that O +disorder O +remain O +unknown O +. O + +CASE O +: O +We O +report O +the O +case O +of O +a O +46 O +- O +year O +- O +old O +woman O +who O +received O +a O +liver O +transplant O +in O +our O +center O +as O +treatment O +for O +alcoholic B +cirrhosis I +and O +in O +whom O +either O +a O +fulminant O +course O +of O +posterior O +leukoencephalopathy B +or O +posterior O +reversible O +encephalopathy B +syndrome I +developed O +110 O +days O +after O +transplant O +. O + +After O +an O +initially O +uneventful O +course O +after O +the O +transplant O +, O +the O +patient O +rapidly O +fell O +into O +deep O +coma B +. O + +RESULTS O +: O +Cerebral O +MRI O +scan O +showed O +typical O +signs O +of O +enhancement O +in O +the O +pontine O +and O +posterior O +regions O +. O + +Switching O +the O +immunosuppressive O +regimen O +from O +tacrolimus O +to O +cyclosporine O +did O +not O +improve O +the O +clinical O +situation O +. O + +The O +termination O +of O +treatment O +with O +any O +calcineurin O +inhibitor O +resulted O +in O +a O +complete O +resolution O +of O +that O +complication O +. O + +CONCLUSIONS O +: O +Posterior O +reversible O +encephalopathy B +syndrome O +after O +liver O +transplant O +is O +rare O +. O + +We O +recommend O +a O +complete O +cessation O +of O +any O +calcineurin O +inhibitor O +rather O +than O +a O +dose O +reduction O +. O + +Prolonged O +hypothermia B +as O +a O +bridge O +to O +recovery O +for O +cerebral B +edema I +and O +intracranial B +hypertension I +associated O +with O +fulminant B +hepatic I +failure I +. O + +BACKGROUND O +: O +To O +review O +evidence O +- O +based O +treatment O +options O +in O +patients O +with O +cerebral B +edema I +complicating O +fulminant B +hepatic I +failure I +( O +FHF B +) O +and O +discuss O +the O +potential O +applications O +of O +hypothermia B +. O + +METHOD O +: O +Case O +- O +based O +observations O +from O +a O +medical O +intensive O +care O +unit O +( O +MICU O +) O +in O +a O +tertiary O +care O +facility O +in O +a O +27 O +- O +year O +- O +old O +female O +with O +FHF B +from O +acetaminophen O +and O +resultant O +cerebral B +edema I +. O + +RESULTS O +: O +Our O +patient O +was O +admitted O +to O +the O +MICU O +after O +being O +found O +unresponsive O +with O +presumed O +toxicity B +from O +acetaminophen O +which O +was O +ingested O +over O +a O +2 O +- O +day O +period O +. O + +The O +patient O +had O +depressed B +of I +mental I +status O +lasting O +at O +least O +24 O +h O +prior O +to O +admission O +. O + +Initial O +evaluation O +confirmed O +FHF B +from O +acetaminophen O +and O +cerebral B +edema I +. O + +The O +patient O +was O +treated O +with O +hyperosmolar O +therapy O +, O +hyperventilation O +, O +sedation O +, O +and O +chemical O +paralysis O +. O + +Her O +intracranial O +pressure O +remained O +elevated O +despite O +maximal O +medical O +therapy O +. O + +We O +then O +initiated O +therapeutic O +hypothermia B +which O +was O +continued O +for O +5 O +days O +. O + +At O +re O +- O +warming O +, O +patient O +had O +resolution O +of O +her O +cerebral B +edema I +and O +intracranial B +hypertension I +. O + +At O +discharge O +, O +she O +had O +complete O +recovery O +of O +neurological O +and O +hepatic O +functions O +. O + +CONCLUSION O +: O +In O +patients O +with O +FHF B +and O +cerebral B +edema I +from O +acetaminophen O +overdose B +, O +prolonged O +therapeutic O +hypothermia B +could O +potentially O +be O +used O +as O +a O +life O +saving O +therapy O +and O +a O +bridge O +to O +hepatic O +and O +neurological O +recovery O +. O + +A O +clinical O +trial O +of O +hypothermia B +in O +patients O +with O +this O +condition O +is O +warranted O +. O + +Binasal O +visual B +field I +defects I +are O +not O +specific O +to O +vigabatrin O +. O + +This O +study O +investigated O +the O +visual B +defects I +associated O +with O +the O +antiepileptic O +drug O +vigabatrin O +( O +VGB O +) O +. O + +Two O +hundred O +four O +people O +with O +epilepsy B +were O +grouped O +on O +the O +basis O +of O +antiepileptic O +drug O +therapy O +( O +current O +, O +previous O +, O +or O +no O +exposure O +to O +VGB O +) O +. O + +Groups O +were O +matched O +with O +respect O +to O +age O +, O +gender O +, O +and O +seizure B +frequency O +. O + +All O +patients O +underwent O +objective O +assessment O +of O +electrophysiological O +function O +( O +wide O +- O +field O +multifocal O +electroretinography O +) O +and O +conventional O +visual O +field O +testing O +( O +static O +perimetry O +) O +. O + +Bilateral O +visual B +field I +constriction I +was O +observed O +in O +59 O +% O +of O +patients O +currently O +taking O +VGB O +, O +43 O +% O +of O +patients O +who O +previously O +took O +VGB O +, O +and O +24 O +% O +of O +patients O +with O +no O +exposure O +to O +VGB O +. O + +Assessment O +of O +retinal O +function O +revealed O +abnormal O +responses O +in O +48 O +% O +of O +current O +VGB O +users O +and O +22 O +% O +of O +prior O +VGB O +users O +, O +but O +in O +none O +of O +the O +patients O +without O +previous O +exposure O +to O +VGB O +. O + +Bilateral O +visual B +field I +abnormalities I +are O +common O +in O +the O +treated O +epilepsy B +population O +, O +irrespective O +of O +drug O +history O +. O + +Assessment O +by O +conventional O +static O +perimetry O +may O +neither O +be O +sufficiently O +sensitive O +nor O +specific O +to O +reliably O +identify O +retinal B +toxicity I +associated O +with O +VGB O +. O + +Smoking O +of O +crack O +cocaine O +as O +a O +risk O +factor O +for O +HIV B +infection I +among O +people O +who O +use O +injection O +drugs O +. O + +BACKGROUND O +: O +Little O +is O +known O +about O +the O +possible O +role O +that O +smoking O +crack O +cocaine O +has O +on O +the O +incidence O +of O +HIV B +infection I +. O + +Given O +the O +increasing O +use O +of O +crack O +cocaine O +, O +we O +sought O +to O +examine O +whether O +use O +of O +this O +illicit O +drug O +has O +become O +a O +risk O +factor O +for O +HIV B +infection I +. O + +METHODS O +: O +We O +included O +data O +from O +people O +participating O +in O +the O +Vancouver O +Injection O +Drug O +Users O +Study O +who O +reported O +injecting O +illicit O +drugs O +at O +least O +once O +in O +the O +month O +before O +enrolment O +, O +lived O +in O +the O +greater O +Vancouver O +area O +, O +were O +HIV O +- O +negative O +at O +enrolment O +and O +completed O +at O +least O +1 O +follow O +- O +up O +study O +visit O +. O + +To O +determine O +whether O +the O +risk O +of O +HIV B +seroconversion O +among O +daily O +smokers O +of O +crack O +cocaine O +changed O +over O +time O +, O +we O +used O +Cox O +proportional O +hazards O +regression O +and O +divided O +the O +study O +into O +3 O +periods O +: O +May O +1 O +, O +1996 O +- O +Nov O +. O + +30 O +, O +1999 O +( O +period O +1 O +) O +, O +Dec O +. O + +1 O +, O +1999 O +- O +Nov O +. O + +30 O +, O +2002 O +( O +period O +2 O +) O +, O +and O +Dec O +. O + +1 O +, O +2002 O +- O +Dec O +. O + +30 O +, O +2005 O +( O +period O +3 O +) O +. O + +RESULTS O +: O +Overall O +, O +1048 O +eligible O +injection O +drug O +users O +were O +included O +in O +our O +study O +. O + +Of O +these O +, O +137 O +acquired O +HIV B +infection I +during O +follow O +- O +up O +. O + +The O +mean O +proportion O +of O +participants O +who O +reported O +daily O +smoking O +of O +crack O +cocaine O +increased O +from O +11 O +. O +6 O +% O +in O +period O +1 O +to O +39 O +. O +7 O +% O +in O +period O +3 O +. O + +After O +adjusting O +for O +potential O +confounders O +, O +we O +found O +that O +the O +risk O +of O +HIV B +seroconversion O +among O +participants O +who O +were O +daily O +smokers O +of O +crack O +cocaine O +increased O +over O +time O +( O +period O +1 O +: O +hazard O +ratio O +[ O +HR O +] O +1 O +. O +03 O +, O +95 O +% O +confidence O +interval O +[ O +CI O +] O +0 O +. O +57 O +- O +1 O +. O +85 O +; O +period O +2 O +: O +HR O +1 O +. O +68 O +, O +95 O +% O +CI O +1 O +. O +01 O +- O +2 O +. O +80 O +; O +and O +period O +3 O +: O +HR O +2 O +. O +74 O +, O +95 O +% O +CI O +1 O +. O +06 O +- O +7 O +. O +11 O +) O +. O + +INTERPRETATION O +: O +Smoking O +of O +crack O +cocaine O +was O +found O +to O +be O +an O +independent O +risk O +factor O +for O +HIV B +seroconversion O +among O +people O +who O +were O +injection O +drug O +users O +. O + +This O +finding O +points O +to O +the O +urgent O +need O +for O +evidence O +- O +based O +public O +health O +initiatives O +targeted O +at O +people O +who O +smoke O +crack O +cocaine O +. O + +Fluoxetine O +improves O +the O +memory B +deficits I +caused O +by O +the O +chemotherapy O +agent O +5 O +- O +fluorouracil O +. O + +Cancer B +patients O +who O +have O +been O +treated O +with O +systemic O +adjuvant O +chemotherapy O +have O +described O +experiencing O +deteriorations B +in I +cognition I +. O + +A O +widely O +used O +chemotherapeutic O +agent O +, O +5 O +- O +fluorouracil O +( O +5 O +- O +FU O +) O +, O +readily O +crosses O +the O +blood O +- O +brain O +barrier O +and O +so O +could O +have O +a O +direct O +effect O +on O +brain O +function O +. O + +In O +particular O +this O +anti O +mitotic O +drug O +could O +reduce O +cell O +proliferation O +in O +the O +neurogenic O +regions O +of O +the O +adult O +brain O +. O + +In O +contrast O +reports O +indicate O +that O +hippocampal O +dependent O +neurogenesis O +and O +cognition O +are O +enhanced O +by O +the O +SSRI O +antidepressant O +Fluoxetine O +. O + +In O +this O +investigation O +the O +behavioural O +effects O +of O +chronic O +( O +two O +week O +) O +treatment O +with O +5 O +- O +FU O +and O +( O +three O +weeks O +) O +with O +Fluoxetine O +either O +separately O +or O +in O +combination O +with O +5 O +- O +FU O +were O +tested O +on O +adult O +Lister O +hooded O +rats O +. O + +Behavioural O +effects O +were O +tested O +using O +a O +context O +dependent O +conditioned O +emotional O +response O +test O +( O +CER O +) O +which O +showed O +that O +animals O +treated O +with O +5 O +- O +FU O +had O +a O +significant O +reduction O +in O +freezing O +time O +compared O +to O +controls O +. O + +A O +separate O +group O +of O +animals O +was O +tested O +using O +a O +hippocampal O +dependent O +spatial O +working O +memory O +test O +, O +the O +object O +location O +recognition O +test O +( O +OLR O +) O +. O + +Animals O +treated O +only O +with O +5 O +- O +FU O +showed O +significant O +deficits O +in O +their O +ability O +to O +carry O +out O +the O +OLR O +task O +but O +co O +administration O +of O +Fluoxetine O +improved O +their O +performance O +. O + +5 O +- O +FU O +chemotherapy O +caused O +a O +significant O +reduction O +in O +the O +number O +of O +proliferating O +cells O +in O +the O +sub O +granular O +zone O +of O +the O +dentate O +gyrus O +compared O +to O +controls O +. O + +This O +reduction O +was O +eliminated O +when O +Fluoxetine O +was O +co O +administered O +with O +5 O +- O +FU O +. O + +Fluoxetine O +on O +its O +own O +had O +no O +effect O +on O +proliferating O +cell O +number O +or O +behaviour O +. O + +These O +findings O +suggest O +that O +5 O +- O +FU O +can O +negatively O +affect O +both O +cell O +proliferation O +and O +hippocampal O +dependent O +working O +memory O +and O +that O +these O +deficits O +can O +be O +reversed O +by O +the O +simultaneous O +administration O +of O +the O +antidepressant O +Fluoxetine O +. O + +Liver O +- O +specific O +ablation O +of O +integrin O +- O +linked O +kinase O +in O +mice O +results O +in O +enhanced O +and O +prolonged O +cell O +proliferation O +and O +hepatomegaly B +after O +phenobarbital O +administration O +. O + +We O +have O +recently O +demonstrated O +that O +disruption O +of O +extracellular O +matrix O +( O +ECM O +) O +/ O +integrin O +signaling O +via O +elimination O +of O +integrin O +- O +linked O +kinase O +( O +ILK O +) O +in O +hepatocytes O +interferes O +with O +signals O +leading O +to O +termination O +of O +liver O +regeneration O +. O + +This O +study O +investigates O +the O +role O +of O +ILK O +in O +liver B +enlargement I +induced O +by O +phenobarbital O +( O +PB O +) O +. O + +Wild O +- O +type O +( O +WT O +) O +and O +ILK O +: O +liver O +- O +/ O +- O +mice O +were O +given O +PB O +( O +0 O +. O +1 O +% O +in O +drinking O +water O +) O +for O +10 O +days O +. O + +Livers O +were O +harvested O +on O +2 O +, O +5 O +, O +and O +10 O +days O +during O +PB O +administration O +. O + +In O +the O +hepatocyte O +- O +specific O +ILK O +/ O +liver O +- O +/ O +- O +mice O +, O +the O +liver O +: O +body O +weight O +ratio O +was O +more O +than O +double O +as O +compared O +to O +0 O +h O +at O +day O +2 O +( O +2 O +. O +5 O +times O +) O +, O +while O +at O +days O +5 O +and O +10 O +, O +it O +was O +enlarged O +three O +times O +. O + +In O +the O +WT O +mice O +, O +the O +increase O +was O +as O +expected O +from O +previous O +literature O +( O +1 O +. O +8 O +times O +) O +and O +seems O +to O +have O +leveled O +off O +after O +day O +2 O +. O + +There O +were O +slightly O +increased O +proliferating O +cell O +nuclear O +antigen O +- O +positive O +cells O +in O +the O +ILK O +/ O +liver O +- O +/ O +- O +animals O +at O +day O +2 O +as O +compared O +to O +WT O +after O +PB O +administration O +. O + +In O +the O +WT O +animals O +, O +the O +proliferative O +response O +had O +come O +back O +to O +normal O +by O +days O +5 O +and O +10 O +. O + +Hepatocytes O +of O +the O +ILK O +/ O +liver O +- O +/ O +- O +mice O +continued O +to O +proliferate O +up O +until O +day O +10 O +. O + +ILK O +/ O +liver O +- O +/ O +- O +mice O +also O +showed O +increased O +expression O +of O +key O +genes O +involved O +in O +hepatocyte O +proliferation O +at O +different O +time O +points O +during O +PB O +administration O +. O + +In O +summary O +, O +ECM O +proteins O +communicate O +with O +the O +signaling O +machinery O +of O +dividing O +cells O +via O +ILK O +to O +regulate O +hepatocyte O +proliferation O +and O +termination O +of O +the O +proliferative O +response O +. O + +Lack O +of O +ILK O +in O +the O +hepatocytes O +imparts O +prolonged O +proliferative O +response O +not O +only O +to O +stimuli O +related O +to O +liver O +regeneration O +but O +also O +to O +xenobiotic O +chemical O +mitogens O +, O +such O +as O +PB O +. O + +Decreased O +Expression O +of O +Na O +/ O +K O +- O +ATPase O +, O +NHE3 O +, O +NBC1 O +, O +AQP1 O +and O +OAT O +in O +Gentamicin O +- O +induced O +Nephropathy B +. O + +The O +present O +study O +was O +aimed O +to O +determine O +whether O +there O +is O +an O +altered O +regulation O +of O +tubular O +transporters O +in O +gentamicin O +- O +induced O +nephropathy B +. O + +Sprague O +- O +Dawley O +male O +rats O +( O +200 O +~ O +250 O +g O +) O +were O +subcutaneously O +injected O +with O +gentamicin O +( O +100 O +mg O +/ O +kg O +per O +day O +) O +for O +7 O +days O +, O +and O +the O +expression O +of O +tubular O +transporters O +was O +determined O +by O +immunoblotting O +and O +immunohistochemistry O +. O + +The O +mRNA O +and O +protein O +expression O +of O +OAT O +was O +also O +determined O +. O + +Gentamicin O +- O +treated O +rats O +exhibited O +significantly O +decreased O +creatinine O +clearance O +along O +with O +increased O +plasma O +creatinine O +levels O +. O + +Accordingly O +, O +the O +fractional O +excretion O +of O +sodium O +increased O +. O + +Urine O +volume O +was O +increased O +, O +while O +urine O +osmolality O +and O +free O +water O +reabsorption O +were O +decreased O +. O + +Immunoblotting O +and O +immunohistochemistry O +revealed O +decreased O +expression O +of O +Na O +( O ++ O +) O +/ O +K O +( O ++ O +) O +- O +ATPase O +, O +NHE3 O +, O +NBC1 O +, O +and O +AQP1 O +in O +the O +kidney O +of O +gentamicin O +- O +treated O +rats O +. O + +The O +expression O +of O +OAT1 O +and O +OAT3 O +was O +also O +decreased O +. O + +Gentamicin O +- O +induced O +nephropathy B +may O +at O +least O +in O +part O +be O +causally O +related O +with O +a O +decreased O +expression O +of O +Na O +( O ++ O +) O +/ O +K O +( O ++ O +) O +- O +ATPase O +, O +NHE3 O +, O +NBC1 O +, O +AQP1 O +and O +OAT O +. O + +Acute B +renal I +failure I +after O +high O +- O +dose O +methotrexate O +therapy O +in O +a O +patient O +with O +ileostomy O +. O + +High O +- O +dose O +methotrexate O +( O +HD O +- O +MTX O +) O +is O +an O +important O +treatment O +for O +Burkitt B +lymphoma I +, O +but O +can O +cause O +hepatic B +and I +renal I +toxicity I +when O +its O +clearance O +is O +delayed O +. O + +We O +report O +a O +case O +of O +acute B +renal I +failure I +after O +HD O +- O +MTX O +therapy O +in O +a O +patient O +with O +ileostomy O +, O +The O +patient O +was O +a O +3 O +- O +year O +- O +old O +boy O +who O +had O +received O +a O +living O +- O +related O +liver O +transplantation O +for O +congenital B +biliary I +atresia I +. O + +At O +day O +833 O +after O +the O +transplantation O +, O +he O +was O +diagnosed O +with O +PTLD B +( O +post B +- I +transplantation I +lymphoproliferative I +disorder I +, O +Burkitt B +- I +type I +malignant I +lymphoma I +) O +. O + +During O +induction O +therapy O +, O +he O +suffered O +ileal B +perforation I +and O +ileostomy O +was O +performed O +. O + +Subsequent O +HD O +- O +MTX O +therapy O +caused O +acute B +renal I +failure I +that O +required O +continuous O +hemodialysis O +. O + +We O +supposed O +that O +intravascular O +hypovolemia B +due O +to O +substantial O +drainage O +from O +the O +ileostoma O +caused O +acute B +prerenal I +failure I +. O + +After O +recovery O +of O +his O +renal O +function O +, O +we O +could O +safely O +treat O +the O +patient O +with O +HD O +- O +MTX O +therapy O +by O +controlling O +drainage O +from O +ileostoma B +with O +total O +parenteral O +nutrition O +. O + +Longitudinal O +association O +of O +alcohol O +use O +with O +HIV B +disease I +progression O +and O +psychological O +health O +of O +women O +with O +HIV B +. O + +We O +evaluated O +the O +association O +of O +alcohol O +consumption O +and O +depression B +, O +and O +their O +effects O +on O +HIV B +disease I +progression O +among O +women O +with O +HIV B +. O + +The O +study O +included O +871 O +women O +with O +HIV B +who O +were O +recruited O +from O +1993 O +- O +1995 O +in O +four O +US O +cities O +. O + +The O +participants O +had O +physical O +examination O +, O +medical O +record O +extraction O +, O +and O +venipuncture O +, O +CD4 O ++ O +T O +- O +cell O +counts O +determination O +, O +measurement O +of O +depression B +symptoms O +( O +using O +the O +self O +- O +report O +Center O +for O +Epidemiological O +Studies O +- O +Depression B +Scale O +) O +, O +and O +alcohol O +use O +assessment O +at O +enrollment O +, O +and O +semiannually O +until O +March O +2000 O +. O + +Multilevel O +random O +coefficient O +ordinal O +models O +as O +well O +as O +multilevel O +models O +with O +joint O +responses O +were O +used O +in O +the O +analysis O +. O + +There O +was O +no O +significant O +association O +between O +level O +of O +alcohol O +use O +and O +CD4 O ++ O +T O +- O +cell O +counts O +. O + +When O +participants O +were O +stratified O +by O +antiretroviral O +therapy O +( O +ART O +) O +use O +, O +the O +association O +between O +alcohol O +and O +CD4 O ++ O +T O +- O +cell O +did O +not O +reach O +statistical O +significance O +. O + +The O +association O +between O +alcohol O +consumption O +and O +depression B +was O +significant O +( O +p O +< O +0 O +. O +001 O +) O +. O + +Depression B +had O +a O +significant O +negative O +effect O +on O +CD4 O ++ O +T O +- O +cell O +counts O +over O +time O +regardless O +of O +ART O +use O +. O + +Our O +findings O +suggest O +that O +alcohol O +consumption O +has O +a O +direct O +association O +with O +depression B +. O + +Moreover O +, O +depression B +is O +associated O +with O +HIV B +disease I +progression O +. O + +Our O +findings O +have O +implications O +for O +the O +provision O +of O +alcohol O +use O +interventions O +and O +psychological O +resources O +to O +improve O +the O +health O +of O +women O +with O +HIV B +. O + +Chemokine O +CCL2 O +and O +its O +receptor O +CCR2 O +are O +increased O +in O +the O +hippocampus O +following O +pilocarpine O +- O +induced O +status B +epilepticus I +. O + +BACKGROUND O +: O +Neuroinflammation B +occurs O +after O +seizures B +and O +is O +implicated O +in O +epileptogenesis B +. O + +CCR2 O +is O +a O +chemokine O +receptor O +for O +CCL2 O +and O +their O +interaction O +mediates O +monocyte O +infiltration O +in O +the O +neuroinflammatory O +cascade O +triggered O +in O +different O +brain B +pathologies I +. O + +In O +this O +work O +CCR2 O +and O +CCL2 O +expression O +were O +examined O +following O +status B +epilepticus I +( O +SE B +) O +induced O +by O +pilocarpine O +injection O +. O + +METHODS O +: O +SE B +was O +induced O +by O +pilocarpine O +injection O +. O + +Control O +rats O +were O +injected O +with O +saline O +instead O +of O +pilocarpine O +. O + +Five O +days O +after O +SE B +, O +CCR2 O +staining O +in O +neurons O +and O +glial O +cells O +was O +examined O +using O +imunohistochemical O +analyses O +. O + +The O +number O +of O +CCR2 O +positive O +cells O +was O +determined O +using O +stereology O +probes O +in O +the O +hippocampus O +. O + +CCL2 O +expression O +in O +the O +hippocampus O +was O +examined O +by O +molecular O +assay O +. O + +RESULTS O +: O +Increased O +CCR2 O +was O +observed O +in O +the O +hippocampus O +after O +SE B +. O + +Seizures B +also O +resulted O +in O +alterations O +to O +the O +cell O +types O +expressing O +CCR2 O +. O + +Increased O +numbers O +of O +neurons O +that O +expressed O +CCR2 O +was O +observed O +following O +SE B +. O + +Microglial O +cells O +were O +more O +closely O +apposed O +to O +the O +CCR2 O +- O +labeled O +cells O +in O +SE B +rats O +. O + +In O +addition O +, O +rats O +that O +experienced O +SE B +exhibited O +CCR2 O +- O +labeling O +in O +populations O +of O +hypertrophied O +astrocytes O +, O +especially O +in O +CA1 O +and O +dentate O +gyrus O +. O + +These O +CCR2 O ++ O +astroctytes O +were O +not O +observed O +in O +control O +rats O +. O + +Examination O +of O +CCL2 O +expression O +showed O +that O +it O +was O +elevated O +in O +the O +hippocampus O +following O +SE B +. O + +CONCLUSION O +: O +The O +data O +show O +that O +CCR2 O +and O +CCL2 O +are O +up O +- O +regulated O +in O +the O +hippocampus O +after O +pilocarpine O +- O +induced O +SE B +. O + +Seizures B +also O +result O +in O +changes O +to O +CCR2 O +receptor O +expression O +in O +neurons O +and O +astrocytes O +. O + +These O +changes O +might O +be O +involved O +in O +detrimental O +neuroplasticity O +and O +neuroinflammatory O +changes O +that O +occur O +following O +seizures B +. O + +Metallothionein O +induction O +reduces O +caspase O +- O +3 O +activity O +and O +TNFalpha O +levels O +with O +preservation O +of O +cognitive O +function O +and O +intact O +hippocampal O +neurons O +in O +carmustine O +- O +treated O +rats O +. O + +Hippocampal O +integrity O +is O +essential O +for O +cognitive O +functions O +. O + +On O +the O +other O +hand O +, O +induction O +of O +metallothionein O +( O +MT O +) O +by O +ZnSO O +( O +4 O +) O +and O +its O +role O +in O +neuroprotection O +has O +been O +documented O +. O + +The O +present O +study O +aimed O +to O +explore O +the O +effect O +of O +MT O +induction O +on O +carmustine O +( O +BCNU O +) O +- O +induced O +hippocampal O +cognitive B +dysfunction I +in O +rats O +. O + +A O +total O +of O +60 O +male O +Wistar O +albino O +rats O +were O +randomly O +divided O +into O +four O +groups O +( O +15 O +/ O +group O +) O +: O +The O +control O +group O +injected O +with O +single O +doses O +of O +normal O +saline O +( O +i O +. O +c O +. O +v O +) O +followed O +24 O +h O +later O +by O +BCNU O +solvent O +( O +i O +. O +v O +) O +. O + +The O +second O +group O +administered O +ZnSO O +( O +4 O +) O +( O +0 O +. O +1 O +micromol O +/ O +10 O +microl O +normal O +saline O +, O +i O +. O +c O +. O +v O +, O +once O +) O +then O +BCNU O +solvent O +( O +i O +. O +v O +) O +after O +24 O +h O +. O + +Third O +group O +received O +BCNU O +( O +20 O +mg O +/ O +kg O +, O +i O +. O +v O +, O +once O +) O +24 O +h O +after O +injection O +with O +normal O +saline O +( O +i O +. O +c O +. O +v O +) O +. O + +Fourth O +group O +received O +a O +single O +dose O +of O +ZnSO O +( O +4 O +) O +( O +0 O +. O +1 O +micromol O +/ O +10 O +microl O +normal O +saline O +, O +i O +. O +c O +. O +v O +) O +then O +BCNU O +( O +20 O +mg O +/ O +kg O +, O +i O +. O +v O +, O +once O +) O +after O +24 O +h O +. O + +The O +obtained O +data O +revealed O +that O +BCNU O +administration O +resulted O +in O +deterioration B +of I +learning I +and I +short I +- I +term I +memory I +( O +STM O +) O +, O +as O +measured O +by O +using O +radial O +arm O +water O +maze O +, O +accompanied O +with O +decreased O +hippocampal O +glutathione O +reductase O +( O +GR O +) O +activity O +and O +reduced O +glutathione O +( O +GSH O +) O +content O +. O + +Also O +, O +BCNU O +administration O +increased O +serum O +tumor B +necrosis O +factor O +- O +alpha O +( O +TNFalpha O +) O +, O +hippocampal O +MT O +and O +malondialdehyde O +( O +MDA O +) O +contents O +as O +well O +as O +caspase O +- O +3 O +activity O +in O +addition O +to O +histological O +alterations O +. O + +ZnSO O +( O +4 O +) O +pretreatment O +counteracted O +BCNU O +- O +induced O +inhibition B +of I +GR I +and O +depletion O +of O +GSH O +and O +resulted O +in O +significant O +reduction O +in O +the O +levels O +of O +MDA O +and O +TNFalpha O +as O +well O +as O +the O +activity O +of O +caspase O +- O +3 O +. O + +The O +histological O +features O +were O +improved O +in O +hippocampus O +of O +rats O +treated O +with O +ZnSO O +( O +4 O +) O ++ O +BCNU O +compared O +to O +only O +BCNU O +- O +treated O +animals O +. O + +In O +conclusion O +, O +MT O +induction O +halts O +BCNU O +- O +induced O +hippocampal B +toxicity I +as O +it O +prevented O +GR O +inhibition O +and O +GSH O +depletion O +and O +counteracted O +the O +increased O +levels O +of O +TNFalpha O +, O +MDA O +and O +caspase O +- O +3 O +activity O +with O +subsequent O +preservation O +of O +cognition O +. O + +Fatal O +carbamazepine O +induced O +fulminant O +eosinophilic B +( I +hypersensitivity I +) I +myocarditis B +: O +emphasis O +on O +anatomical O +and O +histological O +characteristics O +, O +mechanisms O +and O +genetics O +of O +drug B +hypersensitivity I +and O +differential O +diagnosis O +. O + +The O +most O +severe O +adverse O +reactions O +to O +carbamazepine O +have O +been O +observed O +in O +the O +haemopoietic O +system O +, O +the O +liver O +and O +the O +cardiovascular O +system O +. O + +A O +frequently O +fatal O +, O +although O +exceptionally O +rare O +side O +effect O +of O +carbamazepine O +is O +necrotizing B +eosinophilic B +( I +hypersensitivity B +) I +myocarditis B +. O + +We O +report O +a O +case O +of O +hypersensitivity B +myocarditis B +secondary O +to O +administration O +of O +carbamazepine O +. O + +Acute O +hypersensitivity I +myocarditis B +was O +not O +suspected O +clinically O +, O +and O +the O +diagnosis O +was O +made O +post O +- O +mortem O +. O + +Histology O +revealed O +diffuse O +infiltration O +of O +the O +myocardium O +by O +eosinophils O +and O +lymphocytes O +with O +myocyte O +damage O +. O + +Clinically O +, O +death B +was O +due O +to O +cardiogenic B +shock I +. O + +To O +best O +of O +our O +knowledge O +this O +is O +the O +second O +case O +of O +fatal O +carbamazepine O +induced O +myocarditis B +reported O +in O +English O +literature O +. O + +Neuropsychiatric O +behaviors O +in O +the O +MPTP O +marmoset O +model O +of O +Parkinson B +' I +s I +disease I +. O + +OBJECTIVES O +: O +Neuropsychiatric O +symptoms I +are O +increasingly O +recognised O +as O +a O +significant O +problem O +in O +patients O +with O +Parkinson B +' I +s I +disease I +( O +PD B +) O +. O + +These O +symptoms O +may O +be O +due O +to O +' O +sensitisation O +' O +following O +repeated O +levodopa O +treatment O +or O +a O +direct O +effect O +of O +dopamine O +on O +the O +disease O +state O +. O + +The O +levodopa O +- O +treated O +MPTP O +- O +lesioned O +marmoset O +was O +used O +as O +a O +model O +of O +neuropsychiatric O +symptoms I +in O +PD B +patients O +. O + +Here O +we O +compare O +the O +time O +course O +of O +levodopa O +- O +induced O +motor O +fluctuations O +and O +neuropsychiatric O +- O +like O +behaviors O +to O +determine O +the O +relationship O +between O +duration O +of O +treatment O +and O +onset O +of O +symptoms O +. O + +METHODS O +: O +Marmosets O +were O +administered O +1 O +- O +methyl O +- O +4 O +- O +phenyl O +- O +1 O +, O +2 O +, O +3 O +, O +6 O +- O +tetrahydropyridine O +( O +2 O +. O +0 O +mg O +/ O +kg O +s O +. O +c O +. O +) O +for O +five O +days O +, O +resulting O +in O +stable O +parkinsonism B +. O + +Levodopa O +( O +15 O +mg O +/ O +kg O +and O +benserazide O +, O +3 O +. O +75 O +mg O +/ O +kg O +) O +p O +. O +o O +. O + +b O +. O +i O +. O +d O +, O +was O +administered O +for O +30 O +days O +. O + +Animals O +were O +evaluated O +for O +parkinsonian B +disability I +, O +dyskinesia B +and O +on O +- O +time O +( O +motor O +fluctuations O +) O +and O +neuropsychiatric O +- O +like O +behaviors O +on O +Day O +0 O +( O +prior O +to O +levodopa O +) O +and O +on O +Days O +1 O +, O +7 O +, O +13 O +, O +27 O +and O +30 O +of O +treatment O +using O +post O +hoc O +DVD O +analysis O +by O +a O +trained O +rater O +, O +blind O +to O +the O +treatment O +day O +. O + +RESULTS O +: O +The O +neuropsychiatric O +- O +like O +behavior O +rating O +scale O +demonstrated O +high O +interrater O +reliability O +between O +three O +trained O +raters O +of O +differing O +professional O +backgrounds O +. O + +As O +anticipated O +, O +animals O +exhibited O +a O +progressive O +increase O +in O +levodopa O +- O +induced O +motor O +fluctuations O +, O +dyskinesia B +and O +wearing O +- O +off O +, O +that O +correlated O +with O +the O +duration O +of O +levodopa O +therapy O +. O + +In O +contrast O +, O +levodopa O +- O +induced O +neuropsychiatric B +- I +like I +behaviors I +were O +present O +on O +Day O +1 O +of O +levodopa O +treatment O +and O +their O +severity O +did O +not O +correlate O +with O +duration O +of O +treatment O +. O + +CONCLUSIONS O +: O +The O +data O +suggest O +that O +neuropsychiatric B +disorders I +in O +PD B +are O +more O +likely O +an O +interaction O +between O +levodopa O +and O +the O +disease O +state O +than O +a O +consequence O +of O +sensitisation O +to O +repeated O +dopaminergic O +therapy O +. O + +Contrast O +medium O +nephrotoxicity B +after O +renal O +artery O +and O +coronary O +angioplasty O +. O + +BACKGROUND O +: O +Renal B +dysfunction I +induced O +by O +iodinated O +contrast O +medium O +( O +CM O +) O +administration O +can O +minimize O +the O +benefit O +of O +the O +interventional O +procedure O +in O +patients O +undergoing O +renal O +angioplasty O +( O +PTRA O +) O +. O + +PURPOSE O +: O +To O +compare O +the O +susceptibility O +to O +nephrotoxic B +effect O +of O +CM O +in O +patients O +undergoing O +PTRA O +with O +that O +of O +patients O +submitted O +to O +percutaneous O +coronary O +intervention O +( O +PCI O +) O +. O + +MATERIAL O +AND O +METHODS O +: O +A O +total O +of O +33 O +patients O +successfully O +treated O +with O +PTRA O +( O +PTRA O +group O +, O +mean O +age O +70 O ++ O +/ O +- O +12 O +years O +, O +23 O +female O +, O +basal O +creatinine O +1 O +. O +46 O ++ O +/ O +- O +0 O +. O +79 O +, O +range O +0 O +. O +7 O +- O +4 O +. O +9 O +mg O +/ O +dl O +) O +were O +compared O +with O +33 O +patients O +undergoing O +successful O +PCI O +( O +PCI O +group O +) O +, O +matched O +for O +basal O +creatinine O +( O +1 O +. O +44 O ++ O +/ O +- O +0 O +. O +6 O +, O +range O +0 O +. O +7 O +- O +3 O +. O +4 O +mg O +/ O +dl O +) O +, O +gender O +, O +and O +age O +. O + +In O +both O +groups O +postprocedural O +( O +48 O +h O +) O +serum O +creatinine O +was O +measured O +. O + +RESULTS O +: O +Postprocedural O +creatinine O +level O +decreased O +nonsignificantly O +in O +the O +PTRA O +group O +( O +1 O +. O +46 O ++ O +/ O +- O +0 O +. O +8 O +vs O +. O +1 O +. O +34 O ++ O +/ O +- O +0 O +. O +5 O +mg O +/ O +dl O +, O +P O += O +NS O +) O +and O +increased O +significantly O +in O +the O +PCI O +group O +( O +1 O +. O +44 O ++ O +/ O +- O +0 O +. O +6 O +vs O +. O +1 O +. O +57 O ++ O +/ O +- O +0 O +. O +7 O +mg O +/ O +dl O +, O +P O +< O +0 O +. O +02 O +) O +. O + +Changes O +in O +serum O +creatinine O +after O +intervention O +( O +after O +- O +before O +) O +were O +significantly O +different O +between O +the O +PTRA O +and O +PCI O +groups O +( O +- O +0 O +. O +12 O ++ O +/ O +- O +0 O +. O +5 O +vs O +. O +0 O +. O +13 O ++ O +/ O +- O +0 O +. O +3 O +, O +P O += O +0 O +. O +014 O +) O +. O + +This O +difference O +was O +not O +related O +to O +either O +a O +different O +clinical O +risk O +profile O +or O +to O +the O +volume O +of O +CM O +administered O +. O + +CONCLUSION O +: O +In O +this O +preliminary O +study O +patients O +submitted O +to O +PTRA O +showed O +a O +lower O +susceptibility O +to O +renal B +damage I +induced O +by O +CM O +administration O +than O +PCI B +patients O +. O + +The O +effectiveness O +of O +PTRA O +on O +renal O +function O +seems O +to O +be O +barely O +influenced O +by O +CM B +toxicity B +. O + +Diphenhydramine O +prevents O +the O +haemodynamic O +changes O +of O +cimetidine O +in O +ICU B +patients O +. O + +Cimetidine O +, O +a O +histamine O +2 O +( O +H2 O +) O +antagonist O +, O +produces O +a O +decrease B +in I +arterial I +pressure I +due O +to O +vasodilatation O +, O +especially O +in O +critically O +ill O +patients O +. O + +This O +may O +be O +because O +cimetidine O +acts O +as O +a O +histamine O +agonist O +. O + +We O +, O +therefore O +, O +investigated O +the O +effects O +of O +the O +histamine O +1 O +( O +H1 O +) O +receptor O +antagonist O +, O +diphenhydramine O +, O +on O +the O +haemodynamic O +changes O +observed O +after O +cimetidine O +in O +ICU B +patients O +. O + +Each O +patient O +was O +studied O +on O +two O +separate O +days O +. O + +In O +a O +random O +fashion O +, O +they O +received O +cimetidine O +200 O +mg O +iv O +on O +one O +day O +, O +and O +on O +the O +other O +, O +a O +pretreatment O +of O +diphenhydramine O +40 O +mg O +iv O +with O +cimetidine O +200 O +mg O +iv O +. O + +In O +the O +non O +- O +pretreatment O +group O +, O +mean O +arterial O +pressure O +( O +MAP O +) O +decreased O +from O +107 O +. O +4 O ++ O +/ O +- O +8 O +. O +4 O +mmHg O +to O +86 O +. O +7 O ++ O +/ O +- O +11 O +. O +4 O +mmHg O +( O +P O +less O +than O +0 O +. O +01 O +) O +two O +minutes O +after O +cimetidine O +. O + +Also O +, O +systemic O +vascular O +resistance O +( O +SVR O +) O +decreased O +during O +the O +eight O +- O +minute O +observation O +period O +( O +P O +less O +than O +0 O +. O +01 O +) O +. O + +In O +contrast O +, O +in O +the O +pretreatment O +group O +, O +little O +haemodynamic O +change O +was O +seen O +. O + +We O +conclude O +that O +an O +H1 O +antagonist O +may O +be O +useful O +in O +preventing O +hypotension B +caused O +by O +iv O +cimetidine O +, O +since O +the O +vasodilating O +activity O +of O +cimetidine O +is O +mediated O +, O +in O +part O +, O +through O +the O +H1 O +receptor O +. O + +Medical O +and O +psychiatric O +outcomes O +for O +patients O +transplanted O +for O +acetaminophen O +- O +induced O +acute B +liver I +failure I +: O +a O +case O +- O +control O +study O +. O + +BACKGROUND O +: O +Acetaminophen O +- O +induced O +hepatotoxicity B +is O +the O +most O +common O +cause O +of O +acute B +liver I +failure I +( O +ALF B +) O +in O +the O +UK O +. O + +Patients O +often O +consume O +the O +drug O +with O +suicidal O +intent O +or O +with O +a O +background O +of O +substance B +dependence I +. O + +AIMS O +AND O +METHODS O +: O +We O +compared O +the O +severity O +of O +pretransplant O +illness O +, O +psychiatric B +co O +- O +morbidity O +, O +medical O +and O +psychosocial O +outcomes O +of O +all O +patients O +who O +had O +undergone O +liver O +transplantation O +( O +LT O +) O +emergently O +between O +1999 O +- O +2004 O +for O +acetaminophen O +- O +induced O +ALF B +( O +n O += O +36 O +) O +with O +age O +- O +and O +sex O +- O +matched O +patients O +undergoing O +emergent O +LT O +for O +non O +- O +acetaminophen O +- O +induced O +ALF B +( O +n O += O +35 O +) O +and O +elective O +LT O +for O +chronic B +liver I +disease I +( O +CLD B +, O +n O += O +34 O +) O +. O + +RESULTS O +: O +Acetaminophen O +- O +induced O +ALF B +patients O +undergoing O +LT O +had O +a O +greater O +severity O +of O +pre O +- O +LT O +illness O +reflected O +by O +higher O +Acute O +Physiology O +and O +Chronic O +Health O +Evaluation O +II O +scores O +and O +requirement O +for O +organ O +support O +compared O +with O +the O +other O +two O +groups O +. O + +Twenty O +( O +56 O +% O +) O +acetaminophen O +- O +induced O +ALF B +patients O +had O +a O +formal O +psychiatric B +diagnosis O +before O +LT O +( O +non O +- O +acetaminophen O +- O +induced O +ALF B += O +0 O +/ O +35 O +, O +CLD O += O +2 O +/ O +34 O +; O +P O +< O +0 O +. O +01 O +for O +all O +) O +and O +nine O +( O +25 O +% O +) O +had O +a O +previous O +suicide O +attempt O +. O + +During O +follow O +- O +up O +( O +median O +5 O +years O +) O +, O +there O +were O +no O +significant O +differences O +in O +rejection O +( O +acute O +and O +chronic O +) O +, O +graft O +failure O +or O +survival O +between O +the O +groups O +( O +acetaminophen O +- O +induced O +ALF B +1 O +year O +87 O +% O +, O +5 O +years O +75 O +% O +; O +non O +- O +acetaminophen O +- O +induced O +ALF B +88 O +% O +, O +78 O +% O +; O +CLD B +93 O +% O +, O +82 O +% O +: O +P O +> O +0 O +. O +6 O +log O +rank O +) O +. O + +Two O +acetaminophen O +- O +induced O +ALF B +patients O +reattempted O +suicide O +post O +- O +LT O +( O +one O +died O +8 O +years O +post O +- O +LT O +) O +. O + +CONCLUSIONS O +: O +Despite O +a O +high O +prevalence O +of O +psychiatric B +disturbance I +, O +outcomes O +for O +patients O +transplanted O +emergently O +for O +acetaminophen O +- O +induced O +ALF B +were O +comparable O +to O +those O +transplanted O +for O +non O +- O +acetaminophen O +- O +induced O +ALF B +and O +electively O +for O +CLD B +. O + +Multidisciplinary O +approaches O +with O +long O +- O +term O +psychiatric B +follow O +- O +up O +may O +contribute O +to O +low O +post O +- O +transplant O +suicide B +rates O +seen O +and O +low O +rates O +of O +graft O +loss O +because O +of O +non O +- O +compliance O +. O + +Antithrombotic O +drug O +use O +, O +cerebral B +microbleeds I +, O +and O +intracerebral B +hemorrhage I +: O +a O +systematic O +review O +of O +published O +and O +unpublished O +studies O +. O + +BACKGROUND O +AND O +PURPOSE O +: O +Cerebral B +microbleeds I +( O +MB B +) O +are O +potential O +risk O +factors O +for O +intracerebral B +hemorrhage I +( O +ICH B +) O +, O +but O +it O +is O +unclear O +if O +they O +are O +a O +contraindication O +to O +using O +antithrombotic O +drugs O +. O + +Insights O +could O +be O +gained O +by O +pooling O +data O +on O +MB O +frequency O +stratified O +by O +antithrombotic O +use O +in O +cohorts O +with O +ICH B +and O +ischemic B +stroke I +( O +IS B +) O +/ O +transient B +ischemic I +attack I +( O +TIA B +) O +. O + +METHODS O +: O +We O +performed O +a O +systematic O +review O +of O +published O +and O +unpublished O +data O +from O +cohorts O +with O +stroke B +or O +TIA B +to O +compare O +the O +presence O +of O +MB B +in O +: O +( O +1 O +) O +antithrombotic O +users O +vs O +nonantithrombotic O +users O +with O +ICH B +; O +( O +2 O +) O +antithrombotic O +users O +vs O +nonusers O +with O +IS B +/ O +TIA B +; O +and O +( O +3 O +) O +ICH B +vs O +ischemic B +events O +stratified O +by O +antithrombotic O +use O +. O + +We O +also O +analyzed O +published O +and O +unpublished O +follow O +- O +up O +data O +to O +determine O +the O +risk O +of O +ICH B +in O +antithrombotic O +users O +with O +MB B +. O + +RESULTS O +: O +In O +a O +pooled O +analysis O +of O +1460 O +ICH B +and O +3817 O +IS B +/ O +TIA B +, O +MB O +were O +more O +frequent O +in O +ICH B +vs O +IS B +/ O +TIA B +in O +all O +treatment O +groups O +, O +but O +the O +excess O +increased O +from O +2 O +. O +8 O +( O +odds O +ratio O +; O +range O +, O +2 O +. O +3 O +- O +3 O +. O +5 O +) O +in O +nonantithrombotic O +users O +to O +5 O +. O +7 O +( O +range O +, O +3 O +. O +4 O +- O +9 O +. O +7 O +) O +in O +antiplatelet O +users O +and O +8 O +. O +0 O +( O +range O +, O +3 O +. O +5 O +- O +17 O +. O +8 O +) O +in O +warfarin O +users O +( O +P O +difference O += O +0 O +. O +01 O +) O +. O + +There O +was O +also O +an O +excess O +of O +MB O +in O +warfarin O +users O +vs O +nonusers O +with O +ICH B +( O +OR O +, O +2 O +. O +7 O +; O +95 O +% O +CI O +, O +1 O +. O +6 O +- O +4 O +. O +4 O +; O +P O +< O +0 O +. O +001 O +) O +but O +none O +in O +warfarin O +users O +with O +IS B +/ O +TIA O +( O +OR O +, O +1 O +. O +3 O +; O +95 O +% O +CI O +, O +0 O +. O +9 O +- O +1 O +. O +7 O +; O +P O += O +0 O +. O +33 O +; O +P O +difference O += O +0 O +. O +01 O +) O +. O + +There O +was O +a O +smaller O +excess O +of O +MB B +in O +antiplatelet O +users O +vs O +nonusers O +with O +ICH B +( O +OR O +, O +1 O +. O +7 O +; O +95 O +% O +CI O +, O +1 O +. O +3 O +- O +2 O +. O +3 O +; O +P O +< O +0 O +. O +001 O +) O +, O +but O +findings O +were O +similar O +for O +antiplatelet O +users O +with O +IS B +/ O +TIA O +( O +OR O +, O +1 O +. O +4 O +; O +95 O +% O +CI O +, O +1 O +. O +2 O +- O +1 O +. O +7 O +; O +P O +< O +0 O +. O +001 O +; O +P O +difference O += O +0 O +. O +25 O +) O +. O + +In O +pooled O +follow O +- O +up O +data O +for O +768 O +antithrombotic O +users O +, O +presence O +of O +MB B +at O +baseline O +was O +associated O +with O +a O +substantially O +increased O +risk O +of O +subsequent O +ICH B +( O +OR O +, O +12 O +. O +1 O +; O +95 O +% O +CI O +, O +3 O +. O +4 O +- O +42 O +. O +5 O +; O +P O +< O +0 O +. O +001 O +) O +. O + +CONCLUSIONS O +: O +The O +excess O +of O +MB O +in O +warfarin O +users O +with O +ICH B +compared O +to O +other O +groups O +suggests O +that O +MB O +increase O +the O +risk O +of O +warfarin O +- O +associated O +ICH B +. O + +Limited O +prospective O +data O +corroborate O +these O +findings O +, O +but O +larger O +prospective O +studies O +are O +urgently O +required O +. O + +Studies O +of O +synergy O +between O +morphine O +and O +a O +novel O +sodium O +channel O +blocker O +, O +CNSB002 O +, O +in O +rat O +models O +of O +inflammatory B +and I +neuropathic B +pain I +. O + +OBJECTIVE O +: O +This O +study O +determined O +the O +antihyperalgesic O +effect O +of O +CNSB002 O +, O +a O +sodium O +channel O +blocker O +with O +antioxidant O +properties O +given O +alone O +and O +in O +combinations O +with O +morphine O +in O +rat O +models O +of O +inflammatory B +and I +neuropathic B +pain I +. O + +DESIGN O +: O +Dose O +response O +curves O +for O +nonsedating O +doses O +of O +morphine O +and O +CNSB002 O +given O +intraperitoneally O +alone O +and O +together O +in O +combinations O +were O +constructed O +for O +antihyperalgesic O +effect O +using O +paw O +withdrawal O +from O +noxious O +heat O +in O +two O +rat O +pain B +models O +: O +carrageenan O +- O +induced O +paw O +inflammation B +and O +streptozotocin O +( O +STZ O +) O +- O +induced O +diabetic B +neuropathy I +. O + +RESULTS O +: O +The O +maximum O +nonsedating O +doses O +were O +: O +morphine O +, O +3 O +. O +2 O +mg O +/ O +kg O +; O +CNSB002 O +10 O +. O +0 O +mg O +/ O +kg O +; O +5 O +. O +0 O +mg O +/ O +kg O +CNSB002 O +with O +morphine O +3 O +. O +2 O +mg O +/ O +kg O +in O +combination O +. O + +The O +doses O +calculated O +to O +cause O +50 O +% O +reversal O +of O +hyperalgesia B +( O +ED50 O +) O +were O +7 O +. O +54 O +( O +1 O +. O +81 O +) O +and O +4 O +. O +83 O +( O +1 O +. O +54 O +) O +in O +the O +carrageenan O +model O +and O +44 O +. O +18 O +( O +1 O +. O +37 O +) O +and O +9 O +. O +14 O +( O +1 O +. O +24 O +) O +in O +the O +STZ O +- O +induced O +neuropathy B +model O +for O +CNSB002 O +and O +morphine O +, O +respectively O +( O +mg O +/ O +kg O +; O +mean O +, O +SEM O +) O +. O + +These O +values O +were O +greater O +than O +the O +maximum O +nonsedating O +doses O +. O + +The O +ED50 O +values O +for O +morphine O +when O +given O +in O +combination O +with O +CNSB002 O +( O +5 O +mg O +/ O +kg O +) O +were O +less O +than O +the O +maximum O +nonsedating O +dose O +: O +0 O +. O +56 O +( O +1 O +. O +55 O +) O +in O +the O +carrageenan O +model O +and O +1 O +. O +37 O +( O +1 O +. O +23 O +) O +in O +the O +neuropathy B +model O +( O +mg O +/ O +kg O +; O +mean O +, O +SEM O +) O +. O + +The O +antinociception O +after O +morphine O +( O +3 O +. O +2 O +mg O +/ O +kg O +) O +was O +increased O +by O +co O +- O +administration O +with O +CNSB002 O +from O +28 O +. O +0 O +and O +31 O +. O +7 O +% O +to O +114 O +. O +6 O +and O +56 O +. O +9 O +% O +reversal O +of O +hyperalgesia B +in O +the O +inflammatory O +and O +neuropathic B +models O +, O +respectively O +( O +P O +< O +0 O +. O +01 O +; O +one O +- O +way O +analysis O +of O +variance O +- O +significantly O +greater O +than O +either O +drug O +given O +alone O +) O +. O + +CONCLUSIONS O +: O +The O +maximum O +antihyperalgesic O +effect O +achievable O +with O +nonsedating O +doses O +of O +morphine O +may O +be O +increased O +significantly O +when O +the O +drug O +is O +used O +in O +combination O +with O +CNSB002 O +. O + +Heparin O +- O +induced O +thrombocytopenia B +: O +a O +practical O +review O +. O + +Heparin O +- O +induced O +thrombocytopenia B +( O +HIT B +) O +remains O +under O +- O +recognized O +despite O +its O +potentially O +devastating O +outcomes O +. O + +It O +begins O +when O +heparin O +exposure O +stimulates O +the O +formation O +of O +heparin O +- O +platelet O +factor O +4 O +antibodies O +, O +which O +in O +turn O +triggers O +the O +release O +of O +procoagulant O +platelet O +particles O +. O + +Thrombosis B +and O +thrombocytopenia B +that O +follow O +comprise O +the O +2 O +hallmark O +traits O +of O +HIT B +, O +with O +the O +former O +largely O +responsible O +for O +significant O +vascular B +complications I +. O + +The O +prevalence O +of O +HIT B +varies O +among O +several O +subgroups O +, O +with O +greater O +incidence O +in O +surgical O +as O +compared O +with O +medical O +populations O +. O + +HIT B +must O +be O +acknowledged O +for O +its O +intense O +predilection O +for O +thrombosis B +and O +suspected O +whenever O +thrombosis B +occurs O +after O +heparin O +exposure O +. O + +Early O +recognition O +that O +incorporates O +the O +clinical O +and O +serologic O +clues O +is O +paramount O +to O +timely O +institution O +of O +treatment O +, O +as O +its O +delay O +may O +result O +in O +catastrophic O +outcomes O +. O + +The O +treatment O +of O +HIT B +mandates O +an O +immediate O +cessation O +of O +all O +heparin O +exposure O +and O +the O +institution O +of O +an O +antithrombotic O +therapy O +, O +most O +commonly O +using O +a O +direct O +thrombin O +inhibitor O +. O + +Current O +" O +diagnostic O +" O +tests O +, O +which O +primarily O +include O +functional O +and O +antigenic O +assays O +, O +have O +more O +of O +a O +confirmatory O +than O +diagnostic O +role O +in O +the O +management O +of O +HIT B +. O + +Special O +attention O +must O +be O +paid O +to O +cardiac B +patients O +who O +are O +often O +exposed O +to O +heparin O +multiple O +times O +during O +their O +course O +of O +treatment O +. O + +Direct O +thrombin O +inhibitors O +are O +appropriate O +, O +evidence O +- O +based O +alternatives O +to O +heparin O +in O +patients O +with O +a O +history O +of O +HIT B +, O +who O +need O +to O +undergo O +percutaneous O +coronary O +intervention O +. O + +As O +heparin O +remains O +one O +of O +the O +most O +frequently O +used O +medications O +today O +with O +potential O +for O +HIT B +with O +every O +heparin O +exposure O +, O +a O +close O +vigilance O +of O +platelet O +counts O +must O +be O +practiced O +whenever O +heparin O +is O +initiated O +. O + +Abductor B +paralysis I +after O +botox O +injection O +for O +adductor B +spasmodic I +dysphonia I +. O + +OBJECTIVES O +/ O +HYPOTHESIS O +: O +Botulinum O +toxin O +( O +Botox O +) O +injections O +into O +the O +thyroarytenoid O +muscles O +are O +the O +current O +standard O +of O +care O +for O +adductor B +spasmodic I +dysphonia I +( O +ADSD B +) O +. O + +Reported O +adverse O +effects O +include O +a O +period O +of O +breathiness B +, O +throat B +pain I +, O +and O +difficulty O +with O +swallowing O +liquids O +. O + +Here O +we O +report O +multiple O +cases O +of O +bilateral O +abductor I +paralysis I +following O +Botox O +injections O +for O +ADSD B +, O +a O +complication O +previously O +unreported O +. O + +STUDY O +DESIGN O +: O +Retrospective O +case O +series O +. O + +METHODS O +: O +Patients O +that O +received O +Botox O +injections O +for O +spasmodic O +dysphonia B +between O +January O +2000 O +and O +October O +2009 O +were O +evaluated O +. O + +Patients O +with O +ADSD B +were O +identified O +. O + +The O +number O +of O +treatments O +received O +and O +adverse O +effects O +were O +noted O +. O + +For O +patients O +with O +bilateral O +abductor B +paralysis I +, O +age O +, O +sex O +, O +paralytic O +Botox O +dose O +, O +prior O +Botox O +dose O +, O +and O +course O +following O +paralysis B +were O +noted O +. O + +RESULTS O +: O +From O +a O +database O +of O +452 O +patients O +receiving O +Botox O +, O +352 O +patients O +had O +been O +diagnosed O +with O +ADSD B +. O + +Of O +these O +352 O +patients O +, O +eight O +patients O +suffered O +bilateral O +abductor B +paralysis I +, O +and O +two O +suffered O +this O +complication O +twice O +. O + +All O +affected O +patients O +were O +females O +over O +the O +age O +of O +50 O +years O +. O + +Most O +patients O +had O +received O +treatments O +prior O +to O +abductor B +paralysis I +and O +continued O +receiving O +after O +paralysis B +. O + +Seven O +patients O +recovered O +after O +a O +brief O +period O +of O +activity O +restrictions O +, O +and O +one O +underwent O +a O +tracheotomy O +. O + +The O +incidence O +of O +abductor B +paralysis I +after O +Botox O +injection O +for O +ADSD B +was O +0 O +. O +34 O +% O +. O + +CONCLUSIONS O +: O +Bilateral O +abductor B +paralysis I +is O +a O +rare O +complication O +of O +Botox O +injections O +for O +ADSD B +, O +causing O +difficulty O +with O +breathing O +upon O +exertion O +. O + +The O +likely O +mechanism O +of O +paralysis B +is O +diffusion O +of O +Botox O +around O +the O +muscular O +process O +of O +the O +arytenoid O +to O +the O +posterior O +cricoarytenoid O +muscles O +. O + +The O +paralysis B +is O +temporary O +, O +and O +watchful O +waiting O +with O +restriction O +of O +activity O +is O +the O +recommended O +management O +. O + +Mitochondrial B +impairment I +contributes O +to O +cocaine O +- O +induced O +cardiac B +dysfunction I +: O +Prevention O +by O +the O +targeted O +antioxidant O +MitoQ O +. O + +The O +goal O +of O +this O +study O +was O +to O +assess O +mitochondrial O +function O +and O +ROS O +production O +in O +an O +experimental O +model O +of O +cocaine O +- O +induced O +cardiac B +dysfunction I +. O + +We O +hypothesized O +that O +cocaine B +abuse I +may O +lead O +to O +altered O +mitochondrial O +function O +that O +in O +turn O +may O +cause O +left B +ventricular I +dysfunction I +. O + +Seven O +days O +of O +cocaine O +administration O +to O +rats O +led O +to O +an O +increased O +oxygen O +consumption O +detected O +in O +cardiac O +fibers O +, O +specifically O +through O +complex O +I O +and O +complex O +III O +. O + +ROS O +levels O +were O +increased O +, O +specifically O +in O +interfibrillar O +mitochondria O +. O + +In O +parallel O +there O +was O +a O +decrease O +in O +ATP O +synthesis O +, O +whereas O +no O +difference O +was O +observed O +in O +subsarcolemmal O +mitochondria O +. O + +This O +uncoupling O +effect O +on O +oxidative O +phosphorylation O +was O +not O +detectable O +after O +short O +- O +term O +exposure O +to O +cocaine O +, O +suggesting O +that O +these O +mitochondrial B +abnormalities I +were O +a O +late O +rather O +than O +a O +primary O +event O +in O +the O +pathological O +response O +to O +cocaine O +. O + +MitoQ O +, O +a O +mitochondrial O +- O +targeted O +antioxidant O +, O +was O +shown O +to O +completely O +prevent O +these O +mitochondrial B +abnormalities I +as O +well O +as O +cardiac B +dysfunction I +characterized O +here O +by O +a O +diastolic B +dysfunction I +studied O +with O +a O +conductance O +catheter O +to O +obtain O +pressure O +- O +volume O +data O +. O + +Taken O +together O +, O +these O +results O +extend O +previous O +studies O +and O +demonstrate O +that O +cocaine O +- O +induced O +cardiac B +dysfunction I +may O +be O +due O +to O +a O +mitochondrial B +defect O +. O + +Trimethoprim O +- O +induced O +immune O +hemolytic B +anemia I +in O +a O +pediatric O +oncology O +patient O +presenting O +as O +an O +acute O +hemolytic B +transfusion I +reaction I +. O + +A O +10 O +- O +year O +- O +old O +male O +with O +acute B +leukemia I +presented O +with O +post O +- O +chemotherapy O +anemia B +. O + +During O +red O +cell O +transfusion O +, O +he O +developed O +hemoglobinuria B +. O + +Transfusion O +reaction O +workup O +was O +negative O +. O + +Drug O +- O +induced O +immune O +hemolytic B +anemia I +was O +suspected O +because O +of O +positive O +direct O +antiglobulin O +test O +, O +negative O +eluate O +, O +and O +microspherocytes O +on O +smear O +pre O +- O +and O +post O +- O +transfusion O +. O + +Drug O +studies O +using O +the O +indirect O +antiglobulin O +test O +were O +strongly O +positive O +with O +trimethoprim O +and O +trimethoprim O +- O +sulfamethoxazole O +but O +negative O +with O +sulfamethoxazole O +. O + +The O +patient O +recovered O +after O +discontinuing O +the O +drug O +, O +with O +no O +recurrence O +in O +2 O +years O +. O + +Other O +causes O +of O +anemia B +should O +be O +considered O +in O +patients O +with O +worse O +- O +than O +- O +expected O +anemia B +after O +chemotherapy O +. O + +Furthermore O +, O +hemolysis B +during O +transfusion O +is O +not O +always O +a O +transfusion O +reaction O +. O + +Verapamil O +stimulation O +test O +in O +hyperprolactinemia B +: O +loss O +of O +prolactin O +response O +in O +anatomic O +or O +functional O +stalk O +effect O +. O + +AIM O +: O +Verapamil O +stimulation O +test O +was O +previously O +investigated O +as O +a O +tool O +for O +differential O +diagnosis O +of O +hyperprolactinemia B +, O +but O +with O +conflicting O +results O +. O + +Macroprolactinemia B +was O +never O +considered O +in O +those O +previous O +studies O +. O + +Here O +, O +we O +aimed O +to O +re O +- O +investigate O +the O +diagnostic O +value O +of O +verapamil O +in O +a O +population O +who O +were O +all O +screened O +for O +macroprolactinemia B +. O + +Prolactin O +responses O +to O +verapamil O +in O +65 O +female O +patients O +( O +age O +: O +29 O +. O +9 O ++ O +/ O +- O +8 O +. O +1 O +years O +) O +with O +hyperprolactinemia B +were O +tested O +in O +a O +descriptive O +, O +matched O +case O +- O +control O +study O +. O + +METHODS O +: O +Verapamil O +80 O +mg O +, O +p O +. O +o O +. O +was O +administered O +, O +and O +then O +PRL O +levels O +were O +measured O +at O +8th O +and O +16th O +hours O +, O +by O +immunometric O +chemiluminescence O +. O + +Verapamil O +responsiveness O +was O +determined O +by O +peak O +percent O +change O +in O +basal O +prolactin O +levels O +( O +PRL O +) O +. O + +RESULTS O +: O +Verapamil O +significantly O +increased O +PRL O +levels O +in O +healthy O +controls O +( O +N O +. O +8 O +, O +PRL O +: O +183 O +% O +) O +, O +macroprolactinoma B +( O +N O +. O +8 O +, O +PRL O +: O +7 O +% O +) O +, O +microprolactinoma B +( O +N O +. O +19 O +, O +PRL O +: O +21 O +% O +) O +, O +macroprolactinemia B +( O +N O +. O +23 O +, O +PRL O +: O +126 O +% O +) O +, O +but O +not O +in O +pseudoprolactinoma B +( O +N O +. O +8 O +, O +PRL O +: O +0 O +. O +8 O +% O +) O +, O +and O +risperidone O +- O +induced O +hyperprolactinemia B +( O +N O +. O +7 O + +, O +PRL O +: O +3 O +% O +) O +. O + +ROC O +curve O +analysis O +revealed O +that O +unresponsiveness O +to O +verapamil O +defined O +as O +PRL O +< O +7 O +% O +, O +discriminated O +anatomical O +or O +functional O +stalk O +effect O +( O +sensitivity O +: O +74 O +% O +, O +specificity O +: O +73 O +% O +, O +AUC O +: O +0 O +. O +855 O ++ O +/ O +- O +0 O +. O +04 O +, O +P O +< O +0 O +. O +001 O +, O +CI O +: O +0 O +. O +768 O +- O +0 O +. O +942 O +) O +associated O +with O +pseudoprolactinoma B +or O +risperidone O +- O +induced O +hyperprolactinemia B +, O +respectively O +. O + +CONCLUSION O +: O +Verapamil O +responsiveness O +is O +not O +a O +reliable O +finding O +for O +the O +differential O +diagnosis O +of O +hyperprolactinemia B +. O + +However O +, O +verapamil O +unresponsiveness O +discriminates O +stalk O +effect O +( O +i O +. O +e O +. O +, O +anatomically O +or O +functionally O +inhibited O +dopaminergic O +tonus O +) O +from O +other O +causes O +of O +hyperprolactinemia B +with O +varying O +degrees O +of O +responsiveness O +. O + +Blockade O +of O +endothelial O +- O +mesenchymal O +transition O +by O +a O +Smad3 O +inhibitor O +delays O +the O +early O +development O +of O +streptozotocin O +- O +induced O +diabetic B +nephropathy I +. O + +OBJECTIVE O +: O +A O +multicenter O +, O +controlled O +trial O +showed O +that O +early O +blockade O +of O +the O +renin O +- O +angiotensin O +system O +in O +patients O +with O +type B +1 I +diabetes I +and O +normoalbuminuria B +did O +not O +retard O +the O +progression O +of O +nephropathy B +, O +suggesting O +that O +other O +mechanism O +( O +s O +) O +are O +involved O +in O +the O +pathogenesis O +of O +early O +diabetic B +nephropathy I +( O +diabetic B +nephropathy I +) O +. O + +We O +have O +previously O +demonstrated O +that O +endothelial O +- O +mesenchymal O +- O +transition O +( O +EndoMT O +) O +contributes O +to O +the O +early O +development O +of O +renal O +interstitial B +fibrosis I +independently O +of O +microalbuminuria B +in O +mice O +with O +streptozotocin O +( O +STZ O +) O +- O +induced O +diabetes B +. O + +In O +the O +present O +study O +, O +we O +hypothesized O +that O +blocking O +EndoMT O +reduces O +the O +early O +development O +of O +diabetic B +nephropathy I +. O + +RESEARCH O +DESIGN O +AND O +METHODS O +: O +EndoMT B +was O +induced O +in O +a O +mouse O +pancreatic O +microvascular O +endothelial O +cell O +line O +( O +MMEC O +) O +in O +the O +presence O +of O +advanced O +glycation O +end O +products O +( O +AGEs O +) O +and O +in O +the O +endothelial O +lineage O +- O +traceble O +mouse O +line O +Tie2 O +- O +Cre O +; O +Loxp O +- O +EGFP O +by O +administration O +of O +AGEs O +, O +with O +nonglycated O +mouse O +albumin O +serving O +as O +a O +control O +. O + +Phosphorylated O +Smad3 O +was O +detected O +by O +immunoprecipitation O +/ O +Western O +blotting O +and O +confocal O +microscopy O +. O + +Blocking O +studies O +using O +receptor O +for O +AGE O +siRNA O +and O +a O +specific O +inhibitor O +of O +Smad3 O +( O +SIS3 O +) O +were O +performed O +in O +MMECs O +and O +in O +STZ O +- O +induced O +diabetic B +nephropathy I +in O +Tie2 O +- O +Cre O +; O +Loxp O +- O +EGFP O +mice O +. O + +RESULTS O +: O +Confocal O +microscopy O +and O +real O +- O +time O +PCR O +demonstrated O +that O +AGEs O +induced O +EndoMT O +in O +MMECs O +and O +in O +Tie2 O +- O +Cre O +; O +Loxp O +- O +EGFP O +mice O +. O + +Immunoprecipitation O +/ O +Western O +blotting O +showed O +that O +Smad3 O +was O +activated O +by O +AGEs O +but O +was O +inhibited O +by O +SIS3 O +in O +MMECs O +and O +in O +STZ O +- O +induced O +diabetic B +nephropathy I +. O + +Confocal O +microscopy O +and O +real O +- O +time O +PCR O +further O +demonstrated O +that O +SIS3 O +abrogated O +EndoMT O +, O +reduced O +renal O +fibrosis B +, O +and O +retarded O +progression O +of O +nephropathy B +. O + +CONCLUSIONS O +: O +EndoMT O +is O +a O +novel O +pathway O +leading O +to O +early O +development O +of O +diabetic B +nephropathy I +. O + +Blockade O +of O +EndoMT O +by O +SIS3 O +may O +provide O +a O +new O +strategy O +to O +retard O +the O +progression O +of O +diabetic B +nephropathy I +and O +other O +diabetes B +complications O +. O + +Cytostatic O +and O +anti O +- O +angiogenic O +effects O +of O +temsirolimus O +in O +refractory O +mantle B +cell I +lymphoma I +. O + +Mantle B +cell I +lymphoma I +( O +MCL B +) O +is O +a O +rare O +and O +aggressive O +type O +of O +B O +- I +cell I +non B +- I +Hodgkin I +' I +s I +lymphoma I +. O + +Patients O +become O +progressively O +refractory O +to O +conventional O +chemotherapy O +, O +and O +their O +prognosis O +is O +poor O +. O + +However O +, O +a O +38 O +% O +remission O +rate O +has O +been O +recently O +reported O +in O +refractory O +MCL B +treated O +with O +temsirolimus O +, O +a O +mTOR O +inhibitor O +. O +Here O +we O +had O +the O +opportunity O +to O +study O +a O +case O +of O +refractory O +MCL B +who O +had O +tumor B +regression O +two O +months O +after O +temsirolimus O +treatment O +, O +and O +a O +progression O +- O +free O +survival O +of O +10 O +months O +. O + +In O +this O +case O +, O +lymph O +node O +biopsies O +were O +performed O +before O +and O +six O +months O +after O +temsirolimus O +therapy O +. O + +Comparison O +of O +the O +two O +biopsies O +showed O +that O +temsirolimus O +inhibited O +tumor B +cell O +proliferation O +through O +cell O +cycle O +arrest O +, O +but O +did O +not O +induce O +any O +change O +in O +the O +number O +of O +apoptotic O +tumor B +cells O +. O + +Apart O +from O +this O +cytostatic O +effect O +, O +temsirolimus O +had O +an O +antiangiogenic O +effect O +with O +decrease O +of O +tumor B +microvessel O +density O +and O +of O +VEGF O +expression O +. O + +Moreover O +, O +numerous O +patchy O +, O +well O +- O +limited O +fibrotic B +areas O +, O +compatible O +with O +post O +- O +necrotic B +tissue O +repair O +, O +were O +found O +after O +6 O +- O +month O +temsirolimus O +therapy O +. O + +Thus O +, O +temsirolimus O +reduced O +tumor B +burden O +through O +associated O +cytostatic O +and O +anti O +- O +angiogenic O +effects O +. O +This O +dual O +effect O +of O +temsirolimus O +on O +tumor B +tissue O +could O +contribute O +to O +its O +recently O +reported O +efficiency O +in O +refractory O +MCL B +resistant O +to O +conventional O +chemotherapy O +. O + +Acute B +renal I +failure I +due O +to O +rifampicin O +. O + +A O +23 O +- O +year O +- O +old O +male O +patient O +with O +bacteriologically O +proven O +pulmonary B +tuberculosis I +was O +treated O +with O +the O +various O +regimens O +of O +antituberculosis O +drugs O +for O +nearly O +15 O +months O +. O + +Rifampicin O +was O +administered O +thrice O +as O +one O +of O +the O +3 O +- O +4 O +drug O +regimen O +and O +each O +time O +he O +developed O +untoward O +side O +effects O +like O +nausea B +, O +vomiting B +and O +fever B +with O +chills B +and O +rigors O +. O + +The O +last O +such O +episode O +was O +of O +acute B +renal I +failure I +at O +which O +stage O +the O +patient O +was O +seen O +by O +the O +authors O +of O +this O +report O +. O + +The O +patient O +, O +however O +, O +made O +a O +full O +recovery O +. O + +Syncope B +caused O +by O +hyperkalemia B +during O +use O +of O +a O +combined O +therapy O +with O +the O +angiotensin O +- O +converting O +enzyme O +inhibitor O +and O +spironolactone O +. O + +A O +76 O +year O +- O +old O +woman O +with O +a O +history O +of O +coronary O +artery O +bypass O +grafting O +and O +prior O +myocardial B +infarction I +was O +transferred O +to O +the O +emergency O +room O +with O +loss B +of I +consciousness I +due O +to O +marked O +bradycardia B +caused O +by O +hyperkalemia B +. O + +The O +concentration O +of O +serum O +potassium O +was O +high O +, O +and O +normal O +sinus O +rhythm O +was O +restored O +after O +correction O +of O +the O +serum O +potassium O +level O +. O + +The O +cause O +of O +hyperkalemia B +was O +considered O +to O +be O +several O +doses O +of O +spiranolactone O +, O +an O +aldosterone O +antagonist O +, O +in O +addition O +to O +the O +long O +- O +term O +intake O +of O +ramipril O +, O +an O +ACE O +inhibitor O +. O + +This O +case O +is O +a O +good O +example O +of O +electrolyte O +imbalance O +causing O +acute O +life O +- O +threatening O +cardiac O +events O +. O + +Clinicians O +should O +be O +alert O +to O +the O +possibility O +of O +hyperkalemia B +, O +especially O +in O +elderly O +patients O +using O +ACE O +/ O +ARB O +in O +combination O +with O +potassium O +sparing O +agents O +and O +who O +have O +mild O +renal B +disturbance I +. O + +Diffuse O +skeletal O +pain B +after O +administration O +of O +alendronate O +. O + +BACKGROUND O +: O +Osteoporosis B +is O +caused O +by O +bone B +resorption I +in O +excess O +of O +bone O +formation O +, O +and O +bisphosphonates O +, O +are O +used O +to O +inhibit O +bone O +resorption O +. O + +Alendronate O +, O +a O +biphosphonate O +, O +is O +effective O +for O +both O +the O +treatment O +and O +prevention O +of O +osteoporosis B +in O +postmenopausal O +women O +. O + +Side O +effects O +are O +relatively O +few O +and O +prominently O +gastrointestinal B +. O + +Musculoskeletal B +pain I +may O +be O +an O +important O +side O +effect O +in O +these O +patients O +. O + +We O +presented O +a O +patient O +admitted O +to O +our O +out O +- O +patient O +clinic O +with O +diffuse O +skeletal O +pain B +after O +three O +consecutive O +administration O +of O +alendronate O +. O + +CONCLUSION O +: O +We O +conclude O +that O +patients O +with O +osteoporosis B +can O +report O +pain B +, O +and O +bisphosphonate O +- O +related O +pain B +should O +also O +be O +considered O +before O +ascribing O +this O +complaint O +to O +osteoporosis B +. O + +Cerebrospinal O +fluid O +penetration O +of O +high O +- O +dose O +daptomycin O +in O +suspected O +Staphylococcus B +aureus I +meningitis I +. O + +OBJECTIVE O +: O +To O +report O +a O +case O +of O +methicillin B +- O +sensitive I +Staphylococcus I +aureus I +( O +MSSA O +) I +bacteremia I +with O +suspected O +MSSA B +meningitis I +treated O +with O +high O +- O +dose O +daptomycin O +assessed O +with O +concurrent O +serum O +and O +cerebrospinal O +fluid O +( O +CSF O +) O +concentrations O +. O + +CASE O +SUMMARY O +: O +A O +54 O +- O +year O +- O +old O +male O +presented O +to O +the O +emergency O +department O +with O +generalized O +weakness B +and O +presumed O +health O +- O +care O +- O +associated O +pneumonia B +shown O +on O +chest O +radiograph O +. O + +Treatment O +was O +empirically O +initiated O +with O +vancomycin O +, O +levofloxacin O +, O +and O +piperacillin O +/ O +tazobactam O +. O + +Blood O +cultures O +revealed O +S O +. O +aureus O +susceptible O +to O +oxacillin O +. O + +Empiric O +antibiotic O +treatment O +was O +narrowed O +to O +nafcillin O +on O +day O +4 O +. O + +On O +day O +8 O +, O +the O +patient O +developed O +acute B +renal I +failure I +( O +serum O +creatinine O +1 O +. O +9 O +mg O +/ O +dL O +, O +increased O +from O +1 O +. O +2 O +mg O +/ O +dL O +the O +previous O +day O +and O +0 O +. O +8 O +mg O +/ O +dL O +on O +admission O +) O +. O + +The O +patient O +' O +s O +Glasgow O +Coma O +Score O +was O +3 O +, O +with O +normal O +findings O +shown O +on O +computed O +tomography O +scan O +of O +the O +head O +72 O +hours O +following O +an O +episode O +of O +cardiac B +arrest I +on O +day O +10 O +. O + +The O +patient O +experienced O +relapsing O +MSSA O +bacteremia B +on O +day O +9 O +, O +increasing O +the O +suspicion O +for O +a O +central B +nervous I +system I +( I +CNS I +) I +infection I +. O + +Nafcillin O +was O +discontinued O +and O +daptomycin O +9 O +mg O +/ O +kg O +daily O +was O +initiated O +for O +suspected O +meningitis B +and O +was O +continued O +until O +the O +patient O +' O +s O +death O +on O +day O +16 O +. O + +Daptomycin O +serum O +and O +CSF O +trough O +concentrations O +were O +11 O +. O +21 O +ug O +/ O +mL O +and O +0 O +. O +52 O +ug O +/ O +mL O +, O +respectively O +, O +prior O +to O +the O +third O +dose O +. O + +Lumbar O +puncture O +results O +were O +inconclusive O +and O +no O +further O +blood O +cultures O +were O +positive O +for O +MSSA B +. O + +Creatine O +kinase O +levels O +were O +normal O +prior O +to O +daptomycin O +therapy O +and O +were O +not O +reassessed O +. O + +DISCUSSION O +: O +Daptomycin O +was O +initiated O +in O +our O +patient O +secondary O +to O +possible O +nafcillin O +- O +induced O +acute O +interstitial B +nephritis I +and O +relapsing O +bacteremia B +. O + +At O +a O +dose O +of O +9 O +mg O +/ O +kg O +, O +resultant O +penetration O +of O +5 O +% O +was O +higher O +than O +in O +previous O +reports O +, O +more O +consistent O +with O +inflamed O +meninges O +. O + +CONCLUSIONS O +: O +High O +- O +dose O +daptomycin O +may O +be O +an O +alternative O +option O +for O +MSSA B +bacteremia B +with O +or O +without O +a O +CNS O +source O +in O +patients O +who O +have O +failed O +or O +cannot O +tolerate O +standard O +therapy O +. O + +Further O +clinical O +evaluation O +in O +patients O +with O +confirmed O +meningitis B +is O +warranted O +. O + +The O +role O +of O +nitric O +oxide O +in O +convulsions B +induced O +by O +lindane O +in O +rats O +. O + +Lindane O +is O +an O +organochloride O +pesticide O +and O +scabicide O +. O + +It O +evokes O +convulsions B +mainly O +trough O +the O +blockage O +of O +GABA O +( O +A O +) O +receptors O +. O + +Nitric O +oxide O +( O +NO O +) O +, O +gaseous O +neurotransmitter O +, O +has O +contradictor O +role O +in O +epileptogenesis O +due O +to O +opposite O +effects O +of O +L O +- O +arginine O +, O +precursor O +of O +NO O +syntheses O +( O +NOS O +) O +, O +and O +L O +- O +NAME O +( O +NOS O +inhibitor O +) O +observed O +in O +different O +epilepsy B +models O +. O + +The O +aim O +of O +the O +current O +study O +was O +to O +determine O +the O +effects O +of O +NO O +on O +the O +behavioral O +and O +EEG O +characteristics O +of O +lindane O +- O +induced O +epilepsy B +in O +male O +Wistar O +albino O +rats O +. O + +The O +administration O +of O +L O +- O +arginine O +( O +600 O +, O +800 O +and O +1000 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +in O +dose O +- O +dependent O +manner O +significantly O +increased O +convulsion B +incidence O +and O +severity O +and O +shortened O +latency O +time O +to O +first O +convulsion B +elicited O +by O +lower O +lindane O +dose O +( O +4 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +. O + +On O +the O +contrary O +, O +pretreatment O +with O +L O +- O +NAME O +( O +500 O +, O +700 O +and O +900 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +decreased O +convulsion B +incidence O +and O +severity O +and O +prolonged O +latency O +time O +to O +convulsion O +following O +injection O +with O +a O +convulsive B +dose O +of O +lindane O +( O +8 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +. O + +EEG O +analyses O +showed O +increase O +of O +number O +and O +duration O +of O +ictal O +periods O +in O +EEG O +of O +rats O +receiving O +l O +- O +arginine O +prior O +to O +lindane O +and O +decrease O +of O +this O +number O +in O +rats O +pretreated O +with O +L O +- O +NAME O +. O + +These O +results O +support O +the O +conclusion O +that O +NO O +plays O +a O +role O +of O +endogenous O +convulsant O +in O +rat O +model O +of O +lindane O +seizures B +. O + +Severe O +polyneuropathy B +and O +motor B +loss I +after O +intrathecal O +thiotepa O +combination O +chemotherapy O +: O +description O +of O +two O +cases O +. O + +Two O +cases O +of O +severe O +delayed O +neurologic B +toxicity I +related O +to O +the O +administration O +of O +intrathecal O +( O +IT O +) O +combination O +chemotherapy O +including O +thiotepa O +( O +TSPA O +) O +are O +presented O +. O + +Both O +cases O +developed O +axonal B +neuropathy I +with O +motor O +predominance O +in O +the O +lower O +extremities O +1 O +and O +6 O +months O +after O +IT O +chemotherapy O +was O +administered O +. O + +Neurologic B +toxicities I +have O +been O +described O +with O +IT O +- O +methotrexate O +, O +IT O +- O +cytosine O +arabinoside O +and O +IT O +- O +TSPA O +. O + +To O +our O +knowledge O +, O +however O +, O +axonal B +neuropathy I +following O +administration O +of O +these O +three O +agents O +has O +not O +been O +previously O +described O +. O + +In O +spite O +of O +the O +fact O +that O +TSPA O +is O +a O +useful O +IT O +agent O +, O +its O +combination O +with O +MTX O +, O +ara O +- O +C O +and O +radiotherapy O +could O +cause O +severe O +neurotoxicity B +. O + +This O +unexpected O +complication O +indicates O +the O +need O +for O +further O +toxicology O +research O +on O +IT O +- O +TSPA O +. O + +Effects O +of O +cromakalim O +and O +pinacidil O +on O +large O +epicardial O +and O +small O +coronary O +arteries O +in O +conscious O +dogs O +. O + +The O +effects O +of O +i O +. O +v O +. O +bolus O +administration O +of O +cromakalim O +( O +1 O +- O +10 O +micrograms O +/ O +kg O +) O +and O +pinacidil O +( O +3 O +- O +100 O +micrograms O +/ O +kg O +) O +on O +large O +( O +circumflex O +artery O +) O +and O +small O +coronary O +arteries O +and O +on O +systemic O +hemodynamics O +were O +investigated O +in O +chronically O +instrumented O +conscious O +dogs O +and O +compared O +to O +those O +of O +nitroglycerin O +( O +0 O +. O +03 O +- O +10 O +micrograms O +/ O +kg O +) O +. O + +Nitroglycerin O +, O +up O +to O +0 O +. O +3 O +micrograms O +/ O +kg O +, O +selectively O +increased O +circumflex O +artery O +diameter O +( O +CxAD O +) O +without O +simultaneously O +affecting O +any O +other O +cardiac O +or O +systemic O +hemodynamic O +parameter O +. O + +In O +contrast O +, O +cromakalim O +and O +pinacidil O +at O +all O +doses O +and O +nitroglycerin O +at O +doses O +higher O +than O +0 O +. O +3 O +micrograms O +/ O +kg O +simultaneously O +and O +dose O +- O +dependently O +increased O +CxAD O +, O +coronary O +blood O +flow O +and O +heart O +rate O +and O +decreased O +coronary O +vascular O +resistance O +and O +aortic O +pressure O +. O + +Cromakalim O +was O +approximately O +8 O +- O +to O +9 O +. O +5 O +- O +fold O +more O +potent O +than O +pinacidil O +in O +increasing O +CxAD O +. O + +Vasodilation O +of O +large O +and O +small O +coronary O +vessels O +and O +hypotension B +induced O +by O +cromakalim O +and O +pinacidil O +were O +not O +affected O +by O +prior O +combined O +beta O +adrenergic O +and O +muscarinic O +receptors O +blockade O +but O +drug O +- O +induced O +tachycardia B +was O +abolished O +. O + +When O +circumflex O +artery O +blood O +flow O +was O +maintained O +constant O +, O +the O +increases O +in O +CxAD O +induced O +by O +cromakalim O +( O +10 O +micrograms O +/ O +kg O +) O +, O +pinacidil O +( O +30 O +micrograms O +/ O +kg O +) O +and O +nitroglycerin O +( O +10 O +micrograms O +/ O +kg O +) O +were O +reduced O +by O +68 O ++ O +/ O +- O +7 O +, O +54 O ++ O +/ O +- O +9 O +and O +1 O ++ O +/ O +- O +1 O +% O +, O +respectively O +. O + +Thus O +, O +whereas O +nitroglycerin O +preferentially O +and O +flow O +- O +independently O +dilates O +large O +coronary O +arteries O +, O +cromakalim O +and O +pinacidil O +dilate O +both O +large O +and O +small O +coronary O +arteries O +and O +this O +effect O +is O +not O +dependent O +upon O +the O +simultaneous O +beta O +adrenoceptors O +- O +mediated O +rise O +in O +myocardial O +metabolic O +demand O +. O + +Finally O +, O +two O +mechanisms O +at O +least O +, O +direct O +vasodilation O +and O +flow O +dependency O +, O +are O +involved O +in O +the O +cromakalim O +- O +and O +pinacidil O +- O +induced O +increase O +in O +CxAD O +. O + +Mefenamic O +acid O +- O +induced O +neutropenia B +and O +renal B +failure I +in O +elderly O +females O +with O +hypothyroidism B +. O + +We O +report O +mefenamic O +acid O +- O +induced O +non O +- O +oliguric O +renal B +failure I +and O +severe O +neutropenia B +occurring O +simultaneously O +in O +two O +elderly O +females O +. O + +The O +neutropenia B +was O +due O +to O +maturation O +arrest O +of O +the O +myeloid O +series O +in O +one O +patient O +. O + +Both O +patients O +were O +also O +hypothyroid B +, O +but O +it O +is O +not O +clear O +whether O +this O +was O +a O +predisposing O +factor O +to O +the O +development O +of O +these O +adverse O +reactions O +. O + +However O +, O +it O +would O +seem O +prudent O +not O +to O +use O +mefenamic O +acid O +in O +hypothyroid B +patients O +until O +the O +hypothyroidism B +has O +been O +corrected O +. O + +Etiology O +of O +hypercalcemia B +in O +hemodialysis O +patients O +on O +calcium O +carbonate O +therapy O +. O + +Fourteen O +of O +39 O +dialysis O +patients O +( O +36 O +% O +) O +became O +hypercalcemic B +after O +switching O +to O +calcium O +carbonate O +as O +their O +principal O +phosphate O +binder O +. O + +In O +order O +to O +identify O +risk O +factors O +associated O +with O +the O +development O +of O +hypercalcemia B +, O +indirect O +parameters O +of O +intestinal O +calcium O +reabsorption O +and O +bone O +turnover O +rate O +in O +these O +14 O +patients O +were O +compared O +with O +results O +in O +14 O +eucalcemic O +patients O +matched O +for O +age O +, O +sex O +, O +length O +of O +time O +on O +dialysis O +, O +and O +etiology O +of O +renal B +disease I +. O + +In O +addition O +to O +experiencing O +hypercalcemic B +episodes O +with O +peak O +calcium O +values O +of O +2 O +. O +7 O +to O +3 O +. O +8 O +mmol O +/ O +L O +( O +10 O +. O +7 O +to O +15 O +. O +0 O +mg O +/ O +dL O +) O +, O +patients O +in O +the O +hypercalcemic B +group O +exhibited O +a O +significant O +increase O +in O +the O +mean O +calcium O +concentration O +obtained O +during O +6 O +months O +before O +the O +switch O +, O +compared O +with O +the O +mean O +value O +obtained O +during O +the O +7 O +months O +of O +observation O +after O +the O +switch O +( O +2 O +. O +4 O ++ O +/ O +- O +0 O +. O +03 O +to O +2 O +. O +5 O ++ O +/ O +- O +0 O +. O +03 O +mmol O +/ O +L O +[ O +9 O +. O +7 O ++ O +/ O +- O +0 O +. O +2 O +to O +10 O +. O +2 O ++ O +/ O +- O +0 O +. O +1 O +mg O + +/ O +dL O +] O +, O +P O += O +0 O +. O +006 O +) O +. O + +In O +contrast O +, O +eucalcemic O +patients O +exhibited O +no O +change O +in O +mean O +calcium O +values O +over O +the O +same O +time O +period O +( O +2 O +. O +3 O ++ O +/ O +- O +0 O +. O +05 O +to O +2 O +. O +3 O ++ O +/ O +- O +0 O +. O +05 O +mmol O +/ O +L O +[ O +9 O +. O +2 O ++ O +/ O +- O +0 O +. O +2 O +to O +9 O +. O +2 O ++ O +/ O +- O +0 O +. O +2 O +mg O +/ O +dL O +] O +) O +. O + +CaCO3 O +dosage O +, O +calculated O +dietary O +calcium O +intake O +, O +and O +circulating O +levels O +of O +vitamin O +D O +metabolites O +were O +similar O +in O +both O +groups O +. O + +Physical O +activity O +index O +and O +predialysis O +serum O +bicarbonate O +levels O +also O +were O +similar O +in O +both O +groups O +. O + +However O +, O +there O +was O +a O +significant O +difference O +in O +parameters O +reflecting O +bone O +turnover O +rates O +between O +groups O +. O +( O +ABSTRACT O +TRUNCATED O +AT O +250 O +WORDS O +) O + +Late O +- O +onset O +scleroderma B +renal I +crisis I +induced O +by O +tacrolimus O +and O +prednisolone O +: O +a O +case O +report O +. O + +Scleroderma B +renal I +crisis I +( O +SRC B +) O +is O +a O +rare O +complication O +of O +systemic B +sclerosis I +( O +SSc B +) O +but O +can O +be O +severe O +enough O +to O +require O +temporary O +or O +permanent O +renal O +replacement O +therapy O +. O + +Moderate O +to O +high O +dose O +corticosteroid O +use O +is O +recognized O +as O +a O +major O +risk O +factor O +for O +SRC B +. O + +Furthermore O +, O +there O +have O +been O +reports O +of O +thrombotic B +microangiopathy I +precipitated O +by O +cyclosporine O +in O +patients O +with O +SSc B +. O + +In O +this O +article O +, O +we O +report O +a O +patient O +with O +SRC B +induced O +by O +tacrolimus O +and O +corticosteroids O +. O + +The O +aim O +of O +this O +work O +is O +to O +call O +attention O +to O +the O +risk O +of O +tacrolimus O +use O +in O +patients O +with O +SSc B +. O + +Methyldopa O +- O +induced O +hemolytic B +anemia I +in O +a O +15 O +year O +old O +presenting O +as O +near O +- O +syncope B +. O + +Methyldopa O +is O +an O +antihypertensive O +medication O +which O +is O +available O +generically O +and O +under O +the O +trade O +name O +Aldomet O +that O +is O +widely O +prescribed O +in O +the O +adult O +population O +and O +infrequently O +used O +in O +children O +. O + +Methyldopa O +causes O +an O +autoimmune B +hemolytic I +anemia I +in O +a O +small O +percentage O +of O +patients O +who O +take O +the O +drug O +. O + +We O +report O +a O +case O +of O +methyldopa O +- O +induced O +hemolytic B +anemia I +in O +a O +15 O +- O +year O +- O +old O +boy O +who O +presented O +to O +the O +emergency O +department O +with O +near O +- O +syncope B +. O + +The O +boy O +had O +been O +treated O +with O +intravenous O +methyldopa O +during O +a O +trauma B +admission O +seven O +weeks O +prior O +to O +presentation O +. O + +Evaluation O +revealed O +a O +hemoglobin O +of O +three O +grams O +, O +3 O ++ O +Coombs O +' O +test O +with O +polyspecific O +anti O +- O +human O +globulin O +and O +monospecific O +IgG O +reagents O +, O +and O +a O +warm O +reacting O +autoantibody O +. O + +Transfusion O +and O +corticosteroid O +therapy O +resulted O +in O +a O +complete O +recovery O +of O +the O +patient O +. O + +Emergency O +physicians O +treating O +children O +must O +be O +aware O +of O +this O +syndrome O +in O +order O +to O +diagnose O +and O +treat O +it O +correctly O +. O + +A O +brief O +review O +of O +autoimmune O +and O +drug O +- O +induced O +hemolytic B +anemias I +is O +provided O +. O + +The O +risk O +and O +associated O +factors O +of O +methamphetamine O +psychosis B +in O +methamphetamine O +- O +dependent O +patients O +in O +Malaysia O +. O + +OBJECTIVE O +: O +The O +objective O +of O +this O +study O +was O +to O +determine O +the O +risk O +of O +lifetime O +and O +current O +methamphetamine O +- O +induced O +psychosis B +in O +patients O +with O +methamphetamine O +dependence O +. O + +The O +association O +between O +psychiatric B +co O +- O +morbidity O +and O +methamphetamine O +- O +induced O +psychosis B +was O +also O +studied O +. O + +METHODS O +: O +This O +was O +a O +cross O +- O +sectional O +study O +conducted O +concurrently O +at O +a O +teaching O +hospital O +and O +a O +drug O +rehabilitation O +center O +in O +Malaysia O +. O + +Patients O +with O +the O +diagnosis O +of O +methamphetamine O +based O +on O +DSM O +- O +IV O +were O +interviewed O +using O +the O +Mini O +International O +Neuropsychiatric O +Interview O +( O +M O +. O +I O +. O +N O +. O +I O +. O +) O +for O +methamphetamine O +- O +induced O +psychosis B +and O +other O +Axis B +I O +psychiatric B +disorders I +. O + +The O +information O +on O +sociodemographic O +background O +and O +drug O +use O +history O +was O +obtained O +from O +interview O +or O +medical O +records O +. O + +RESULTS O +: O +Of O +292 O +subjects O +, O +47 O +. O +9 O +% O +of O +the O +subjects O +had O +a O +past O +history O +of O +psychotic B +symptoms I +and O +13 O +. O +0 O +% O +of O +the O +patients O +were O +having O +current O +psychotic B +symptoms I +. O + +Co O +- O +morbid O +major O +depressive B +disorder I +( O +OR O += O +7 O +. O +18 O +, O +95 O +CI O += O +2 O +. O +612 O +- O +19 O +. O +708 O +) O +, O +bipolar B +disorder I +( O +OR O += O +13 O +. O +807 O +, O +95 O +CI O += O +5 O +. O +194 O +- O +36 O +. O +706 O +) O +, O +antisocial B +personality I +disorder I +( O +OR O += O +12 O +. O +619 O +, O +95 O +CI O += O +6 O +. O +702 O +- O +23 O +. O +759 O +) O +and O +heavy O +methamphetamine O +uses O +were O +significantly O +associated O +with O +lifetime O +methamphetamine O +- O +induced O +psychosis B +after O +adjusted O +for O +other O +factors O +. O + +Major O +depressive B +disorder I +( O +OR O += O +2 O +. O +870 O +, O +CI O += O +1 O +. O +154 O +- O +7 O +. O +142 O +) O +and O +antisocial B +personality I +disorder I +( O +OR O += O +3 O +. O +299 O +, O +95 O +CI O += O +1 O +. O +375 O +- O +7 O +. O +914 O +) O +were O +the O +only O +factors O +associated O +with O +current O +psychosis B +. O + +CONCLUSION O +: O +There O +was O +a O +high O +risk O +of O +psychosis B +in O +patients O +with O +methamphetamine O +dependence O +. O + +It O +was O +associated O +with O +co O +- O +morbid O +affective B +disorder I +, O +antisocial B +personality I +, O +and O +heavy O +methamphetamine O +use O +. O + +It O +is O +recommended O +that O +all O +cases O +of O +methamphetamine O +dependence O +should O +be O +screened O +for O +psychotic B +symptoms I +. O + +Cerebellar O +sensory O +processing O +alterations O +impact O +motor O +cortical O +plasticity O +in O +Parkinson B +' I +s I +disease I +: O +clues O +from O +dyskinetic B +patients O +. O + +The O +plasticity O +of O +primary O +motor O +cortex O +( O +M1 O +) O +in O +patients O +with O +Parkinson B +' I +s I +disease I +( O +PD B +) O +and O +levodopa O +- O +induced O +dyskinesias B +( O +LIDs B +) O +is O +severely O +impaired O +. O + +We O +recently O +reported O +in O +young O +healthy O +subjects O +that O +inhibitory O +cerebellar O +stimulation O +enhanced O +the O +sensorimotor O +plasticity O +of O +M1 O +that O +was O +induced O +by O +paired O +associative O +stimulation O +( O +PAS O +) O +. O + +This O +study O +demonstrates O +that O +the O +deficient O +sensorimotor O +M1 O +plasticity O +in O +16 O +patients O +with O +LIDs B +could O +be O +reinstated O +by O +a O +single O +session O +of O +real O +inhibitory O +cerebellar O +stimulation O +but O +not O +sham O +stimulation O +. O + +This O +was O +evident O +only O +when O +a O +sensory O +component O +was O +involved O +in O +the O +induction O +of O +plasticity O +, O +indicating O +that O +cerebellar O +sensory O +processing O +function O +is O +involved O +in O +the O +resurgence O +of O +M1 O +plasticity O +. O + +The O +benefit O +of O +inhibitory O +cerebellar O +stimulation O +on O +LIDs O +is O +known O +. O + +To O +explore O +whether O +this O +benefit O +is O +linked O +to O +the O +restoration O +of O +sensorimotor O +plasticity O +of O +M1 O +, O +we O +conducted O +an O +additional O +study O +looking O +at O +changes O +in O +LIDs O +and O +PAS O +- O +induced O +plasticity O +after O +10 O +sessions O +of O +either O +bilateral O +, O +real O +inhibitory O +cerebellar O +stimulation O +or O +sham O +stimulation O +. O + +Only O +real O +and O +not O +sham O +stimulation O +had O +an O +antidyskinetic O +effect O +and O +it O +was O +paralleled O +by O +a O +resurgence O +in O +the O +sensorimotor O +plasticity O +of O +M1 O +. O + +These O +results O +suggest O +that O +alterations O +in O +cerebellar O +sensory O +processing O +function O +, O +occurring O +secondary O +to O +abnormal O +basal O +ganglia O +signals O +reaching O +it O +, O +may O +be O +an O +important O +element O +contributing O +to O +the O +maladaptive O +sensorimotor O +plasticity O +of O +M1 O +and O +the O +emergence O +of O +abnormal B +involuntary I +movements I +. O + +The O +long O +- O +term O +safety O +of O +danazol O +in O +women O +with O +hereditary B +angioedema I +. O + +Although O +the O +short O +- O +term O +safety O +( O +less O +than O +or O +equal O +to O +6 O +months O +) O +of O +danazol O +has O +been O +established O +in O +a O +variety O +of O +settings O +, O +no O +information O +exists O +as O +to O +its O +long O +- O +term O +safety O +. O + +We O +therefore O +investigated O +the O +long O +- O +term O +safety O +of O +danazol O +by O +performing O +a O +retrospective O +chart O +review O +of O +60 O +female O +patients O +with O +hereditary B +angioedema I +treated O +with O +danazol O +for O +a O +continuous O +period O +of O +6 O +months O +or O +longer O +. O + +The O +mean O +age O +of O +the O +patients O +was O +35 O +. O +2 O +years O +and O +the O +mean O +duration O +of O +therapy O +was O +59 O +. O +7 O +months O +. O + +Virtually O +all O +patients O +experienced O +one O +or O +more O +adverse O +reactions O +. O + +Menstrual B +abnormalities I +( O +79 O +% O +) O +, O +weight B +gain I +( O +60 O +% O +) O +, O +muscle B +cramps I +/ O +myalgias B +( O +40 O +% O +) O +, O +and O +transaminase O +elevations O +( O +40 O +% O +) O +were O +the O +most O +common O +adverse O +reactions O +. O + +The O +drug O +was O +discontinued O +due O +to O +adverse O +reactions O +in O +8 O +patients O +. O + +No O +patient O +has O +died O +or O +suffered O +any O +apparent O +long O +- O +term O +sequelae O +that O +were O +directly O +attributable O +to O +the O +drug O +. O + +We O +conclude O +that O +, O +despite O +a O +relatively O +high O +incidence O +of O +adverse O +reactions O +, O +danazol O +has O +proven O +to O +be O +remarkably O +safe O +over O +the O +long O +- O +term O +in O +this O +group O +of O +patients O +. O + +The O +function O +of O +P2X3 O +receptor O +and O +NK1 O +receptor O +antagonists O +on O +cyclophosphamide O +- O +induced O +cystitis B +in O +rats O +. O + +PURPOSE O +: O +The O +purpose O +of O +the O +study O +is O +to O +explore O +the O +function O +of O +P2X3 O +and O +NK1 O +receptors O +antagonists O +on O +cyclophosphamide O +( O +CYP O +) O +- O +induced O +cystitis B +in O +rats O +. O + +METHODS O +: O +Sixty O +female O +Sprague O +- O +Dawley O +( O +SD O +) O +rats O +were O +randomly O +divided O +into O +three O +groups O +. O + +The O +rats O +in O +the O +control O +group O +were O +intraperitoneally O +( O +i O +. O +p O +. O +) O +injected O +with O +0 O +. O +9 O +% O +saline O +( O +4 O +ml O +/ O +kg O +) O +; O +the O +rats O +in O +the O +model O +group O +were O +i O +. O +p O +. O +injected O +with O +CYP O +( O +150 O +mg O +/ O +kg O +) O +; O +and O +the O +rats O +in O +the O +intervention O +group O +were O +i O +. O +p O +. O +injected O +with O +CYP O +with O +subsequently O +perfusion O +of O +bladder O +with O +P2X3 O +and O +NK1 O +receptors O +' O +antagonists O +, O +Suramin O +and O +GR O +82334 O +. O + +Spontaneous O +pain B +behaviors O +following O +the O +administration O +of O +CYP O +were O +observed O +. O + +Urodynamic O +parameters O +, O +bladder O +pressure O +- O +volume O +curve O +, O +maximum O +voiding O +pressure O +( O +MVP O +) O +, O +and O +maximum O +cystometric O +capacity O +( O +MCC O +) O +, O +were O +recorded O +. O + +Pathological O +changes O +in O +bladder O +tissue O +were O +observed O +. O + +Immunofluorescence O +was O +used O +to O +detect O +the O +expression O +of O +P2X3 O +and O +NK1 O +receptors O +in O +bladder O +. O + +RESULTS O +: O +Cyclophosphamide O +treatment O +increased O +the O +spontaneous O +pain B +behaviors O +scores O +. O + +The O +incidence O +of O +bladder B +instability I +during O +urine O +storage O +period O +of O +model O +group O +was O +significantly O +higher O +than O +intervention O +group O +( O +X O +( O +2 O +) O += O +7 O +. O +619 O +, O +P O += O +0 O +. O +007 O +) O +and O +control O +group O +( O +X O +( O +2 O +) O += O +13 O +. O +755 O +, O +P O += O +0 O +. O +000 O +) O +. O + +MCC O +in O +the O +model O +group O +was O +lower O +than O +the O +control O +and O +intervention O +groups O +( O +P O +< O +0 O +. O +01 O +) O +. O + +Histological O +changes O +evident O +in O +model O +and O +intervention O +groups O +rats O +' O +bladder O +included O +edema B +, O +vasodilation O +, O +and O +infiltration O +of O +inflammatory O +cells O +. O + +In O +model O +group O +, O +the O +expression O +of O +P2X3 O +receptor O +increased O +in O +urothelium O +and O +suburothelium O +, O +and O +NK1 O +receptor O +increased O +in O +suburothelium O +, O +while O +the O +expression O +of O +them O +in O +intervention O +group O +was O +lower O +. O + +CONCLUSIONS O +: O +In O +CYP O +- O +induced O +cystitis B +, O +the O +expression O +of O +P2X3 O +and O +NK1 O +receptors O +increased O +in O +urothelium O +and O +/ O +or O +suburothelium O +. O + +Perfusion O +of O +bladder O +with O +P2X3 O +and O +NK1 O +receptors O +antagonists O +ameliorated O +the O +bladder O +function O +. O + +Patient O +tolerance O +study O +of O +topical O +chlorhexidine O +diphosphanilate O +: O +a O +new O +topical O +agent O +for O +burns B +. O + +Effective O +topical O +antimicrobial O +agents O +decrease O +infection B +and O +mortality O +in O +burn B +patients O +. O + +Chlorhexidine O +phosphanilate O +( O +CHP O +) O +, O +a O +new O +broad O +- O +spectrum O +antimicrobial O +agent O +, O +has O +been O +evaluated O +as O +a O +topical O +burn B +wound O +dressing O +in O +cream O +form O +, O +but O +preliminary O +clinical O +trials O +reported O +that O +it O +was O +painful B +upon O +application O +. O + +This O +study O +compared O +various O +concentrations O +of O +CHP O +to O +determine O +if O +a O +tolerable O +concentration O +could O +be O +identified O +with O +retention O +of O +antimicrobial O +efficacy O +. O + +Twenty O +- O +nine O +burn B +patients O +, O +each O +with O +two O +similar O +burns B +which O +could O +be O +separately O +treated O +, O +were O +given O +pairs O +of O +treatments O +at O +successive O +12 O +- O +h O +intervals O +over O +a O +3 O +- O +day O +period O +. O + +One O +burn B +site O +was O +treated O +with O +each O +of O +four O +different O +CHP O +concentrations O +, O +from O +0 O +. O +25 O +per O +cent O +to O +2 O +per O +cent O +, O +their O +vehicle O +, O +and O +1 O +per O +cent O +silver O +sulphadiazine O +( O +AgSD O +) O +cream O +, O +an O +antimicrobial O +agent O +frequently O +used O +for O +topical O +treatment O +of O +burn B +wounds I +. O + +The O +other O +site O +was O +always O +treated O +with O +AgSD O +cream O +. O + +There O +was O +a O +direct O +relationship O +between O +CHP O +concentration O +and O +patients O +' O +ratings O +of O +pain B +on O +an O +analogue O +scale O +. O + +The O +0 O +. O +25 O +per O +cent O +CHP O +cream O +was O +closest O +to O +AgSD O +in O +pain B +tolerance O +; O +however O +, O +none O +of O +the O +treatments O +differed O +statistically O +from O +AgSD O +or O +from O +each O +other O +. O + +In O +addition O +, O +ease O +of O +application O +of O +CHP O +creams O +was O +less O +satisfactory O +than O +that O +of O +AgSD O +. O + +It O +was O +concluded O +that O +formulations O +at O +or O +below O +0 O +. O +5 O +per O +cent O +CHP O +may O +prove O +acceptable O +for O +wound O +care O +, O +but O +the O +vehicle O +system O +needs O +pharmaceutical O +improvement O +to O +render O +it O +more O +tolerable O +and O +easier O +to O +use O +. O + +Acute O +hepatitis B +associated O +with O +clopidogrel O +: O +a O +case O +report O +and O +review O +of O +the O +literature O +. O + +Drug O +- O +induced O +hepatotoxicity B +is O +a O +common O +cause O +of O +acute O +hepatitis B +, O +and O +the O +recognition O +of O +the O +responsible O +drug O +may O +be O +difficult O +. O + +We O +describe O +a O +case O +of O +clopidogrel O +- O +related O +acute O +hepatitis B +. O + +The O +diagnosis O +is O +strongly O +suggested O +by O +an O +accurate O +medical O +history O +and O +liver O +biopsy O +. O + +Reports O +about O +cases O +of O +hepatotoxicity B +due O +to O +clopidogrel O +are O +increasing O +in O +the O +last O +few O +years O +, O +after O +the O +increased O +use O +of O +this O +drug O +. O + +In O +conclusion O +, O +we O +believe O +that O +physicians O +should O +carefully O +consider O +the O +risk O +of O +drug O +- O +induced O +hepatic B +injury I +when O +clopidogrel O +is O +prescribed O +. O + +Bortezomib O +and O +dexamethasone O +as O +salvage O +therapy O +in O +patients O +with O +relapsed O +/ O +refractory O +multiple B +myeloma I +: O +analysis O +of O +long O +- O +term O +clinical O +outcomes O +. O + +Bortezomib O +( O +bort O +) O +- O +dexamethasone O +( O +dex O +) O +is O +an O +effective O +therapy O +for O +relapsed O +/ O +refractory O +( O +R O +/ O +R O +) O +multiple B +myeloma I +( O +MM B +) O +. O + +This O +retrospective O +study O +investigated O +the O +combination O +of O +bort O +( O +1 O +. O +3 O +mg O +/ O +m O +( O +2 O +) O +on O +days O +1 O +, O +4 O +, O +8 O +, O +and O +11 O +every O +3 O +weeks O +) O +and O +dex O +( O +20 O +mg O +on O +the O +day O +of O +and O +the O +day O +after O +bort O +) O +as O +salvage O +treatment O +in O +85 O +patients O +with O +R O +/ O +R O +MM O +after O +prior O +autologous O +stem O +cell O +transplantation O +or O +conventional O +chemotherapy O +. O + +The O +median O +number O +of O +prior O +lines O +of O +therapy O +was O +2 O +. O + +Eighty O +- O +seven O +percent O +of O +the O +patients O +had O +received O +immunomodulatory O +drugs O +included O +in O +some O +line O +of O +therapy O +before O +bort O +- O +dex O +. O + +The O +median O +number O +of O +bort O +- O +dex O +cycles O +was O +6 O +, O +up O +to O +a O +maximum O +of O +12 O +cycles O +. O + +On O +an O +intention O +- O +to O +- O +treat O +basis O +, O +55 O +% O +of O +the O +patients O +achieved O +at O +least O +partial O +response O +, O +including O +19 O +% O +CR O +and O +35 O +% O +achieved O +at O +least O +very O +good O +partial O +response O +. O + +Median O +durations O +of O +response O +, O +time O +to O +next O +therapy O +and O +treatment O +- O +free O +interval O +were O +8 O +, O +11 O +. O +2 O +, O +and O +5 O +. O +1 O +months O +, O +respectively O +. O + +The O +most O +relevant O +adverse O +event O +was O +peripheral B +neuropathy I +, O +which O +occurred O +in O +78 O +% O +of O +the O +patients O +( O +grade O +II O +, O +38 O +% O +; O +grade O +III O +, O +21 O +% O +) O +and O +led O +to O +treatment O +discontinuation O +in O +6 O +% O +. O + +With O +a O +median O +follow O +up O +of O +22 O +months O +, O +median O +time O +to O +progression O +, O +progression O +- O +free O +survival O +( O +PFS O +) O +and O +overall O +survival O +( O +OS O +) O +were O +8 O +. O +9 O +, O +8 O +. O +7 O +, O +and O +22 O +months O +, O +respectively O +. O + +Prolonged O +PFS O +and O +OS O +were O +observed O +in O +patients O +achieving O +CR O +and O +receiving O +bort O +- O +dex O +a O +single O +line O +of O +prior O +therapy O +. O + +Bort O +- O +dex O +was O +an O +effective O +salvage O +treatment O +for O +MM B +patients O +, O +particularly O +for O +those O +in O +first O +relapse O +. 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O + +An O +unexpected O +diagnosis O +in O +a O +renal O +- O +transplant O +patient O +with O +proteinuria B +treated O +with O +everolimus O +: O +AL B +amyloidosis I +. O + +Proteinuria B +is O +an O +expected O +complication O +in O +transplant O +patients O +treated O +with O +mammalian O +target O +of O +rapamycin O +inhibitors O +( O +mTOR O +- O +i O +) O +. O + +However O +, O +clinical O +suspicion O +should O +always O +be O +supported O +by O +histological O +evidence O +in O +order O +to O +investigate O +potential O +alternate O +diagnoses O +such O +as O +acute O +or O +chronic O +rejection O +, O +interstitial B +fibrosis I +and O +tubular B +atrophy I +, O +or O +recurrent O +or O +de O +novo O +glomerulopathy B +. O + +In O +this O +case O +we O +report O +the O +unexpected O +diagnosis O +of O +amyloidosis B +in O +a O +renal O +- O +transplant O +patient O +with O +pre O +- O +transplant O +monoclonal B +gammapathy I +of I +undetermined I +significance O +who O +developed O +proteinuria B +after O +conversion O +from O +tacrolimus O +to O +everolimus O +. O + +Long O +- O +term O +oral O +galactose O +treatment O +prevents O +cognitive B +deficits I +in O +male O +Wistar O +rats O +treated O +intracerebroventricularly O +with O +streptozotocin O +. O + +Basic O +and O +clinical O +research O +has O +demonstrated O +that O +dementia B +of O +sporadic O +Alzheimer B +' I +s I +disease I +( O +sAD B +) O +type O +is O +associated O +with O +dysfunction O +of O +the O +insulin O +- O +receptor O +( O +IR O +) O +system O +followed O +by O +decreased O +glucose O +transport O +via O +glucose O +transporter O +GLUT4 O +and O +decreased O +glucose O +metabolism O +in O +brain O +cells O +. O + +An O +alternative O +source O +of O +energy O +is O +d O +- O +galactose O +( O +the O +C O +- O +4 O +- O +epimer O +of O +d O +- O +glucose O +) O +which O +is O +transported O +into O +the O +brain O +by O +insulin O +- O +independent O +GLUT3 O +transporter O +where O +it O +might O +be O +metabolized O +to O +glucose O +via O +the O +Leloir O +pathway O +. O + +Exclusively O +parenteral O +daily O +injections O +of O +galactose O +induce O +memory B +deterioration I +in O +rodents O +and O +are O +used O +to O +generate O +animal O +aging O +model O +, O +but O +the O +effects O +of O +oral O +galactose O +treatment O +on O +cognitive O +functions O +have O +never O +been O +tested O +. O + +We O +have O +investigated O +the O +effects O +of O +continuous O +daily O +oral O +galactose O +( O +200 O +mg O +/ O +kg O +/ O +day O +) O +treatment O +on O +cognitive B +deficits I +in O +streptozotocin O +- O +induced O +( O +STZ O +- O +icv O +) O +rat O +model O +of O +sAD B +, O +tested O +by O +Morris O +Water O +Maze O +and O +Passive O +Avoidance O +test O +, O +respectively O +. O + +One O +month O +of O +oral O +galactose O +treatment O +initiated O +immediately O +after O +the O +STZ O +- O +icv O +administration O +, O +successfully O +prevented O +development O +of O +the O +STZ O +- O +icv O +- O +induced O +cognitive B +deficits I +. O + +Beneficial O +effect O +of O +oral O +galactose O +was O +independent O +of O +the O +rat O +age O +and O +of O +the O +galactose O +dose O +ranging O +from O +100 O +to O +300 O +mg O +/ O +kg O +/ O +day O +. O + +Additionally O +, O +oral O +galactose O +administration O +led O +to O +the O +appearance O +of O +galactose O +in O +the O +blood O +. O + +The O +increase O +of O +galactose O +concentration O +in O +the O +cerebrospinal O +fluid O +was O +several O +times O +lower O +after O +oral O +than O +after O +parenteral O +administration O +of O +the O +same O +galactose O +dose O +. O + +Oral O +galactose O +exposure O +might O +have O +beneficial O +effects O +on O +learning O +and O +memory O +ability O +and O +could O +be O +worth O +investigating O +for O +improvement O +of O +cognitive B +deficits I +associated O +with O +glucose B +hypometabolism I +in O +AD B +. O + +An O +investigation O +of O +the O +pattern O +of O +kidney B +injury I +in O +HIV B +- I +positive I +persons O +exposed O +to O +tenofovir O +disoproxil O +fumarate O +: O +an O +examination O +of O +a O +large O +population O +database O +( O +MHRA O +database O +) O +. O + +The O +potential O +for O +tenofovir O +to O +cause O +a O +range O +of O +kidney B +syndromes I +has O +been O +established O +from O +mechanistic O +and O +randomised O +clinical O +trials O +. O + +However O +, O +the O +exact O +pattern O +of O +kidney O +involvement O +is O +still O +uncertain O +. O + +We O +undertook O +a O +descriptive O +analysis O +of O +Yellow O +Card O +records O +of O +407 O +HIV B +- I +positive I +persons O +taking O +tenofovir O +disoproxil O +fumarate O +( O +TDF O +) O +as O +part O +of O +their O +antiretroviral O +therapy O +regimen O +and O +submitted O +to O +the O +Medicines O +and O +Healthcare O +Products O +Regulatory O +Agency O +( O +MHRA O +) O +with O +suspected O +kidney B +adverse I +effects O +. O + +Reports O +that O +satisfy O +defined O +criteria O +were O +classified O +as O +acute B +kidney I +injury I +, O +kidney B +tubular I +dysfunction I +and O +Fanconi B +syndrome I +. O + +Of O +the O +407 O +Yellow O +Card O +records O +analysed O +, O +106 O +satisfied O +criteria O +for O +TDF O +- O +related O +kidney B +disease I +, O +of O +which O +53 O +( O +50 O +% O +) O +had O +features O +of O +kidney B +tubular I +dysfunction I +, O +35 O +( O +33 O +% O +) O +were O +found O +to O +have O +features O +of O +glomerular B +dysfunction I +and O +18 O +( O +17 O +% O +) O +had O +Fanconi B +syndrome I +. O + +The O +median O +TDF O +exposure O +was O +316 O +days O +( O +interquartile O +range O +120 O +- O +740 O +) O +. O + +The O +incidence O +of O +hospitalisation O +for O +TDF O +kidney O +adverse O +effects O +was O +high O +, O +particularly O +amongst O +patients O +with O +features O +of O +Fanconi B +syndrome I +. O + +The O +pattern O +of O +kidney B +syndromes I +in O +this O +population O +series O +mirrors O +that O +reported O +in O +randomised O +clinical O +trials O +. O + +Cessation O +of O +TDF O +was O +associated O +with O +complete O +restoration O +of O +kidney O +function O +in O +up O +half O +of O +the O +patients O +in O +this O +report O +. O + +Incidence O +of O +postoperative B +delirium I +is O +high O +even O +in O +a O +population O +without O +known O +risk O +factors O +. O + +PURPOSE O +: O +Postoperative B +delirium I +is O +a O +recognized O +complication O +in O +populations O +at O +risk O +. O + +The O +aim O +of O +this O +study O +is O +to O +assess O +the O +prevalence O +of O +early O +postoperative B +delirium I +in O +a O +population O +without O +known O +risk O +factors O +admitted O +to O +the O +ICU O +for O +postoperative O +monitoring O +after O +elective O +major O +surgery O +. O + +The O +secondary O +outcome O +investigated O +is O +to O +identify O +eventual O +independent O +risk O +factors O +among O +demographic O +data O +and O +anesthetic O +drugs O +used O +. O + +METHODS O +: O +An O +observational O +, O +prospective O +study O +was O +conducted O +on O +a O +consecutive O +cohort O +of O +patients O +admitted O +to O +our O +ICU O +within O +and O +for O +at O +least O +24 O +h O +after O +major O +surgical O +procedures O +. O + +Exclusion O +criteria O +were O +any O +preexisting O +predisposing O +factor O +for O +delirium B +or O +other O +potentially O +confounding O +neurological B +dysfunctions I +. O + +Patients O +were O +assessed O +daily O +using O +the O +confusion O +assessment O +method O +for O +the O +ICU O +scale O +for O +3 O +days O +after O +the O +surgical O +procedure O +. O + +Early O +postoperative O +delirium I +incidence O +risk O +factors O +were O +then O +assessed O +through O +three O +different O +multiple O +regression O +models O +. O + +RESULTS O +: O +According O +to O +the O +confusion O +assessment O +method O +for O +the O +ICU O +scale O +, O +28 O +% O +of O +patients O +were O +diagnosed O +with O +early O +postoperative B +delirium I +. O + +The O +use O +of O +thiopentone O +was O +significantly O +associated O +with O +an O +eight O +- O +fold O +- O +higher O +risk O +for O +delirium B +compared O +to O +propofol O +( O +57 O +. O +1 O +% O +vs O +. O +7 O +. O +1 O +% O +, O +RR O += O +8 O +. O +0 O +, O +X2 O += O +4 O +. O +256 O +; O +df O += O +1 O +; O +0 O +. O +05 O +< O +p O +< O +0 O +. O +02 O +) O +. O + +CONCLUSION O +: O +In O +this O +study O +early O +postoperative B +delirium I +was O +found O +to O +be O +a O +very O +common O +complication O +after O +major O +surgery O +, O +even O +in O +a O +population O +without O +known O +risk O +factors O +. O + +Thiopentone O +was O +independently O +associated O +with O +an O +increase O +in O +its O +relative O +risk O +. O + +A O +single O +neurotoxic B +dose O +of O +methamphetamine O +induces O +a O +long O +- O +lasting O +depressive B +- I +like I +behaviour I +in O +mice O +. O + +Methamphetamine O +( O +METH O +) O +triggers O +a O +disruption O +of O +the O +monoaminergic O +system O +and O +METH O +abuse B +leads O +to O +negative O +emotional O +states O +including O +depressive B +symptoms I +during O +drug O +withdrawal O +. O + +However O +, O +it O +is O +currently O +unknown O +if O +the O +acute O +toxic O +dosage O +of O +METH O +also O +causes O +a O +long O +- O +lasting O +depressive B +phenotype O +and O +persistent O +monoaminergic O +deficits I +. O + +Thus O +, O +we O +now O +assessed O +the O +depressive B +- I +like I +behaviour I +in O +mice O +at O +early O +and O +long O +- O +term O +periods O +following O +a O +single O +high O +METH O +dose O +( O +30 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +. O + +METH O +did O +not O +alter O +the O +motor O +function O +and O +procedural O +memory O +of O +mice O +as O +assessed O +by O +swimming O +speed O +and O +escape O +latency O +to O +find O +the O +platform O +in O +a O +cued O +version O +of O +the O +water O +maze O +task O +. O + +However O +, O +METH O +significantly O +increased O +the O +immobility O +time O +in O +the O +tail O +suspension O +test O +at O +3 O +and O +49 O +days O +post O +- O +administration O +. O + +This O +depressive B +- O +like O +profile O +induced O +by O +METH O +was O +accompanied O +by O +a O +marked O +depletion O +of O +frontostriatal O +dopaminergic O +and O +serotonergic O +neurotransmission O +, O +indicated O +by O +a O +reduction O +in O +the O +levels O +of O +dopamine O +, O +DOPAC O +and O +HVA O +, O +tyrosine O +hydroxylase O +and O +serotonin O +, O +observed O +at O +both O +3 O +and O +49 O +days O +post O +- O +administration O +. O + +In O +parallel O +, O +another O +neurochemical O +feature O +of O +depression B +- O +- O +astroglial B +dysfunction I +- O +- O +was O +unaffected O +in O +the O +cortex O +and O +the O +striatal O +levels O +of O +the O +astrocytic O +protein O +marker O +, O +glial O +fibrillary O +acidic O +protein O +, O +were O +only O +transiently O +increased O +at O +3 O +days O +. O + +These O +findings O +demonstrate O +for O +the O +first O +time O +that O +a O +single O +high O +dose O +of O +METH O +induces O +long O +- O +lasting O +depressive B +- I +like I +behaviour I +in O +mice O +associated O +with O +a O +persistent O +disruption O +of O +frontostriatal O +dopaminergic O +and O +serotonergic O +homoeostasis O +. O + +Linezolid O +- O +induced O +optic B +neuropathy I +. O + +Many O +systemic O +antimicrobials O +have O +been O +implicated O +to O +cause O +ocular O +adverse I +effects O +. O + +This O +is O +especially O +relevant O +in O +multidrug O +therapy O +where O +more O +than O +one O +drug O +can O +cause O +a O +similar O +ocular O +adverse O +effect O +. O + +We O +describe O +a O +case O +of O +progressive O +loss B +of I +vision I +associated O +with O +linezolid O +therapy O +. O + +A O +45 O +- O +year O +- O +old O +male O +patient O +who O +was O +on O +treatment O +with O +multiple O +second O +- O +line O +anti O +- O +tuberculous B +drugs O +including O +linezolid O +and O +ethambutol O +for O +extensively O +drug O +- I +resistant I +tuberculosis I +( O +XDR B +- I +TB I +) O +presented O +to O +us O +with O +painless O +progressive O +loss B +of I +vision I +in O +both O +eyes O +. O + +Color B +vision I +was I +defective I +and O +fundus O +examination O +revealed O +optic B +disc I +edema I +in O +both O +eyes O +. O + +Ethambutol O +- O +induced O +toxic B +optic B +neuropathy I +was O +suspected O +and O +tablet O +ethambutol O +was O +withdrawn O +. O + +Deterioration B +of I +vision I +occurred O +despite O +withdrawal O +of O +ethambutol O +. O + +Discontinuation O +of O +linezolid O +resulted O +in O +marked O +improvement O +of O +vision O +. O + +Our O +report O +emphasizes O +the O +need O +for O +monitoring O +of O +visual O +function O +in O +patients O +on O +long O +- O +term O +linezolid O +treatment O +. O + +Resuscitation O +with O +lipid O +, O +epinephrine O +, O +or O +both O +in O +levobupivacaine O +- O +induced O +cardiac B +toxicity I +in O +newborn O +piglets O +. O + +BACKGROUND O +: O +The O +optimal O +dosing O +regimens O +of O +lipid O +emulsion O +, O +epinephrine O +, O +or O +both O +are O +not O +yet O +determined O +in O +neonates O +in O +cases O +of O +local O +anaesthetic O +systemic O +toxicity B +( O +LAST O +) O +. O + +METHODS O +: O +Newborn O +piglets O +received O +levobupivacaine O +until O +cardiovascular B +collapse I +occurred O +. O + +Standard O +cardiopulmonary O +resuscitation O +was O +started O +and O +electrocardiogram O +( O +ECG O +) O +was O +monitored O +for O +ventricular B +tachycardia I +, I +fibrillation I +, O +or O +QRS B +prolongation I +. O + +Piglets O +were O +then O +randomly O +allocated O +to O +four O +groups O +: O +control O +( O +saline O +) O +, O +Intralipid O +( O +) O +alone O +, O +epinephrine O +alone O +, O +or O +a O +combination O +of O +Intralipd O +plus O +epinephrine O +. O + +Resuscitation O +continued O +for O +30 O +min O +or O +until O +there O +was O +a O +return O +of O +spontaneous O +circulation O +( O +ROSC O +) O +accompanied O +by O +a O +mean O +arterial O +pressure O +at O +or O +superior O +to O +the O +baseline O +pressure O +and O +normal O +sinus O +rhythm O +for O +a O +period O +of O +30 O +min O +. O + +RESULTS O +: O +ROSC O +was O +achieved O +in O +only O +one O +of O +the O +control O +piglets O +compared O +with O +most O +of O +the O +treated O +piglets O +. O + +Mortality O +was O +not O +significantly O +different O +between O +the O +three O +treatment O +groups O +, O +but O +was O +significantly O +lower O +in O +all O +the O +treatment O +groups O +compared O +with O +control O +. O + +The O +number O +of O +ECG O +abnormalities O +was O +zero O +in O +the O +Intralipid O +only O +group O +, O +but O +14 O +and O +17 O +, O +respectively O +, O +in O +the O +epinephrine O +and O +epinephrine O +plus O +lipid O +groups O +( O +P O +< O +0 O +. O +05 O +) O +. O + +CONCLUSIONS O +: O +Lipid O +emulsion O +with O +or O +without O +epinephrine O +, O +or O +epinephrine O +alone O +were O +equally O +effective O +in O +achieving O +a O +return O +to O +spontaneous O +circulation O +in O +this O +model O +of O +LAST B +. O + +Epinephrine O +alone O +or O +in O +combination O +with O +lipid O +was O +associated O +with O +an O +increased O +number O +of O +ECG B +abnormalities I +compared O +with O +lipid O +emulsion O +alone O +. O + +Incidence O +of O +heparin O +- O +induced O +thrombocytopenia B +type I +II I +and O +postoperative O +recovery O +of O +platelet O +count O +in O +liver O +graft O +recipients O +: O +a O +retrospective O +cohort O +analysis O +. O + +BACKGROUND O +: O +Thrombocytopenia B +in O +patients O +with O +end B +- I +stage I +liver I +disease I +is O +a O +common O +disorder O +caused O +mainly O +by O +portal B +hypertension I +, O +low O +levels O +of O +thrombopoetin O +, O +and O +endotoxemia B +. O + +The O +impact O +of O +immune O +- O +mediated O +heparin O +- O +induced O +thrombocytopenia B +type I +II I +( O +HIT B +type I +II I +) O +as O +a O +cause O +of O +thrombocytopenia B +after O +liver O +transplantation O +is O +not O +yet O +understood O +, O +with O +few O +literature O +citations O +reporting O +contradictory O +results O +. O + +The O +aim O +of O +our O +study O +was O +to O +demonstrate O +the O +perioperative O +course O +of O +thrombocytopenia B +after O +liver O +transplantation O +and O +determine O +the O +occurrence O +of O +clinical O +HIT B +type O +II I +. O + +METHOD O +: O +We O +retrospectively O +evaluated O +the O +medical O +records O +of O +205 O +consecutive O +adult O +patients O +who O +underwent O +full O +- O +size O +liver O +transplantation O +between O +January O +2006 O +and O +December O +2010 O +due O +to O +end B +- I +stage I +or O +malignant B +liver I +disease I +. O + +Preoperative O +platelet O +count O +, O +postoperative O +course O +of O +platelets O +, O +and O +clinical O +signs O +of O +HIT B +type I +II I +were O +analyzed O +. O + +RESULTS O +: O +A O +total O +of O +155 O +( O +75 O +. O +6 O +% O +) O +of O +205 O +patients O +had O +thrombocytopenia B +before O +transplantation O +, O +significantly O +influenced O +by O +Model O +of O +End O +- I +Stage I +Liver I +Disease I +score O +and O +liver B +cirrhosis I +. O + +The O +platelet O +count O +exceeded O +100 O +, O +000 O +/ O +uL O +in O +most O +of O +the O +patients O +( O +n O += O +193 O +) O +at O +a O +medium O +of O +7 O +d O +. O + +Regarding O +HIT B +II I +, O +there O +were O +four O +( O +1 O +. O +95 O +% O +) O +patients O +with O +a O +background O +of O +HIT B +type I +II I +. O + +CONCLUSIONS O +: O +The O +incidence O +of O +HIT B +in O +patients O +with O +end B +- I +stage I +hepatic I +failure I +is O +, O +with O +about O +1 O +. O +95 O +% O +, O +rare O +. O + +For O +further O +reduction O +of O +HIT B +type I +II I +, O +the O +use O +of O +intravenous O +heparin O +should O +be O +avoided O +and O +the O +prophylactic O +anticoagulation O +should O +be O +performed O +with O +low O +- O +molecular O +- O +weight O +heparin O +after O +normalization O +of O +platelet O +count O +. O + +Takotsubo B +syndrome I +( O +or O +apical B +ballooning I +syndrome I +) O +secondary O +to O +Zolmitriptan O +. O + +Takotsubo B +syndrome I +( O +TS B +) O +, O +also O +known O +as O +broken B +heart I +syndrome I +, O +is O +characterized O +by O +left B +ventricle I +apical I +ballooning I +with O +elevated O +cardiac O +biomarkers O +and O +electrocardiographic O +changes O +suggestive O +of O +an O +acute B +coronary I +syndrome I +( O +ie O +, O +ST O +- O +segment O +elevation O +, O +T O +wave O +inversions O +, O +and O +pathologic O +Q O +waves O +) O +. O + +We O +report O +a O +case O +of O +54 O +- O +year O +- O +old O +woman O +with O +medical O +history O +of O +mitral B +valve I +prolapse I +and O +migraines B +, O +who O +was O +admitted O +to O +the O +hospital O +for O +substernal O +chest B +pain I +and O +electrocardiogram O +demonstrated O +1 O +/ O +2 O +mm O +ST O +- O +segment O +elevation O +in O +leads O +II O +, O +III O +, O +aVF O +, O +V5 O +, O +and O +V6 O +and O +positive O +troponin O +I O +. O + +Emergent O +coronary O +angiogram O +revealed O +normal O +coronary O +arteries O +with O +moderately O +reduced O +left O +ventricular O +ejection O +fraction O +with O +wall O +motion O +abnormalities O +consistent O +with O +TS B +. O + +Detailed O +history O +obtained O +retrospectively O +revealed O +that O +the O +patient O +took O +zolmitriptan O +sparingly O +only O +when O +she O +had O +migraines B +. O + +But O +before O +this O +event O +, O +she O +was O +taking O +zolmitriptan O +2 O +- O +3 O +times O +daily O +for O +several O +days O +because O +of O +a O +persistent O +migraine B +headache B +. O + +She O +otherwise O +reported O +that O +she O +is O +quite O +active O +, O +rides O +horses O +, O +and O +does O +show O +jumping O +without O +any O +limitations O +in O +her O +physical O +activity O +. O + +There O +was O +no O +evidence O +of O +any O +recent O +stress O +or O +status O +migrainosus B +. O + +Extensive O +literature O +search O +revealed O +multiple O +cases O +of O +coronary B +artery I +vasospasm I +secondary O +to O +zolmitriptan O +, O +but O +none O +of O +the O +cases O +were O +associated O +with O +TS B +. O + +Depression B +, O +impulsiveness B +, O +sleep O +, O +and O +memory O +in O +past O +and O +present O +polydrug O +users O +of O +3 O +, O +4 O +- O +methylenedioxymethamphetamine O +( O +MDMA O +, O +ecstasy O +) O +. O + +RATIONALE O +: O +Ecstasy O +( O +3 O +, O +4 O +- O +methylenedioxymethamphetamine O +, O +MDMA O +) 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 O +users O +with O +past O +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 +, O +alcohol O +/ O +nicotine O +( O +AN O +) O +, O +cannabis O +/ O +alcohol O +/ O +nicotine O +( O +CAN O +) O +, O +non O +- O +ecstasy O +polydrug O +( O +PD O +) O +) O +, O +and O +two O +ecstasy O +polydrug O +groups O +( O +present O +( O +MDMA O +) O +and O +past O +users O +( O +EX O +- O +MDMA O +) O +. O + +Participants O +completed O +a O +drug O +history O +questionnaire O +, O +Beck O +Depression B +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 O +and O +EX O +- O +MDMA O +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 +, O +past O +ecstasy O +users O +showed O +few O +signs O +of O +recovery O +. O + +Compared O +with O +present O +ecstasy O +users O +, O +the O +past O +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 B +memory I +and O +clinically O +significant O +levels O +of O +depression B +, O +impulsiveness B +, O +and O +sleep B +disturbance I +, O +the O +prognosis O +for O +the O +current O +generation O +of O +ecstasy O +users O +is O +a O +major O +cause O +for O +concern O +. O + +Association O +of O +common O +genetic O +variants O +of O +HOMER1 O +gene O +with O +levodopa O +adverse O +effects O +in O +Parkinson B +' I +s I +disease I +patients O +. O + +Levodopa O +is O +the O +most O +effective O +symptomatic O +therapy O +for O +Parkinson B +' I +s I +disease I +, O +but O +its O +chronic O +use O +could O +lead O +to O +chronic O +adverse O +outcomes O +, O +such O +as O +motor O +fluctuations O +, O +dyskinesia B +and O +visual B +hallucinations I +. O + +HOMER1 O +is O +a O +protein O +with O +pivotal O +function O +in O +glutamate O +transmission O +, O +which O +has O +been O +related O +to O +the O +pathogenesis O +of O +these O +complications O +. O + +This O +study O +investigates O +whether O +polymorphisms O +in O +the O +HOMER1 O +gene O +promoter O +region O +are O +associated O +with O +the O +occurrence O +of O +the O +chronic O +complications O +of O +levodopa O +therapy O +. O + +A O +total O +of O +205 O +patients O +with O +idiopathic B +Parkinson I +' I +s I +disease I +were O +investigated O +. O + +Patients O +were O +genotyped O +for O +rs4704559 O +, O +rs10942891 O +and O +rs4704560 O +by O +allelic O +discrimination O +with O +Taqman O +assays O +. O + +The O +rs4704559 O +G O +allele O +was O +associated O +with O +a O +lower O +prevalence O +of O +dyskinesia B +( O +prevalence O +ratio O +( O +PR O +) O += O +0 O +. O +615 O +, O +95 O +% O +confidence O +interval O +( O +CI O +) O +0 O +. O +426 O +- O +0 O +. O +887 O +, O +P O += O +0 O +. O +009 O +) O +and O +visual B +hallucinations I +( O +PR O += O +0 O +. O +515 O +, O +95 O +% O +CI O +0 O +. O +295 O +- O +0 O +. O +899 O +, O +P O += O +0 O +. O +020 O +) O +. O + +Our O +data O +suggest O +that O +HOMER1 O +rs4704559 O +G O +allele O +has O +a O +protective O +role O +for O +the O +development O +of O +levodopa O +adverse O +effects O +. O + +Crocin O +improves O +lipid O +dysregulation O +in O +subacute O +diazinon O +exposure O +through O +ERK1 O +/ O +2 O +pathway O +in O +rat O +liver O +. O + +INTRODUCTION O +: O +Diazinon O +Yis O +one O +of O +the O +most O +broadly O +used O +organophosphorus O +insecticides O +in O +agriculture O +. O + +It O +has O +been O +shown O +that O +exposure O +to O +diazinon O +may O +interfere O +with O +lipid O +metabolism O +. O + +Moreover O +, O +the O +hypolipidemic O +effect O +of O +crocin O +has O +been O +established O +. O + +Earlier O +studies O +revealed O +the O +major O +role O +of O +Extracellular O +signal O +- O +regulated O +kinase O +( O +ERK O +) O +pathways O +in O +low O +- O +density O +lipoprotein O +receptor O +( O +LDLr O +) O +expression O +. O + +The O +aim O +of O +this O +study O +was O +to O +evaluate O +changes O +in O +the O +regulation O +of O +lipid O +metabolism O +, O +ERK O +and O +LDLr O +expression O +in O +the O +liver O +of O +rats O +exposed O +to O +subacute O +diazinon O +. O + +Furthermore O +ameliorating O +effect O +of O +crocin O +on O +diazinon O +induced O +disturbed O +cholesterol O +homeostasis O +was O +studied O +. O + +METHODS O +: O +24 O +Rats O +were O +divided O +into O +4 O +groups O +and O +received O +following O +treatments O +for O +4 O +weeks O +; O +Corn O +oil O +( O +control O +) O +, O +diazinon O +( O +15mg O +/ O +kg O +per O +day O +, O +orally O +) O +and O +crocin O +( O +12 O +. O +5 O +and O +25mg O +/ O +kg O +per O +day O +, O +intraperitoneally O +) O +in O +combination O +with O +diazinon O +( O +15 O +mg O +/ O +kg O +) O +. O + +The O +levels O +of O +cholesterol O +, O +triglyceride O +and O +LDL O +in O +blood O +of O +rats O +were O +analyzed O +. O + +Moreover O +mRNA O +levels O +of O +LDLr O +and O +ERK1 O +/ O +2 O +as O +well O +as O +protein O +levels O +of O +total O +and O +activated O +forms O +of O +ERK1 O +/ O +2 O +in O +rat O +liver O +were O +evaluated O +by O +Western O +blotting O +and O +quantitative O +real O +time O +polymerase O +chain O +reaction O +analysis O +. O + +RESULTS O +: O +Our O +data O +showed O +that O +subacute O +exposure O +to O +diazinon O +significantly O +increased O +concentrations O +of O +cholesterol O +, O +triglyceride O +and O +LDL O +. O + +Moreover O +diazinon O +decreased O +ERK1 O +/ O +2 O +protein O +phosphorylation O +and O +LDLr O +transcript O +. O + +Crocin O +reduced O +inhibition O +of O +ERK O +activation O +and O +diazinon O +- O +induced O +hyperlipemia B +and O +increased O +levels O +of O +LDLr O +transcript O +. O + +CONCLUSIONS O +: O +Crocin O +may O +be O +considered O +as O +a O +novel O +protective O +agent O +in O +diazinon O +- O +induced O +hyperlipemia B +through O +modulating O +of O +ERK O +pathway O +and O +increase O +of O +LDLr O +expression O +. O + +GEM O +- O +P O +chemotherapy O +is O +active O +in O +the O +treatment O +of O +relapsed O +Hodgkin B +lymphoma I +. O + +Hodgkin B +lymphoma I +( O +HL B +) O +is O +a O +relatively O +chemosensitive O +malignancy B +. O + +However O +, O +for O +those O +who O +relapse O +, O +high O +- O +dose O +chemotherapy O +with O +autologous O +stem O +cell O +transplant O +is O +the O +treatment O +of O +choice O +which O +relies O +on O +adequate O +disease O +control O +with O +salvage O +chemotherapy O +. O + +Regimens O +commonly O +used O +often O +require O +inpatient O +administration O +and O +can O +be O +difficult O +to O +deliver O +due O +to O +toxicity B +. O + +Gemcitabine O +and O +cisplatin O +have O +activity O +in O +HL B +, O +non O +- O +overlapping O +toxicity B +with O +first O +- O +line O +chemotherapeutics O +, O +and O +may O +be O +delivered O +in O +an O +outpatient O +setting O +. O + +In O +this O +retrospective O +single O +- O +centre O +analysis O +, O +patients O +with O +relapsed O +or O +refractory O +HL B +treated O +with O +gemcitabine O +1 O +, O +000 O +mg O +/ O +m O +( O +2 O +) O +day O +( O +D O +) O +1 O +, O +D8 O +and O +D15 O +; O +methylprednisolone O +1 O +, O +000 O +mg O +D1 O +- O +5 O +; O +and O +cisplatin O +100 O +mg O +/ O +m O +( O +2 O +) O +D15 O +, O +every O +28 O +days O +( O +GEM O +- O +P O +) O +were O +included O +. O + +Demographic O +, O +survival O +, O +response O +and O +toxicity B +data O +were O +recorded O +. O + +Forty O +- O +one O +eligible O +patients O +were O +identified O +: O +median O +age O +27 O +. O + +One O +hundred O +and O +twenty O +- O +two O +cycles O +of O +GEM O +- O +P O +were O +administered O +in O +total O +( O +median O +3 O +cycles O +; O +range O +1 O +- O +6 O +) O +. O + +Twenty O +of O +41 O +( O +48 O +% O +) O +patients O +received O +GEM O +- O +P O +as O +second O +- O +line O +treatment O +and O +11 O +/ O +41 O +( O +27 O +% O +) O +as O +third O +- O +line O +therapy O +. O + +Overall O +response O +rate O +( O +ORR O +) O +to O +GEM O +- O +P O +in O +the O +entire O +cohort O +was O +80 O +% O +( O +complete O +response O +( O +CR O +) O +37 O +% O +, O +partial O +response O +44 O +% O +) O +with O +14 O +/ O +15 O +CR O +confirmed O +as O +a O +metabolic O +CR O +on O +PET O +and O +ORR O +of O +85 O +% O +in O +the O +20 O +second O +- O +line O +patients O +. O + +The O +most O +common O +grade O +3 O +/ O +4 O +toxicities B +were O +haematological O +: O +neutropenia B +54 O +% O +and O +thrombocytopenia B +51 O +% O +. O + +Median O +follow O +- O +up O +from O +the O +start O +of O +GEM O +- O +P O +was O +4 O +. O +5 O +years O +. O + +Following O +GEM O +- O +P O +, O +5 O +- O +year O +progression O +- O +free O +survival O +was O +46 O +% O +( O +95 O +% O +confidence O +interval O +( O +CI O +) O +, O +30 O +- O +62 O +% O +) O +and O +5 O +- O +year O +overall O +survival O +was O +59 O +% O +( O +95 O +% O +CI O +, O +43 O +- O +74 O +% O +) O +. O + +Fourteen O +of O +41 O +patients O +proceeded O +directly O +to O +autologous O +transplant O +. O + +GEM O +- O +P O +is O +a O +salvage O +chemotherapy O +with O +relatively O +high O +response O +rates O +, O +leading O +to O +successful O +transplantation O +in O +appropriate O +patients O +, O +in O +the O +treatment O +of O +relapsed O +or O +refractory O +HL B +. O + +Basal O +functioning O +of O +the O +hypothalamic O +- O +pituitary O +- O +adrenal O +( O +HPA O +) O +axis O +and O +psychological B +distress I +in O +recreational O +ecstasy O +polydrug O +users O +. O + +RATIONALE O +: O +Ecstasy O +( O +MDMA O +) O +is O +a O +psychostimulant O +drug O +which O +is O +increasingly O +associated O +with O +psychobiological O +dysfunction O +. O + +While O +some O +recent O +studies O +suggest O +acute O +changes O +in O +neuroendocrine O +function O +, O +less O +is O +known O +about O +long O +- O +term O +changes O +in O +HPA O +functionality O +in O +recreational O +users O +. O + +OBJECTIVES O +: O +The O +current O +study O +is O +the O +first O +to O +explore O +the O +effects O +of O +ecstasy O +- O +polydrug O +use O +on O +psychological B +distress I +and O +basal O +functioning O +of O +the O +HPA O +axis O +through O +assessing O +the O +secretion O +of O +cortisol O +across O +the O +diurnal O +period O +. O + +METHOD O +: O +Seventy O +- O +six O +participants O +( O +21 O +nonusers O +, O +29 O +light O +ecstasy O +- O +polydrug O +users O +, O +26 O +heavy O +ecstasy O +- O +polydrug O +users O +) O +completed O +a O +substance O +use O +inventory O +and O +measures O +of O +psychological O +distress O +at O +baseline O +, O +then O +two O +consecutive O +days O +of O +cortisol O +sampling O +( O +on O +awakening O +, O +30 O +min O +post O +awakening O +, O +between O +1400 O +and O +1600 O +hours O +and O +pre O +bedtime O +) O +. O + +On O +day O +2 O +, O +participants O +also O +attended O +the O +laboratory O +to O +complete O +a O +20 O +- O +min O +multitasking O +stressor O +. O + +RESULTS O +: O +Both O +user O +groups O +exhibited O +significantly O +greater O +levels O +of O +anxiety B +and O +depression B +than O +nonusers O +. O + +On O +day O +1 O +, O +all O +participants O +exhibited O +a O +typical O +cortisol O +profile O +, O +though O +light O +users O +had O +significantly O +elevated O +levels O +pre O +- O +bed O +. O + +On O +day O +2 O +, O +heavy O +users O +demonstrated O +elevated O +levels O +upon O +awakening O +and O +all O +ecstasy O +- O +polydrug O +users O +demonstrated O +elevated O +pre O +- O +bed O +levels O +compared O +to O +non O +- O +users O +. O + +Significant O +between O +group O +differences O +were O +also O +observed O +in O +afternoon O +cortisol O +levels O +and O +in O +overall O +cortisol O +secretion O +across O +the O +day O +. O + +CONCLUSIONS O +: O +The O +increases O +in O +anxiety B +and O +depression B +are O +in O +line O +with O +previous O +observations O +in O +recreational O +ecstasy O +- O +polydrug O +users O +. O + +Dysregulated O +diurnal O +cortisol O +may O +be O +indicative O +of O +inappropriate O +anticipation O +of O +forthcoming O +demands O +and O +hypersecretion O +may O +lead O +to O +the O +increased O +psychological O +and O +physical O +morbidity O +associated O +with O +heavy O +recreational O +use O +of O +ecstasy O +. O + +Ifosfamide O +related O +encephalopathy B +: O +the O +need O +for O +a O +timely O +EEG O +evaluation O +. O + +BACKGROUND O +: O +Ifosfamide O +is O +an O +alkylating O +agent O +useful O +in O +the O +treatment O +of O +a O +wide O +range O +of O +cancers B +including O +sarcomas B +, O +lymphoma B +, O +gynecologic B +and I +testicular I +cancers I +. O + +Encephalopathy B +has O +been O +reported O +in O +10 O +- O +40 O +% O +of O +patients O +receiving O +high O +- O +dose O +IV O +ifosfamide O +. O + +OBJECTIVE O +: O +To O +highlight O +the O +role O +of O +electroencephalogram O +( O +EEG O +) O +in O +the O +early O +detection O +and O +management O +of O +ifosfamide O +related O +encephalopathy B +. O + +METHODS O +: O +Retrospective O +chart O +review O +including O +clinical O +data O +and O +EEG O +recordings O +was O +done O +on O +five O +patients O +, O +admitted O +to O +MD O +Anderson O +Cancer B +Center O +between O +years O +2009 O +and O +2012 O +, O +who O +developed O +ifosfamide O +related O +acute O +encephalopathy B +. O + +RESULTS O +: O +All O +five O +patients O +experienced O +symptoms O +of O +encephalopathy B +soon O +after O +( O +within O +12 O +h O +- O +2 O +days O +) O +receiving O +ifosfamide O +. O + +Two O +patients O +developed O +generalized O +convulsions B +while O +one O +patient O +developed O +continuous O +non B +- I +convulsive I +status B +epilepticus I +( O +NCSE B +) O +that O +required O +ICU O +admission O +and O +intubation O +. O + +Initial O +EEG O +showed O +epileptiform B +discharges I +in O +three O +patients O +; O +run O +of O +triphasic O +waves O +in O +one O +patient O +and O +moderate O +degree O +diffuse O +generalized O +slowing O +. O + +Mixed O +pattern O +with O +the O +presence O +of O +both O +sharps O +and O +triphasic O +waves O +were O +also O +noted O +. O + +Repeat O +EEGs O +within O +24 O +_ O +h O +of O +symptom O +onset O +showed O +marked O +improvement O +that O +was O +correlated O +with O +clinical O +improvement O +. O + +CONCLUSIONS O +: O +Severity O +of O +ifosfamide O +related O +encephalopathy B +correlates O +with O +EEG O +changes O +. O + +We O +suggest O +a O +timely O +EEG O +evaluation O +for O +patients O +receiving O +ifosfamide O +who O +develop O +features O +of O +encephalopathy B +. O + +Incidence O +of O +contrast O +- O +induced O +nephropathy B +in O +hospitalised O +patients O +with O +cancer B +. O + +OBJECTIVES O +: O +To O +determine O +the O +frequency O +of O +and O +possible O +factors O +related O +to O +contrast O +- O +induced O +nephropathy B +( O +CIN B +) O +in O +hospitalised O +patients O +with O +cancer B +. O + +METHODS O +: O +Ninety O +adult O +patients O +were O +enrolled O +. O + +Patients O +with O +risk O +factors O +for O +acute B +renal I +failure I +were O +excluded O +. O + +Blood O +samples O +were O +examined O +the O +day O +before O +contrast O +- O +enhanced O +computed O +tomography O +( O +CT O +) O +and O +serially O +for O +3 O +days O +thereafter O +. O + +CIN B +was O +defined O +as O +an O +increase O +in O +serum O +creatinine O +( O +Cr O +) O +of O +0 O +. O +5 O +mg O +/ O +dl O +or O +more O +, O +or O +elevation O +of O +Cr O +to O +25 O +% O +over O +baseline O +. O + +Relationships O +between O +CIN B +and O +possible O +risk O +factors O +were O +investigated O +. O + +RESULTS O +: O +CIN O +was O +detected O +in O +18 O +/ O +90 O +( O +20 O +% O +) O +patients O +. O + +CIN B +developed O +in O +25 O +. O +5 O +% O +patients O +who O +underwent O +chemotherapy O +and O +in O +11 O +% O +patients O +who O +did O +not O +( O +P O += O +0 O +. O +1 O +) O +. O + +CIN B +more O +frequently O +developed O +in O +patients O +who O +had O +undergone O +CT O +within O +45 O +days O +after O +the O +last O +chemotherapy O +( O +P O += O +0 O +. O +005 O +) O +; O +it O +was O +also O +an O +independent O +risk O +factor O +( O +P O += O +0 O +. O +017 O +) O +. O + +CIN O +was O +significantly O +more O +after O +treatment O +with O +bevacizumab O +/ O +irinotecan O +( O +P O += O +0 O +. O +021 O +) O +and O +in O +patients O +with O +hypertension B +( O +P O += O +0 O +. O +044 O +) O +. O + +CONCLUSIONS O +: O +The O +incidence O +of O +CIN B +after O +CT O +in O +hospitalised O +oncological O +patients O +was O +20 O +% O +. O + +CIN B +developed O +4 O +. O +5 O +- O +times O +more O +frequently O +in O +patients O +with O +cancer B +who O +had O +undergone O +recent O +chemotherapy O +. O + +Hypertension B +and O +the O +combination O +of O +bevacizumab O +/ O +irinotecan O +may O +be O +additional O +risk O +factors O +for O +CIN B +development O +. O + +KEY O +POINTS O +: O +. O + +Contrast O +- O +induced O +nephropathy B +( O +CIN B +) O +is O +a O +concern O +for O +oncological O +patients O +undergoing O +CT O +. O + +. O +CIN B +occurs O +more O +often O +when O +CT O +is O +performed O +< O +45 O +days O +after O +chemotherapy O +. O + +. O +Hypertension B +and O +treatment O +with O +bevacizumab O +appear O +to O +be O +additional O +risk O +factors O +. O + +Syndrome B +of I +inappropriate I +antidiuretic I +hormone I +secretion I +associated O +with O +desvenlafaxine O +. O + +OBJECTIVE O +: O +To O +report O +a O +case O +of O +syndrome B +of I +inappropriate I +anti I +- I +diuretic I +hormone I +( O +SIADH B +) I +secretion I +associated O +with O +desvenlafaxine O +. O + +CASE O +SUMMARY O +: O +A O +57 O +- O +year O +old O +female O +with O +hyponatraemia B +. O + +Her O +medications O +included O +desvenlafaxine O +, O +and O +symptoms O +included O +nausea B +, O +anxiety B +and O +confusion B +. O + +The O +serum O +sodium O +at O +this O +time O +was O +120 O +mmol O +/ O +L O +, O +serum O +osmolality O +was O +263 O +mosmol O +/ O +kg O +, O +urine O +osmolality O +410 O +mosmol O +/ O +kg O +and O +urine O +sodium O +63 O +mmol O +/ O +L O +, O +consistent O +with O +a O +diagnosis O +of O +SIADH B +. O + +Desvenlafaxine O +was O +ceased O +and O +fluid O +restriction O +implemented O +. O + +After O +4 O +days O +the O +sodium O +increased O +to O +128 O +mmol O +/ O +L O +and O +fluid O +restriction O +was O +relaxed O +. O + +During O +her O +further O +3 O +weeks O +inpatient O +admission O +the O +serum O +sodium O +ranged O +from O +134 O +to O +137 O +mmol O +/ O +L O +during O +treatment O +with O +mirtazapine O +. O + +DISCUSSION O +: O +SIADH B +has O +been O +widely O +reported O +with O +a O +range O +of O +antidepressants O +. O + +This O +case O +report O +suggests O +that O +desvenlafaxine O +might O +cause O +clinically O +significant O +hyponatremia B +. O + +CONCLUSIONS O +: O +Clinicians O +should O +be O +aware O +of O +the O +potential O +for O +antidepressants O +to O +cause O +hyponatremia B +, O +and O +take O +appropriate O +corrective O +action O +where O +necessary O +. O + +Oxidative O +stress O +on O +cardiotoxicity B +after O +treatment O +with O +single O +and O +multiple O +doses O +of O +doxorubicin O +. O + +The O +mechanism O +of O +doxorubicin O +( O +DOX O +) O +- O +induced O +cardiotoxicity B +remains O +controversial O +. O + +Wistar O +rats O +( O +n O += O +66 O +) O +received O +DOX O +injections O +intraperitoneally O +and O +were O +randomly O +assigned O +to O +2 O +experimental O +protocols O +: O +( O +1 O +) O +rats O +were O +killed O +before O +( O +- O +24 O +h O +, O +n O += O +8 O +) O +and O +24 O +h O +after O +( O ++ O +24 O +h O +, O +n O += O +8 O +) O +a O +single O +dose O +of O +DOX O +( O +4 O +mg O +/ O +kg O +body O +weight O +) O +to O +determine O +the O +DOX O +acute O +effect O +and O +( O +2 O +) O +rats O +( O +n O += O +58 O +) O +received O +4 O +injections O +of O +DOX O +( O +4 O +mg O +/ O +kg O +body O +weight O +/ O +week O +) O +and O +were O +killed O +before O +the O +first O +injection O +( O +M0 O +) O +and O +1 O +week O +after O +each O +injection O +( O +M1 O + +M2 O +, O +M3 O +, O +and O +M4 O +) O +to O +determine O +the O +chronological O +effects O +. O + +Animals O +used O +at O +M0 O +( O +n O += O +8 O +) O +were O +also O +used O +at O +moment O +- O +24 O +h O +of O +acute O +study O +. O + +Cardiac O +total O +antioxidant O +performance O +( O +TAP O +) O +, O +DNA O +damage O +, O +and O +morphology O +analyses O +were O +carried O +out O +at O +each O +time O +point O +. O + +Single O +dose O +of O +DOX O +was O +associated O +with O +increased O +cardiac B +disarrangement I +, O +necrosis B +, O +and O +DNA O +damage O +( O +strand O +breaks O +( O +SBs O +) O +and O +oxidized O +pyrimidines O +) O +and O +decreased O +TAP O +. O + +The O +chronological O +study O +showed O +an O +effect O +of O +a O +cumulative O +dose O +on O +body O +weight O +( O +R O += O +- O +0 O +. O +99 O +, O +p O += O +0 O +. O +011 O +) O +, O +necrosis B +( O +R O += O +1 O +. O +00 O +, O +p O += O +0 O +. O +004 O +) O +, O +TAP B +( O +R O += O +0 O +. O +95 O +, O +p O += O +0 O +. O +049 O +) O +, O +and O +DNA O +SBs O +( O +R O += O +- O +0 O +. O +95 O +, O +p O += O +0 O +. O +049 O +) O +. O + +DNA O +SBs O +damage O +was O +negatively O +associated O +with O +TAP B +( O +R O += O +- O +0 O +. O +98 O +, O +p O += O +0 O +. O +018 O +) O +, O +and O +necrosis B +( O +R O += O +- O +0 O +. O +97 O +, O +p O += O +0 O +. O +027 O +) O +. O + +Our O +results O +suggest O +that O +oxidative O +damage O +is O +associated O +with O +acute O +cardiotoxicity B +induced O +by O +a O +single O +dose O +of O +DOX O +only O +. O + +Increased O +resistance O +to O +the O +oxidative O +stress O +is O +plausible O +for O +the O +multiple O +dose O +of O +DOX O +. O + +Thus O +, O +different O +mechanisms O +may O +be O +involved O +in O +acute O +toxicity B +versus O +chronic O +toxicity B +. O + +Tacrolimus O +- O +related O +seizure B +after O +pediatric O +liver O +transplantation O +- O +- O +a O +single O +- O +center O +experience O +. O + +To O +identify O +the O +risk O +factors O +for O +new O +- O +onset O +seizures B +after O +pediatric O +LT B +and O +to O +assess O +their O +clinical O +implications O +and O +long O +- O +term O +prognosis O +. O + +The O +clinical O +and O +laboratory O +data O +of O +27 O +consecutive O +children O +who O +underwent O +LT O +from O +January O +2007 O +to O +December O +2010 O +in O +our O +center O +were O +analyzed O +retrospectively O +. O + +Patients O +were O +divided O +into O +seizures B +group O +and O +a O +non O +- O +seizures B +group O +. O + +Pre O +- O +operative O +, O +intra O +- O +operative O +, O +and O +post O +- O +operative O +data O +were O +collected O +. O + +Seizures B +occurred O +in O +four O +children O +, O +an O +incidence O +of O +14 O +. O +8 O +% O +. O + +All O +exhibited O +generalized O +tonic B +- I +clonic I +seizures I +within O +the O +first O +two O +wk O +after O +LT O +. O + +Univariate O +analysis O +showed O +that O +the O +risk O +factors O +associated O +with O +seizures B +after O +pediatric O +LT O +included O +gender O +, O +pediatric O +end B +- I +stage I +liver I +disease I +score O +before O +surgery O +, O +Child O +- O +Pugh O +score O +before O +surgery O +, O +serum O +total O +bilirubin O +after O +surgery O +, O +and O +trough O +TAC O +level O +. O + +Multivariate O +analysis O +showed O +that O +trough O +TAC O +level O +was O +the O +only O +independent O +risk O +factor O +associated O +with O +the O +seizures B +. O + +All O +children O +who O +experienced O +seizures B +survived O +with O +good O +graft O +function O +and O +remained O +seizure B +- O +free O +without O +anti O +- O +epileptic B +drugs O +over O +a O +mean O +follow O +- O +up O +period O +of O +33 O +. O +7 O ++ O +14 O +. O +6 O +months O +. O + +High O +trough O +TAC O +level O +was O +the O +predominant O +factor O +that O +contributed O +to O +seizures B +in O +the O +early O +post O +- O +operative O +period O +after O +pediatric O +LT O +. O + +High O +PELD O +and O +Child O +- O +Pugh O +scores O +before O +LT O +and O +high O +post O +- O +operative O +serum O +Tbil O +may O +be O +contributory O +risk O +factors O +for O +TAC O +- O +related O +seizures B +. O + +The O +flavonoid O +apigenin O +delays O +forgetting O +of O +passive O +avoidance O +conditioning O +in O +rats O +. O + +The O +present O +experiments O +were O +performed O +to O +study O +the O +effect O +of O +the O +flavonoid O +apigenin O +( O +20 O +mg O +/ O +kg O +intraperitoneally O +( O +i O +. O +p O +. O +) O +, O +1 O +h O +before O +acquisition O +) O +, O +on O +24 O +h O +retention O +performance O +and O +forgetting O +of O +a O +step O +- O +through O +passive O +avoidance O +task O +, O +in O +young O +male O +Wistar O +rats O +. O + +There O +were O +no O +differences O +between O +saline O +- O +and O +apigenin O +- O +treated O +groups O +in O +the O +24 O +h O +retention O +trial O +. O + +Furthermore O +, O +apigenin O +did O +not O +prevent O +the O +amnesia B +induced O +by O +scopolamine O +( O +1mg O +/ O +kg O +, O +i O +. O +p O +. O +, O +30 O +min O +before O +the O +acquisition O +) O +. O + +The O +saline O +- O +and O +apigenin O +- O +treated O +rats O +that O +did O +not O +step O +through O +into O +the O +dark O +compartment O +during O +the O +cut O +- O +off O +time O +( O +540 O +s O +) O +were O +retested O +weekly O +for O +up O +to O +eight O +weeks O +. O + +In O +the O +saline O +treated O +group O +, O +the O +first O +significant O +decline O +in O +passive O +avoidance O +response O +was O +observed O +at O +four O +weeks O +, O +and O +complete O +memory B +loss I +was O +found O +five O +weeks O +after O +the O +acquisition O +of O +the O +passive O +avoidance O +task O +. O + +At O +the O +end O +of O +the O +experimental O +period O +, O +60 O +% O +of O +the O +animals O +treated O +with O +apigenin O +still O +did O +not O +step O +through O +. O + +These O +data O +suggest O +that O +1 O +) O +apigenin O +delays O +the O +long O +- O +term O +forgetting O +but O +did O +not O +modulate O +the O +24 O +h O +retention O +of O +fear O +memory O +and O +2 O +) O +the O +obtained O +beneficial O +effect O +of O +apigenin O +on O +the O +passive O +avoidance O +conditioning O +is O +mediated O +by O +mechanisms O +that O +do O +not O +implicate O +its O +action O +on O +the O +muscarinic O +cholinergic O +system O +. O + +Histamine O +antagonists O +and O +d O +- O +tubocurarine O +- O +induced O +hypotension B +in O +cardiac O +surgical O +patients O +. O + +Hemodynamic O +effects O +and O +histamine O +release O +by O +bolus O +injection O +of O +0 O +. O +35 O +mg O +/ O +kg O +of O +d O +- O +tubocurarine O +were O +studied O +in O +24 O +patients O +. O + +H1 O +- O +and O +H2 O +- O +histamine O +antagonists O +or O +placebo O +were O +given O +before O +dosing O +with O +d O +- O +tubocurarine O +in O +a O +randomized O +double O +- O +blind O +fashion O +to O +four O +groups O +: O +group O +1 O +- O +- O +placebo O +; O +group O +2 O +- O +- O +cimetidine O +, O +4 O +mg O +/ O +kg O +, O +plus O +placebo O +; O +group O +3 O +- O +- O +chlorpheniramine O +, O +0 O +. O +1 O +mg O +/ O +kg O +, O +plus O +placebo O +; O +and O +group O +4 O +- O +- O +cimetidine O +plus O +chlorpheniramine O +. O + +Histamine O +release O +occurred O +in O +most O +patients O +, O +the O +highest O +level O +2 O +minutes O +after O +d O +- O +tubocurarine O +dosing O +. O + +Group O +1 O +had O +a O +moderate O +negative O +correlation O +between O +plasma O +histamine O +change O +and O +systemic O +vascular O +resistance O +( O +r O += O +0 O +. O +58 O +; O +P O +less O +than O +0 O +. O +05 O +) O +not O +present O +in O +group O +4 O +. O + +Prior O +dosing O +with O +antagonists O +partially O +prevented O +the O +fall O +in O +systemic O +vascular O +resistance O +. O + +These O +data O +demonstrate O +that O +the O +hemodynamic O +changes O +associated O +with O +d O +- O +tubocurarine O +dosing O +are O +only O +partially O +explained O +by O +histamine O +release O +. O + +Thus O +prior O +dosing O +with O +H1 O +- O +and O +H2 O +- O +antagonists O +provides O +only O +partial O +protection O +. O + +Cholecystokinin O +- O +octapeptide O +restored O +morphine O +- O +induced O +hippocampal O +long O +- O +term O +potentiation O +impairment O +in O +rats O +. O + +Cholecystokinin O +- O +octapeptide O +( O +CCK O +- O +8 O +) O +, O +which O +is O +a O +typical O +brain O +- O +gut O +peptide O +, O +exerts O +a O +wide O +range O +of O +biological O +activities O +on O +the O +central O +nervous O +system O +. O + +We O +have O +previously O +reported O +that O +CCK O +- O +8 O +significantly O +alleviated O +morphine O +- O +induced O +amnesia B +and O +reversed O +spine O +density O +decreases O +in O +the O +CA1 O +region O +of O +the O +hippocampus O +in O +morphine O +- O +treated O +animals O +. O + +Here O +, O +we O +investigated O +the O +effects O +of O +CCK O +- O +8 O +on O +long O +- O +term O +potentiation O +( O +LTP O +) O +in O +the O +lateral O +perforant O +path O +( O +LPP O +) O +- O +granule O +cell O +synapse O +of O +rat O +dentate O +gyrus O +( O +DG O +) O +in O +acute O +saline O +or O +morphine O +- O +treated O +rats O +. O + +Population O +spikes O +( O +PS O +) O +, O +which O +were O +evoked O +by O +stimulation O +of O +the O +LPP O +, O +were O +recorded O +in O +the O +DG O +region O +. O + +Acute O +morphine O +( O +30mg O +/ O +kg O +, O +s O +. O +c O +. O +) O +treatment O +significantly O +attenuated O +hippocampal O +LTP O +and O +CCK O +- O +8 O +( O +1ug O +, O +i O +. O +c O +. O +v O +. O +) O +restored O +the O +amplitude O +of O +PS O +that O +was O +attenuated O +by O +morphine O +injection O +. O + +Furthermore O +, O +microinjection O +of O +CCK O +- O +8 O +( O +0 O +. O +1 O +and O +1ug O +, O +i O +. O +c O +. O +v O +. O +) O +also O +significantly O +augmented O +hippocampal O +LTP O +in O +saline O +- O +treated O +( O +1ml O +/ O +kg O +, O +s O +. O +c O +. O +) O +rats O +. O + +Pre O +- O +treatment O +of O +the O +CCK2 O +receptor O +antagonist O +L O +- O +365 O +, O +260 O +( O +10ug O +, O +i O +. O +c O +. O +v O +) O +reversed O +the O +effects O +of O +CCK O +- O +8 O +, O +but O +the O +CCK1 O +receptor O +antagonist O +L O +- O +364 O +, O +718 O +( O +10ug O +, O +i O +. O +c O +. O +v O +) O +did O +not O +. O + +The O +present O +results O +demonstrate O +that O +CCK O +- O +8 O +attenuates O +the O +effect O +of O +morphine O +on O +hippocampal O +LTP O +through O +CCK2 O +receptors O +and O +suggest O +an O +ameliorative O +function O +of O +CCK O +- O +8 O +on O +morphine O +- O +induced O +memory B +impairment I +. O + +Glial O +activation O +and O +post O +- O +synaptic O +neurotoxicity B +: O +the O +key O +events O +in O +Streptozotocin O +( O +ICV O +) O +induced O +memory B +impairment I +in O +rats O +. O + +In O +the O +present O +study O +the O +role O +of O +glial O +activation O +and O +post O +synaptic O +toxicity B +in O +ICV O +Streptozotocin O +( O +STZ O +) O +induced O +memory B +impaired I +rats O +was O +explored O +. O + +In O +experiment O +set O +up O +1 O +: O +Memory B +deficit I +was O +found O +in O +Morris O +water O +maze O +test O +on O +14 O +- O +16 O +days O +after O +STZ O +( O +ICV O +; O +3mg O +/ O +Kg O +) O +administration O +. O + +STZ O +causes O +increased O +expression O +of O +GFAP O +, O +CD11b O +and O +TNF O +- O +a O +indicating O +glial O +activation O +and O +neuroinflammation B +. O + +STZ O +also O +significantly O +increased O +the O +level O +of O +ROS O +, O +nitrite O +, O +Ca O +( O +2 O ++ O +) O +and O +reduced O +the O +mitochondrial O +activity O +in O +synaptosomal O +preparation O +illustrating O +free O +radical O +generation O +and O +excitotoxicity B +. O + +Increased O +expression O +and O +activity O +of O +Caspase O +- O +3 O +was O +also O +observed O +in O +STZ O +treated O +rat O +which O +specify O +apoptotic O +cell O +death O +in O +hippocampus O +and O +cortex O +. O + +STZ O +treatment O +showed O +decrease O +expression O +of O +post O +synaptic O +markers O +CaMKIIa O +and O +PSD O +- O +95 O +, O +while O +, O +expression O +of O +pre O +synaptic O +markers O +( O +synaptophysin O +and O +SNAP O +- O +25 O +) O +remains O +unaltered O +indicating O +selective O +post O +synaptic O +neurotoxicity B +. O + +Oral O +treatment O +with O +Memantine O +( O +10mg O +/ O +kg O +) O +and O +Ibuprofen O +( O +50 O +mg O +/ O +kg O +) O +daily O +for O +13 O +days O +attenuated O +STZ O +induced O +glial O +activation O +, O +apoptotic O +cell O +death O +and O +post O +synaptic O +neurotoxicity B +in O +rat O +brain O +. O + +Further O +, O +in O +experiment O +set O +up O +2 O +: O +where O +memory O +function O +was O +not O +affected O +i O +. O +e O +. O +7 O +- O +9 O +days O +after O +STZ O +treatment O +. O + +The O +level O +of O +GFAP O +, O +CD11b O +, O +TNF O +- O +a O +, O +ROS O +and O +nitrite O +levels O +were O +increased O +. O + +On O +the O +other O +hand O +, O +apoptotic O +marker O +, O +synaptic O +markers O +, O +mitochondrial O +activity O +and O +Ca O +( O +2 O ++ O +) O +levels O +remained O +unaffected O +. O + +Collective O +data O +indicates O +that O +neuroinflammatory O +process O +and O +oxidative O +stress O +occurs O +earlier O +to O +apoptosis O +and O +does O +not O +affect O +memory O +function O +. O + +Present O +study O +clearly O +suggests O +that O +glial O +activation O +and O +post O +synaptic O +neurotoxicity B +are O +the O +key O +factors O +in O +STZ O +induced O +memory B +impairment I +and O +neuronal O +cell O +death O +. O + +Comparison O +of O +effects O +of O +isotonic O +sodium O +chloride O +with O +diltiazem O +in O +prevention O +of O +contrast O +- O +induced O +nephropathy B +. O + +INTRODUCTION O +AND O +OBJECTIVE O +: O +Contrast O +- O +induced O +nephropathy B +( O +CIN B +) O +significantly O +increases O +the O +morbidity O +and O +mortality O +of O +patients O +. O + +The O +aim O +of O +this O +study O +is O +to O +investigate O +and O +compare O +the O +protective O +effects O +of O +isotonic O +sodium O +chloride O +with O +sodium O +bicarbonate O +infusion O +and O +isotonic O +sodium O +chloride O +infusion O +with O +diltiazem O +, O +a O +calcium O +channel O +blocker O +, O +in O +preventing O +CIN B +. O + +MATERIALS O +AND O +METHODS O +: O +Our O +study O +included O +patients O +who O +were O +administered O +30 O +- O +60 O +mL O +of O +iodinated O +contrast O +agent O +for O +percutaneous O +coronary O +angiography O +( O +PCAG O +) O +, O +all O +with O +creatinine O +values O +between O +1 O +. O +1 O +and O +3 O +. O +1 O +mg O +/ O +dL O +. O + +Patients O +were O +divided O +into O +three O +groups O +and O +each O +group O +had O +20 O +patients O +. O + +The O +first O +group O +of O +patients O +was O +administered O +isotonic O +sodium O +chloride O +; O +the O +second O +group O +was O +administered O +a O +solution O +that O +of O +5 O +% O +dextrose O +and O +sodium O +bicarbonate O +, O +while O +the O +third O +group O +was O +administered O +isotonic O +sodium O +chloride O +before O +and O +after O +the O +contrast O +injection O +. O + +The O +third O +group O +received O +an O +additional O +injection O +of O +diltiazem O +the O +day O +before O +and O +first O +2 O +days O +after O +the O +contrast O +injection O +. O + +All O +of O +the O +patients O +' O +plasma O +blood O +urea O +nitrogen O +( O +BUN O +) O +and O +creatinine O +levels O +were O +measured O +on O +the O +second O +and O +seventh O +day O +after O +the O +administration O +of O +intravenous O +contrast O +material O +. O + +RESULTS O +: O +The O +basal O +creatinine O +levels O +were O +similar O +for O +all O +three O +groups O +( O +p O +> O +0 O +. O +05 O +) O +. O + +Among O +a O +total O +of O +60 O +patients O +included O +in O +the O +study O +, O +16 O +patients O +developed O +acute B +renal I +failure I +( O +ARF B +) O +on O +the O +second O +day O +after O +contrast O +material O +was O +injected O +( O +26 O +. O +6 O +% O +) O +. O + +The O +number O +of O +patients O +who O +developed O +ARF B +on O +the O +second O +day O +after O +the O +injection O +in O +the O +first O +group O +was O +five O +( O +25 O +% O +) O +, O +in O +the O +second O +group O +was O +six O +( O +30 O +% O +) O +and O +the O +third O +group O +was O +five O +( O +25 O +% O +) O +( O +p O +> O +0 O +. O +05 O +) O +. O + +CONCLUSION O +: O +There O +was O +no O +significant O +difference O +between O +isotonic O +sodium O +chloride O +, O +sodium O +bicarbonate O +and O +isotonic O +sodium O +chloride O +with O +diltiazem O +application O +in O +prevention O +of O +CIN B +. O + +Neurocognitive O +and O +neuroradiologic O +central O +nervous O +system O +late O +effects O +in O +children O +treated O +on O +Pediatric O +Oncology O +Group O +( O +POG O +) O +P9605 O +( O +standard O +risk O +) O +and O +P9201 O +( O +lesser O +risk O +) O +acute B +lymphoblastic I +leukemia I +protocols O +( O +ACCL0131 O +) O +: O +a O +methotrexate O +consequence O +? O + +A O +report O +from O +the O +Children O +' O +s O +Oncology O +Group O +. O + +Concerns O +about O +long O +- O +term O +methotrexate O +( O +MTX O +) O +neurotoxicity B +in O +the O +1990s O +led O +to O +modifications O +in O +intrathecal O +( O +IT O +) O +therapy O +, O +leucovorin O +rescue O +, O +and O +frequency O +of O +systemic O +MTX O +administration O +in O +children O +with O +acute B +lymphoblastic I +leukemia I +. O + +In O +this O +study O +, O +neurocognitive O +outcomes O +and O +neuroradiologic O +evidence O +of O +leukoencephalopathy B +were O +compared O +in O +children O +treated O +with O +intense O +central O +nervous O +system O +( O +CNS O +) O +- O +directed O +therapy O +( O +P9605 O +) O +versus O +those O +receiving O +fewer O +CNS O +- O +directed O +treatment O +days O +during O +intensive O +consolidation O +( O +P9201 O +) O +. O + +A O +total O +of O +66 O +children O +from O +16 O +Pediatric O +Oncology O +Group O +institutions O +with O +" O +standard O +- O +risk O +" O +acute B +lymphoblastic I +leukemia I +, O +1 O +. O +00 O +to O +9 O +. O +99 O +years O +at O +diagnosis O +, O +without O +evidence O +of O +CNS B +leukemia I +at O +diagnosis O +were O +enrolled O +on O +ACCL0131 O +: O +28 O +from O +P9201 O +and O +38 O +from O +P9605 O +. O + +Magnetic O +resonance O +imaging O +scans O +and O +standard O +neuropsychological O +tests O +were O +performed O +> O +2 O +. O +6 O +years O +after O +the O +end O +of O +treatment O +. O + +Significantly O +more O +P9605 O +patients O +developed O +leukoencephalopathy B +compared O +with O +P9201 O +patients O +( O +68 O +% O +, O +95 O +% O +confidence O +interval O +49 O +% O +- O +83 O +% O +vs O +. O +22 O +% O +, O +95 O +% O +confidence O +interval O +5 O +% O +- O +44 O +% O +; O +P O += O +0 O +. O +001 O +) O +identified O +as O +late O +as O +7 O +. O +7 O +years O +after O +the O +end O +of O +treatment O +. O + +Overall O +, O +40 O +% O +of O +patients O +scored O +< O +85 O +on O +either O +Verbal O +or O +Performance O +IQ O +. O + +Children O +on O +both O +studies O +had O +significant O +attention B +problems I +, O +but O +P9605 O +children O +scored O +below O +average O +on O +more O +neurocognitive O +measures O +than O +those O +treated O +on O +P9201 O +( O +82 O +% O +, O +14 O +/ O +17 O +measures O +vs O +. O +24 O +% O +, O +4 O +/ O +17 O +measures O +) O +. O + +This O +supports O +ongoing O +concerns O +about O +intensive O +MTX O +exposure O +as O +a O +major O +contributor O +to O +CNS O +late O +effects O +. O + +Tranexamic O +acid O +overdosage B +- O +induced O +generalized O +seizure B +in O +renal B +failure I +. O + +We O +report O +a O +45 O +- O +year O +- O +old O +lady O +with O +chronic B +kidney I +disease I +stage O +4 O +due O +to O +chronic B +tubulointerstial I +disease I +. O + +She O +was O +admitted O +to O +our O +center O +for O +severe O +anemia B +due O +to O +menorrhagia B +and O +deterioration B +of I +renal I +function I +. O + +She O +was O +infused O +three O +units O +of O +packed O +cells O +during O +a O +session O +of O +hemodialysis O +. O + +Tranexamic O +acid O +( O +TNA O +) O +1 O +g O +8 O +- O +hourly O +was O +administered O +to O +her O +to O +control O +bleeding B +per O +vaginum O +. O + +Two O +hours O +after O +the O +sixth O +dose O +of O +TNA O +, O +she O +had O +an O +episode O +of O +generalized O +tonic O +clonic I +convulsions I +. O + +TNA O +was O +discontinued O +. O + +Investigations O +of O +the O +patient O +revealed O +no O +biochemical O +or O +structural O +central B +nervous I +system I +abnormalities I +that O +could O +have O +provoked O +the O +convulsions B +. O + +She O +did O +not O +require O +any O +further O +dialytic O +support O +. O + +She O +had O +no O +further O +episodes O +of O +convulsion B +till O +dis O +- O +charge O +and O +during O +the O +two O +months O +of O +follow O +- O +up O +. O + +Thus O +, O +the O +precipitating O +cause O +of O +convulsions B +was O +believed O +to O +be O +an O +overdose B +of I +TNA O +. O + +Pre O +- O +treatment O +of O +bupivacaine O +- O +induced O +cardiovascular B +depression I +using O +different O +lipid O +formulations O +of O +propofol O +. O + +BACKGROUND O +: O +Pre O +- O +treatment O +with O +lipid O +emulsions O +has O +been O +shown O +to O +increase O +lethal O +doses O +of O +bupivacaine O +, O +and O +the O +lipid O +content O +of O +propofol O +may O +alleviate O +bupivacaine O +- O +induced O +cardiotoxicity B +. O + +The O +aim O +of O +this O +study O +is O +to O +investigate O +the O +effects O +of O +propofol O +in O +intralipid O +or O +medialipid O +emulsions O +on O +bupivacaine O +- O +induced O +cardiotoxicity B +. O + +METHODS O +: O +Rats O +were O +anaesthetised O +with O +ketamine O +and O +were O +given O +0 O +. O +5 O +mg O +/ O +kg O +/ O +min O +propofol O +in O +intralipid O +( O +Group O +P O +) O +, O +propofol O +in O +medialipid O +( O +Group O +L O +) O +, O +or O +saline O +( O +Group O +C O +) O +over O +20 O +min O +. O + +Thereafter O +, O +2 O +mg O +/ O +kg O +/ O +min O +bupivacaine O +0 O +. O +5 O +% O +was O +infused O +. O + +We O +recorded O +time O +to O +first O +dysrhythmia B +occurrence O +, O +respective O +times O +to O +25 O +% O +and O +50 O +% O +reduction O +of O +the O +heart O +rate O +( O +HR O +) O +and O +mean O +arterial O +pressure O +, O +and O +time O +to O +asystole B +and O +total O +amount O +of O +bupivacaine O +consumption O +. O + +Blood O +and O +tissue O +samples O +were O +collected O +following O +asystole B +. O + +RESULTS O +: O +The O +time O +to O +first O +dysrhythmia B +occurrence O +, O +time O +to O +25 O +% O +and O +50 O +% O +reductions O +in O +HR O +, O +and O +time O +to O +asystole B +were O +longer O +in O +Group O +P O +than O +the O +other O +groups O +. O + +The O +cumulative O +bupivacaine O +dose O +given O +at O +those O +time O +points O +was O +higher O +in O +Group O +P O +. O +Plasma O +bupivacaine O +levels O +were O +significantly O +lower O +in O +Group O +P O +than O +in O +Group O +C O +. O +Bupivacaine O +levels O +in O +the O +brain O +and O +heart O +were O +significantly O +lower O +in O +Group O +P O +and O +Group O +L O +than O +in O +Group O +C O +. O + +CONCLUSION O +: O +We O +conclude O +that O +pre O +- O +treatment O +with O +propofol O +in O +intralipid O +, O +compared O +with O +propofol O +in O +medialipid O +or O +saline O +, O +delayed O +the O +onset O +of O +bupivacaine O +- O +induced O +cardiotoxic B +effects O +as O +well O +as O +reduced O +plasma O +bupivacaine O +levels O +. O + +Further O +studies O +are O +needed O +to O +explore O +tissue O +bupivacaine O +levels O +of O +propofol O +in O +medialipid O +and O +adapt O +these O +results O +to O +clinical O +practice O +. O + +Drug O +- O +Induced O +Acute B +Liver I +Injury I +Within O +12 O +Hours O +After O +Fluvastatin O +Therapy O +. O + +Although O +statins O +are O +generally O +well O +- O +tolerated O +drugs O +, O +recent O +cases O +of O +drug O +- O +induced O +liver B +injury I +associated O +with O +their O +use O +have O +been O +reported O +. O + +A O +52 O +- O +year O +- O +old O +Chinese O +man O +reported O +with O +liver B +damage I +, O +which O +appeared O +12 O +hours O +after O +beginning O +treatment O +with O +fluvastatin O +. O + +Patient O +presented O +with O +complaints O +of O +increasing O +nausea B +, O +anorexia B +, O +and O +upper B +abdominal I +pain I +. O + +His O +laboratory O +values O +showed O +elevated O +creatine O +kinase O +and O +transaminases O +. O + +Testing O +for O +autoantibodies O +was O +also O +negative O +. O + +The O +liver O +biochemistries O +eventually O +normalized O +within O +3 O +weeks O +of O +stopping O +the O +fluvastatin O +. O + +Therefore O +, O +when O +prescribing O +statins O +, O +the O +possibility O +of O +hepatic B +damage I +should O +be O +taken O +into O +account O +. O + +Fluconazole O +associated O +agranulocytosis B +and O +thrombocytopenia B +. O + +CASE O +: O +We O +describe O +a O +second O +case O +of O +fluconazole O +associated O +agranulocytosis B +with O +thrombocytopenia B +and O +recovery O +upon O +discontinuation O +of O +therapy O +. O + +The O +patient O +began O +to O +have O +changes O +in O +white O +blood O +cells O +and O +platelets O +within O +48 O +h O +of O +administration O +of O +fluconazole O +and O +began O +to O +recover O +with O +48 O +h O +of O +discontinuation O +. O + +This O +case O +highlights O +that O +drug O +- O +induced O +blood B +dyscrasias I +can O +occur O +unexpectedly O +as O +a O +result O +of O +treatment O +with O +a O +commonly O +used O +drug O +thought O +to O +be O +" O +safe O +" O +. O + +CONCLUSION O +: O +According O +to O +Naranjo O +' O +s O +algorithm O +the O +likelihood O +that O +our O +patient O +' O +s O +agranulocytosis B +and O +thrombocytopenia B +occurred O +as O +a O +result O +of O +therapy O +with O +fluconazole O +is O +probable O +, O +with O +a O +total O +of O +six O +points O +. O + +We O +feel O +that O +the O +weight O +of O +the O +overall O +evidence O +of O +this O +evidence O +is O +strong O +. O + +In O +particular O +the O +temporal O +relationship O +of O +bone B +marrow I +suppression I +to O +the O +initiation O +of O +fluconazole O +and O +the O +abatement O +of O +symptoms O +that O +rapidly O +reversed O +immediately O +following O +discontinuation O +. O + +Two O +- O +dimensional O +speckle O +tracking O +echocardiography O +combined O +with O +high O +- O +sensitive O +cardiac O +troponin O +T O +in O +early O +detection O +and O +prediction O +of O +cardiotoxicity B +during O +epirubicine O +- O +based O +chemotherapy O +. O + +AIMS O +: O +To O +investigate O +whether O +alterations O +of O +myocardial O +strain O +and O +high O +- O +sensitive O +cardiac O +troponin O +T O +( O +cTnT O +) O +could O +predict O +future O +cardiac B +dysfunction I +in O +patients O +after O +epirubicin O +exposure O +. O + +METHODS O +: O +Seventy O +- O +five O +patients O +with O +non B +- I +Hodgkin I +lymphoma I +treated O +with O +epirubicin O +were O +studied O +. O + +Blood O +collection O +and O +echocardiography O +were O +performed O +at O +baseline O +, O +1 O +day O +after O +the O +third O +cycle O +, O +and O +1 O +day O +after O +completion O +of O +chemotherapy O +. O + +Patients O +were O +studied O +using O +echocardiography O +during O +follow O +- O +up O +. O + +Global O +longitudinal O +( O +GLS O +) O +, O +circumferential O +( O +GCS O +) O +, O +and O +radial O +strain O +( O +GRS O +) O +were O +calculated O +using O +speckle O +tracking O +echocardiography O +. O + +Left O +ventricular O +ejection O +fraction O +was O +analysed O +by O +real O +- O +time O +3D O +echocardiography O +. O + +Cardiotoxicity B +was O +defined O +as O +a O +reduction O +of O +the O +LVEF O +of O +> O +5 O +% O +to O +< O +55 O +% O +with O +symptoms O +of O +heart B +failure I +or O +an O +asymptomatic O +reduction O +of O +the O +LVEF O +of O +> O +10 O +% O +to O +< O +55 O +% O +. O + +RESULTS O +: O +Fourteen O +patients O +( O +18 O +. O +67 O +% O +) O +developed O +cardiotoxicity B +after O +treatment O +. O + +GLS O +( O +- O +18 O +. O +48 O ++ O +1 O +. O +72 O +% O +vs O +. O +- O +15 O +. O +96 O ++ O +1 O +. O +6 O +% O +) O +, O +GCS O +( O +- O +20 O +. O +93 O ++ O +2 O +. O +86 O +% O +vs O +. O +- O +19 O +. O +20 O ++ O +3 O +. O +21 O +% O +) O +, O +and O +GRS O +( O +39 O +. O +23 O ++ O +6 O +. O +44 O +% O +vs O +. O +34 O +. O +98 O ++ O +6 O +. O +2 O +% O +) O +were O +markedly O +reduced O +and O +cTnT O +was O +elevated O +from O +0 O +. O +0010 O ++ O +0 O +. O +0020 O +to O +0 O +. O +0073 O ++ O +0 O +. O +0038 O +ng O +/ O +mL O +( O +P O +all O +< O +0 O +. O +01 O +) O +at O +the O +completion O +of O +chemotherapy O +compared O +with O + +baseline O +values O +. O + +A O +> O +15 O +. O +9 O +% O +decrease O +in O +GLS O +[ O +sensitivity O +, O +86 O +% O +; O +specificity O +, O +75 O +% O +; O +area O +under O +the O +curve O +( O +AUC O +) O += O +0 O +. O +815 O +; O +P O += O +0 O +. O +001 O +] O +and O +a O +> O +0 O +. O +004 O +ng O +/ O +mL O +elevation O +in O +cTnT O +( O +sensitivity O +, O +79 O +% O +; O +specificity O +, O +64 O +% O +; O +AUC O += O +0 O +. O +757 O +; O +P O += O +0 O +. O +005 O +) O +from O +baseline O +to O +the O +third O +cycle O +of O +chemotherapy O +predicted O +later O +cardiotoxicity B +. O + +The O +decrease O +in O +GLS O +remained O +the O +only O +independent O +predictor O +of O +cardiotoxicity B +( O +P O += O +0 O +. O +000 O +) O +. O + +CONCLUSIONS O +: O +GLS O +combined O +with O +cTnT O +may O +provide O +a O +reliable O +and O +non O +- O +invasive O +method O +to O +predict O +cardiac B +dysfunction I +in O +patients O +receiving O +anthracycline O +- O +based O +chemotherapy O +. O + +Prevention O +of O +etomidate O +- O +induced O +myoclonus B +: O +which O +is O +superior O +: O +Fentanyl O +, O +midazolam O +, O +or O +a O +combination O +? O + +A O +Retrospective O +comparative O +study O +. O + +BACKGROUND O +: O +In O +this O +retrospective O +comparative O +study O +, O +we O +aimed O +to O +compare O +the O +effectiveness O +of O +fentanyl O +, O +midazolam O +, O +and O +a O +combination O +of O +fentanyl O +and O +midazolam O +to O +prevent O +etomidate O +- O +induced O +myoclonus B +. O + +MATERIAL O +AND O +METHODS O +: O +This O +study O +was O +performed O +based O +on O +anesthesia O +records O +. O + +Depending O +on O +the O +drugs O +that O +would O +be O +given O +before O +the O +induction O +of O +anesthesia O +with O +etomidate O +, O +the O +patients O +were O +separated O +into O +4 O +groups O +: O +no O +pretreatment O +( O +Group O +NP O +) O +, O +fentanyl O +1 O +ug O +. O +kg O +- O +1 O +( O +Group O +F O +) O +, O +midazolam O +0 O +. O +03 O +mg O +. O +kg O +- O +1 O +( O +Group O +M O +) O +, O +and O +midazolam O +0 O +. O +015 O +mg O +. O +kg O +- O +1 O ++ O +fentanyl O +0 O +. O +5 O +ug O +. O +kg O +- O +1 O +( O +Group O +FM O +) O +. O + +Patients O +who O +received O +the O +same O +anesthetic O +procedure O +were O +selected O +: O +2 O +minutes O +after O +intravenous O +injections O +of O +the O +pretreatment O +drugs O +, O +anesthesia O +is O +induced O +with O +0 O +. O +3 O +mg O +. O +kg O +- O +1 O +etomidate O +injected O +intravenously O +over O +a O +period O +of O +20 O +- O +30 O +seconds O +. O + +Myoclonic B +movements I +are O +evaluated O +, O +which O +were O +observed O +and O +graded O +according O +to O +clinical O +severity O +during O +the O +2 O +minutes O +after O +etomidate O +injection O +. O + +The O +severity O +of O +pain B +due O +to O +etomidate O +injection O +, O +mean O +arterial O +pressure O +, O +heart O +rate O +, O +and O +adverse O +effects O +were O +also O +evaluated O +. O + +RESULTS O +: O +Study O +results O +showed O +that O +myoclonus B +incidence O +was O +85 O +% O +, O +40 O +% O +, O +70 O +% O +, O +and O +25 O +% O +in O +Group O +NP O +, O +Group O +F O +, O +Group O +M O +, O +and O +Group O +FM O +, O +respectively O +, O +and O +were O +significantly O +lower O +in O +Group O +F O +and O +Group O +FM O +. O + +CONCLUSIONS O +: O +We O +conclude O +that O +pretreatment O +with O +fentanyl O +or O +combination O +of O +fentanyl O +and O +midazolam O +was O +effective O +in O +preventing O +etomidate O +- O +induced O +myoclonus B +. O + +Convulsant O +effect O +of O +lindane O +and O +regional O +brain O +concentration O +of O +GABA O +and O +dopamine O +. O + +Lindane O +( O +gamma O +- O +hexachlorocyclohexane O +) O +is O +an O +organochlorine O +insecticide O +with O +known O +neurotoxic B +effects O +. O + +Its O +mechanism O +of O +action O +is O +not O +well O +understood O +although O +it O +has O +been O +proposed O +that O +lindane O +acts O +as O +a O +non O +- O +competitive O +antagonist O +at O +the O +gamma O +- O +aminobutyric O +acid O +( O +GABA O +) O +- O +A O +receptor O +. O + +We O +studied O +the O +effect O +of O +lindane O +( O +150 O +mg O +/ O +kg O +) O +on O +the O +GABAergic O +and O +dopaminergic O +systems O +by O +measuring O +the O +concentration O +of O +GABA O +, O +dopamine O +and O +its O +metabolites O +in O +7 O +brain O +areas O +at O +the O +onset O +of O +seizures B +. O + +All O +animals O +suffered O +tonic B +convulsions B +at O +18 O +. O +3 O ++ O +/ O +- O +1 O +. O +4 O +min O +after O +lindane O +administration O +. O + +The O +concentration O +of O +GABA O +was O +only O +slightly O +but O +significantly O +decreased O +in O +the O +colliculi O +without O +modifications O +in O +the O +other O +areas O +. O + +The O +concentration O +of O +dopamine O +was O +increased O +in O +the O +mesencephalon O +and O +that O +of O +its O +metabolite O +DOPAC O +was O +also O +increased O +in O +the O +mesencephalon O +and O +the O +striatum O +. O + +Cholestatic O +presentation O +of O +yellow O +phosphorus I +poisoning I +. O + +Yellow O +phosphorus O +, O +a O +component O +of O +certain O +pesticide O +pastes O +and O +fireworks O +, O +is O +well O +known O +to O +cause O +hepatotoxicity B +. O + +Poisoning B +with O +yellow O +phosphorus O +classically O +manifests O +with O +acute O +hepatitis B +leading O +to O +acute B +liver I +failure I +which O +may O +need O +liver O +transplantation O +. O + +We O +present O +a O +case O +of O +yellow O +phosphorus O +poisoning B +in O +which O +a O +patient O +presented O +with O +florid O +clinical O +features O +of O +cholestasis B +highlighting O +the O +fact O +that O +cholestasis B +can O +rarely O +be O +a O +presenting O +feature O +of O +yellow O +phosphorus O +hepatotoxicity B +. O + +Vasovagal O +syncope B +and O +severe O +bradycardia B +following O +intranasal O +dexmedetomidine O +for O +pediatric O +procedural O +sedation O +. O + +We O +report O +syncope B +and O +bradycardia B +in O +an O +11 O +- O +year O +- O +old O +girl O +following O +administration O +of O +intranasal O +dexmedetomidine O +for O +sedation O +for O +a O +voiding O +cystourethrogram O +. O + +Following O +successful O +completion O +of O +VCUG O +and O +a O +60 O +- O +min O +recovery O +period O +, O +the O +patient O +' O +s O +level O +of O +consciousness O +and O +vital O +signs O +returned O +to O +presedation O +levels O +. O + +Upon O +leaving O +the O +sedation O +area O +, O +the O +patient O +collapsed O +, O +with O +no O +apparent O +inciting O +event O +. O + +The O +patient O +quickly O +regained O +consciousness O +and O +no O +injury O +occurred O +. O + +The O +primary O +abnormality O +found O +was O +persistent O +bradycardia B +, O +and O +she O +was O +admitted O +to O +the O +hospital O +for O +telemetric O +observation O +. O + +The O +bradycardia B +lasted O +~ O +2 O +h O +, O +and O +further O +cardiac O +workup O +revealed O +no O +underlying O +abnormality O +. O + +Unanticipated O +and O +previously O +unreported O +outcomes O +may O +be O +witnessed O +as O +we O +expand O +the O +use O +of O +certain O +sedatives O +to O +alternative O +routes O +of O +administration O +. O + +Paradoxical O +severe O +agitation B +induced O +by O +add O +- O +on O +high O +- O +doses O +quetiapine O +in O +schizo B +- I +affective I +disorder I +. O + +We O +report O +the O +case O +of O +a O +35 O +- O +year O +- O +old O +patient O +suffering O +from O +schizo B +- I +affective I +disorder I +since O +the O +age O +of O +19 O +years O +, O +treated O +by O +a O +combination O +of O +first O +- O +generation O +antipsychotics O +, O +zuclopenthixol O +( O +100 O +mg O +/ O +day O +) O +and O +lithium O +( O +1200 O +mg O +/ O +day O +) O +( O +serum O +lithium O += O +0 O +. O +85 O +mEq O +/ O +l O +) O +. O + +This O +patient O +had O +no O +associated O +personality B +disorder I +( O +particularly O +no O +antisocial B +disorder I +) O +and O +no O +substance B +abuse I +disorder I +. O + +Within O +the O +48 O +h O +following O +the O +gradual O +introduction O +of O +quetiapine O +( O +up O +to O +600 O +mg O +/ O +day O +) O +, O +the O +patient O +presented O +severe O +agitation B +without O +an O +environmental O +explanation O +, O +contrasting O +with O +the O +absence O +of O +a O +history O +of O +aggressiveness B +or O +personality B +disorder I +. O + +The O +diagnoses O +of O +manic B +shift I +and O +akathisia B +were O +dismissed O +. O + +The O +withdrawal O +and O +the O +gradual O +reintroduction O +of O +quetiapine O +2 O +weeks O +later O +, O +which O +led O +to O +another O +severe O +agitation B +, O +enabled O +us O +to O +attribute O +the O +agitation B +specifically O +to O +quetiapine O +. O + +Antioxidant O +effects O +of O +bovine O +lactoferrin O +on O +dexamethasone O +- O +induced O +hypertension B +in O +rat O +. O + +Dexamethasone O +- O +( O +Dex O +- O +) O +induced O +hypertension B +is O +associated O +with O +enhanced O +oxidative O +stress O +. O + +Lactoferrin O +( O +LF O +) O +is O +an O +iron O +- O +binding O +glycoprotein O +with O +antihypertensive O +properties O +. O + +In O +this O +study O +, O +we O +investigated O +the O +effect O +of O +chronic O +administration O +of O +LF O +on O +oxidative O +stress O +and O +hypertension B +upon O +Dex O +administration O +. O + +Male O +Wistar O +rats O +were O +treated O +by O +Dex O +( O +30 O +u O +g O +/ O +kg O +/ O +day O +subcutaneously O +) O +or O +saline O +for O +14 O +days O +. O + +Oral O +bovine O +LF O +( O +30 O +, O +100 O +, O +300 O +mg O +/ O +kg O +) O +was O +given O +from O +day O +8 O +to O +14 O +in O +a O +reversal O +study O +. O + +In O +a O +prevention O +study O +, O +rats O +received O +4 O +days O +of O +LF O +treatment O +followed O +by O +Dex O +and O +continued O +during O +the O +test O +period O +. O + +Systolic O +blood O +pressure O +( O +SBP O +) O +was O +measured O +using O +tail O +- O +cuff O +method O +. O + +Thymus O +weight O +was O +used O +as O +a O +marker O +of O +glucocorticoid O +activity O +. O + +Plasma O +hydrogen O +peroxide O +( O +H2O2 O +) O +concentration O +and O +ferric O +reducing O +antioxidant O +power O +( O +FRAP O +) O +value O +were O +determined O +. O + +Dexamethasone O +significantly O +increased O +SBP O +and O +plasma O +H2O2 O +level O +and O +decreased O +thymus O +and I +body O +weights O +. O + +LF O +lowered O +( O +P O +< O +0 O +. O +01 O +) O +and O +dose O +dependently O +prevented O +( O +P O +< O +0 O +. O +001 O +) O +Dex O +- O +induced O +hypertension B +. O + +LF O +prevented O +body O +weight B +loss I +and O +significantly O +reduced O +the O +elevated O +plasma O +H2O2 O +and O +increased O +FRAP O +values O +. O + +Chronic O +administration O +of O +LF O +strongly O +reduced O +the O +blood O +pressure O +and O +production O +of O +ROS O +and O +improved O +antioxidant O +capacity O +in O +Dex O +- O +induced O +hypertension B +, O +suggesting O +the O +role O +of O +inhibition O +of O +oxidative O +stress O +as O +another O +mechanism O +of O +antihypertensive O +action O +of O +LF O +. O + +The O +association O +between O +tranexamic O +acid O +and O +convulsive B +seizures I +after O +cardiac O +surgery O +: O +a O +multivariate O +analysis O +in O +11 O +529 O +patients O +. O + +Because O +of O +a O +lack O +of O +contemporary O +data O +regarding O +seizures B +after O +cardiac O +surgery O +, O +we O +undertook O +a O +retrospective O +analysis O +of O +prospectively O +collected O +data O +from O +11 O +529 O +patients O +in O +whom O +cardiopulmonary O +bypass O +was O +used O +from O +January O +2004 O +to O +December O +2010 O +. O + +A O +convulsive B +seizure I +was O +defined O +as O +a O +transient O +episode O +of O +disturbed B +brain I +function I +characterised O +by O +abnormal B +involuntary I +motor I +movements I +. O + +Multivariate O +regression O +analysis O +was O +performed O +to O +identify O +independent O +predictors O +of O +postoperative B +seizures I +. O + +A O +total O +of O +100 O +( O +0 O +. O +9 O +% O +) O +patients O +developed O +postoperative B +convulsive I +seizures I +. O + +Generalised O +and O +focal O +seizures B +were O +identified O +in O +68 O +and O +32 O +patients O +, O +respectively O +. O + +The O +median O +( O +IQR O +[ O +range O +] O +) O +time O +after O +surgery O +when O +the O +seizure B +occurred O +was O +7 O +( O +6 O +- O +12 O +[ O +1 O +- O +216 O +] O +) O +h O +and O +8 O +( O +6 O +- O +11 O +[ O +4 O +- O +18 O +] O +) O +h O +, O +respectively O +. O + +Epileptiform B +findings O +on O +electroencephalography O +were O +seen O +in O +19 O +patients O +. O + +Independent O +predictors O +of O +postoperative B +seizures B +included O +age O +, O +female O +sex O +, O +redo O +cardiac O +surgery O +, O +calcification B +of I +ascending I +aorta I +, O +congestive B +heart I +failure I +, O +deep O +hypothermic B +circulatory I +arrest I +, O +duration O +of O +aortic O +cross O +- O +clamp O +and O +tranexamic O +acid O +. O + +When O +tested O +in O +a O +multivariate O +regression O +analysis O +, O +tranexamic O +acid O +was O +a O +strong O +independent O +predictor O +of O +seizures B +( O +OR O +14 O +. O +3 O +, O +95 O +% O +CI O +5 O +. O +5 O +- O +36 O +. O +7 O +; O +p O +< O +0 O +. O +001 O +) O +. O + +Patients O +with O +convulsive B +seizures I +had O +2 O +. O +5 O +times O +higher O +in O +- O +hospital O +mortality O +rates O +and O +twice O +the O +length O +of O +hospital O +stay O +compared O +with O +patients O +without O +convulsive B +seizures I +. O + +Mean O +( O +IQR O +[ O +range O +] O +) O +length O +of O +stay O +in O +the O +intensive O +care O +unit O +was O +115 O +( O +49 O +- O +228 O +[ O +32 O +- O +481 O +] O +) O +h O +in O +patients O +with O +convulsive B +seizures I +compared O +with O +26 O +( O +22 O +- O +69 O +[ O +14 O +- O +1080 O +] O +) O +h O +in O +patients O +without O +seizures B +( O +p O +< O +0 O +. O +001 O +) O +. O + +Convulsive B +seizures I +are O +a O +serious O +postoperative O +complication O +after O +cardiac O +surgery O +. O + +As O +tranexamic O +acid O +is O +the O +only O +modifiable O +factor O +, O +its O +administration O +, O +particularly O +in O +doses O +exceeding O +80 O +mg O +. O +kg O +( O +- O +1 O +) O +, O +should O +be O +weighed O +against O +the O +risk O +of O +postoperative B +seizures I +. O + +Dysfunctional O +overnight O +memory O +consolidation O +in O +ecstasy O +users O +. O + +Sleep O +plays O +an O +important O +role O +in O +the O +consolidation O +and O +integration O +of O +memory O +in O +a O +process O +called O +overnight O +memory O +consolidation O +. O + +Previous O +studies O +indicate O +that O +ecstasy O +users O +have O +marked O +and O +persistent O +neurocognitive B +and I +sleep I +- I +related I +impairments I +. O + +We O +extend O +past O +research O +by O +examining O +overnight O +memory O +consolidation O +among O +regular O +ecstasy O +users O +( O +n O += O +12 O +) O +and O +drug O +naive O +healthy O +controls O +( O +n O += O +26 O +) O +. O + +Memory O +recall O +of O +word O +pairs O +was O +evaluated O +before O +and O +after O +a O +period O +of O +sleep O +, O +with O +and O +without O +interference O +prior O +to O +testing O +. O + +In O +addition O +, O +we O +assessed O +neurocognitive O +performances O +across O +tasks O +of O +learning O +, O +memory O +and O +executive O +functioning O +. O + +Ecstasy O +users O +demonstrated O +impaired O +overnight O +memory O +consolidation O +, O +a O +finding O +that O +was O +more O +pronounced O +following O +associative O +interference O +. O + +Additionally O +, O +ecstasy O +users O +demonstrated O +impairments O +on O +tasks O +recruiting O +frontostriatal O +and O +hippocampal O +neural O +circuitry O +, O +in O +the O +domains O +of O +proactive O +interference O +memory O +, O +long O +- O +term O +memory O +, O +encoding O +, O +working O +memory O +and O +complex O +planning O +. O + +We O +suggest O +that O +ecstasy O +- O +associated O +dysfunction O +in O +fronto O +- O +temporal O +circuitry O +may O +underlie O +overnight O +consolidation O +memory B +impairments I +in O +regular O +ecstasy O +users O +. O + +Normoammonemic O +encephalopathy B +: O +solely O +valproate O +induced O +or O +multiple O +mechanisms O +? O + +A O +77 O +- O +year O +- O +old O +woman O +presented O +with O +subacute O +onset O +progressive O +confusion B +, O +aggression B +, O +auditory B +hallucinations I +and O +delusions B +. O + +In O +the O +preceding O +months O +, O +the O +patient O +had O +a O +number O +of O +admissions O +with O +transient O +unilateral B +hemiparesis B +with O +facial O +droop I +, O +and O +had O +been O +started O +on O +valproate O +for O +presumed O +hemiplegic B +migraine I +. O + +Valproate O +was O +withdrawn O +soon O +after O +admission O +and O +her O +cognitive O +abilities O +have O +gradually O +improved O +over O +3 O +months O +of O +follow O +- O +up O +. O + +Valproate O +levels O +taken O +prior O +to O +withdrawal O +were O +subtherapeutic O +and O +the O +patient O +was O +normoammonaemic O +. O + +EEG O +undertaken O +during O +inpatient O +stay O +showed O +changes O +consistent O +with O +encephalopathy B +, O +and O +low O +titre O +N O +- O +methyl O +- O +D O +- O +aspartate O +( O +NMDA O +) O +receptor O +antibodies O +were O +present O +in O +this O +patient O +. O + +The O +possible O +aetiologies O +of O +valproate O +- O +induced O +encephalopathy B +and O +NMDA O +receptor O +- O +associated O +encephalitis B +present O +a O +diagnostic O +dilemma O +. O + +We O +present O +a O +putative O +combinatorial O +hypothesis O +to O +explain O +this O +patient O +' O +s O +symptoms O +. O + +Cerebellar B +and I +oculomotor I +dysfunction I +induced O +by O +rapid O +infusion O +of O +pethidine O +. O + +Pethidine O +is O +an O +opioid O +that O +gains O +its O +popularity O +for O +the O +effective O +pain B +control O +through O +acting O +on O +the O +opioid O +- O +receptors O +. O + +However O +, O +rapid O +pain B +relief O +sometimes O +brings O +about O +unfavourable O +side O +effects O +that O +largely O +limit O +its O +clinical O +utility O +. O + +Common O +side O +effects O +include O +nausea B +, O +vomiting B +and O +hypotension B +. O + +In O +patients O +with O +impaired B +renal I +and I +liver I +function I +, O +and O +those O +who O +need O +long O +- O +term O +pain B +control O +, O +pethidine O +may O +cause O +excitatory O +central O +nervous O +system O +( O +CNS O +) O +effects O +through O +its O +neurotoxic B +metabolite O +, O +norpethidine O +, O +resulting O +in O +irritability B +and O +seizure B +attack O +. O + +On O +the O +contrary O +, O +though O +not O +clinically O +apparent O +, O +pethidine O +potentially O +causes O +inhibitory O +impacts O +on O +the O +CNS O +and O +impairs O +normal O +cerebellar O +and O +oculomotor O +function O +in O +the O +short O +term O +. O + +In O +this O +case O +report O +, O +we O +highlight O +opioid O +' O +s O +inhibitory O +side O +effects O +on O +the O +cerebellar O +structure O +that O +causes O +dysmetria B +, O +dysarthria B +, O +reduced O +smooth O +pursuit O +gain O +and O +decreased O +saccadic O +velocity O +. O + +Baboon B +syndrome I +induced O +by O +ketoconazole O +. O + +A O +27 O +- O +year O +- O +old O +male O +patient O +presented O +with O +a O +maculopapular O +eruption I +on O +the O +flexural O +areas O +and O +buttocks O +after O +using O +oral O +ketoconazole O +. O + +The O +patient O +was O +diagnosed O +with O +drug O +- O +induced O +baboon B +syndrome I +based O +on O +his O +history O +, O +which O +included O +prior O +sensitivity O +to O +topical O +ketoconazole O +, O +a O +physical O +examination O +, O +and O +histopathological O +findings O +. O + +Baboon B +syndrome I +is O +a O +drug O +- O +or O +contact O +allergen O +- O +related O +maculopapular B +eruption I +that O +typically O +involves O +the O +flexural O +and O +gluteal O +areas O +. O + +To O +the O +best O +of O +our O +knowledge O +, O +this O +is O +the O +first O +reported O +case O +of O +ketoconazole O +- O +induced O +baboon B +syndrome I +in O +the O +English O +literature O +. O + +A O +Case O +of O +Sudden B +Cardiac I +Death I +due O +to O +Pilsicainide O +- O +Induced O +Torsades B +de I +Pointes I +. O + +An O +84 O +- O +year O +- O +old O +male O +received O +oral O +pilsicainide O +, O +a O +pure O +sodium O +channel O +blocker O +with O +slow O +recovery O +kinetics O +, O +to O +convert O +his O +paroxysmal O +atrial B +fibrillation I +to O +a O +sinus O +rhythm O +; O +the O +patient O +developed O +sudden B +cardiac I +death I +two O +days O +later O +. O + +The O +Holter O +electrocardiogram O +, O +which O +was O +worn O +by O +chance O +, O +revealed O +torsade B +de I +pointes I +with O +gradually O +prolonged O +QT O +intervals O +. O + +This O +drug O +is O +rapidly O +absorbed O +from O +the O +gastrointestinal O +tract O +, O +and O +most O +of O +it O +is O +excreted O +from O +the O +kidney O +. O + +Although O +the O +patient O +' O +s O +renal O +function O +was O +not O +highly O +impaired O +and O +the O +dose O +of O +pilsicainide O +was O +low O +, O +the O +plasma O +concentration O +of O +pilsicainide O +may O +have O +been O +high O +, O +which O +can O +produce O +torsades B +de I +pointes I +in O +the O +octogenarian O +. O + +Although O +the O +oral O +administration O +of O +class O +IC O +drugs O +, O +including O +pilsicainide O +, O +is O +effective O +to O +terminate O +atrial B +fibrillation I +, O +careful O +consideration O +must O +be O +taken O +before O +giving O +these O +drugs O +to O +octogenarians O +. O + +All O +- O +trans O +retinoic O +acid O +- O +induced O +inflammatory B +myositis I +in O +a O +patient O +with O +acute B +promyelocytic I +leukemia I +. 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O +1 O +% O +dexamethasone O +led O +to O +elevation O +of O +intraocular O +pressure O +( O +IOP O +) O +, O +functional O +and O +structural O +loss O +of O +retinal O +ganglion O +cells O +, O +and O +axonal B +degeneration I +, O +resembling O +glucocorticoid O +- O +induced O +glaucoma B +in O +human O +patients O +. O + +Furthermore O +, O +dexamethasone O +- O +induced O +ocular B +hypertension I +was O +associated O +with O +chronic O +ER O +stress O +of O +the O +trabecular O +meshwork O +( O +TM O +) O +. O + +Similar O +to O +patients O +, O +withdrawal O +of O +dexamethasone O +treatment O +reduced O +elevated O +IOP O +and O +ER O +stress O +in O +this O +animal O +model O +. 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O + +Opioid O +- O +induced I +hyperalgesia B +( O +OIH B +) O +is O +characterized O +by O +nociceptive O +sensitization O +caused O +by O +the O +cessation O +of O +chronic O +opioid O +use O +. O + +OIH B +can O +limit O +the O +clinical O +use O +of O +opioid O +analgesics O +and O +complicate O +withdrawal O +from O +opioid O +addiction O +. O + +In O +this O +study O +, O +we O +investigated O +the O +effects O +of O +Re O +, O +Rg1 O +, O +and O +Rb1 O +ginsenosides O +, O +the O +bioactive O +components O +of O +ginseng O +, O +on O +OIH B +. O + +OIH B +was O +achieved O +in O +mice O +after O +subcutaneous O +administration O +of O +morphine O +for O +7 O +consecutive O +days O +three O +times O +per O +day O +. O + +During O +withdrawal O +( O +days O +8 O +and O +9 O +) O +, O +these O +mice O +were O +administered O +Re O +, O +Rg1 O +, O +or O +Rb1 O +intragastrically O +two O +times O +per O +day O +. O + +On O +the O +test O +day O +( O +day O +10 O +) O +, O +mice O +were O +subjected O +to O +the O +thermal O +sensitivity O +test O +and O +the O +acetic O +acid O +- O +induced O +writhing O +test O +. O + +Re O +( O +300 O +mg O +/ O +kg O +) O +inhibited O +OIH B +in O +both O +the O +thermal O +sensitivity O +test O +and O +the O +acetic O +acid O +- O +induced O +writhing O +test O +. O + +However O +, O +the O +Rg1 O +and O +Rb1 O +ginsenosides O +failed O +to O +prevent O +OIH B +in O +either O +test O +. O + +Furthermore O +, O +Rg1 O +showed O +a O +tendency O +to O +aggravate O +OIH B +in O +the O +acetic O +acid O +- O +induced O +writhing O +test O +. O + +Our O +data O +suggested O +that O +the O +ginsenoside O +Re O +, O +but O +not O +Rg1 O +or O +Rb1 O +, O +may O +contribute O +toward O +reversal O +of O +OIH B +. O + +A O +comparison O +of O +severe O +hemodynamic O +disturbances O +between O +dexmedetomidine O +and O +propofol O +for O +sedation O +in O +neurocritical O +care O +patients O +. O + +OBJECTIVE O +: O +Dexmedetomidine O +and O +propofol O +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 O +and O +propofol O +. 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 O +or O +propofol O +. O + +MEASUREMENTS O +AND O +MAIN O +RESULTS O +: O +A O +total O +of O +342 O +patients O +( O +105 O +dexmedetomidine O +and O +237 O +propofol O +) 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 B +( O +mean O +arterial O +pressure O +< O +60 O +mm O +Hg O +) O +and O +bradycardia B +( 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 +, 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 +, 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 B +or O +bradycardia B +in O +either O +the O +unmatched O +or O +matched O +cohorts O +. O + +CONCLUSIONS O +: O +Severe O +hypotension B +and O +bradycardia B +occur O +at O +similar O +prevalence O +in O +neurocritical O +care O +patients O +who O +receive O +dexmedetomidine O +or O +propofol O +. O + +Providers O +should O +similarly O +consider O +the O +likelihood O +of O +hypotension B +or O +bradycardia B +before O +starting O +either O +sedative O +. O + +Hydroxytyrosol O +ameliorates O +oxidative O +stress O +and O +mitochondrial B +dysfunction I +in O +doxorubicin O +- O +induced O +cardiotoxicity B +in O +rats O +with O +breast B +cancer I +. O + +Oxidative O +stress O +is O +involved O +in O +several O +processes O +including O +cancer B +, O +aging O +and O +cardiovascular B +disease I +, O +and O +has O +been O +shown O +to O +potentiate O +the O +therapeutic O +effect O +of O +drugs O +such O +as O +doxorubicin O +. O + +Doxorubicin O +causes O +significant O +cardiotoxicity B +characterized O +by O +marked O +increases O +in O +oxidative O +stress O +and O +mitochondrial B +dysfunction I +. O + +Herein O +, O +we O +investigate O +whether O +doxorubicin O +- O +associated O +chronic O +cardiac B +toxicity I +can O +be O +ameliorated O +with O +the O +antioxidant O +hydroxytyrosol O +in O +rats O +with O +breast B +cancer I +. O + +Thirty O +- O +six O +rats O +bearing O +breast B +tumors I +induced O +chemically O +were O +divided O +into O +4 O +groups O +: O +control O +, O +hydroxytyrosol O +( O +0 O +. O +5mg O +/ O +kg O +, O +5days O +/ O +week O +) O +, O +doxorubicin O +( O +1mg O +/ O +kg O +/ O +week O +) O +, O +and O +doxorubicin O +plus O +hydroxytyrosol O +. O + +Cardiac B +disturbances I +at O +the O +cellular O +and O +mitochondrial O +level O +, O +mitochondrial O +electron O +transport O +chain O +complexes O +I O +- O +IV O +and O +apoptosis O +- O +inducing O +factor O +, O +and O +oxidative O +stress O +markers O +have O +been O +analyzed O +. O + +Hydroxytyrosol O +improved O +the O +cardiac B +disturbances I +enhanced O +by O +doxorubicin O +by O +significantly O +reducing O +the O +percentage O +of O +altered O +mitochondria O +and O +oxidative O +damage O +. O + +These O +results O +suggest O +that O +hydroxytyrosol O +improve O +the O +mitochondrial O +electron O +transport O +chain O +. O + +This O +study O +demonstrates O +that O +hydroxytyrosol O +protect O +rat O +heart B +damage I +provoked O +by O +doxorubicin O +decreasing O +oxidative O +damage O +and O +mitochondrial O +alterations O +. O + +Amiodarone O +- O +induced O +myxoedema B +coma I +. O + +A O +62 O +- O +year O +- O +old O +man O +was O +found O +to O +have O +bradycardia B +, O +hypothermia B +and O +respiratory B +failure I +3 O +weeks O +after O +initiation O +of O +amiodarone O +therapy O +for O +atrial B +fibrillation I +. O + +Thyroid O +- O +stimulating O +hormone O +was O +found O +to O +be O +168 O +uIU O +/ O +mL O +( O +nl O +. O +0 O +. O +3 O +- O +5 O +uIU O +/ O +mL O +) O +and O +free O +thyroxine O +( O +FT4 O +) O +was O +< O +0 O +. O +2 O +ng O +/ O +dL O +( O +nl O +. O +0 O +. O +8 O +- O +1 O +. O +8 O +ng O +/ O +dL O +) O +. O + +He O +received O +intravenous O +fluids O +, O +vasopressor O +therapy O +and O +stress O +dose O +steroids O +; O +he O +was O +intubated O +and O +admitted O +to O +the O +intensive O +care O +unit O +. O + +He O +received O +500 O +ug O +of O +intravenous O +levothyroxine O +in O +the O +first O +18 O +h O +of O +therapy O +, O +and O +150 O +ug O +intravenous O +daily O +thereafter O +. O + +Haemodynamic O +improvement O +, O +along O +with O +complete O +recovery O +of O +mental O +status O +, O +occurred O +after O +48 O +h O +. O + +Twelve O +hours O +after O +the O +initiation O +of O +therapy O +, O +FT4 O +was O +0 O +. O +96 O +ng O +/ O +dL O +. O + +The O +patient O +was O +maintained O +on O +levothyroxine O +175 O +( O +g O +POorally O +daily O +. O + +A O +thyroid O +ultrasound O +showed O +diffuse O +heterogeneity O +. O + +The O +24 O +hour O +excretion O +of O +iodine O +was O +3657 O +( O +mcg O +( O +25 O +- O +756 O +( O +mcg O +) O +. O + +The O +only O +two O +cases O +of O +amiodarone O +- O +induced O +myxoedema B +coma I +in O +the O +literature O +report O +patient O +death B +despite O +supportive O +therapy O +and O +thyroid O +hormone O +replacement O +. O + +This O +case O +represents O +the O +most O +thoroughly O +investigated O +case O +of O +amiodarone O +- O +induced O +myxoedema B +coma I +with O +a O +history O +significant O +for O +subclinical O +thyroid B +disease I +. O + +Use O +of O +argatroban O +and O +catheter O +- O +directed O +thrombolysis O +with O +alteplase O +in O +an O +oncology O +patient O +with O +heparin O +- O +induced O +thrombocytopenia B +with O +thrombosis B +. O + +PURPOSE O +: O +The O +case O +of O +an O +oncology O +patient O +who O +developed O +heparin O +- O +induced O +thrombocytopenia B +with O +thrombosis B +( O +HITT B +) O +and O +was O +treated O +with O +argatroban O +plus O +catheter O +- O +directed O +thrombolysis O +( O +CDT O +) O +with O +alteplase O +is O +presented O +. O + +SUMMARY O +: O +A O +63 O +- O +year O +- O +old O +Caucasian O +man O +with O +renal B +amyloidosis I +undergoing O +peripheral O +blood O +stem O +cell O +collection O +for O +an O +autologous O +stem O +cell O +transplant O +developed O +extensive O +bilateral O +upper O +- O +extremity O +deep B +venous I +thrombosis I +( O +DVT B +) O +and O +pulmonary B +embolism I +secondary O +to O +heparin O +- O +induced O +thrombocytopenia B +. O + +A O +continuous O +i O +. O +v O +. O +infusion O +of O +argatroban O +was O +initiated O +, O +and O +the O +patient O +was O +managed O +on O +the O +general O +medical O +floor O +. O + +After O +one O +week O +of O +therapy O +, O +he O +was O +transferred O +to O +the O +intensive O +care O +unit O +with O +cardiopulmonary B +compromise I +related O +to O +superior B +vena I +cava I +( I +SVC I +) I +syndrome I +. O + +A O +percutaneous O +mechanical O +thrombectomy O +and O +CDT O +with O +alteplase O +were O +attempted O +, O +but O +the O +procedure O +was O +aborted O +due O +to O +epistaxis B +. O + +The O +epistaxis B +resolved O +the O +next O +day O +, O +and O +the O +patient O +was O +restarted O +on O +argatroban O +. O + +A O +second O +percutaneous O +mechanical O +thrombectomy O +was O +performed O +six O +days O +later O +and O +resulted O +in O +partial O +revascularization O +of O +the O +SVC O +and O +central O +veins O +. O + +Postthrombectomy O +continuous O +CDT O +with O +alteplase O +was O +commenced O +while O +argatroban O +was O +withheld O +, O +and O +complete O +patency O +of O +the O +SVC O +and O +central O +veins O +was O +achieved O +after O +three O +days O +of O +therapy O +. O + +Alteplase O +was O +discontinued O +, O +and O +the O +patient O +was O +reinitiated O +on O +argatroban O +; O +ultimately O +, O +he O +was O +transitioned O +to O +warfarin O +for O +long O +- O +term O +anticoagulation O +. O + +Although O +the O +patient O +recovered O +, O +he O +experienced O +permanent O +vision B +and I +hearing I +loss I +, O +as O +well O +as O +end B +- I +stage I +renal I +disease I +. O + +CONCLUSION O +: O +A O +63 O +- O +year O +- O +old O +man O +with O +renal B +amyloidosis I +and O +SVC B +syndrome I +secondary O +to O +HITT B +was O +successfully O +treated O +with O +argatroban O +and O +CDT O +with O +alteplase O +. O + +Effects O +of O +dehydroepiandrosterone O +in O +amphetamine O +- O +induced O +schizophrenia B +models O +in O +mice O +. O + +OBJECTIVE O +: O +To O +examine O +the O +effects O +of O +dehydroepiandrosterone O +( O +DHEA O +) O +on O +animal O +models O +of O +schizophrenia B +. 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 O +- O +free O +( O +control O +) O +, O +amphetamine O +, 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 O +( O +3 O +mg O +/ O +kg O +ip O +) O +induced O +hyper B +locomotion O +, O +apomorphine O +( O +1 O +. O +5 O +mg O +/ O +kg O +subcutaneously O +[ O +sc O +] O +) O +induced O +climbing O +, O +and O +haloperidol O +( O +1 O +. O +5 O +mg O +/ O +kg O +sc O +) O +induced O +catalepsy B +tests O +were O +used O +as O +animal O +models O +of O +schizophrenia B +. 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 O +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 B +tests O +. O + +RESULTS O +: O +In O +the O +amphetamine O +- 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 O +- O +free O +group O +. O + +Both O +DHEA O +50 O +mg O +/ O +kg O +( O +p O +< O +0 O +. O +05 O +) O +, O +and O +100 O +mg O +/ O +kg O +( O +p O +< O +0 O +. O +01 O +) O +significantly O +decreased O +all O +movements O +compared O +with O +the O +amphetamine O +- 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 O +- O +induced O +catalepsy B +test O +( O +p O +< O +0 O +. O +05 O +) 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 O +- O +induced O +climbing O +test O +( O +p O +> O +0 O +. O +05 O +) O +. O + +CONCLUSION O +: O +We O +observed O +that O +DHEA O +reduced O +locomotor O +activity O +and O +increased O +catalepsy B +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 O +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 B +. O + +Availability O +of O +human O +induced O +pluripotent O +stem O +cell O +- O +derived O +cardiomyocytes O +in O +assessment O +of O +drug O +potential O +for O +QT B +prolongation I +. O + +Field O +potential O +duration O +( O +FPD O +) O +in O +human O +- O +induced O +pluripotent O +stem O +cell O +- O +derived O +cardiomyocytes O +( O +hiPS O +- O +CMs O +) O +, O +which O +can O +express O +QT O +interval O +in O +an O +electrocardiogram O +, O +is O +reported O +to O +be O +a O +useful O +tool O +to O +predict O +K O +( O ++ O +) O +channel O +and O +Ca O +( O +2 O ++ O +) O +channel O +blocker O +effects O +on O +QT O +interval O +. O + +However O +, O +there O +is O +no O +report O +showing O +that O +this O +technique O +can O +be O +used O +to O +predict O +multichannel O +blocker O +potential O +for O +QT B +prolongation I +. O + +The O +aim O +of O +this O +study O +is O +to O +show O +that O +FPD O +from O +MEA O +( O +Multielectrode O +array O +) O +of O +hiPS O +- O +CMs O +can O +detect O +QT B +prolongation I +induced O +by O +multichannel O +blockers O +. O + +hiPS O +- O +CMs O +were O +seeded O +onto O +MEA O +and O +FPD O +was O +measured O +for O +2min O +every O +10min O +for O +30min O +after O +drug O +exposure O +for O +the O +vehicle O +and O +each O +drug O +concentration O +. O + +IKr O +and O +IKs O +blockers O +concentration O +- O +dependently O +prolonged O +corrected O +FPD O +( O +FPDc O +) O +, O +whereas O +Ca O +( O +2 O ++ O +) O +channel O +blockers O +concentration O +- O +dependently O +shortened O +FPDc O +. O + +Also O +, O +the O +multichannel O +blockers O +Amiodarone O +, O +Paroxetine O +, O +Terfenadine O +and O +Citalopram O +prolonged O +FPDc O +in O +a O +concentration O +dependent O +manner O +. O + +Finally O +, O +the O +IKr O +blockers O +, O +Terfenadine O +and O +Citalopram O +, O +which O +are O +reported O +to O +cause O +Torsade B +de I +Pointes I +( O +TdP B +) O +in O +clinical O +practice O +, O +produced O +early O +afterdepolarization O +( O +EAD O +) O +. O + +hiPS O +- O +CMs O +using O +MEA O +system O +and O +FPDc O +can O +predict O +the O +effects O +of O +drug O +candidates O +on O +QT O +interval O +. O + +This O +study O +also O +shows O +that O +this O +assay O +can O +help O +detect O +EAD O +for O +drugs O +with O +TdP B +potential O +. O + +Dermal O +developmental O +toxicity B +of O +N O +- O +phenylimide O +herbicides O +in O +rats O +. O + +BACKGROUND O +: O +S O +- O +53482 O +and O +S O +- O +23121 O +are O +N O +- O +phenylimide O +herbicides O +and O +produced O +embryolethality B +, O +teratogenicity O +( O +mainly O +ventricular B +septal I +defects I +and O +wavy B +ribs I +) O +, O +and O +growth B +retardation I +in O +rats O +in O +conventional O +oral O +developmental O +toxicity B +studies O +. O + +Our O +objective O +in O +this O +study O +was O +to O +investigate O +whether O +the O +compounds O +induce O +developmental O +toxicity B +via O +the O +dermal O +route O +, O +which O +is O +more O +relevant O +to O +occupational O +exposure O +, O +hence O +better O +addressing O +human O +health O +risks O +. O + +METHODS O +: O +S O +- O +53482 O +was O +administered O +dermally O +to O +rats O +at O +30 O +, O +100 O +, O +and O +300 O +mg O +/ O +kg O +during O +organogenesis O +, O +and O +S O +- O +23121 O +was O +administered O +at O +200 O +, O +400 O +, O +and O +800 O +mg O +/ O +kg O +( O +the O +maximum O +applicable O +dose O +level O +) O +. O + +Fetuses O +were O +obtained O +by O +a O +Cesarean O +section O +and O +examined O +for O +external O +, O +visceral O +, O +and O +skeletal O +alterations O +. O + +RESULTS O +: O +Dermal O +exposure O +of O +rats O +to O +S O +- O +53482 O +at O +300 O +mg O +/ O +kg O +produced O +patterns O +of O +developmental O +toxicity B +similar O +to O +those O +resulting O +from O +oral O +exposure O +. O + +Toxicity B +included O +embryolethality O +, O +teratogenicity O +, O +and O +growth B +retardation I +. O + +Dermal O +administration O +of O +S O +- O +23121 O +at O +800 O +mg O +/ O +kg O +resulted O +in O +an O +increased O +incidence O +of O +embryonic B +death I +and O +ventricular B +septal I +defect I +, O +but O +retarded B +fetal I +growth I +was O +not O +observed O +as O +it O +was O +following O +oral O +exposure O +to O +S O +- O +23121 O +. O + +CONCLUSIONS O +: O +Based O +on O +the O +results O +, O +S O +- O +53482 O +and O +S O +- O +23121 O +were O +teratogenic O +when O +administered O +dermally O +to O +pregnant O +rats O +as O +were O +the O +compounds O +administered O +orally O +. O + +Thus O +, O +investigation O +of O +the O +mechanism O +and O +its O +human O +relevancy O +become O +more O +important O +. O + +Rates O +of O +Renal B +Toxicity I +in O +Cancer B +Patients O +Receiving O +Cisplatin O +With O +and O +Without O +Mannitol O +. O + +BACKGROUND O +: O +Cisplatin O +is O +a O +widely O +used O +antineoplastic O +. O + +One O +of O +the O +major O +complications O +of O +cisplatin O +use O +is O +dose O +- O +limiting O +nephrotoxicity B +. O + +There O +are O +many O +strategies O +to O +prevent O +this O +toxicity B +, O +including O +the O +use O +of O +mannitol O +as O +a O +nephroprotectant O +in O +combination O +with O +hydration O +. O + +OBJECTIVE O +: O +We O +aimed O +to O +evaluate O +the O +rates O +of O +cisplatin O +- O +induced O +nephrotoxicity B +in O +cancer B +patients O +receiving O +single O +- O +agent O +cisplatin O +with O +and O +without O +mannitol O +. O + +METHODS O +: O +This O +single O +- O +center O +retrospective O +analysis O +was O +a O +quasi O +experiment O +created O +by O +the O +national O +mannitol O +shortage O +. O + +Data O +were O +collected O +on O +adult O +cancer B +patients O +receiving O +single O +- O +agent O +cisplatin O +as O +an O +outpatient O +from O +January O +2011 O +to O +September O +2012 O +. O + +The O +primary O +outcome O +was O +acute B +kidney I +injury I +( O +AKI O +) O +. O + +RESULTS O +: O +We O +evaluated O +143 O +patients O +who O +received O +single O +- O +agent O +cisplatin O +; O +97 O +. O +2 O +% O +of O +patients O +had O +head B +and I +neck I +cancer I +as O +their O +primary O +malignancy B +. O + +Patients O +who O +did O +not O +receive O +mannitol O +were O +more O +likely O +to O +develop O +nephrotoxicity B +: O +odds O +ratio O +[ O +OR O +] O += O +2 O +. O +646 O +( O +95 O +% O +CI O += O +1 O +. O +008 O +, O +6 O +. O +944 O +; O +P O += O +0 O +. O +048 O +) O +. O + +Patients O +who O +received O +the O +100 O +mg O +/ O +m O +( O +2 O +) O +dosing O +and O +patients O +who O +had O +a O +history O +of O +hypertension B +also O +had O +a O +higher O +likelihood O +of O +developing O +nephrotoxicity B +: O +OR O += O +11 O +. O +494 O +( O +95 O +% O +CI O += O +4 O +. O +149 O +, O +32 O +. O +258 O +; O +P O +< O +0 O +. O +0001 O +) O +and O +OR O += O +3 O +. O +219 O +( O +95 O +% O +CI O += O +1 O +. O +228 O +, O +8 O +. O +439 O +; O +P O += O +0 O +. O +017 O +) O +, O +respectively O +. O + +CONCLUSIONS O +: O +When O +limited O +quantities O +of O +mannitol O +are O +available O +, O +it O +should O +preferentially O +be O +given O +to O +patients O +at O +particularly O +high O +risk O +of O +nephrotoxicity B +. O + +Our O +analysis O +suggests O +that O +those O +patients O +receiving O +the O +dosing O +schedule O +of O +100 O +mg O +/ O +m O +( O +2 O +) O +cisplatin O +every O +3 O +weeks O +and O +those O +with O +hypertension B +are O +at O +the O +greatest O +risk O +of O +nephrotoxicity B +and O +would O +benefit O +from O +the O +addition O +of O +mannitol O +. O + +Metformin O +protects O +against O +seizures B +, O +learning B +and I +memory I +impairments I +and O +oxidative O +damage O +induced O +by O +pentylenetetrazole O +- O +induced O +kindling O +in O +mice O +. O + +Cognitive B +impairment I +, O +the O +most O +common O +and O +severe O +comorbidity O +of O +epilepsy B +, O +greatly O +diminishes O +the O +quality O +of O +life O +. O + +However O +, O +current O +therapeutic O +interventions O +for O +epilepsy B +can O +also O +cause O +untoward O +cognitive O +effects O +. O + +Thus O +, O +there O +is O +an O +urgent O +need O +for O +new O +kinds O +of O +agents O +targeting O +both O +seizures B +and O +cognition B +deficits I +. O + +Oxidative O +stress O +is O +considered O +to O +play O +an O +important O +role O +in O +epileptogenesis B +and O +cognitive B +deficits I +, O +and O +antioxidants O +have O +a O +putative O +antiepileptic O +potential O +. O + +Metformin O +, O +the O +most O +commonly O +prescribed O +antidiabetic O +oral O +drug O +, O +has O +antioxidant O +properties O +. O + +This O +study O +was O +designed O +to O +evaluate O +the O +ameliorative O +effects O +of O +metformin O +on O +seizures B +, O +cognitive B +impairment I +and O +brain O +oxidative O +stress O +markers O +observed O +in O +pentylenetetrazole O +- O +induced O +kindling O +animals O +. O + +Male O +C57BL O +/ O +6 O +mice O +were O +administered O +with O +subconvulsive O +dose O +of O +pentylenetetrazole O +( O +37 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +every O +other O +day O +for O +14 O +injections O +. O + +Metformin O +was O +injected O +intraperitoneally O +in O +dose O +of O +200mg O +/ O +kg O +along O +with O +alternate O +- O +day O +PTZ O +. O + +We O +found O +that O +metformin O +suppressed O +the O +progression O +of O +kindling O +, O +ameliorated O +the O +cognitive B +impairment I +and O +decreased O +brain O +oxidative O +stress O +. O + +Thus O +the O +present O +study O +concluded O +that O +metformin O +may O +be O +a O +potential O +agent O +for O +the O +treatment O +of O +epilepsy B +as O +well O +as O +a O +protective O +medicine O +against O +cognitive B +impairment I +induced O +by O +seizures B +. O + +P53 O +inhibition O +exacerbates O +late O +- O +stage O +anthracycline O +cardiotoxicity B +. O + +AIMS O +: O +Doxorubicin O +( O +DOX O +) O +is O +an O +effective O +anti O +- O +cancer B +therapeutic O +, O +but O +is O +associated O +with O +both O +acute O +and O +late O +- O +stage O +cardiotoxicity B +. O + +Children O +are O +particularly O +sensitive O +to O +DOX O +- O +induced O +heart B +failure I +. O + +Here O +, O +the O +impact O +of O +p53 O +inhibition O +on O +acute O +vs O +. O +late O +- O +stage O +DOX O +cardiotoxicity B +was O +examined O +in O +a O +juvenile O +model O +. O + +METHODS O +AND O +RESULTS O +: O +Two O +- O +week O +- O +old O +MHC O +- O +CB7 O +mice O +( O +which O +express O +dominant O +- O +interfering O +p53 O +in O +cardiomyocytes O +) O +and O +their O +non O +- O +transgenic O +( O +NON O +- O +TXG O +) O +littermates O +received O +weekly O +DOX O +injections O +for O +5 O +weeks O +( O +25 O +mg O +/ O +kg O +cumulative O +dose O +) O +. O + +One O +week O +after O +the O +last O +DOX O +treatment O +( O +acute O +stage O +) O +, O +MHC O +- O +CB7 O +mice O +exhibited O +improved O +cardiac O +function O +and O +lower O +levels O +of O +cardiomyocyte O +apoptosis O +when O +compared O +with O +the O +NON O +- O +TXG O +mice O +. O + +Surprisingly O +, O +by O +13 O +weeks O +following O +the O +last O +DOX O +treatment O +( O +late O +stage O +) O +, O +MHC O +- O +CB7 O +exhibited O +a O +progressive O +decrease O +in O +cardiac I +function I +and O +higher O +rates O +of O +cardiomyocyte O +apoptosis O +when O +compared O +with O +NON O +- O +TXG O +mice O +. O + +p53 O +inhibition O +blocked O +transient O +DOX O +- O +induced O +STAT3 O +activation O +in O +MHC O +- O +CB7 O +mice O +, O +which O +was O +associated O +with O +enhanced O +induction O +of O +the O +DNA O +repair O +proteins O +Ku70 O +and O +Ku80 O +. O + +Mice O +with O +cardiomyocyte O +- O +restricted O +deletion O +of O +STAT3 O +exhibited O +worse O +cardiac O +function O +, O +higher O +levels O +of O +cardiomyocyte O +apoptosis O +, O +and O +a O +greater O +induction O +of O +Ku70 O +and O +Ku80 O +in O +response O +to O +DOX O +treatment O +during O +the O +acute O +stage O +when O +compared O +with O +control O +animals O +. O + +CONCLUSION O +: O +These O +data O +support O +a O +model O +wherein O +a O +p53 O +- O +dependent O +cardioprotective O +pathway O +, O +mediated O +via O +STAT3 O +activation O +, O +mitigates O +DOX O +- O +induced O +myocardial B +stress I +during O +drug O +delivery O +. O + +Furthermore O +, O +these O +data O +suggest O +an O +explanation O +as O +to O +how O +p53 O +inhibition O +can O +result O +in O +cardioprotection O +during O +drug O +treatment O +and O +, O +paradoxically O +, O +enhanced O +cardiotoxicity B +long O +after O +the O +cessation O +of O +drug O +treatment O +. O + +Metronidazole O +- O +induced O +encephalopathy B +: O +an O +uncommon O +scenario O +. O + +Metronidazole O +can O +produce O +neurological B +complications I +although O +it O +is O +not O +a O +common O +scenario O +. O + +We O +present O +a O +case O +where O +a O +patient O +developed O +features O +of O +encephalopathy B +following O +prolonged O +metronidazole O +intake O +. O + +Magnetic O +resonance O +imaging O +( O +MRI O +) O +brain O +showed O +abnormal O +signal O +intensity O +involving O +both O +dentate O +nuclei O +of O +cerebellum O +and O +splenium O +of O +corpus O +callosum O +. O + +The O +diagnosis O +of O +metronidazole O +toxicity B +was O +made O +by O +the O +MRI O +findings O +and O +supported O +clinically O +. O + +Aconitine O +- O +induced O +Ca2 O ++ O +overload O +causes O +arrhythmia B +and O +triggers O +apoptosis O +through O +p38 O +MAPK O +signaling O +pathway O +in O +rats O +. O + +Aconitine O +is O +a O +major O +bioactive O +diterpenoid O +alkaloid O +with O +high O +content O +derived O +from O +herbal O +aconitum O +plants O +. O + +Emerging O +evidence O +indicates O +that O +voltage O +- O +dependent O +Na O +( O ++ O +) O +channels O +have O +pivotal O +roles O +in O +the O +cardiotoxicity B +of O +aconitine O +. O + +However O +, O +no O +reports O +are O +available O +on O +the O +role O +of O +Ca O +( O +2 O ++ O +) O +in O +aconitine O +poisoning B +. O + +In O +this O +study O +, O +we O +explored O +the O +importance O +of O +pathological O +Ca O +( O +2 O ++ O +) O +signaling O +in O +aconitine O +poisoning B +in O +vitro O +and O +in O +vivo O +. O + +We O +found O +that O +Ca O +( O +2 O ++ O +) O +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 B +in O +conscious O +freely O +moving O +rats O +. O + +To O +investigate O +effects O +of O +aconitine O +on O +myocardial B +injury I +, O +we O +performed O +cytotoxicity O +assay O +in O +neonatal O +rat O +ventricular O +myocytes O +( O +NRVMs O +) 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 O +resulted O +in O +myocardial B +injury I +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 O +- O +biotin O +nick O +end O +labeling O +assay O +. O + +The O +results O +showed O +that O +aconitine O +stimulated O +apoptosis O +time O +- O +dependently O +. O + +The O +expression O +analysis O +of O +Ca O +( O +2 O ++ O +) O +handling O +proteins O +demonstrated O +that O +aconitine O +promoted O +Ca O +( O +2 O ++ O +) O +overload O +through O +the O +expression O +regulation O +of O +Ca O +( O +2 O ++ O +) O +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 O +significantly O +aggravates O +Ca O +( O +2 O ++ O +) O +overload O +and O +causes O +arrhythmia B +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 + +Chronic O +treatment O +with O +metformin O +suppresses O +toll O +- O +like O +receptor O +4 O +signaling O +and O +attenuates O +left B +ventricular I +dysfunction I +following O +myocardial B +infarction I +. O + +Acute O +treatment O +with O +metformin O +has O +a O +protective O +effect O +in O +myocardial B +infarction I +by O +suppression O +of O +inflammatory O +responses O +due O +to O +activation O +of O +AMP O +- O +activated O +protein O +kinase O +( O +AMPK O +) O +. O + +In O +the O +present O +study O +, O +the O +effect O +of O +chronic O +pre O +- O +treatment O +with O +metformin O +on O +cardiac B +dysfunction I +and O +toll O +- O +like O +receptor O +4 O +( O +TLR4 O +) O +activities O +following O +myocardial B +infarction I +and O +their O +relation O +with O +AMPK O +were O +assessed O +. O + +Male O +Wistar O +rats O +were O +randomly O +assigned O +to O +one O +of O +5 O +groups O +( O +n O += O +6 O +) O +: O +normal O +control O +and O +groups O +were O +injected O +isoproterenol O +after O +chronic O +pre O +- O +treatment O +with O +0 O +, O +25 O +, O +50 O +, O +or O +100mg O +/ O +kg O +of O +metformin O +twice O +daily O +for O +14 O +days O +. O + +Isoproterenol O +( O +100mg O +/ O +kg O +) O +was O +injected O +subcutaneously O +on O +the O +13th O +and O +14th O +days O +to O +induce O +acute B +myocardial I +infarction I +. O + +Isoproterenol O +alone O +decreased O +left O +ventricular O +systolic O +pressure O +and O +myocardial O +contractility O +indexed O +as O +LVdp O +/ O +dtmax O +and O +LVdp O +/ O +dtmin O +. O + +The O +left B +ventricular I +dysfunction I +was O +significantly O +lower O +in O +the O +groups O +treated O +with O +25 O +and O +50mg O +/ O +kg O +of O +metformin O +. O + +Metfromin O +markedly O +lowered O +isoproterenol O +- O +induced O +elevation O +in O +the O +levels O +of O +TLR4 O +mRNA O +, O +myeloid O +differentiation O +protein O +88 O +( O +MyD88 O +) O +, O +tumor B +necrosis O +factor O +- O +alpha O +( O +TNF O +- O +a O +) O +, O +and O +interleukin O +6 O +( O +IL O +- O +6 O +) O +in O +the O +heart O +tissues O +. O + +Similar O +changes O +were O +also O +seen O +in O +the O +serum O +levels O +of O +TNF O +- O +a O +and O +IL O +- O +6 O +. O + +However O +, O +the O +lower O +doses O +of O +25 O +and O +50mg O +/ O +kg O +were O +more O +effective O +than O +100mg O +/ O +kg O +. O + +Phosphorylated O +AMPKa O +( O +p O +- O +AMPK O +) O +in O +the O +myocardium O +was O +significantly O +elevated O +by O +25mg O +/ O +kg O +of O +metformin O +, O +slightly O +by O +50mg O +/ O +kg O +, O +but O +not O +by O +100mg O +/ O +kg O +. O + +Chronic O +pre O +- O +treatment O +with O +metformin O +reduces O +post O +- O +myocardial B +infarction I +cardiac B +dysfunction I +and O +suppresses O +inflammatory O +responses O +, O +possibly O +through O +inhibition O +of O +TLR4 O +activities O +. O + +This O +mechanism O +can O +be O +considered O +as O +a O +target O +to O +protect O +infarcted B +myocardium O +. O + +Unusual O +complications O +of O +antithyroid O +drug O +therapy O +: O +four O +case O +reports O +and O +review O +of O +literature O +. O + +Two O +cases O +of O +propylthiouracil O +- O +associated O +acute O +hepatitis B +, O +one O +case O +of O +fatal O +methimazole O +- O +associated O +hepatocellular B +necrosis I +and O +one O +case O +of O +propylthiouracil O +- O +associated O +lupus B +- I +like I +syndrome I +are O +described O +. O + +The O +literature O +related O +to O +antithyroid O +drug O +side O +effects O +and O +the O +mechanisms O +for O +their O +occurrence O +are O +reviewed O +and O +the O +efficacy O +and O +complications O +of O +thyroidectomy O +and O +radioiodine O +compared O +to O +those O +of O +antithyroid O +drugs O +. O + +It O +is O +concluded O +that O +in O +most O +circumstances O +131I O +is O +the O +therapy O +of O +choice O +for O +hyperthyroidism B +. O + +Neuroleptic B +malignant I +syndrome I +induced O +by O +combination O +therapy O +with O +tetrabenazine O +and O +tiapride O +in O +a O +Japanese O +patient O +with O +Huntington B +' I +s I +disease I +at O +the O +terminal O +stage O +of O +recurrent O +breast B +cancer I +. O + +We O +herein O +describe O +the O +case O +of O +an O +81 O +- O +year O +- O +old O +Japanese O +woman O +with O +neuroleptic B +malignant I +syndrome I +that O +occurred O +36 O +days O +after O +the O +initiation O +of O +combination O +therapy O +with O +tiapride O +( O +75 O +mg O +/ O +day O +) O +and O +tetrabenazine O +( O +12 O +. O +5 O +mg O +/ O +day O +) O +for O +Huntington B +' I +s I +disease I +. O + +The O +patient O +had O +been O +treated O +with O +tiapride O +or O +tetrabenazine O +alone O +without O +any O +adverse O +effects O +before O +the O +administration O +of O +the O +combination O +therapy O +. O + +She O +also O +had O +advanced B +breast B +cancer I +when O +the O +combination O +therapy O +was O +initiated O +. O + +To O +the O +best O +of O +our O +knowledge O +, O +the O +occurrence O +of O +neuroleptic B +malignant I +syndrome I +due O +to O +combination O +therapy O +with O +tetrabenazine O +and O +tiapride O +has O +not O +been O +previously O +reported O +. O + +Tetrabenazine O +should O +be O +administered O +very O +carefully O +in O +combination O +with O +other O +neuroleptic O +drugs O +, O +particularly O +in O +patients O +with O +a O +worsening O +general O +condition O +. O + +A O +metoprolol O +- O +terbinafine O +combination O +induced O +bradycardia B +. O + +To O +report O +a O +sinus O +bradycardia B +induced O +by O +metoprolol O +and O +terbinafine O +drug O +- O +drug O +interaction O +and O +its O +management O +. O + +A O +63 O +year O +- O +old O +Caucasian O +man O +on O +metoprolol O +200 O +mg O +/ O +day O +for O +stable O +coronary B +artery I +disease I +was O +prescribed O +a O +90 O +- O +day O +course O +of O +oral O +terbinafine O +250 O +mg O +/ O +day O +for O +onychomycosis B +. O + +On O +the O +49th O +day O +of O +terbinafine O +therapy O +, O +he O +was O +brought O +to O +the O +emergency O +room O +for O +a O +decrease O +of O +his O +global O +health O +status O +, O +confusion B +and O +falls B +. O + +The O +electrocardiogram O +revealed O +a O +37 O +beats O +/ O +min O +sinus O +bradycardia B +. O + +A O +score O +of O +7 O +on O +the O +Naranjo O +adverse B +drug I +reaction I +probability O +scale O +indicates O +a O +probable O +relationship O +between O +the O +patient O +' O +s O +sinus O +bradycardia B +and O +the O +drug O +interaction O +between O +metoprolol O +and O +terbinafine O +. O + +The O +heart O +rate O +ameliorated O +first O +with O +a O +decrease O +in O +the O +dose O +of O +metoprolol O +. O + +It O +was O +subsequently O +changed O +to O +bisoprolol O +and O +the O +heart O +rate O +remained O +normal O +. O + +By O +inhibiting O +the O +cytochrome O +P450 O +2D6 O +, O +terbinafine O +had O +decreased O +metoprolol O +' O +s O +clearance O +, O +leading O +in O +metoprolol O +accumulation O +which O +has O +resulted O +in O +clinically O +significant O +sinus B +bradycardia I +. O + +Optochiasmatic B +and I +peripheral I +neuropathy I +due O +to O +ethambutol O +overtreatment O +. O + +Ethambutol O +is O +known O +to O +cause O +optic B +neuropathy I +and O +, O +more O +rarely O +, O +axonal O +polyneuropathy I +. O + +We O +characterize O +the O +clinical O +, O +neurophysiological O +, O +and O +neuroimaging O +findings O +in O +a O +72 O +- O +year O +- O +old O +man O +who O +developed O +visual B +loss I +and O +paresthesias B +after O +11 O +weeks O +of O +exposure O +to O +a O +supratherapeutic O +dose O +of O +ethambutol O +. O + +This O +case O +demonstrates O +the O +selective O +vulnerability O +of O +the O +anterior O +visual O +pathways O +and O +peripheral O +nerves O +to O +ethambutol O +toxicity B +. O + +Testosterone O +ameliorates O +streptozotocin O +- O +induced O +memory B +impairment I +in O +male O +rats O +. O + +AIM O +: O +To O +study O +the O +effects O +of O +testosterone O +on O +streptozotocin O +( O +STZ O +) O +- O +induced O +memory B +impairment I +in O +male O +rats O +. O + +METHODS O +: O +Adult O +male O +Wistar O +rats O +were O +intracerebroventricularly O +( O +icv O +) O +infused O +with O +STZ O +( O +750 O +ug O +) O +on O +d O +1 O +and O +d O +3 O +, O +and O +a O +passive O +avoidance O +task O +was O +assessed O +2 O +weeks O +after O +the O +first O +injection O +of O +STZ O +. O + +Castration O +surgery O +was O +performed O +in O +another O +group O +of O +rats O +, O +and O +the O +passive O +avoidance O +task O +was O +assessed O +4 O +weeks O +after O +the O +operation O +. O + +Testosterone O +( O +1 O +mg O +. O +kg O +( O +- O +1 O +) O +. O +d O +( O +- O +1 O +) O +, O +sc O +) O +, O +the O +androgen O +receptor O +antagonist O +flutamide O +( O +10 O +mg O +. O +kg O +( O +- O +1 O +) O +. O +d O +( O +- O +1 O +) O +, O +ip O +) O +, O +the O +estrogen O +receptor O +antagonist O +tamoxifen O +( O +1 O +mg O +. O +kg O +( O +- O +1 O +) O +. O +d O +( O +- O +1 O +) O +, O +ip O +) O +or O +the O +aromatase O +inhibitor O +letrozole O +( O +4 O +mg O +. O +kg O +( O +- O +1 O +) O +. O +d O +( O +- O +1 O +) O +, O +ip O +) O +were O +administered O +for O +6 O +d O +after O +the O +first O +injection O +of O +STZ O +. O + +RESULTS O +: O +STZ O +administration O +and O +castration O +markedly O +decreased O +both O +STL1 O +( O +the O +short O +memory O +) O +and O +STL2 O +( O +the O +long O +memory O +) O +in O +passive O +avoidance O +tests O +. O + +Testosterone O +replacement O +almost O +restored O +the O +STL1 O +and O +STL2 O +in O +castrated O +rats O +, O +and O +significantly O +prolonged O +the O +STL1 O +and O +STL2 O +in O +STZ O +- O +treated O +rats O +. O + +Administration O +of O +flutamide O +, O +letrozole O +or O +tamoxifen O +significantly O +impaired O +the O +memory O +in O +intact O +rats O +, O +and O +significantly O +attenuated O +the O +testosterone O +replacement O +in O +improving O +STZ O +- O +and O +castration O +- O +induced O +memory B +impairment I +. O + +CONCLUSION O +: O +Testosterone O +administration O +ameliorates O +STZ O +- O +and O +castration O +- O +induced O +memory B +impairment I +in O +male O +Wistar O +rats O +. O + +Behavioral O +and O +neurochemical O +studies O +in O +mice O +pretreated O +with O +garcinielliptone O +FC O +in O +pilocarpine O +- O +induced O +seizures B +. O + +Garcinielliptone O +FC O +( O +GFC O +) O +isolated O +from O +hexanic O +fraction O +seed O +extract O +of O +species O +Platonia O +insignis O +Mart O +. O + +It O +is O +widely O +used O +in O +folk O +medicine O +to O +treat O +skin B +diseases I +in O +both O +humans O +and O +animals O +as O +well O +as O +the O +seed O +decoction O +has O +been O +used O +to O +treat O +diarrheas B +and O +inflammatory B +diseases I +. O + +However O +, O +there O +is O +no O +research O +on O +GFC O +effects O +in O +the O +central O +nervous O +system O +of O +rodents O +. O + +The O +present O +study O +aimed O +to O +evaluate O +the O +GFC O +effects O +at O +doses O +of O +25 O +, O +50 O +or O +75 O +mg O +/ O +kg O +on O +seizure B +parameters O +to O +determine O +their O +anticonvulsant O +activity O +and O +its O +effects O +on O +amino O +acid O +( O +r O +- O +aminobutyric O +acid O +( O +GABA O +) O +, O +glutamine O +, O +aspartate O +and O +glutathione O +) O +levels O +as O +well O +as O +on O +acetylcholinesterase O +( O +AChE O +) O +activity O +in O +mice O +hippocampus O +after O +seizures B +. O + +GFC O +produced O +an O +increased O +latency O +to O +first O +seizure B +, O +at O +doses O +25mg O +/ O +kg O +( O +20 O +. O +12 O ++ O +2 O +. O +20 O +min O +) O +, O +50mg O +/ O +kg O +( O +20 O +. O +95 O ++ O +2 O +. O +21 O +min O +) O +or O +75 O +mg O +/ O +kg O +( O +23 O +. O +43 O ++ O +1 O +. O +99 O +min O +) O +when O +compared O +with O +seized O +mice O +. O + +In O +addition O +, O +GABA O +content O +of O +mice O +hippocampus O +treated O +with O +GFC75 O +plus O +P400 O +showed O +an O +increase O +of O +46 O +. O +90 O +% O +when O +compared O +with O +seized O +mice O +. O + +In O +aspartate O +, O +glutamine O +and O +glutamate O +levels O +detected O +a O +decrease O +of O +5 O +. O +21 O +% O +, O +13 O +. O +55 O +% O +and O +21 O +. O +80 O +% O +, O +respectively O +in O +mice O +hippocampus O +treated O +with O +GFC75 O +plus O +P400 O +when O +compared O +with O +seized O +mice O +. O + +Hippocampus O +mice O +treated O +with O +GFC75 O +plus O +P400 O +showed O +an O +increase O +in O +AChE O +activity O +( O +63 O +. O +30 O +% O +) O +when O +compared O +with O +seized O +mice O +. O + +The O +results O +indicate O +that O +GFC O +can O +exert O +anticonvulsant O +activity O +and O +reduce O +the O +frequency O +of O +installation O +of O +pilocarpine O +- O +induced O +status B +epilepticus I +, O +as O +demonstrated O +by O +increase O +in O +latency O +to O +first O +seizure B +and O +decrease O +in O +mortality O +rate O +of O +animals O +. O + +In O +conclusion O +, O +our O +data O +suggest O +that O +GFC O +may O +influence O +in O +epileptogenesis B +and O +promote O +anticonvulsant O +actions O +in O +pilocarpine O +model O +by O +modulating O +the O +GABA O +and O +glutamate O +contents O +and O +of O +AChE O +activity O +in O +seized O +mice O +hippocampus O +. O + +This O +compound O +may O +be O +useful O +to O +produce O +neuronal O +protection O +and O +it O +can O +be O +considered O +as O +an O +anticonvulsant O +agent O +. O + +Standard O +operating O +procedures O +for O +antibiotic O +therapy O +and O +the O +occurrence O +of O +acute B +kidney I +injury I +: O +a O +prospective O +, O +clinical O +, O +non O +- O +interventional O +, O +observational O +study O +. O + +INTRODUCTION O +: O +Acute B +kidney I +injury I +( O +AKI B +) O +occurs O +in O +7 O +% O +of O +hospitalized O +and O +66 O +% O +of O +Intensive O +Care O +Unit O +( O +ICU O +) O +patients O +. O + +It O +increases O +mortality O +, O +hospital O +length O +of O +stay O +, O +and O +costs O +. O + +The O +aim O +of O +this O +study O +was O +to O +investigate O +, O +whether O +there O +is O +an O +association O +between O +adherence O +to O +guidelines O +( O +standard O +operating O +procedures O +( O +SOP O +) O +) O +for O +potentially O +nephrotoxic B +antibiotics O +and O +the O +occurrence O +of O +AKI O +. O + +METHODS O +: O +This O +study O +was O +carried O +out O +as O +a O +prospective O +, O +clinical O +, O +non O +- O +interventional O +, O +observational O +study O +. O + +Data O +collection O +was O +performed O +over O +a O +total O +of O +170 O +days O +in O +three O +ICUs O +at O +Charite O +- O +Universitaetsmedizin O +Berlin O +. O + +A O +total O +of O +675 O +patients O +were O +included O +; O +163 O +of O +these O +had O +therapy O +with O +vancomycin O +, O +gentamicin O +, O +or O +tobramycin O +; O +were O +> O +18 O +years O +; O +and O +treated O +in O +the O +ICU O +for O +> O +24 O +hours O +. O + +Patients O +with O +an O +adherence O +to O +SOP O +> O +70 O +% O +were O +classified O +into O +the O +high O +adherence O +group O +( O +HAG O +) O +and O +patients O +with O +an O +adherence O +of O +< O +70 O +% O +into O +the O +low O +adherence O +group O +( O +LAG O +) O +. O + +AKI O +was O +defined O +according O +to O +RIFLE O +criteria O +. O + +Adherence O +to O +SOPs O +was O +evaluated O +by O +retrospective O +expert O +audit O +. O + +Development O +of O +AKI B +was O +compared O +between O +groups O +with O +exact O +Chi2 O +- O +test O +and O +multivariate O +logistic O +regression O +analysis O +( O +two O +- O +sided O +P O +< O +0 O +. O +05 O +) O +. O + +RESULTS O +: O +LAG O +consisted O +of O +75 O +patients O +( O +46 O +% O +) O +versus O +88 O +HAG B +patients O +( O +54 O +% O +) O +. O + +AKI O +occurred O +significantly O +more O +often O +in O +LAG O +with O +36 O +% O +versus O +21 O +% O +in O +HAG O +( O +P O += O +0 O +. O +035 O +) O +. O + +Basic O +characteristics O +were O +comparable O +, O +except O +an O +increased O +rate O +of O +soft B +tissue I +infections I +in O +LAG O +. O + +Multivariate O +analysis O +revealed O +an O +odds O +ratio O +of O +2 O +. O +5 O +- O +fold O +for O +LAG O +to O +develop O +AKI B +compared O +with O +HAG B +( O +95 O +% O +confidence O +interval O +1 O +. O +195 O +to O +5 O +. O +124 O +, O +P O += O +0 O +. O +039 O +) O +. O + +CONCLUSION O +: O +Low O +adherence O +to O +SOPs O +for O +potentially O +nephrotoxic B +antibiotics O +was O +associated O +with O +a O +higher O +occurrence O +of O +AKI O +. O + +TRIAL O +REGISTRATION O +: O +Current O +Controlled O +Trials O +ISRCTN54598675 O +. O + +Registered O +17 O +August O +2007 O +. O + +Rhabdomyolysis B +in O +a O +hepatitis B +C I +virus I +infected I +patient O +treated O +with O +telaprevir O +and O +simvastatin O +. O + +A O +46 O +- O +year O +old O +man O +with O +a O +chronic B +hepatitis I +C I +virus I +infection I +received O +triple O +therapy O +with O +ribavirin O +, O +pegylated O +interferon O +and O +telaprevir O +. O + +The O +patient O +also O +received O +simvastatin O +. O + +One O +month O +after O +starting O +the O +antiviral O +therapy O +, O +the O +patient O +was O +admitted O +to O +the O +hospital O +because O +he O +developed O +rhabdomyolysis B +. O + +At O +admission O +simvastatin O +and O +all O +antiviral O +drugs O +were O +discontinued O +because O +toxicity B +due O +to O +a O +drug O +- O +drug O +interaction O +was O +suspected O +. O + +The O +creatine O +kinase O +peaked O +at O +62 O +, O +246 O +IU O +/ O +L O +and O +the O +patient O +was O +treated O +with O +intravenous O +normal O +saline O +. O + +The O +patient O +' O +s O +renal O +function O +remained O +unaffected O +. O + +Fourteen O +days O +after O +hospitalization O +, O +creatine O +kinase O +level O +had O +returned O +to O +230 O +IU O +/ O +L O +and O +the O +patient O +was O +discharged O +. O + +Telaprevir O +was O +considered O +the O +probable O +causative O +agent O +of O +an O +interaction O +with O +simvastatin O +according O +to O +the O +Drug O +Interaction O +Probability O +Scale O +. O + +The O +interaction O +is O +due O +to O +inhibition O +of O +CYP3A4 O +- O +mediated O +simvastatin O +clearance O +. O + +Simvastatin O +plasma O +concentration O +increased O +30 O +times O +in O +this O +patient O +and O +statin O +induced O +muscle B +toxicity I +is O +related O +to O +the O +concentration O +of O +the O +statin O +in O +blood O +. O + +In O +conclusion O +, O +with O +this O +case O +we O +illustrate O +that O +telaprevir O +as O +well O +as O +statins O +are O +susceptible O +to O +clinical O +relevant O +drug O +- O +drug O +interactions O +. O + +Combination O +of O +bortezomib O +, O +thalidomide O +, O +and O +dexamethasone O +( O +VTD O +) O +as O +a O +consolidation O +therapy O +after O +autologous O +stem O +cell O +transplantation O +for O +symptomatic O +multiple B +myeloma I +in O +Japanese O +patients O +. O + +Consolidation O +therapy O +for O +patients O +with O +multiple B +myeloma I +( O +MM B +) O +has O +been O +widely O +adopted O +to O +improve O +treatment O +response O +following O +autologous O +stem O +cell O +transplantation O +. O + +In O +this O +study O +, O +we O +retrospectively O +analyzed O +the O +safety O +and O +efficacy O +of O +combination O +regimen O +of O +bortezomib O +, O +thalidomide O +, O +and O +dexamethasone O +( O +VTD O +) O +as O +consolidation O +therapy O +in O +24 O +Japanese O +patients O +with O +newly O +diagnosed O +MM B +. O + +VTD O +consisted O +of O +bortezomib O +at O +a O +dose O +of O +1 O +. O +3 O +mg O +/ O +m O +( O +2 O +) O +and O +dexamethasone O +at O +a O +dose O +of O +40 O +mg O +/ O +day O +on O +days O +1 O +, O +8 O +, O +15 O +, O +and O +22 O +of O +a O +35 O +- O +day O +cycle O +, O +with O +daily O +oral O +thalidomide O +at O +a O +dose O +of O +100 O +mg O +/ O +day O +. O + +Grade O +3 O +- O +4 O +neutropenia B +and O +thrombocytopenia B +were O +documented O +in O +four O +and O +three O +patients O +( O +17 O +and O +13 O +% O +) O +, O +respectively O +, O +but O +drug O +dose O +reduction O +due O +to O +cytopenia B +was O +not O +required O +in O +any O +case O +. O + +Peripheral B +neuropathy I +was O +common O +( O +63 O +% O +) O +, O +but O +severe O +grade O +3 O +- O +4 O +peripheral B +neuropathy I +was O +not O +observed O +. O + +Very O +good O +partial O +response O +or O +better O +response O +( O +> O +VGPR O +) O +rates O +before O +and O +after O +consolidation O +therapy O +were O +54 O +and O +79 O +% O +, O +respectively O +. O + +Patients O +had O +a O +significant O +probability O +of O +improving O +from O +< O +VGPR O +before O +consolidation O +therapy O +to O +> O +VGPR O +after O +consolidation O +therapy O +( O +p O += O +0 O +. O +041 O +) O +. O + +The O +VTD O +regimen O +may O +be O +safe O +and O +effective O +as O +a O +consolidation O +therapy O +in O +the O +treatment O +of O +MM B +in O +Japanese O +population O +. O + +Conversion O +to O +sirolimus O +ameliorates O +cyclosporine O +- O +induced O +nephropathy B +in O +the O +rat O +: O +focus O +on O +serum O +, O +urine O +, O +gene O +, O +and O +protein O +renal O +expression O +biomarkers O +. O + +Protocols O +of O +conversion O +from O +cyclosporin O +A O +( O +CsA O +) O +to O +sirolimus O +( O +SRL O +) O +have O +been O +widely O +used O +in O +immunotherapy O +after O +transplantation O +to O +prevent O +CsA O +- O +induced O +nephropathy B +, O +but O +the O +molecular O +mechanisms O +underlying O +these O +protocols O +remain O +nuclear O +. O + +This O +study O +aimed O +to O +identify O +the O +molecular O +pathways O +and O +putative O +biomarkers O +of O +CsA O +- O +to O +- O +SRL O +conversion O +in O +a O +rat O +model O +. O + +Four O +animal O +groups O +( O +n O += O +6 O +) O +were O +tested O +during O +9 O +weeks O +: O +control O +, O +CsA O +, O +SRL O +, O +and O +conversion O +( O +CsA O +for O +3 O +weeks O +followed O +by O +SRL O +for O +6 O +weeks O +) O +. O + +Classical O +and O +emergent O +serum O +, O +urinary O +, O +and O +kidney O +tissue O +( O +gene O +and O +protein O +expression O +) O +markers O +were O +assessed O +. O + +Renal B +lesions I +were O +analyzed O +in O +hematoxylin O +and O +eosin O +, O +periodic O +acid O +- O +Schiff O +, O +and O +Masson O +' O +s O +trichrome O +stains O +. O + +SRL O +- O +treated O +rats O +presented O +proteinuria B +and O +NGAL O +( O +serum O +and O +urinary O +) O +as O +the O +best O +markers O +of O +renal B +impairment I +. O + +Short O +CsA O +treatment O +presented O +slight O +or O +even O +absent O +kidney B +lesions I +and O +TGF O +- O +b O +, O +NF O +- O +kb O +, O +mTOR O +, O +PCNA O +, O +TP53 O +, O +KIM O +- O +1 O +, O +and O +CTGF O +as O +relevant O +gene O +and O +protein O +changes O +. O + +Prolonged O +CsA O +exposure O +aggravated O +renal B +damage I +, O +without O +clear O +changes O +on O +the O +traditional O +markers O +, O +but O +with O +changes O +in O +serums O +TGF O +- O +b O +and O +IL O +- O +7 O +, O +TBARs O +clearance O +, O +and O +kidney O +TGF O +- O +b O +and O +mTOR O +. O + +Conversion O +to O +SRL O +prevented O +CsA O +- O +induced O +renal B +damage I +evolution O +( O +absent O +/ O +mild O +grade O +lesions O +) O +, O +while O +NGAL O +( O +serum O +versus O +urine O +) O +seems O +to O +be O +a O +feasible O +biomarker O +of O +CsA O +replacement O +to O +SRL O +. O + +Kinin O +B2 O +receptor O +deletion O +and O +blockage O +ameliorates O +cisplatin O +- O +induced O +acute B +renal I +injury I +. O + +Cisplatin O +treatment O +has O +been O +adopted O +in O +some O +chemotherapies O +; O +however O +, O +this O +drug O +can O +induce O +acute B +kidney I +injury I +due O +its O +ability O +to O +negatively O +affect O +renal O +function O +, O +augment O +serum O +levels O +of O +creatinine O +and O +urea O +, O +increase O +the O +acute B +tubular I +necrosis I +score O +and O +up O +- O +regulate O +cytokines O +( O +e O +. O +g O +. O +, O +IL O +- O +1b O +and O +TNF O +- O +a O +) O +. O + +The O +kinin O +B2 O +receptor O +has O +been O +associated O +with O +the O +inflammation B +process O +, O +as O +well O +as O +the O +regulation O +of O +cytokine O +expression O +, O +and O +its O +deletion O +resulted O +in O +an O +improvement O +in O +the O +diabetic B +nephropathy I +status O +. O + +To O +examine O +the O +role O +of O +the O +kinin O +B2 O +receptor O +in O +cisplatin O +- O +induced O +acute B +kidney I +injury I +, O +kinin O +B2 O +receptor O +knockout O +mice O +were O +challenged O +with O +cisplatin O +. O + +Additionally O +, O +WT O +mice O +were O +treated O +with O +a O +B2 O +receptor O +antagonist O +after O +cisplatin O +administration O +. O + +B2 O +receptor O +- O +deficient O +mice O +were O +less O +sensitive O +to O +this O +drug O +than O +the O +WT O +mice O +, O +as O +shown O +by O +reduced O +weight B +loss I +, O +better O +preservation O +of O +kidney O +function O +, O +down O +regulation O +of O +inflammatory O +cytokines O +and O +less O +acute B +tubular I +necrosis I +. O + +Moreover O +, O +treatment O +with O +the O +kinin O +B2 O +receptor O +antagonist O +effectively O +reduced O +the O +levels O +of O +serum O +creatinine O +and O +blood O +urea O +after O +cisplatin O +administration O +. O + +Thus O +, O +our O +data O +suggest O +that O +the O +kinin O +B2 O +receptor O +is O +involved O +in O +cisplatin O +- O +induced O +acute B +kidney I +injury I +by O +mediating O +the O +necrotic B +process O +and O +the O +expression O +of O +inflammatory O +cytokines O +, O +thus O +resulting O +in O +declined B +renal I +function I +. O + +These O +results O +highlight O +the O +kinin O +B2 O +receptor O +antagonist O +treatment O +in O +amelioration O +of O +nephrotoxicity B +induced O +by O +cisplatin O +therapy O +. O + +Safety O +and O +efficacy O +of O +fluocinolone O +acetonide O +intravitreal O +implant O +( O +0 O +. O +59 O +mg O +) O +in O +birdshot B +retinochoroidopathy I +. O + +PURPOSE O +: O +To O +report O +the O +treatment O +outcomes O +of O +the O +fluocinolone O +acetonide O +intravitreal O +implant O +( O +0 O +. O +59 O +mg O +) O +in O +patients O +with O +birdshot B +retinochoroidopathy I +whose O +disease O +is O +refractory O +or O +intolerant O +to O +conventional O +immunomodulatory O +therapy O +. O + +METHODS O +: O +A O +retrospective O +case O +series O +involving O +11 O +birdshot B +retinochoroidopathy I +patients O +( O +11 O +eyes O +) O +. O + +Eleven O +patients O +( O +11 O +eyes O +) O +underwent O +surgery O +for O +fluocinolone O +acetonide O +implant O +( O +0 O +. O +59 O +mg O +) O +. O + +Treatment O +outcomes O +of O +interest O +were O +noted O +at O +baseline O +, O +before O +fluocinolone O +acetonide O +implant O +, O +and O +then O +at O +6 O +months O +, O +1 O +year O +, O +2 O +years O +, O +3 O +years O +, O +and O +beyond O +3 O +years O +. O + +Disease O +activity O +markers O +, O +including O +signs O +of O +ocular B +inflammation I +, O +evidence O +of O +retinal B +vasculitis I +, O +Swedish O +interactive O +threshold O +algorithm O +- O +short O +wavelength O +automated O +perimetry O +Humphrey O +visual O +field O +analysis O +, O +electroretinographic O +parameters O +, O +and O +optical O +coherence O +tomography O +were O +recorded O +. O + +Data O +on O +occurrence O +of O +cataract B +and O +raised O +intraocular O +pressure O +were O +collected O +in O +all O +eyes O +. O + +RESULTS O +: O +Intraocular B +inflammation I +was O +present O +in O +54 O +. O +5 O +, O +9 O +. O +9 O +, O +11 O +. O +1 O +, O +and O +0 O +% O +of O +patients O +at O +baseline O +, O +6 O +months O +, O +1 O +year O +, O +2 O +years O +, O +3 O +years O +, O +and O +beyond O +3 O +years O +after O +receiving O +the O +implant O +, O +respectively O +. O + +Active O +vasculitis B +was O +noted O +in O +36 O +. O +3 O +% O +patients O +at O +baseline O +and O +0 O +% O +at O +3 O +years O +of O +follow O +- O +up O +. O + +More O +than O +20 O +% O +( O +47 O +. O +61 O +- O +67 O +. O +2 O +% O +) O +reduction O +in O +central O +retinal O +thickness O +was O +noted O +in O +all O +patients O +with O +cystoid B +macular I +edema I +at O +6 O +months O +, O +1 O +year O +, O +2 O +years O +, O +and O +3 O +years O +postimplant O +. O + +At O +baseline O +, O +54 O +. O +5 O +% O +patients O +were O +on O +immunomodulatory O +agents O +. O + +This O +percentage O +decreased O +to O +45 O +. O +45 O +, O +44 O +. O +4 O +, O +and O +14 O +. O +28 O +% O +at O +1 O +year O +, O +2 O +years O +, O +and O +3 O +years O +postimplant O +, O +respectively O +. O + +Adverse O +events O +included O +increased O +intraocular O +pressure O +( O +54 O +. O +5 O +% O +) O +and O +cataract B +formation O +( O +100 O +% O +) O +. O + +CONCLUSION O +: O +The O +data O +suggest O +that O +fluocinolone O +acetonide O +implant O +( O +0 O +. O +59 O +mg O +) O +helps O +to O +control O +inflammation B +in O +otherwise O +treatment O +- O +refractory O +cases O +of O +birdshot B +retinochoroidopathy I +. O + +It O +is O +associated O +with O +significant O +side O +effects O +of O +cataract B +and O +ocular B +hypertension I +requiring O +treatment O +. O + +Optimal O +precurarizing O +dose O +of O +rocuronium O +to O +decrease O +fasciculation B +and O +myalgia B +following O +succinylcholine O +administration O +. O + +BACKGROUND O +: O +Succinylcholine O +commonly O +produces O +frequent O +adverse O +effects O +, O +including O +muscle B +fasciculation I +and O +myalgia B +. O + +The O +current O +study O +identified O +the O +optimal O +dose O +of O +rocuronium O +to O +prevent O +succinylcholine O +- O +induced O +fasciculation B +and O +myalgia B +and O +evaluated O +the O +influence O +of O +rocuronium O +on O +the O +speed O +of O +onset O +produced O +by O +succinylcholine O +. O + +METHODS O +: O +This O +randomized O +, O +double O +- O +blinded O +study O +was O +conducted O +in O +100 O +patients O +randomly O +allocated O +into O +five O +groups O +of O +20 O +patients O +each O +. O + +Patients O +were O +randomized O +to O +receive O +0 O +. O +02 O +, O +0 O +. O +03 O +, O +0 O +. O +04 O +, O +0 O +. O +05 O +and O +0 O +. O +06 O +mg O +/ O +kg O +rocuronium O +as O +a O +precurarizing O +dose O +. O + +Neuromuscular O +monitoring O +after O +each O +precurarizing O +dose O +was O +recorded O +from O +the O +adductor O +pollicis O +muscle O +using O +acceleromyography O +with O +train O +- O +of O +- O +four O +stimulation O +of O +the O +ulnar O +nerve O +. O + +All O +patients O +received O +succinylcholine O +1 O +. O +5 O +mg O +/ O +kg O +at O +2 O +minutes O +after O +the O +precurarization O +, O +and O +were O +assessed O +the O +incidence O +and O +severity O +of O +fasciculations B +, O +while O +myalgia B +was O +assessed O +at O +24 O +hours O +after O +surgery O +. O + +RESULTS O +: O +The O +incidence O +and O +severity O +of O +visible O +muscle B +fasciculation I +was O +significantly O +less O +with O +increasing O +the O +amount O +of O +precurarizing O +dose O +of O +rocuronium O +( O +P O +< O +0 O +. O +001 O +) O +. O + +Those O +of O +myalgia B +tend O +to O +decrease O +according O +to O +increasing O +the O +amount O +of O +precurarizing O +dose O +of O +rocuronium O +, O +but O +there O +was O +no O +significance O +( O +P O += O +0 O +. O +072 O +) O +. O + +The O +onset O +time O +of O +succinylcholine O +was O +significantly O +longer O +with O +increasing O +the O +amount O +of O +precurarizing O +dose O +of O +rocuronium O +( O +P O +< O +0 O +. O +001 O +) O +. O + +CONCLUSIONS O +: O +Precurarization O +with O +0 O +. O +04 O +mg O +/ O +kg O +rocuronium O +was O +the O +optimal O +dose O +considering O +the O +reduction O +in O +the O +incidence O +and O +severity O +of O +fasciculation B +and O +myalgia B +with O +acceptable O +onset O +time O +, O +and O +the O +safe O +and O +effective O +precurarization O +. O + +Absence O +of O +PKC O +- O +alpha O +attenuates O +lithium O +- O +induced O +nephrogenic B +diabetes I +insipidus I +. O + +Lithium O +, O +an O +effective O +antipsychotic O +, O +induces O +nephrogenic B +diabetes I +insipidus I +( O +NDI B +) 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 O +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 O +- O +induced O +polyuria B +. 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 O +for O +0 O +, O +3 O +or O +5 O +days O +. O + +WT O +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 O +for O +6 O +weeks O +. O + +Lithium O +- 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 O +- 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 O +, O +potassium O +and O +calcium O +were O +elevated O +in O +lithium O +- O +fed O +WT O +but O +not O +in O +lithium O +- 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 O +- O +induced O +NDI B +, O +and O +prevents O +the O +development O +of O +the O +severe O +polyuria B +associated O +with O +lithium O +therapy O +. O + +Is O +Dysguesia B +Going O +to O +be O +a O +Rare O +or O +a O +Common O +Side O +- O +effect O +of O +Amlodipine O +? O + +A O +very O +rare O +side O +- O +effect O +of O +amlodipine O +is O +dysguesia B +. O + +A O +review O +of O +the O +literature O +produced O +only O +one O +case O +. O + +We O +report O +a O +case O +about O +a O +female O +with O +essential O +hypertension B +on O +drug O +treatment O +with O +amlodipine O +developed O +loss B +of I +taste I +sensation I +. O + +Condition O +moderately O +improved O +on O +stoppage O +of O +the O +drug O +for O +25 O +days O +. O + +We O +conclude O +that O +amlodipine O +can O +cause O +dysguesia B +. O + +Here O +, O +we O +describe O +the O +clinical O +presentation O +and O +review O +the O +relevant O +literature O +on O +amlodipine O +and O +dysguesia B +. O + +Rhabdomyolysis B +in O +association O +with O +simvastatin O +and O +dosage O +increment O +in O +clarithromycin O +. O + +Clarithromycin O +is O +the O +most O +documented O +cytochrome O +P450 O +3A4 O +( O +CYP3A4 O +) O +inhibitor O +to O +cause O +an O +adverse O +interaction O +with O +simvastatin O +. O + +This O +particular O +case O +is O +of O +interest O +as O +rhabdomyolysis B +only O +occurred O +after O +an O +increase O +in O +the O +dose O +of O +clarithromycin O +. O + +The O +patient O +developed O +raised O +cardiac O +biomarkers O +without O +any O +obvious O +cardiac O +issues O +, O +a O +phenomenon O +that O +has O +been O +linked O +to O +rhabdomyolysis B +previously O +. O + +To O +date O +, O +there O +has O +been O +no O +reported O +effect O +of O +rhabdomyolysis B +on O +the O +structure O +and O +function O +of O +cardiac O +muscle O +. O + +Clinicians O +need O +to O +be O +aware O +of O +prescribing O +concomitant O +medications O +that O +increase O +the O +risk O +of O +myopathy B +or O +inhibit O +the O +CYP3A4 O +enzyme O +. O + +Our O +case O +suggests O +that O +troponin O +elevation O +could O +be O +associated O +with O +statin O +induced O +rhabdomyolysis B +, O +which O +may O +warrant O +further O +studies O +. O + +Characterization O +of O +a O +novel O +BCHE O +" O +silent O +" O +allele O +: O +point O +mutation O +( O +p O +. O +Val204Asp O +) O +causes O +loss O +of O +activity O +and O +prolonged O +apnea B +with O +suxamethonium O +. O + +Butyrylcholinesterase B +deficiency I +is O +characterized O +by O +prolonged O +apnea B +after O +the O +use O +of O +muscle O +relaxants O +( O +suxamethonium O +or O +mivacurium O +) O +in O +patients O +who O +have O +mutations O +in O +the O +BCHE O +gene O +. O + +Here O +, O +we O +report O +a O +case O +of O +prolonged O +neuromuscular B +block I +after O +administration O +of O +suxamethonium O +leading O +to O +the O +discovery O +of O +a O +novel O +BCHE O +variant O +( O +c O +. O +695T O +> O +A O +, O +p O +. O +Val204Asp O +) O +. O + +Inhibition O +studies O +, O +kinetic O +analysis O +and O +molecular O +dynamics O +were O +undertaken O +to O +understand O +how O +this O +mutation O +disrupts O +the O +catalytic O +triad O +and O +determines O +a O +" O +silent O +" O +phenotype O +. O + +Low O +activity O +of O +patient O +plasma O +butyrylcholinesterase O +with O +butyrylthiocholine O +( O +BTC O +) O +and O +benzoylcholine O +, O +and O +values O +of O +dibucaine O +and O +fluoride O +numbers O +fit O +with O +heterozygous O +atypical O +silent O +genotype O +. O + +Electrophoretic O +analysis O +of O +plasma O +BChE O +of O +the O +proband O +and O +his O +mother O +showed O +that O +patient O +has O +a O +reduced O +amount O +of O +tetrameric O +enzyme O +in O +plasma O +and O +that O +minor O +fast O +- O +moving O +BChE O +components O +: O +monomer O +, O +dimer O +, O +and O +monomer O +- O +albumin O +conjugate O +are O +missing O +. O + +Kinetic O +analysis O +showed O +that O +the O +p O +. O +Val204Asp O +/ O +p O +. O +Asp70Gly O +- O +p O +. O +Ala539Thr O +BChE O +displays O +a O +pure O +Michaelian O +behavior O +with O +BTC O +as O +the O +substrate O +. O + +Both O +catalytic O +parameters O +Km O += O +265 O +uM O +for O +BTC O +, O +two O +times O +higher O +than O +that O +of O +the O +atypical O +enzyme O +, O +and O +a O +low O +Vmax O +are O +consistent O +with O +the O +absence O +of O +activity O +against O +suxamethonium O +. O + +Molecular O +dynamic O +( O +MD O +) O +simulations O +showed O +that O +the O +overall O +effect O +of O +the O +mutation O +p O +. O +Val204Asp O +is O +disruption O +of O +hydrogen O +bonding O +between O +Gln223 O +and O +Glu441 O +, O +leading O +Ser198 O +and O +His438 O +to O +move O +away O +from O +each O +other O +with O +subsequent O +disruption O +of O +the O +catalytic O +triad O +functionality O +regardless O +of O +the O +type O +of O +substrate O +. O + +MD O +also O +showed O +that O +the O +enzyme O +volume O +is O +increased O +, O +suggesting O +a O +pre O +- O +denaturation O +state O +. O + +This O +fits O +with O +the O +reduced O +concentration O +of O +p O +. O +Ala204Asp O +/ O +p O +. O +Asp70Gly O +- O +p O +. O +Ala539Thr O +tetrameric O +enzyme O +in O +the O +plasma O +and O +non O +- O +detectable O +fast O +moving O +- O +bands O +on O +electrophoresis O +gels O +. O + +Delayed O +anemia B +after O +treatment O +with O +injectable O +artesunate O +in O +the O +Democratic O +Republic O +of O +the O +Congo O +: O +a O +manageable O +issue O +. O + +Cases O +of O +delayed O +hemolytic B +anemia I +have O +been O +described O +after O +treatment O +with O +injectable O +artesunate O +, O +the O +current O +World O +Health O +Organization O +( O +WHO O +) O +- O +recommended O +first O +- O +line O +drug O +for O +the O +treatment O +of O +severe O +malaria B +. O + +A O +total O +of O +350 O +patients O +( O +215 O +[ O +61 O +. O +4 O +% O +] O +< O +5 O +years O +of O +age O +and O +135 O +[ O +38 O +. O +6 O +% O +] O +> O +5 O +years O +of O +age O +) O +were O +followed O +- O +up O +after O +treatment O +with O +injectable O +artesunate O +for O +severe O +malaria B +in O +hospitals O +and O +health O +centers O +of O +the O +Democratic O +Republic O +of O +the O +Congo O +. O + +Complete O +series O +of O +hemoglobin O +( O +Hb O +) O +measurements O +were O +available O +for O +201 O +patients O +. O + +A O +decrease O +in O +Hb O +levels O +between O +2 O +and O +5 O +g O +/ O +dL O +was O +detected O +in O +23 O +( O +11 O +. O +4 O +% O +) O +patients O +during O +the O +follow O +- O +up O +period O +. O + +For O +five O +patients O +, O +Hb O +levels O +decreased O +below O +5 O +g O +/ O +dL O +during O +at O +least O +one O +follow O +- O +up O +visit O +. O + +All O +cases O +of O +delayed O +anemia B +were O +clinically O +manageable O +and O +resolved O +within O +one O +month O +. O + +Regulation O +of O +signal O +transducer O +and O +activator O +of O +transcription O +3 O +and O +apoptotic O +pathways O +by O +betaine O +attenuates O +isoproterenol O +- O +induced O +acute O +myocardial B +injury I +in O +rats O +. O + +The O +present O +study O +was O +designed O +to O +investigate O +the O +cardioprotective O +effects O +of O +betaine O +on O +acute O +myocardial B +ischemia I +induced O +experimentally O +in O +rats O +focusing O +on O +regulation O +of O +signal O +transducer O +and O +activator O +of O +transcription O +3 O +( O +STAT3 O +) O +and O +apoptotic O +pathways O +as O +the O +potential O +mechanism O +underlying O +the O +drug O +effect O +. O + +Male O +Sprague O +Dawley O +rats O +were O +treated O +with O +betaine O +( O +100 O +, O +200 O +, O +and O +400 O +mg O +/ O +kg O +) O +orally O +for O +40 O +days O +. O + +Acute O +myocardial B +ischemic I +injury I +was O +induced O +in O +rats O +by O +subcutaneous O +injection O +of O +isoproterenol O +( O +85 O +mg O +/ O +kg O +) O +, O +for O +two O +consecutive O +days O +. O + +Serum O +cardiac O +marker O +enzyme O +, O +histopathological O +variables O +and O +expression O +of O +protein O +levels O +were O +analyzed O +. O + +Oral O +administration O +of O +betaine O +( O +200 O +and O +400 O +mg O +/ O +kg O +) O +significantly O +reduced O +the O +level O +of O +cardiac O +marker O +enzyme O +in O +the O +serum O +and O +prevented O +left B +ventricular I +remodeling I +. O + +Western O +blot O +analysis O +showed O +that O +isoproterenol O +- O +induced O +phosphorylation O +of O +STAT3 O +was O +maintained O +or O +further O +enhanced O +by O +betaine O +treatment O +in O +myocardium O +. O + +Furthermore O +, O +betaine O +( O +200 O +and O +400 O +mg O +/ O +kg O +) O +treatment O +increased O +the O +ventricular O +expression O +of O +Bcl O +- O +2 O +and O +reduced O +the O +level O +of O +Bax O +, O +therefore O +causing O +a O +significant O +increase O +in O +the O +ratio O +of O +Bcl O +- O +2 O +/ O +Bax O +. O + +The O +protective O +role O +of O +betaine O +on O +myocardial B +damage I +was O +further O +confirmed O +by O +histopathological O +examination O +. O + +In O +summary O +, O +our O +results O +showed O +that O +betaine O +pretreatment O +attenuated O +isoproterenol O +- O +induced O +acute O +myocardial B +ischemia I +via O +the O +regulation O +of O +STAT3 O +and O +apoptotic O +pathways O +. O + +Quetiapine O +- O +induced O +neutropenia B +in O +a O +bipolar B +patient O +with O +hepatocellular B +carcinoma I +. O + +OBJECTIVE O +: O +Quetiapine O +is O +a O +dibenzothiazepine O +derivative O +, O +similar O +to O +clozapine O +, O +which O +has O +the O +highest O +risk O +of O +causing O +blood B +dyscrasias I +, O +especially O +neutropenia B +. O + +There O +are O +some O +case O +reports O +about O +this O +side O +effect O +of O +quetiapine O +, O +but O +possible O +risk O +factors O +are O +seldom O +discussed O +and O +identified O +. O + +A O +case O +of O +a O +patient O +with O +hepatocellular B +carcinoma I +that O +developed O +neutropenia B +after O +treatment O +with O +quetiapine O +is O +described O +here O +. O + +CASE O +REPORT O +: O +A O +62 O +- O +year O +- O +old O +Taiwanese O +widow O +with O +bipolar B +disorder I +was O +diagnosed O +with O +hepatocellular B +carcinoma I +at O +age O +60 O +. O + +She O +developed O +leucopenia B +after O +being O +treated O +with O +quetiapine O +. O + +After O +quetiapine O +was O +discontinued O +, O +her O +white O +blood O +cell O +count O +returned O +to O +normal O +. O + +CONCLUSIONS O +: O +Although O +neutropenia B +is O +not O +a O +common O +side O +effect O +of O +quetiapine O +, O +physicians O +should O +be O +cautious O +about O +its O +presentation O +and O +associated O +risk O +factors O +. O + +Hepatic B +dysfunction I +may O +be O +one O +of O +the O +possible O +risk O +factors O +, O +and O +concomitant O +fever B +may O +be O +a O +diagnostic O +marker O +for O +adverse O +reaction O +to O +quetiapine O +. O + +Lateral O +antebrachial O +cutaneous I +neuropathy I +after O +steroid O +injection O +at O +lateral O +epicondyle O +. O + +BACKGROUND O +AND O +OBJECTIVES O +: O +This O +report O +aimed O +to O +present O +a O +case O +of O +lateral B +antebrachial I +cutaneous I +neuropathy I +( O +LACNP B +) O +that O +occurred O +after O +a O +steroid O +injection O +in O +the O +lateral O +epicondyle O +to O +treat O +lateral B +epicondylitis I +in O +a O +40 O +- O +year O +- O +old O +woman O +. O + +MATERIAL O +AND O +METHOD O +: O +A O +40 O +- O +year O +- O +old O +woman O +presented O +with O +decreased B +sensation I +and O +paresthesia B +over O +her O +right O +lateral O +forearm O +; O +the O +paresthesia B +had O +occurred O +after O +a O +steroid O +injection O +in O +the O +right O +lateral O +epicondyle O +3 O +months O +before O +. O + +Her O +sensation O +of O +light O +touch O +and O +pain B +was O +diminished O +over O +the O +lateral O +side O +of O +the O +right O +forearm O +and O +wrist O +area O +. O + +RESULTS O +: O +The O +sensory O +action O +potential O +amplitude O +of O +the O +right O +lateral O +antebrachial O +cutaneous O +nerve O +( O +LACN O +) O +( O +6 O +. O +2 O +uV O +) O +was O +lower O +than O +that O +of O +the O +left O +( O +13 O +. O +1 O +uV O +) O +. O + +The O +difference O +of O +amplitude O +between O +both O +sides O +was O +significant O +because O +there O +was O +more O +than O +a O +50 O +% O +reduction O +. O + +She O +was O +diagnosed O +with O +right O +LACNP B +( O +mainly O +axonal O +involvement O +) O +on O +the O +basis O +of O +the O +clinical O +manifestation O +and O +the O +electrodiagnostic O +findings O +. O + +Her O +symptoms O +improved O +through O +physical O +therapy O +but O +persisted O +to O +some O +degree O +. O + +CONCLUSION O +: O +This O +report O +describes O +the O +case O +of O +a O +woman O +with O +LACNP B +that O +developed O +after O +a O +steroid O +injection O +for O +the O +treatment O +of O +lateral B +epicondylitis I +. O + +An O +electrodiagnostic O +study O +, O +including O +a O +nerve O +conduction O +study O +of O +the O +LACN O +, O +was O +helpful O +to O +diagnose O +right O +LACNP B +and O +to O +find O +the O +passage O +of O +the O +LACN O +on O +the O +lateral O +epicondyle O +. O + +Curcumin O +prevents O +maleate O +- O +induced O +nephrotoxicity B +: O +relation O +to O +hemodynamic O +alterations O +, O +oxidative O +stress O +, O +mitochondrial O +oxygen O +consumption O +and O +activity O +of O +respiratory O +complex O +I O +. O + +The O +potential O +protective O +effect O +of O +the O +dietary O +antioxidant O +curcumin O +( O +120 O +mg O +/ O +Kg O +/ O +day O +for O +6 O +days O +) O +against O +the O +renal B +injury I +induced O +by O +maleate O +was O +evaluated O +. O + +Tubular O +proteinuria B +and O +oxidative O +stress O +were O +induced O +by O +a O +single O +injection O +of O +maleate O +( O +400 O +mg O +/ O +kg O +) O +in O +rats O +. O + +Maleate O +- O +induced O +renal B +injury I +included O +increase O +in O +renal O +vascular O +resistance O +and O +in O +the O +urinary O +excretion O +of O +total O +protein O +, O +glucose O +, O +sodium O +, O +neutrophil O +gelatinase O +- O +associated O +lipocalin O +( O +NGAL O +) O +and O +N O +- O +acetyl O +b O +- O +D O +- O +glucosaminidase O +( O +NAG O +) O +, O +upregulation O +of O +kidney B +injury O +molecule O +( O +KIM O +) O +- O +1 O +, O +decrease O +in O +renal O +blood O +flow O +and O +claudin O +- O +2 O +expression O +besides O +of O +necrosis B +and O +apoptosis O +of O +tubular O +cells O +on O +24 O +h O +. O + +Oxidative O +stress O +was O +determined O +by O +measuring O +the O +oxidation O +of O +lipids O +and O +proteins O +and O +diminution O +in O +renal O +Nrf2 O +levels O +. O + +Studies O +were O +also O +conducted O +in O +renal O +epithelial O +LLC O +- O +PK1 O +cells O +and O +in O +mitochondria O +isolated O +from O +kidneys O +of O +all O +the O +experimental O +groups O +. O + +Maleate O +induced O +cell O +damage O +and O +reactive O +oxygen O +species O +( O +ROS O +) O +production O +in O +LLC O +- O +PK1 O +cells O +in O +culture O +. O + +In O +addition O +, O +maleate O +treatment O +reduced O +oxygen O +consumption O +in O +ADP O +- O +stimulated O +mitochondria O +and O +diminished O +respiratory O +control O +index O +when O +using O +malate O +/ O +glutamate O +as O +substrate O +. O + +The O +activities O +of O +both O +complex O +I O +and O +aconitase O +were O +also O +diminished O +. O + +All O +the O +above O +- O +described O +alterations O +were O +prevented O +by O +curcumin O +. O + +It O +is O +concluded O +that O +curcumin O +is O +able O +to O +attenuate O +in O +vivo O +maleate O +- O +induced O +nephropathy B +and O +in O +vitro O +cell O +damage O +. O + +The O +in O +vivo O +protection O +was O +associated O +to O +the O +prevention O +of O +oxidative O +stress O +and O +preservation O +of O +mitochondrial O +oxygen O +consumption O +and O +activity O +of O +respiratory O +complex O +I O +, O +and O +the O +in O +vitro O +protection O +was O +associated O +to O +the O +prevention O +of O +ROS O +production O +. O + +Anticonvulsant O +actions O +of O +MK O +- O +801 O +on O +the O +lithium O +- O +pilocarpine O +model O +of O +status B +epilepticus I +in O +rats O +. O + +MK O +- O +801 O +, O +a O +noncompetitive O +N O +- O +methyl O +- O +D O +- O +aspartate O +( O +NMDA O +) O +receptor O +antagonist O +, O +was O +tested O +for O +anticonvulsant O +effects O +in O +rats O +using O +two O +seizure B +models O +, O +coadministration O +of O +lithium O +and O +pilocarpine O +and O +administration O +of O +a O +high O +dose O +of O +pilocarpine O +alone O +. O + +Three O +major O +results O +are O +reported O +. O + +First O +, O +pretreatment O +with O +MK O +- O +801 O +produced O +an O +effective O +and O +dose O +- O +dependent O +anticonvulsant O +action O +with O +the O +lithium O +- O +pilocarpine O +model O +but O +not O +with O +rats O +treated O +with O +pilocarpine O +alone O +, O +suggesting O +that O +different O +biochemical O +mechanisms O +control O +seizures B +in O +these O +two O +models O +. O + +Second O +, O +the O +anticonvulsant O +effect O +of O +MK O +- O +801 O +in O +the O +lithium O +- O +pilocarpine O +model O +only O +occurred O +after O +initial O +periods O +of O +seizure B +activity O +. O + +This O +observation O +is O +suggested O +to O +be O +an O +in O +vivo O +demonstration O +of O +the O +conclusion O +derived O +from O +in O +vitro O +experiments O +that O +MK O +- O +801 O +binding O +requires O +agonist O +- O +induced O +opening O +of O +the O +channel O +sites O +of O +the O +NMDA O +receptor O +. O + +Third O +, O +although O +it O +is O +relatively O +easy O +to O +block O +seizures B +induced O +by O +lithium O +and O +pilocarpine O +by O +administration O +of O +anticonvulsants O +prior O +to O +pilocarpine O +, O +it O +is O +more O +difficult O +to O +terminate O +ongoing O +status B +epilepticus I +and O +block O +the O +lethality O +of O +the O +seizures B +. O + +Administration O +of O +MK O +- O +801 O +30 O +or O +60 O +min O +after O +pilocarpine O +, O +i O +. O +e O +. O +, O +during O +status B +epilepticus I +, O +gradually O +reduced O +electrical O +and O +behavioral O +seizure B +activity O +and O +greatly O +enhanced O +the O +survival O +rate O +. O + +These O +results O +suggest O +that O +activation O +of O +NMDA O +receptors O +plays O +an O +important O +role O +in O +status B +epilepticus I +and O +brain B +damage I +in O +the O +lithium O +- O +pilocarpine O +model O +. O + +This O +was O +further O +supported O +by O +results O +showing O +that O +nonconvulsive O +doses O +of O +NMDA O +and O +pilocarpine O +were O +synergistic O +, O +resulting O +in O +status B +epilepticus I +and O +subsequent O +mortality O +. O + +Continuous O +infusion O +tobramycin O +combined O +with O +carbenicillin O +for O +infections B +in O +cancer B +patients O +. O + +The O +cure O +rate O +of O +infections B +in O +cancer B +patients O +is O +adversely O +affected O +by O +neutropenia B +( O +less O +than O +1 O +, O +000 O +/ O +mm3 O +) O +. O + +In O +particular O +, O +patients O +with O +severe O +neutropenia B +( O +less O +than O +100 O +/ O +mm3 O +) O +have O +shown O +a O +poor O +response O +to O +antibiotics O +. O + +To O +overcome O +the O +adverse O +effects O +of O +neutropenia B +, O +tobramycin O +was O +given O +by O +continuous O +infusion O +and O +combined O +with O +intermittent O +carbenicillin O +. O + +Tobramycin O +was O +given O +to O +a O +total O +daily O +dose O +of O +300 O +mg O +/ O +m2 O +and O +carbenicillin O +was O +given O +at O +a O +dose O +of O +5 O +gm O +every O +four O +hours O +. O + +There O +were O +125 O +infectious B +episodes O +in O +116 O +cancer B +patients O +receiving O +myelosuppressive O +chemotherapy O +. O + +The O +overall O +cure O +rate O +was O +70 O +% O +. O + +Pneumonia B +was O +the O +most O +common O +infection B +and O +61 O +% O +of O +59 O +episodes O +were O +cured O +. O + +Gram O +- O +negative O +bacilli O +were O +the O +most O +common O +causative O +organisms O +and O +69 O +% O +of O +these O +infections B +were O +cured O +. O + +The O +most O +common O +pathogen O +was O +Klebsiella O +pneumoniae O +and O +this O +, O +together O +with O +Escherichia O +coli O +and O +Pseudomonas O +aeruginosa O +, O +accounted O +for O +74 O +% O +of O +all O +gram B +- I +negative I +bacillary I +infections I +. O + +Response O +was O +not O +influenced O +by O +the O +initial O +neutrophil O +count O +, O +with O +a O +62 O +% O +cure O +rate O +for O +39 O +episodes O +associated O +with O +severe O +neutropenia B +. O + +However O +, O +failure O +of O +the O +neutrophil O +count O +to O +increase O +during O +therapy O +adversely O +affected O +response O +. O + +Azotemia B +was O +the O +major O +side O +effect O +recognized O +, O +and O +it O +occurred O +in O +11 O +% O +of O +episodes O +. O + +Major O +azotemia B +( O +serum O +creatinine O +greater O +than O +2 O +. O +5 O +mg O +/ O +dl O +or O +BUN O +greater O +than O +50 O +mg O +/ O +dl O +) O +occurred O +in O +only O +2 O +% O +. O + +Azotemia B +was O +not O +related O +to O +duration O +of O +therapy O +or O +serum O +tobramycin O +concentration O +. O + +This O +antibiotic O +regimen O +showed O +both O +therapeutic O +efficacy O +and O +acceptable O +renal B +toxicity I +for O +these O +patients O +. O + +Incidence O +of O +solid O +tumours B +among O +pesticide O +applicators O +exposed O +to O +the O +organophosphate O +insecticide O +diazinon O +in O +the O +Agricultural O +Health O +Study O +: O +an O +updated O +analysis O +. O + +OBJECTIVE O +: O +Diazinon O +, O +a O +common O +organophosphate O +insecticide O +with O +genotoxic O +properties O +, O +was O +previously O +associated O +with O +lung B +cancer I +in O +the O +Agricultural O +Health O +Study O +( O +AHS O +) O +cohort O +, O +but O +few O +other O +epidemiological O +studies O +have O +examined O +diazinon O +- O +associated O +cancer B +risk O +. O + +We O +used O +updated O +diazinon O +exposure O +and O +cancer B +incidence O +information O +to O +evaluate O +solid O +tumour B +risk O +in O +the O +AHS O +. O + +METHODS O +: O +Male O +pesticide O +applicators O +in O +Iowa O +and O +North O +Carolina O +reported O +lifetime O +diazinon O +use O +at O +enrolment O +( O +1993 O +- O +1997 O +) O +and O +follow O +- O +up O +( O +1998 O +- O +2005 O +) O +; O +cancer B +incidence O +was O +assessed O +through O +2010 O +( O +North O +Carolina O +) O +/ O +2011 O +( O +Iowa O +) O +. O + +Among O +applicators O +with O +usage O +information O +sufficient O +to O +evaluate O +exposure O +- O +response O +patterns O +, O +we O +used O +Poisson O +regression O +to O +estimate O +adjusted O +rate O +ratios O +( O +RRs O +) O +and O +95 O +% O +CI O +for O +cancer B +sites O +with O +> O +10 O +exposed O +cases O +for O +both O +lifetime O +( O +LT O +) O +exposure O +days O +and O +intensity O +- O +weighted O +( O +IW O +) O +lifetime O +exposure O +days O +( O +accounting O +for O +factors O +impacting O +exposure O +) O +. O + +RESULTS O +: O +We O +observed O +elevated O +lung B +cancer I +risks O +( O +N O += O +283 O +) O +among O +applicators O +with O +the O +greatest O +number O +of O +LT O +( O +RR O += O +1 O +. O +60 O +; O +95 O +% O +CI O +1 O +. O +11 O +to O +2 O +. O +31 O +; O +Ptrend O += O +0 O +. O +02 O +) O +and O +IW O +days O +of O +diazinon O +use O +( O +RR O += O +1 O +. O +41 O +; O +95 O +% O +CI O +0 O +. O +98 O +to O +2 O +. O +04 O +; O +Ptrend O += O +0 O +. O +08 O +) O +. O + +Kidney B +cancer I +( O +N O += O +94 O +) O +risks O +were O +non O +- O +significantly O +elevated O +( O +RRLT O +days O += O +1 O +. O +77 O +; O +95 O +% O +CI O +0 O +. O +90 O +to O +3 O +. O +51 O +; O +Ptrend O += O +0 O +. O +09 O +; O +RRIW O +days O +1 O +. O +37 O +; O +95 O +% O +CI O +0 O +. O +64 O +to O +2 O +. O +92 O +; O +Ptrend O += O +0 O +. O +50 O +) O +, O +as O +were O +risks O +for O +aggressive B +prostate I +cancer I +( O +N O += O +656 O +) O +. O + +CONCLUSIONS O +: O +Our O +updated O +evaluation O +of O +diazinon O +provides O +additional O +evidence O +of O +an O +association O +with O +lung B +cancer I +risk O +. O + +Newly O +identified O +links O +to O +kidney B +cancer I +and O +associations O +with O +aggressive B +prostate I +cancer I +require O +further O +evaluation O +. O + +Associations O +of O +Ozone O +and O +PM2 O +. O +5 O +Concentrations O +With O +Parkinson B +' I +s I +Disease I +Among O +Participants O +in O +the O +Agricultural O +Health O +Study O +. O + +OBJECTIVE O +: O +This O +study O +describes O +associations O +of O +ozone O +and O +fine O +particulate O +matter O +with O +Parkinson B +' I +s I +disease I +observed O +among O +farmers O +in O +North O +Carolina O +and O +Iowa O +. O + +METHODS O +: O +We O +used O +logistic O +regression O +to O +determine O +the O +associations O +of O +these O +pollutants O +with O +self O +- O +reported O +, O +doctor O +- O +diagnosed O +Parkinson B +' I +s I +disease I +. O + +Daily O +predicted O +pollutant O +concentrations O +were O +used O +to O +derive O +surrogates O +of O +long O +- O +term O +exposure O +and O +link O +them O +to O +study O +participants O +' O +geocoded O +addresses O +. O + +RESULTS O +: O +We O +observed O +positive O +associations O +of O +Parkinson B +' I +s I +disease I +with O +ozone O +( O +odds O +ratio O += O +1 O +. O +39 O +; O +95 O +% O +CI O +: O +0 O +. O +98 O +to O +1 O +. O +98 O +) O +and O +fine O +particulate O +matter O +( O +odds O +ratio O += O +1 O +. O +34 O +; O +95 O +% O +CI O +: O +0 O +. O +93 O +to O +1 O +. O +93 O +) O +in O +North O +Carolina O +but O +not O +in O +Iowa O +. O + +CONCLUSIONS O +: O +The O +plausibility O +of O +an O +effect O +of O +ambient O +concentrations O +of O +these O +pollutants O +on O +Parkinson B +' I +s I +disease I +risk O +is O +supported O +by O +experimental O +data O +demonstrating O +damage O +to I +dopaminergic I +neurons I +at O +relevant O +concentrations O +. O + +Additional O +studies O +are O +needed O +to O +address O +uncertainties O +related O +to O +confounding O +and O +to O +examine O +temporal O +aspects O +of O +the O +associations O +we O +observed O +. O + +Low O +functional O +programming O +of O +renal O +AT2R O +mediates O +the O +developmental O +origin O +of O +glomerulosclerosis B +in O +adult O +offspring O +induced O +by O +prenatal O +caffeine O +exposure O +. O + +UNASSIGNED O +: O +Our O +previous O +study O +has O +indicated O +that O +prenatal O +caffeine O +exposure O +( O +PCE O +) O +could O +induce O +intrauterine B +growth I +retardation I +( O +IUGR B +) O +of O +offspring O +. O + +Recent O +research O +suggested O +that O +IUGR O +is O +a O +risk O +factor O +for O +glomerulosclerosis B +. O + +However O +, O +whether O +PCE O +could O +induce O +glomerulosclerosis B +and O +its O +underlying O +mechanisms O +remain O +unknown O +. O + +This O +study O +aimed O +to O +demonstrate O +the O +induction O +to O +glomerulosclerosis B +in O +adult O +offspring O +by O +PCE O +and O +its O +intrauterine O +programming O +mechanisms O +. O + +A O +rat O +model O +of O +IUGR B +was O +established O +by O +PCE O +, O +male O +fetuses O +and O +adult O +offspring O +at O +the O +age O +of O +postnatal O +week O +24 O +were O +euthanized O +. O + +The O +results O +revealed O +that O +the O +adult O +offspring O +kidneys O +in O +the O +PCE O +group O +exhibited O +glomerulosclerosis B +as O +well O +as O +interstitial B +fibrosis I +, O +accompanied O +by O +elevated O +levels O +of O +serum O +creatinine O +and O +urine O +protein O +. O + +Renal O +angiotensin O +II O +receptor O +type O +2 O +( O +AT2R O +) O +gene O +expression O +in O +adult O +offspring O +was O +reduced O +by O +PCE O +, O +whereas O +the O +renal O +angiotensin O +II O +receptor O +type O +1a O +( O +AT1aR O +) O +/ O +AT2R O +expression O +ratio O +was O +increased O +. 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O + +A O +61 O +year O +old O +female O +developed O +fatal O +hepatic B +failure I +after O +phenytoin O +administration O +. O + +A O +typical O +multisystem O +clinical O +pattern O +precedes O +the O +manifestations O +of O +hepatic B +injury I +. O + +The O +hematologic O +, O +biochemical O +and O +pathologic O +features O +indicate O +a O +mixed O +hepatocellular B +damage I +due O +to O +drug B +hypersensitivity I +. O + +In O +a O +patient O +receiving O +phenytoin O +who O +presents O +a O +viral B +- I +like I +illness I +, O +early O +recognition O +and O +discontinuation O +of O +the O +drug O +are O +mandatory O +. O + +Treatment O +of O +lethal O +pertussis B +vaccine O +reaction O +with O +histamine O +H1 O +antagonists O +. O + +We O +studied O +mortality O +after O +pertussis B +immunization O +in O +the O +mouse O +. 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O + +In O +a O +double O +blind O +, O +crossover O +study O +6 O +h O +infusions O +of O +adrenaline O +( O +15 O +ng O +/ O +kg O +/ O +min O +; O +1 O +ng O += O +5 O +. O +458 O +pmol O +) O +, O +noradrenaline O +( O +30 O +ng O +/ O +kg O +/ O +min O +; O +1 O +ng O += O +5 O +. O +911 O +pmol O +) O +, O +and O +a O +5 O +% O +dextrose O +solution O +( O +5 O +. O +4 O +ml O +/ O +h O +) O +, O +were O +given O +to O +ten O +healthy O +volunteers O +in O +random O +order O +2 O +weeks O +apart O +. O + +By O +means O +of O +intra O +- O +arterial O +ambulatory O +monitoring O +the O +haemodynamic O +effects O +were O +followed O +for O +18 O +h O +after O +the O +infusions O +were O +stopped O +. O + +Adrenaline O +, O +but O +not O +noradrenaline O +, O +caused O +a O +delayed O +and O +protracted O +pressor O +effect O +. 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O + +In O +the O +present O +study O +, O +the O +effects O +of O +three O +alkylxanthines O +with O +different O +potencies O +as O +adenosine O +antagonists O +8 O +- O +phenyltheophylline O +, O +theophylline O +and O +enprofylline O +, O +were O +examined O +in O +rats O +developing O +acute B +renal I +failure I +after O +4 O +daily O +injections O +of O +gentamicin O +( O +200 O +mg O +kg O +- O +1 O +) O +. O + +Renal O +function O +was O +assessed O +by O +biochemical O +( O +plasma O +urea O +and O +creatinine O +) O +, O +functional O +( O +urine O +analysis O +and O +[ O +3H O +] O +inulin O +and O +[ O +14C O +] O +p O +- O +aminohippuric O +acid O +clearances O +) O +and O +morphological O +( O +degree O +of O +necrosis B +) O +indices O +. O + +The O +various O +drug O +treatments O +produced O +improvements O +in O +some O +, O +but O +not O +all O +, O +measurements O +of O +renal O +function O +. O + +However O +, O +any O +improvement O +produced O +by O +drug O +treatment O +was O +largely O +a O +result O +of O +a O +beneficial O +effect O +exerted O +by O +its O +vehicle O +( O +polyethylene O +glycol O +and O +NaOH O +) O +. O + +The O +lack O +of O +any O +consistent O +protective O +effect O +noted O +with O +the O +alkylxanthines O +tested O +in O +the O +present O +study O +indicates O +that O +adenosine O +plays O +little O +, O +if O +any O +, O +pathophysiological O +role O +in O +gentamicin O +- O +induced O +ARF B +. O + +Adverse O +ocular O +reactions O +possibly O +associated O +with O +isotretinoin O +. O + +A O +total O +of O +261 O +adverse O +ocular O +reactions O +occurred O +in O +237 O +patients O +who O +received O +isotretinoin O +, O +a O +commonly O +used O +drug O +in O +the O +treatment O +of O +severe O +cystic B +acne I +. O + +Blepharoconjunctivitis B +, O +subjective O +complaints O +of O +dry B +eyes I +, O +blurred B +vision I +, O +contact B +lens I +intolerance I +, O +and O +photodermatitis B +are O +reversible O +side O +effects O +. O + +More O +serious O +ocular O +adverse O +reactions O +include O +papilledema B +, O +pseudotumor B +cerebri I +, O +and O +white O +or O +gray O +subepithelial O +corneal I +opacities I +; O +all O +of O +these O +are O +reversible O +if O +the O +drug O +is O +discontinued O +. O + +Reported O +cases O +of O +decreased B +dark I +adaptation I +are O +under O +investigation O +. O + +Isotretinoin O +is O +contraindicated O +in O +pregnancy O +because O +of O +the O +many O +reported O +congenital B +abnormalities I +after O +maternal O +use O +( O +including O +microphthalmos B +, O +orbital B +hypertelorism I +, O +and O +optic B +nerve I +hypoplasia I +) O +. O + +Procaterol O +and O +terbutaline O +in O +bronchial B +asthma I +. O + +A O +double O +- O +blind O +, O +placebo O +- O +controlled O +, O +cross O +- O +over O +study O +. O + +Procaterol O +, O +a O +new O +beta O +- O +2 O +adrenoceptor O +stimulant O +, O +was O +studied O +in O +a O +double O +- O +blind O +, O +placebo O +- O +controlled O +, O +cross O +- O +over O +trial O +in O +patients O +with O +bronchial B +asthma I +. O + +Oral O +procaterol O +50 O +micrograms O +b O +. O +d O +. O +, O +procaterol O +100 O +micrograms O +b O +. O +d O +. O +, O +and O +terbutaline O +5 O +mg O +t O +. O +i O +. O +d O +. O +, O +were O +compared O +when O +given O +randomly O +in O +1 O +- O +week O +treatment O +periods O +. O + +The O +best O +clinical O +effect O +was O +found O +with O +terbutaline O +. O + +Both O +anti O +- O +asthmatic B +and O +tremorgenic B +effects O +of O +procaterol O +were O +dose O +- O +related O +. O + +Procaterol O +appeared O +effective O +in O +the O +doses O +tested O +, O +and O +a O +twice O +daily O +regimen O +would O +appear O +to O +be O +suitable O +with O +this O +drug O +. O + +Subacute O +effects O +of O +propranolol O +and O +B O +24 O +/ O +76 O +on O +isoproterenol O +- O +induced O +rat O +heart B +hypertrophy I +in O +correlation O +with O +blood O +pressure O +. O + +We O +compared O +the O +potential O +beta O +- O +receptor O +blocker O +, O +B O +24 O +/ O +76 O +i O +. O +e O +. O +1 O +- O +( O +2 O +, O +4 O +- O +dichlorophenoxy O +) O +- O +3 O +[ O +2 O +- O +3 O +, O +4 O +- O +dimethoxyphenyl O +) O +ethanolamino O +] O +- O +prop O +an O +- O +2 O +- O +ol O +, O +which O +is O +characterized O +by O +beta O +1 O +- O +adrenoceptor O +blocking O +and O +beta O +2 O +- O +adrenoceptor O +stimulating O +properties O +with O +propranolol O +. O + +The O +studies O +were O +performed O +using O +an O +experimental O +model O +of O +isoproterenol O +- O +induced O +heart B +hypertrophy I +in O +rats O +. O + +A O +correlation O +of O +the O +blood O +pressure O +was O +neither O +found O +in O +the O +development O +nor O +in O +the O +attempt O +to O +suppress O +the O +development O +of O +heart B +hypertrophy I +with O +the O +two O +beta O +- O +receptor O +blockers O +. O + +Both O +beta O +- O +blockers O +influenced O +the O +development O +of O +hypertrophy B +to O +a O +different O +, O +but O +not O +reproducible O +extent O +. O + +It O +was O +possible O +to O +suppress O +the O +increased O +ornithine O +decarboxylase O +activity O +with O +both O +beta O +- O +blockers O +in O +hypertrophied B +hearts O +, O +but O +there O +was O +no O +effect O +on O +the O +heart O +mass O +. O + +Neither O +propranolol O +nor O +B O +24 O +/ O +76 O +could O +stop O +the O +changes O +in O +the O +characteristic O +myosin O +isoenzyme O +pattern O +of O +the O +hypertrophied B +rat O +heart O +. O + +Thus O +, O +the O +investigations O +did O +not O +provide O +any O +evidence O +that O +the O +beta O +- O +receptor O +blockers O +propranolol O +and O +B O +24 O +/ O +76 O +have O +the O +potency O +to O +prevent O +isoproterenol O +from O +producing O +heart B +hypertrophy I +. O + +Increased O +anxiogenic O +effects O +of O +caffeine O +in O +panic B +disorders I +. O + +The O +effects O +of O +oral O +administration O +of O +caffeine O +( O +10 O +mg O +/ O +kg O +) O +on O +behavioral O +ratings O +, O +somatic O +symptoms O +, O +blood O +pressure O +and O +plasma O +levels O +of O +3 O +- O +methoxy O +- O +4 O +- O +hydroxyphenethyleneglycol O +( O +MHPG O +) O +and O +cortisol O +were O +determined O +in O +17 O +healthy O +subjects O +and O +21 O +patients O +meeting O +DSM O +- O +III O +criteria O +for O +agoraphobia B +with O +panic B +attacks I +or O +panic B +disorder I +. O + +Caffeine O +produced O +significantly O +greater O +increases O +in O +subject O +- O +rated O +anxiety B +, O +nervousness B +, O +fear B +, O +nausea B +, O +palpitations B +, O +restlessness B +, O +and O +tremors B +in O +the O +patients O +compared O +with O +healthy O +subjects O +. 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O + +Patients O +with O +anxiety B +disorders I +may O +benefit O +by O +avoiding O +caffeine O +- O +containing O +foods O +and O +beverages O +. O + +Comparison O +of O +the O +effect O +of O +oxitropium O +bromide O +and O +of O +slow O +- O +release O +theophylline O +on O +nocturnal B +asthma I +. O + +The O +effects O +of O +a O +new O +inhaled O +antimuscarinic O +drug O +, O +oxitropium O +bromide O +, O +and O +of O +a O +slow O +- O +release O +theophylline O +preparation O +upon O +nocturnal B +asthma I +were O +compared O +in O +a O +placebo O +- O +controlled O +double O +- O +blind O +study O +. O + +Two O +samples O +were O +studied O +: O +12 O +patients O +received O +oxitropium O +at O +600 O +micrograms O +( O +6 O +subjects O +) O +or O +at O +400 O +micrograms O +t O +. O +i O +. O +d O +. O + +( O +6 O +subjects O +) O +whereas O +11 O +received O +theophylline O +at O +300 O +mg O +b O +. O +i O +. O +d O +. 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O + +Male O +Sprague O +- O +Dawley O +rats O +, O +uninephrectomized O +three O +weeks O +before O +, O +received O +daily O +injections O +of O +subcutaneous O +AMNS O +( O +1 O +mg O +/ O +100 O +g O +body O +wt O +) O +and O +intravenous O +PS O +( O +2 O +separated O +doses O +of O +2 O +. O +5 O +mg O +/ O +100 O +g O +body O +wt O +) O +for O +four O +days O +. O + +The O +series O +of O +injections O +were O +repeated O +another O +three O +times O +at O +10 O +day O +intervals O +. O + +The O +animals O +were O +sacrificed O +on O +days O +24 O +, O +52 O +, O +and O +80 O +. O + +They O +developed O +nephrotic B +syndrome I +and O +finally O +renal B +failure I +. O + +The O +time O +- O +course O +curve O +of O +creatinine O +clearance O +dropped O +and O +showed O +significant O +difference O +( O +P O +less O +than O +0 O +. O +01 O +) O +from O +that O +of O +each O +control O +group O +, O +such O +as O +, O +AMNS O +alone O +, O +PS O +alone O +or O +saline O +injected O +. O + +Their O +glomeruli O +showed O +changes O +of O +progressive O +FSGS B +. O + +The O +ultrastructural O +studies O +in O +the O +initial O +stage O +revealed O +significant O +lack O +of O +particles O +of O +perfused O +ruthenium O +red O +on O +the O +lamina O +rara O +externa O +and O +marked O +changes O +in O +epithelial O +cell O +cytoplasm O +. O + +Therefore O +, O +it O +is O +suggested O +that O +the O +administration O +of O +PS O +enhances O +the O +toxicity B +of O +AMNS O +on O +the O +glomerulus O +and O +readily O +produces O +progressive O +FSGS B +in O +rats O +resulting O +in O +the O +end B +- I +stage I +renal I +disease I +. O + +Theophylline O +neurotoxicity B +in O +pregnant O +rats O +. O + +The O +purpose O +of O +this O +investigation O +was O +to O +determine O +whether O +the O +neurotoxicity B +of O +theophylline O +is O +altered O +in O +advanced O +pregnancy O +. O + +Sprague O +- O +Dawley O +rats O +that O +were O +20 O +days O +pregnant O +and O +nonpregnant O +rats O +of O +the O +same O +age O +and O +strain O +received O +infusions O +of O +aminophylline O +until O +onset O +of O +maximal O +seizures B +which O +occurred O +after O +28 O +and O +30 O +minutes O +respectively O +. O + +Theophylline O +concentrations O +at O +this O +endpoint O +in O +serum O +( O +total O +) O +and O +CSF O +were O +similar O +but O +serum O +( O +free O +) O +and O +brain O +concentrations O +were O +slightly O +different O +in O +pregnant O +rats O +. O + +Theophylline O +serum O +protein O +binding O +determined O +by O +equilibrium O +dialysis O +was O +lower O +in O +pregnant O +rats O +. O + +Fetal O +serum O +concentrations O +at O +onset O +of O +seizures B +in O +the O +mother O +were O +similar O +to O +maternal O +brain O +and O +CSF O +concentrations O +and O +correlated O +significantly O +with O +the O +former O +. O + +It O +is O +concluded O +that O +advanced O +pregnancy O +has O +a O +negligible O +effect O +on O +the O +neurotoxic B +response O +to O +theophylline O +in O +rats O +. O + +Hyperkalemia B +induced O +by O +indomethacin O +and O +naproxen O +and O +reversed O +by O +fludrocortisone O +. O + +We O +have O +described O +a O +patient O +with O +severe O +rheumatoid B +arthritis I +and O +a O +history O +of O +mefenamic O +acid O +nephropathy B +in O +whom O +hyperkalemia B +and O +inappropriate B +hypoaldosteronism I +were O +caused O +by O +both O +indomethacin O +and O +naproxen O +, O +without O +major O +decline O +in O +renal O +function O +. O + +It O +is O +likely O +that O +preexisting O +renal B +disease I +predisposed O +this O +patient O +to O +type B +IV I +renal I +tubular I +acidosis I +with O +prostaglandin O +synthetase O +inhibitors O +. O + +Because O +he O +was O +unable O +to O +discontinue O +nonsteroidal O +anti O +- O +inflammatory O +drug O +therapy O +, O +fludrocortisone O +was O +added O +, O +correcting O +the O +hyperkalemia B +and O +allowing O +indomethacin O +therapy O +to O +be O +continued O +safely O +. O + +Hypotension B +as O +a O +manifestation O +of O +cardiotoxicity B +in O +three O +patients O +receiving O +cisplatin O +and O +5 O +- O +fluorouracil O +. O + +Cardiac B +symptoms I +, O +including O +hypotension B +, O +developed O +in O +three O +patients O +with O +advanced O +colorectal B +carcinoma I +while O +being O +treated O +with O +cisplatin O +( O +CDDP O +) O +and O +5 O +- O +fluorouracil O +( O +5 O +- O +FU O +) O +. O + +In O +two O +patients O +, O +hypotension B +was O +associated O +with O +severe O +left B +ventricular I +dysfunction I +. O + +All O +three O +patients O +required O +therapy O +discontinuation O +. O + +Cardiac O +enzymes O +remained O +normal O +despite O +transient O +electrocardiographic O +( O +EKG O +) O +changes O +. O + +The O +presentation O +and O +cardiac O +evaluation O +( O +hemodynamic O +, O +echocardiographic O +, O +and O +scintigraphic O +) O +of O +these O +patients O +suggest O +new O +manifestations O +of O +5 O +- O +FU O +cardiotoxicity B +that O +may O +be O +influenced O +by O +CDDP O +. O + +The O +possible O +pathophysiologic O +mechanisms O +are O +discussed O +. O + +Fatal O +aplastic B +anemia I +in O +a O +patient O +treated O +with O +carbamazepine O +. O + +A O +case O +of O +fatal O +aplastic B +anemia I +due O +to O +carbamazepine O +treatment O +in O +an O +epileptic B +woman O +is O +reported O +. O + +Despite O +concerns O +of O +fatal O +bone B +marrow I +toxicity I +due O +to O +carbamazepine O +, O +this O +is O +only O +the O +fourth O +documented O +and O +published O +report O +. O + +Carbamazepine O +is O +a O +safe O +drug O +, O +but O +physicians O +and O +patients O +should O +be O +aware O +of O +the O +exceedingly O +rare O +but O +potentially O +fatal O +side O +effects O +, O +better O +prevented O +by O +clinical O +than O +by O +laboratory O +monitoring O +. O + +Participation O +of O +a O +bulbospinal O +serotonergic O +pathway O +in O +the O +rat O +brain O +in O +clonidine O +- O +induced O +hypotension B +and O +bradycardia B +. O + +The O +effects O +of O +microinjection O +of O +clonidine O +( O +1 O +- O +10 O +micrograms O +in O +1 O +microliter O +) O +into O +a O +region O +adjacent O +to O +the O +ventrolateral O +surface O +of O +the O +medulla O +oblongata O +on O +cardiovascular O +function O +were O +assessed O +in O +urethane O +- O +anesthetized O +rats O +. O + +Intramedullary O +administration O +of O +clonidine O +, O +but O +not O +saline O +vehicle O +, O +caused O +a O +dose O +- O +dependent O +decrease O +in O +both O +the O +mean O +arterial O +pressure O +and O +the O +heart O +rate O +. O + +The O +clonidine O +- O +induced O +hypotension B +was O +antagonized O +by O +prior O +spinal O +transection O +, O +but O +not O +bilateral O +vagotomy O +. O + +On O +the O +other O +hand O +, O +the O +clonidine O +- O +induced O +bradycardia B +was O +antagonized O +by O +prior O +bilateral O +vagotomy O +, O +but O +not O +spinal O +transection O +. O + +Furthermore O +, O +selective O +destruction O +of O +the O +spinal O +5 O +- O +HT O +nerves O +, O +produced O +by O +bilateral O +spinal O +injection O +of O +5 O +, O +7 O +- O +dihydroxytryptamine O +, O +reduced O +the O +magnitude O +of O +the O +vasodepressor O +or O +the O +bradycardiac O +responses O +to O +clonidine O +microinjected O +into O +the O +area O +near O +the O +ventrolateral O +surface O +of O +the O +medulla O +oblongata O +in O +rats O +. O + +The O +data O +indicate O +that O +a O +bulbospinal O +serotonergic O +pathway O +is O +involved O +in O +development O +of O +clonidine O +- O +induced O +hypotension B +and O +bradycardia B +. O + +The O +induced O +hypotension B +is O +brought O +about O +by O +a O +decrease O +in O +sympathetic O +efferent O +activity O +, O +whereas O +the O +induced O +bradycardia B +was O +due O +to O +an O +increase O +in O +vagal O +efferent O +activity O +. O + +Hypertension B +in O +neuroblastoma B +induced O +by O +imipramine O +. O + +Hypertension B +is O +a O +well O +- O +known O +finding O +in O +some O +patients O +with O +neuroblastoma B +. O + +However O +, O +it O +has O +not O +previously O +been O +described O +in O +association O +with O +the O +use O +of O +Imipramine O +. O + +We O +report O +the O +occurrence O +of O +severe O +hypertension B +( O +blood O +pressure O +190 O +/ O +160 O +) O +in O +a O +4 O +- O +year O +- O +old O +girl O +with O +neuroblastoma B +who O +was O +given O +Imipramine O +to O +control O +a O +behavior B +disorder I +. O + +It O +was O +determined O +later O +that O +this O +patient O +' O +s O +tumor B +was O +recurring O +at O +the O +time O +of O +her O +hypertensive B +episode O +. O + +Since O +she O +had O +no O +blood O +pressure O +elevation O +at O +initial O +diagnosis O +and O +none O +following O +discontinuation O +of O +the O +Imipramine O +( O +when O +she O +was O +in O +florid O +relapse O +) O +, O +we O +believe O +that O +this O +drug O +rather O +than O +her O +underlying O +disease O +alone O +caused O +her O +hypertension B +. O + +The O +mechanism O +for O +this O +reaction O +is O +believed O +to O +be O +increased O +levels O +of O +vasoactive O +catecholamines O +due O +to O +interference O +of O +their O +physiologic O +inactivation O +by O +Imipramine O +. O + +From O +this O +experience O +, O +we O +urge O +extreme O +caution O +in O +the O +use O +of O +tricyclic O +antidepressants O +in O +children O +with O +active O +neuroblastoma B +. O + +Rechallenge O +of O +patients O +who O +developed O +oral B +candidiasis I +or O +hoarseness B +with O +beclomethasone O +dipropionate O +. O + +Of O +158 O +asthmatic B +patients O +who O +were O +placed O +on O +inhaled O +beclomethasone O +, O +15 O +( O +9 O +. O +5 O +% O +) O +developed O +either O +hoarseness B +( O +8 O +) O +, O +oral B +thrush B +( O +6 O +) O +, O +or O +both O +( O +1 O +) O +. O + +When O +their O +adverse O +reactions O +subsided O +, O +seven O +of O +these O +15 O +patients O +were O +rechallenged O +with O +inhaled O +beclomethasone O +. O + +These O +included O +five O +cases O +who O +developed O +hoarseness B +and O +three O +who O +developed O +Candidiasis B +. O + +One O +patient O +had O +both O +. O + +Oral O +thrush B +did O +not O +recur O +, O +but O +60 O +% O +( O +3 O +/ O +5 O +) O +of O +patients O +with O +hoarseness B +had O +recurrence O +. O + +We O +conclude O +that O +patients O +may O +be O +restarted O +on O +inhaled O +beclomethasone O +when O +clinically O +indicated O +; O +however O +, O +because O +of O +the O +high O +recurrence O +rate O +, O +patients O +who O +develop O +hoarseness B +should O +not O +be O +re O +- O +challenged O +. O + +Concomitant O +use O +of O +oral O +prednisone O +and O +topical O +beclomethasone O +may O +increase O +the O +risk O +of O +developing O +hoarseness B +or O +candidiasis B +. O + +Cyclophosphamide O +cardiotoxicity B +: O +an O +analysis O +of O +dosing O +as O +a O +risk O +factor O +. O + +Patients O +who O +undergo O +bone O +marrow O +transplantation O +are O +generally O +immunosuppressed O +with O +a O +dose O +of O +cyclophosphamide O +( O +CYA O +) O +which O +is O +usually O +calculated O +based O +on O +the O +patient O +' O +s O +weight O +. O + +At O +these O +high O +doses O +of O +CYA O +, O +serious O +cardiotoxicity B +may O +occur O +, O +but O +definitive O +risk O +factors O +for O +the O +development O +of O +such O +cardiotoxicity B +have O +not O +been O +described O +. O + +Since O +chemotherapeutic O +agent O +toxicity B +generally O +correlates O +with O +dose O +per O +body O +surface O +area O +, O +we O +retrospectively O +calculated O +the O +dose O +of O +CYA O +in O +patients O +transplanted O +at O +our O +institution O +to O +determine O +whether O +the O +incidence O +of O +CYA O +cardiotoxicity B +correlated O +with O +the O +dose O +per O +body O +surface O +area O +. O + +Eighty O +patients O +who O +were O +to O +receive O +CYA O +50 O +mg O +/ O +kg O +/ O +d O +for O +four O +days O +as O +preparation O +for O +marrow O +grafting O +underwent O +a O +total O +of O +84 O +transplants O +for O +aplastic B +anemia I +, O +Wiskott B +- I +Aldrich I +syndrome I +, O +or O +severe B +combined I +immunodeficiency I +syndrome I +. O + +Fourteen O +of O +84 O +( O +17 O +% O +) O +patients O +had O +symptoms O +and O +signs O +consistent O +with O +CYA O +cardiotoxicity B +within O +ten O +days O +of O +receiving O +1 O +to O +4 O +doses O +of O +CYA O +. O + +Six O +of O +the O +14 O +patients O +died O +with O +congestive B +heart I +failure I +. O + +The O +dose O +of O +CYA O +per O +body O +surface O +area O +was O +calculated O +for O +all O +patients O +and O +the O +patients O +were O +divided O +into O +two O +groups O +based O +on O +daily O +CYA O +dose O +: O +Group O +1 O +, O +CYA O +less O +than O +or O +equal O +to O +1 O +. O +55 O +g O +/ O +m2 O +/ O +d O +; O +Group O +2 O +, O +CYA O +greater O +than O +1 O +. O +55 O +g O +/ O +m2 O +/ O +d O +. O + +Cardiotoxicity B +that O +was O +thought O +to O +be O +related O +to O +CYA O +occurred O +in O +1 O +/ O +32 O +( O +3 O +% O +) O +of O +patients O +in O +Group O +1 O +and O +in O +13 O +/ O +52 O +( O +25 O +% O +) O +patients O +in O +Group O +2 O +( O +P O +less O +than O +0 O +. O +025 O +) O +. O + +Congestive B +heart I +failure I +caused O +or O +contributed O +to O +death B +in O +0 O +/ O +32 O +patients O +in O +Group O +1 O +v O +6 O +/ O +52 O +( O +12 O +% O +) O +of O +patients O +in O +Group O +2 O +( O +P O +less O +than O +0 O +. O +25 O +) O +. O + +There O +was O +no O +difference O +in O +the O +rate O +of O +engraftment O +of O +evaluable O +patients O +in O +the O +two O +groups O +( O +P O +greater O +than O +0 O +. O +5 O +) O +. O + +We O +conclude O +that O +the O +CYA O +cardiotoxicity B +correlates O +with O +CYA O +dosage O +as O +calculated O +by O +body O +surface O +area O +, O +and O +that O +patients O +with O +aplastic B +anemia I +and O +immunodeficiencies B +can O +be O +effectively O +prepared O +for O +bone O +marrow O +grafting O +at O +a O +CYA O +dose O +of O +1 O +. O +55 O +g O +/ O +m2 O +/ O +d O +for O +four O +days O +with O +a O +lower O +incidence O +of O +cardiotoxicity B +than O +patients O +whose O +CYA O +dosage O +is O +calculated O +based O +on O +weight O +. O + +This O +study O +reaffirms O +the O +principle O +that O +drug O +toxicity B +correlates O +with O +dose O +per O +body O +surface O +area O +. O + +Studies O +of O +risk O +factors O +for O +aminoglycoside O +nephrotoxicity B +. O + +The O +epidemiology O +of O +aminoglycoside O +- O +induced O +nephrotoxicity B +is O +not O +fully O +understood O +. O + +Experimental O +studies O +in O +healthy O +human O +volunteers O +indicate O +aminoglycosides O +cause O +proximal B +tubular I +damage I +in O +most O +patients O +, O +but O +rarely O +, O +if O +ever O +, O +cause O +glomerular B +or I +tubular I +dysfunction I +. O + +Clinical O +trials O +of O +aminoglycosides O +in O +seriously O +ill O +patients O +indicate O +that O +the O +relative O +risk O +for O +developing O +acute B +renal I +failure I +during O +therapy O +ranges O +from O +8 O +to O +10 O +and O +that O +the O +attributable O +risk O +is O +70 O +% O +to O +80 O +% O +. O + +Further O +analysis O +of O +these O +data O +suggests O +that O +the O +duration O +of O +therapy O +, O +plasma O +aminoglycoside O +levels O +, O +liver B +disease I +, O +advanced O +age O +, O +high O +initial O +estimated O +creatinine O +clearance O +and O +, O +possibly O +, O +female O +gender O +all O +increase O +the O +risk O +for O +nephrotoxicity B +. O + +Other O +causes O +of O +acute B +renal I +failure I +, O +such O +as O +shock B +, O +appear O +to O +have O +an O +additive O +effect O +. O + +Predictive O +models O +have O +been O +developed O +from O +these O +analyses O +that O +should O +be O +useful O +for O +identifying O +patients O +at O +high O +risk O +. O + +These O +models O +may O +also O +be O +useful O +in O +developing O +insights O +into O +the O +pathophysiology O +of O +aminoglycoside O +- O +induced O +nephrotoxicity B +. O + +Central O +action O +of O +narcotic O +analgesics O +. O + +Part O +IV O +. O + +Noradrenergic O +influences O +on O +the O +activity O +of O +analgesics O +in O +rats O +. O + +The O +effect O +of O +clonidine O +, O +naphazoline O +and O +xylometazoline O +on O +analgesia B +induced O +by O +morphine O +, O +codeine O +, O +fentanyl O +and O +pentazocine O +, O +and O +on O +cataleptic B +effect O +of O +morphine O +, O +codine O +and O +fentanyl O +was O +studied O +in O +rats O +. O + +The O +biochemical O +assays O +on O +the O +influence O +of O +four O +analgesics O +on O +the O +brain O +concentration O +and O +turnover O +of O +noradrenaline O +( O +NA O +) O +were O +also O +performed O +. O + +It O +was O +found O +that O +three O +drugs O +stimulating O +central O +NA O +receptors O +failed O +to O +affect O +the O +analgesic O +ED50 O +of O +all O +antinociceptive O +agents O +and O +they O +enhanced O +catalepsy B +induced O +by O +morphine O +and O +fentanyl O +. O + +Codeine O +catalepsy B +was O +increased O +by O +clonidine O +and O +decreased O +by O +naphazoline O +and O +xylometazoline O +. O + +The O +brain O +concentration O +of O +NA O +was O +not O +changed O +by O +morphine O +and O +fentanyl O +, O +but O +one O +of O +the O +doses O +of O +codeine O +( O +45 O +mg O +/ O +kg O +) O +slightly O +enhanced O +it O +. O + +Pentazocine O +dose O +- O +dependently O +decreased O +the O +brain O +level O +of O +NA O +. O + +The O +rate O +of O +NA O +turnover O +was O +not O +altered O +by O +analgesics O +except O +for O +the O +higher O +dose O +of O +fentanyl O +( O +0 O +. O +2 O +mg O +/ O +kg O +) O +following O +which O +the O +disappearance O +of O +NA O +from O +the O +brain O +was O +diminished O +. O + +The O +results O +are O +discussed O +in O +the O +light O +of O +various O +and O +non O +- O +uniform O +data O +from O +the O +literature O +. O + +It O +is O +suggested O +that O +in O +rats O +the O +brain O +NA O +plays O +a O +less O +important O +function O +than O +the O +other O +monoamines O +in O +the O +behavioural O +activity O +of O +potent O +analgesics O +. O + +Flurothyl O +seizure B +thresholds O +in O +mice O +treated O +neonatally O +with O +a O +single O +injection O +of O +monosodium O +glutamate O +( O +MSG O +) O +: O +evaluation O +of O +experimental O +parameters O +in O +flurothyl O +seizure B +testing O +. O + +Monosodium O +glutamate O +( O +MSG O +) O +administration O +to O +neonatal O +rodents O +produces O +convulsions B +and O +results O +in O +numerous O +biochemical O +and O +behavioral O +deficits I +. O + +These O +studies O +were O +undertaken O +to O +determine O +if O +neonatal O +administration O +of O +MSG O +produced O +permanent O +alterations O +in O +seizure B +susceptibility O +, O +since O +previous O +investigations O +were O +inconclusive O +. O + +A O +flurothyl O +ether O +seizure B +screening O +technique O +was O +used O +to O +evaluate O +seizure B +susceptibility O +in O +adult O +mice O +that O +received O +neonatal O +injections O +of O +MSG O +( O +4 O +mg O +/ O +g O +and O +1 O +mg O +/ O +g O +) O +. O + +MSG O +treatment O +resulted O +in O +significant O +reductions O +in O +whole O +brain O +weight O +but O +did O +not O +alter O +seizure B +threshold O +. O + +A O +naloxone O +( O +5 O +mg O +/ O +kg O +) O +challenge O +was O +also O +ineffective O +in O +altering O +the O +seizure B +thresholds O +of O +either O +control O +of O +MSG O +- O +treated O +mice O +. O + +Flurothyl O +ether O +produced O +hypothermia B +which O +was O +correlated O +with O +the O +duration O +of O +flurothyl O +exposure O +; O +however O +, O +the O +relationship O +of O +hypothermia B +to O +seizure B +induction O +was O +unclear O +. O + +Flurothyl O +seizure B +testing O +proved O +to O +be O +a O +rapid O +and O +reliable O +technique O +with O +which O +to O +evaluate O +seizure B +susceptibility O +. O + +Susceptibility O +to O +seizures B +produced O +by O +pilocarpine O +in O +rats O +after O +microinjection O +of O +isoniazid O +or O +gamma O +- O +vinyl O +- O +GABA O +into O +the O +substantia O +nigra O +. O + +Pilocarpine O +, O +given O +intraperitoneally O +to O +rats O +, O +reproduces O +the O +neuropathological O +sequelae O +of O +temporal B +lobe I +epilepsy I +and O +provides O +a O +relevant O +animal O +model O +for O +studying O +mechanisms O +of O +buildup O +of O +convulsive B +activity O +and O +pathways O +operative O +in O +the O +generalization O +and O +propagation O +of O +seizures B +within O +the O +forebrain O +. O + +In O +the O +present O +study O +, O +the O +effects O +of O +manipulating O +the O +activity O +of O +the O +gamma O +- O +aminobutyric O +acid O +( O +GABA O +) O +- O +mediated O +synaptic O +inhibition O +within O +the O +substantia O +nigra O +on O +seizures B +produced O +by O +pilocarpine O +in O +rats O +, O +were O +investigated O +. O + +In O +animals O +pretreated O +with O +microinjections O +of O +isoniazid O +, O +150 O +micrograms O +, O +an O +inhibitor O +of O +activity O +of O +the O +GABA O +- O +synthesizing O +enzyme O +, O +L O +- O +glutamic O +acid O +decarboxylase O +, O +into O +the O +substantia O +nigra O +pars O +reticulata O +( O +SNR O +) O +, O +bilaterally O +, O +non O +- O +convulsant O +doses O +of O +pilocarpine O +, O +100 O +and O +200 O +mg O +/ O +kg O +, O +resulted O +in O +severe O +motor O +limbic O +seizures B +and O +status B +epilepticus I +. O + +Electroencephalographic O +and O +behavioral O +monitoring O +revealed O +a O +profound O +reduction O +of O +the O +threshold O +for O +pilocarpine O +- O +induced O +convulsions B +. O + +Morphological O +analysis O +of O +frontal O +forebrain O +sections O +with O +light O +microscopy O +revealed O +seizure B +- O +related O +damage B +to I +the O +hippocampal O +formation O +, O +thalamus O +, O +amygdala O +, O +olfactory O +cortex O +, O +substantia O +nigra O +and O +neocortex O +, O +which O +is O +typically O +observed O +with O +pilocarpine O +in O +doses O +exceeding O +350 O +mg O +/ O +kg O +. O + +Bilateral O +intrastriatal O +injections O +of O +isoniazid O +did O +not O +augment O +seizures B +produced O +by O +pilocarpine O +, O +200 O +mg O +/ O +kg O +. O + +Application O +of O +an O +irreversible O +inhibitor O +of O +GABA O +transaminase O +, O +gamma O +- O +vinyl O +- O +GABA O +( O +D O +, O +L O +- O +4 O +- O +amino O +- O +hex O +- O +5 O +- O +enoic O +acid O +) O +, O +5 O +micrograms O +, O +into O +the O +SNR O +, O +bilaterally O +, O +suppressed O +the O +appearance O +of O +electrographic O +and O +behavioral O +seizures B +produced O +by O +pilocarpine O +, O +380 O +mg O +/ O +kg O +. O + +This O +treatment O +was O +also O +sufficient O +to O +protect O +animals O +from O +the O +occurrence O +of O +brain B +damage I +. O + +Microinjections O +of O +gamma O +- O +vinyl O +- O +GABA O +, O +5 O +micrograms O +, O +into O +the O +dorsal O +striatum O +, O +bilaterally O +, O +failed O +to O +prevent O +the O +development O +of O +convulsions B +produced O +by O +pilocarpine O +, O +380 O +mg O +/ O +kg O +. O + +The O +results O +demonstrate O +that O +the O +threshold O +for O +pilocarpine O +- O +induced O +seizures B +in O +rats O +is O +subjected O +to O +the O +regulation O +of O +the O +GABA O +- O +mediated O +synaptic O +inhibition O +within O +the O +substantia O +nigra O +. O + +Human O +and O +canine O +ventricular O +vasoactive O +intestinal O +polypeptide O +: O +decrease O +with O +heart B +failure I +. O + +Vasoactive O +intestinal O +polypeptide O +( O +VIP O +) O +is O +a O +systemic O +and O +coronary O +vasodilator O +that O +may O +have O +positive O +inotropic O +properties O +. O + +Myocardial O +levels O +of O +VIP O +were O +assayed O +before O +and O +after O +the O +development O +of O +heart B +failure I +in O +two O +canine O +models O +. O + +In O +the O +first O +, O +cobalt O +cardiomyopathy B +was O +induced O +in O +eight O +dogs O +; O +VIP O +( O +by O +radioimmunoassay O +) O +decreased O +from O +35 O ++ O +/ O +- O +11 O +pg O +/ O +mg O +protein O +( O +mean O ++ O +/ O +- O +SD O +) O +to O +5 O ++ O +/ O +- O +4 O +pg O +/ O +mg O +protein O +( O +P O +less O +than O +0 O +. O +05 O +) O +. O + +In O +six O +dogs O +with O +doxorubicin O +- O +induced O +heart B +failure I +, O +VIP O +decreased O +from O +31 O ++ O +/ O +- O +7 O +to O +11 O ++ O +/ O +- O +4 O +pg O +/ O +mg O +protein O +( O +P O +less O +than O +0 O +. O +05 O +) O +. O + +In O +addition O +, O +VIP O +content O +of O +left O +ventricular O +muscle O +of O +resected O +failing O +hearts O +in O +10 O +patients O +receiving O +a O +heart O +transplant O +was O +compared O +with O +the O +papillary O +muscles O +in O +14 O +patients O +( O +five O +with O +rheumatic B +disease I +, O +nine O +with O +myxomatous B +degeneration I +) O +receiving O +mitral O +valve O +prostheses O +. O + +The O +lowest O +myocardial O +VIP O +concentration O +was O +found O +in O +the O +hearts O +of O +patients O +with O +coronary B +disease I +( O +one O +patient O +receiving O +a O +transplant O +and O +three O +receiving O +mitral O +prostheses O +) O +( O +6 O +. O +3 O ++ O +/ O +- O +1 O +. O +9 O +pg O +/ O +mg O +protein O +) O +. O + +The O +other O +patients O +undergoing O +transplantation O +had O +an O +average O +ejection O +fraction O +of O +17 O +% O ++ O +/ O +- O +6 O +% O +and O +a O +VIP O +level O +of O +8 O +. O +8 O ++ O +/ O +- O +3 O +. O +9 O +pg O +/ O +mg O +protein O +. O + +The O +hearts O +without O +coronary B +artery I +disease I +( O +average O +ejection O +fraction O +of O +this O +group O +62 O +% O ++ O +/ O +- O +10 O +% O +) O +had O +a O +VIP O +concentration O +of O +14 O +. O +1 O ++ O +/ O +- O +7 O +. O +9 O +pg O +/ O +mg O +protein O +, O +and O +this O +was O +greater O +than O +in O +hearts O +of O +the O +patients O +with O +coronary B +disease I +and O +the O +hearts O +of O +patients O +receiving O +a O +transplant O +( O +P O +less O +than O +0 O +. O +05 O +) O +. O + +Myocardial O +catecholamines O +were O +also O +determined O +in O +14 O +subjects O +; O +a O +weak O +correlation O +( O +r O += O +0 O +. O +57 O +, O +P O +less O +than O +0 O +. O +05 O +) O +between O +the O +tissue O +concentrations O +of O +VIP O +and O +norepinephrine O +was O +noted O +. O +( O +ABSTRACT O +TRUNCATED O +AT O +250 O +WORDS O +) O + +Non O +- O +invasive O +detection O +of O +coronary B +artery I +disease I +by O +body O +surface O +electrocardiographic O +mapping O +after O +dipyridamole O +infusion O +. O + +Electrocardiographic O +changes O +after O +dipyridamole O +infusion O +( O +0 O +. O +568 O +mg O +/ O +kg O +/ O +4 O +min O +) O +were O +studied O +in O +41 O +patients O +with O +coronary B +artery I +disease I +and O +compared O +with O +those O +after O +submaximal O +treadmill O +exercise O +by O +use O +of O +the O +body O +surface O +mapping O +technique O +. O + +Patients O +were O +divided O +into O +three O +groups O +; O +19 O +patients O +without O +myocardial B +infarction I +( O +non O +- O +MI O +group O +) O +, O +14 O +with O +anterior O +infarction I +( O +ANT O +- O +MI O +) O +and O +eight O +with O +inferior B +infarction I +( O +INF O +- O +MI O +) O +. O + +Eighty O +- O +seven O +unipolar O +electrocardiograms O +( O +ECGs O +) O +distributed O +over O +the O +entire O +thoracic O +surface O +were O +simultaneously O +recorded O +. O + +After O +dipyridamole O +, O +ischemic B +ST O +- O +segment O +depression B +( O +0 O +. O +05 O +mV O +or O +more O +) O +was O +observed O +in O +84 O +% O +of O +the O +non O +- O +MI O +group O +, O +29 O +% O +of O +the O +ANT O +- O +MI O +group O +, O +63 O +% O +of O +the O +INF O +- O +MI O +group O +and O +61 O +% O +of O +the O +total O +population O +. O + +Exercise O +- O +induced O +ST B +depression I +was O +observed O +in O +84 O +% O +of O +the O +non O +- O +MI O +group O +, O +43 O +% O +of O +the O +ANT O +- O +MI O +group O +, O +38 O +% O +of O +the O +INF O +- O +MI O +group O +and O +61 O +% O +of O +the O +total O +. O + +For O +individual O +patients O +, O +there O +were O +no O +obvious O +differences O +between O +the O +body O +surface O +distribution O +of O +ST B +depression I +in O +both O +tests O +. O + +The O +increase O +in O +pressure O +rate O +product O +after O +dipyridamole O +was O +significantly O +less O +than O +that O +during O +the O +treadmill O +exercise O +. O + +The O +data O +suggest O +that O +the O +dipyridamole O +- O +induced O +myocardial B +ischemia I +is O +caused O +by O +the O +inhomogenous O +distribution O +of O +myocardial O +blood O +flow O +. O + +We O +conclude O +that O +the O +dipyridamole O +ECG O +test O +is O +as O +useful O +as O +the O +exercise O +ECG O +test O +for O +the O +assessment O +of O +coronary B +artery I +disease I +. O + +Bradycardia B +after O +high O +- O +dose O +intravenous O +methylprednisolone O +therapy O +. O + +In O +5 O +consecutive O +patients O +with O +rheumatoid B +arthritis I +who O +received O +intravenous O +high O +- O +dose O +methylprednisolone O +( O +MP O +) O +therapy O +( O +1 O +g O +daily O +for O +2 O +or O +3 O +consecutive O +days O +) O +, O +a O +decline O +in O +pulse O +rate O +was O +observed O +, O +most O +pronounced O +on O +day O +4 O +. O + +In O +one O +of O +the O +5 O +patients O +the O +bradycardia B +was O +associated O +with O +complaints O +of O +substernal O +pressure O +. O + +Reversal O +to O +normal O +heart O +rate O +was O +found O +on O +day O +7 O +. O + +Electrocardiographic O +registrations O +showed O +sinus O +bradycardia B +in O +all O +cases O +. O + +No O +significant O +changes O +in O +plasma O +concentrations O +of O +electrolytes O +were O +found O +. O + +Careful O +observation O +of O +patients O +receiving O +high O +- O +dose O +MP O +is O +recommended O +. O + +High O +- O +dose O +MP O +may O +be O +contraindicated O +in O +patients O +with O +known O +heart B +disease I +. O + +Two O +cases O +of O +downbeat B +nystagmus I +and O +oscillopsia B +associated O +with O +carbamazepine O +. O + +Downbeat B +nystagmus I +is O +often O +associated O +with O +structural O +lesions O +at O +the O +craniocervical O +junction O +, O +but O +has O +occasionally O +been O +reported O +as O +a O +manifestation O +of O +metabolic O +imbalance O +or O +drug O +intoxication O +. O + +We O +recorded O +the O +eye O +movements O +of O +two O +patients O +with O +reversible O +downbeat O +nystagmus B +related O +to O +carbamazepine O +therapy O +. O + +The O +nystagmus B +of O +both O +patients O +resolved O +after O +reduction O +of O +the O +serum O +carbamazepine O +levels O +. O + +Neuroradiologic O +investigations O +including O +magnetic O +resonance O +imaging O +scans O +in O +both O +patients O +showed O +no O +evidence O +of O +intracranial B +abnormality I +. O + +In O +patients O +with O +downbeat O +nystagmus B +who O +are O +taking O +anticonvulsant O +medications O +, O +consideration O +should O +be O +given O +to O +reduction O +in O +dose O +before O +further O +investigation O +is O +undertaken O +. O + +Improvement O +by O +denopamine O +( O +TA O +- O +064 O +) O +of O +pentobarbital O +- O +induced O +cardiac B +failure I +in O +the O +dog O +heart O +- O +lung O +preparation O +. O + +The O +efficacy O +of O +denopamine O +, O +an O +orally O +active O +beta O +1 O +- O +adrenoceptor O +agonist O +, O +in O +improving O +cardiac B +failure I +was O +assessed O +in O +dog O +heart O +- O +lung O +preparations O +. O + +Cardiac O +functions O +depressed O +by O +pentobarbital O +( O +118 O ++ O +/ O +- O +28 O +mg O +; O +mean O +value O ++ O +/ O +- O +SD O +) O +such O +that O +cardiac O +output O +and O +maximum O +rate O +of O +rise O +of O +left O +ventricular O +pressure O +( O +LV O +dP O +/ O +dt O +max O +) O +had O +been O +reduced O +by O +about O +35 O +% O +and O +26 O +% O +of O +the O +respective O +controls O +were O +improved O +by O +denopamine O +( O +10 O +- O +300 O +micrograms O +) O +in O +a O +dose O +- O +dependent O +manner O +. O + +With O +100 O +micrograms O +denopamine O +, O +almost O +complete O +restoration O +of O +cardiac O +performance O +was O +attained O +, O +associated O +with O +a O +slight O +increase O +in O +heart O +rate O +. O + +No O +arrhythmias B +were O +induced O +by O +these O +doses O +of O +denopamine O +. O + +The O +results O +warrant O +clinical O +trials O +of O +denopamine O +in O +the O +treatment O +of O +cardiac B +failure I +. O + +Clonazepam O +monotherapy O +for O +epilepsy B +in O +childhood O +. O + +Sixty O +patients O +( O +age O +- O +range O +one O +month O +to O +14 O +years O +) O +with O +other O +types O +of O +epilepsy B +than O +infantile B +spasms I +were O +treated O +with O +clonazepam O +. O + +Disappearance O +of O +seizures B +and O +normalization O +of O +abnormal O +EEG O +with O +disappearance O +of O +seizures B +were O +recognized O +in O +77 O +% O +and O +50 O +% O +, O +respectively O +. O + +Seizures B +disappeared O +in O +71 O +% O +of O +the O +patients O +with O +generalized O +seizures B +and O +89 O +% O +of O +partial O +seizures B +. O + +Improvement O +of O +abnormal O +EEG O +was O +noticed O +in O +76 O +% O +of O +diffuse O +paroxysms O +and O +in O +67 O +% O +of O +focal O +paroxysms O +. O + +In O +excellent O +cases O +, O +mean O +effective O +dosages O +were O +0 O +. O +086 O ++ O +/ O +- O +0 O +. O +021 O +mg O +/ O +kg O +/ O +day O +in O +infants O +and O +0 O +. O +057 O ++ O +/ O +- O +0 O +. O +022 O +mg O +/ O +kg O +/ O +day O +in O +schoolchildren O +, O +this O +difference O +was O +statistically O +significant O +( O +p O +less O +than O +0 O +. O +005 O +) O +. O + +The O +incidence O +of O +side O +effects O +such O +as O +drowsiness O +and O +ataxia B +was O +only O +5 O +% O +. O + +Postmarketing O +study O +of O +timolol O +- O +hydrochlorothiazide O +antihypertensive O +therapy O +. O + +A O +postmarketing O +surveillance O +study O +was O +conducted O +to O +determine O +the O +safety O +and O +efficacy O +of O +a O +fixed O +- O +ratio O +combination O +containing O +10 O +mg O +of O +timolol O +maleate O +and O +25 O +mg O +of O +hydrochlorothiazide O +, O +administered O +twice O +daily O +for O +one O +month O +to O +hypertensive B +patients O +. O + +Data O +on O +9 O +, O +037 O +patients O +were O +collected O +by O +1 O +, O +455 O +participating O +physicians O +. O + +Mean O +systolic O +blood O +pressure O +decreased O +25 O +mmHg O +and O +mean O +diastolic O +blood O +pressure O +declined O +15 O +mmHg O +after O +one O +month O +of O +timolol O +- O +hydrochlorothiazide O +therapy O +( O +P O +less O +than O +0 O +. O +01 O +, O +both O +comparisons O +) O +. O + +Age O +, O +race O +, O +and O +sex O +appeared O +to O +have O +no O +influence O +on O +the O +decrease O +in I +blood I +pressure I +. O + +The O +antihypertensive O +effect O +of O +the O +drug O +was O +greater O +in O +patients O +with O +more O +severe O +hypertension B +. O + +Overall O +, O +1 O +, O +453 O +patients O +experienced O +a O +total O +of O +2 O +, O +658 O +adverse O +events O +, O +the O +most O +common O +being O +fatigue B +, O +dizziness B +, O +and O +weakness B +. O + +Treatment O +in O +590 O +patients O +was O +discontinued O +because O +of O +adverse O +events O +. O + +Salicylate O +nephropathy B +in O +the O +Gunn O +rat O +: O +potential O +role O +of O +prostaglandins O +. O + +We O +examined O +the O +potential O +role O +of O +prostaglandins O +in O +the O +development O +of O +analgesic O +nephropathy B +in O +the O +Gunn O +strain O +of O +rat O +. O + +The O +homozygous O +Gunn O +rats O +have O +unconjugated O +hyperbilirubinemia B +due O +to O +the O +absence O +of O +glucuronyl O +transferase O +, O +leading O +to O +marked O +bilirubin O +deposition O +in O +renal O +medulla O +and O +papilla O +. O + +These O +rats O +are O +also O +highly O +susceptible O +to O +develop O +papillary B +necrosis I +with O +analgesic O +administration O +. O + +We O +used O +homozygous O +( O +jj O +) O +and O +phenotypically O +normal O +heterozygous O +( O +jJ O +) O +animals O +. O + +Four O +groups O +of O +rats O +( O +n O += O +7 O +) O +were O +studied O +: O +jj O +and O +jJ O +rats O +treated O +either O +with O +aspirin O +300 O +mg O +/ O +kg O +every O +other O +day O +or O +sham O +- O +treated O +. O + +After O +one O +week O +, O +slices O +of O +cortex O +, O +outer O +and O +inner O +medulla O +from O +one O +kidney O +were O +incubated O +in O +buffer O +and O +prostaglandin O +synthesis O +was O +determined O +by O +radioimmunoassay O +. O + +The O +other O +kidney O +was O +examined O +histologically O +. O + +A O +marked O +corticomedullary O +gradient O +of O +prostaglandin O +synthesis O +was O +observed O +in O +all O +groups O +. O + +PGE2 O +synthesis O +was O +significantly O +higher O +in O +outer O +medulla O +, O +but O +not O +cortex O +or O +inner O +medulla O +, O +of O +jj O +( O +38 O ++ O +/ O +- O +6 O +ng O +/ O +mg O +prot O +) O +than O +jJ O +rats O +( O +15 O ++ O +/ O +- O +3 O +) O +( O +p O +less O +than O +0 O +. O +01 O +) O +. O + +Aspirin O +treatment O +reduced O +PGE2 O +synthesis O +in O +all O +regions O +, O +but O +outer O +medullary O +PGE2 O +remained O +higher O +in O +jj O +( O +18 O ++ O +/ O +- O +3 O +) O +than O +jJ O +rats O +( O +9 O ++ O +/ O +- O +2 O +) O +( O +p O +less O +than O +0 O +. O +05 O +) O +. O + +PGF2 O +alpha O +was O +also O +significantly O +higher O +in O +the O +outer O +medulla O +of O +jj O +rats O +with O +and O +without O +aspirin O +administration O +( O +p O +less O +than O +0 O +. O +05 O +) O +. O + +The O +changes O +in O +renal O +prostaglandin O +synthesis O +were O +accompanied O +by O +evidence O +of O +renal B +damage I +in O +aspirin O +- O +treated O +jj O +but O +not O +jJ O +rats O +as O +evidenced O +by O +: O +increased O +incidence O +and O +severity O +of O +hematuria B +( O +p O +less O +than O +0 O +. O +01 O +) O +; O +increased O +serum O +creatinine O +( O +p O +less O +than O +0 O +. O +05 O +) O +; O +and O +increase O +in O +outer O +medullary O +histopathologic O +lesions O +( O +p O +less O +than O +0 O +. O +005 O +compared O +to O +either O +sham O +- O +treated O +jj O +or O +aspirin O +- O +treated O +jJ O +) O +. O + +These O +results O +suggest O +that O +enhanced O +prostaglandin O +synthesis O +contributes O +to O +maintenance O +of O +renal O +function O +and O +morphological O +integrity O +, O +and O +that O +inhibition O +of O +prostaglandin O +synthesis O +may O +lead O +to O +pathological O +renal B +medullary I +lesions I +and O +deterioration O +of I +renal I +function I +. O + +Prophylactic O +lidocaine O +in O +the O +early O +phase O +of O +suspected O +myocardial B +infarction I +. O + +Four O +hundred O +two O +patients O +with O +suspected O +myocardial B +infarction I +seen O +within O +6 O +hours O +of O +the O +onset O +of O +symptoms O +entered O +a O +double O +- O +blind O +randomized O +trial O +of O +lidocaine O +vs O +placebo O +. O + +During O +the O +1 O +hour O +after O +administration O +of O +the O +drug O +the O +incidence O +of O +ventricular B +fibrillation I +or O +sustained O +ventricular B +tachycardia I +among O +the O +204 O +patients O +with O +acute B +myocardial I +infarction I +was O +low O +, O +1 O +. O +5 O +% O +. O + +Lidocaine O +, O +given O +in O +a O +300 O +mg O +dose O +intramuscularly O +followed O +by O +100 O +mg O +intravenously O +, O +did O +not O +prevent O +sustained O +ventricular B +tachycardia I +, O +although O +there O +was O +a O +significant O +reduction O +in O +the O +number O +of O +patients O +with O +warning O +arrhythmias B +between O +15 O +and O +45 O +minutes O +after O +the O +administration O +of O +lidocaine O +( O +p O +less O +than O +0 O +. O +05 O +) O +. O + +The O +average O +plasma O +lidocaine O +level O +10 O +minutes O +after O +administration O +for O +patients O +without O +a O +myocardial B +infarction I +was O +significantly O +higher O +than O +that O +for O +patients O +with O +an O +acute B +infarction I +. O + +The O +mean O +plasma O +lidocaine O +level O +of O +patients O +on O +beta O +- O +blocking O +agents O +was O +no O +different O +from O +that O +in O +patients O +not O +on O +beta O +blocking O +agents O +. O + +During O +the O +1 O +- O +hour O +study O +period O +, O +the O +incidence O +of O +central O +nervous O +system O +side O +effects O +was O +significantly O +greater O +in O +the O +lidocaine O +group O +, O +hypotension B +occurred O +in O +11 O +patients O +, O +nine O +of O +whom O +had O +received O +lidocaine O +, O +and O +four O +patients O +died O +from O +asystole B +, O +three O +of O +whom O +had O +had O +lidocaine O +. O + +We O +cannot O +advocate O +the O +administration O +of O +lidocaine O +prophylactically O +in O +the O +early O +hours O +of O +suspected O +myocardial B +infarction I +. O + +Evidence O +for O +a O +cholinergic O +role O +in O +haloperidol O +- O +induced O +catalepsy B +. O + +Experiments O +in O +mice O +tested O +previous O +evidence O +that O +activation O +of O +cholinergic O +systems O +promotes O +catalepsy B +and O +that O +cholinergic O +mechanisms O +need O +to O +be O +intact O +for O +full O +expression O +of O +neuroleptic O +- O +induced O +catalepsy B +. O + +Large O +doses O +of O +the O +cholinomimetic O +, O +pilocarpine O +, O +could O +induce O +catalepsy B +when O +peripheral O +cholinergic O +receptors O +were O +blocked O +. O + +Low O +doses O +of O +pilocarpine O +caused O +a O +pronounced O +enhancement O +of O +the O +catalepsy B +that O +was O +induced O +by O +the O +dopaminergic O +blocker O +, O +haloperidol O +. O + +A O +muscarinic O +receptor O +blocker O +, O +atropine O +, O +disrupted O +haloperidol O +- O +induced O +catalepsy B +. O + +Intracranial O +injection O +of O +an O +acetylcholine O +- O +synthesis O +inhibitor O +, O +hemicholinium O +, O +prevented O +the O +catalepsy B +that O +is O +usually O +induced O +by O +haloperidol O +. O + +These O +findings O +suggest O +the O +hypothesis O +that O +the O +catalepsy B +that O +is O +produced O +by O +neuroleptics O +such O +as O +haloperidol O +is O +actually O +mediated O +by O +intrinsic O +central O +cholinergic O +systems O +. O + +Alternatively O +, O +activation O +of O +central O +cholinergic O +systems O +could O +promote O +catalepsy B +by O +suppression O +of O +dopaminergic O +systems O +. O + +Cardiovascular B +dysfunction I +and O +hypersensitivity B +to O +sodium O +pentobarbital O +induced O +by O +chronic O +barium O +chloride O +ingestion O +. O + +Barium O +- O +supplemented O +Long O +- O +Evans O +hooded O +rats O +were O +characterized O +by O +a O +persistent O +hypertension B +that O +was O +evident O +after O +1 O +month O +of O +barium O +( O +100 O +micrograms O +/ O +ml O +mineral O +fortified O +water O +) O +treatment O +. O + +Analysis O +of O +in O +vivo O +myocardial O +excitability O +, O +contractility O +, O +and O +metabolic O +characteristics O +at O +16 O +months O +revealed O +other O +significant O +barium O +- O +induced O +disturbances O +within O +the O +cardiovascular O +system O +. O + +The O +most O +distinctive O +aspect O +of O +the O +barium O +effect O +was O +a O +demonstrated O +hypersensitivity B +of I +the I +cardiovascular I +system O +to O +sodium O +pentobarbital O +. O + +Under O +barbiturate O +anesthesia O +, O +virtually O +all O +of O +the O +myocardial O +contractile O +indices O +were O +depressed O +significantly O +in O +barium O +- O +exposed O +rats O +relative O +to O +the O +corresponding O +control O +- O +fed O +rats O +. O + +The O +lack O +of O +a O +similar O +response O +to O +ketamine O +and O +xylazine O +anesthesia O +revealed O +that O +the O +cardiovascular O +actions O +of O +sodium O +pentobarbital O +in O +barium O +- O +treated O +rats O +were O +linked O +specifically O +to O +this O +anesthetic O +, O +and O +were O +not O +representative O +of O +a O +generalized O +anesthetic O +response O +. O + +Other O +myocardial O +pathophysiologic O +and O +metabolic O +changes O +induced O +by O +barium O +were O +manifest O +, O +irrespective O +of O +the O +anesthetic O +employed O +. O + +The O +contractile O +element O +shortening O +velocity O +of O +the O +cardiac O +muscle O +fibers O +was O +significantly O +slower O +in O +both O +groups O +of O +barium O +- O +treated O +rats O +relative O +to O +the O +control O +groups O +, O +irrespective O +of O +the O +anesthetic O +regimen O +. O + +Similarly O +, O +significant O +disturbances O +in O +myocardial O +energy O +metabolism O +were O +detected O +in O +the O +barium O +- O +exposed O +rats O +which O +were O +consistent O +with O +the O +reduced O +contractile O +element O +shortening O +velocity O +. O + +In O +addition O +, O +the O +excitability O +of O +the O +cardiac O +conduction O +system O +was O +depressed O +preferentially O +in O +the O +atrioventricular O +nodal O +region O +of O +hearts O +from O +barium O +- O +exposed O +rats O +. O + +Overall O +, O +the O +altered O +cardiac O +contractility O +and O +excitability O +characteristics O +, O +the O +myocardial B +metabolic O +disturbances O +, O +and O +the O +hypersensitivity O +of O +the O +cardiovascular O +system O +to O +sodium O +pentobarbital O +suggest O +the O +existence O +of O +a O +heretofore O +undescribed O +cardiomyopathic B +disorder I +induced O +by O +chronic O +barium O +exposure O +. O + +These O +experimental O +findings O +represent O +the O +first O +indication O +that O +life O +- O +long O +barium O +ingestion O +may O +have O +significant O +adverse O +effects O +on O +the O +mammalian O +cardiovascular O +system O +. O + +Propranolol O +antagonism O +of O +phenylpropanolamine O +- O +induced O +hypertension B +. O + +Phenylpropanolamine O +( O +PPA O +) O +overdose B +can O +cause O +severe O +hypertension B +, O +intracerebral B +hemorrhage I +, O +and O +death B +. O + +We O +studied O +the O +efficacy O +and O +safety O +of O +propranolol O +in O +the O +treatment O +of O +PPA O +- O +induced O +hypertension B +. O + +Subjects O +received O +propranolol O +either O +by O +mouth O +for O +48 O +hours O +before O +PPA O +or O +as O +a O +rapid O +intravenous O +infusion O +after O +PPA O +. O + +PPA O +, O +75 O +mg O +alone O +, O +increased O +blood O +pressure O +( O +31 O ++ O +/ O +- O +14 O +mm O +Hg O +systolic O +, O +20 O ++ O +/ O +- O +5 O +mm O +Hg O +diastolic O +) O +, O +and O +propranolol O +pretreatment O +antagonized O +this O +increase O +( O +12 O ++ O +/ O +- O +10 O +mm O +Hg O +systolic O +, O +10 O ++ O +/ O +- O +7 O +mm O +Hg O +diastolic O +) O +. O + +Intravenous O +propranolol O +after O +PPA O +also O +decreased O +blood O +pressure O +. O + +Left O +ventricular O +function O +( O +assessed O +by O +echocardiography O +) O +showed O +that O +PPA O +increased O +the O +stroke B +volume O +30 O +% O +( O +from O +62 O +. O +5 O ++ O +/ O +- O +20 O +. O +9 O +to O +80 O +. O +8 O ++ O +/ O +- O +22 O +. O +4 O +ml O +) O +, O +the O +ejection O +fraction O +9 O +% O +( O +from O +64 O +% O ++ O +/ O +- O +10 O +% O +to O +70 O +% O ++ O +/ O +- O +7 O +% O +) O +, O +and O +cardiac O +output O +14 O +% O +( O +from O +3 O +. O +6 O ++ O +/ O +- O +0 O +. O +6 O +to O +4 O +. O +1 O ++ O +/ O +- O +1 O +. O +0 O +L O +/ O +min O +) O +. O + +Intravenous O +propranolol O +reversed O +these O +effects O +. O + +Systemic O +vascular O +resistance O +was O +increased O +by O +PPA O +28 O +% O +( O +from O +1710 O ++ O +/ O +- O +200 O +to O +2190 O ++ O +/ O +- O +700 O +dyne O +X O +sec O +/ O +cm5 O +) O +and O +was O +further O +increased O +by O +propranolol O +22 O +% O +( O +to O +2660 O ++ O +/ O +- O +1200 O +dyne O +X O +sec O +/ O +cm5 O +) O +. O + +We O +conclude O +that O +PPA O +increases O +blood O +pressure O +by O +increasing O +systemic O +vascular O +resistance O +and O +cardiac O +output O +, O +and O +that O +propranolol O +antagonizes O +this O +increase O +by O +reversing O +the O +effect O +of O +PPA O +on O +cardiac O +output O +. O + +That O +propranolol O +antagonizes O +the O +pressor O +effect O +of O +PPA O +is O +in O +contrast O +to O +the O +interaction O +in O +which O +propranolol O +enhances O +the O +pressor O +effect O +of O +norepinephrine O +. O + +This O +is O +probably O +because O +PPA O +has O +less O +beta O +2 O +activity O +than O +does O +norepinephrine O +. O + +Mesangial O +function O +and O +glomerular B +sclerosis I +in O +rats O +with O +aminonucleoside O +nephrosis B +. O + +The O +possible O +relationship O +between O +mesangial B +dysfunction I +and O +development O +of O +glomerular B +sclerosis I +was O +studied O +in O +the O +puromycin O +aminonucleoside O +( O +PAN O +) O +model O +. O + +Five O +male O +Wistar O +rats O +received O +repeated O +subcutaneous O +PAN O +injections O +; O +five O +controls O +received O +saline O +only O +. O + +After O +4 O +weeks O +the O +PAN O +rats O +were O +severely O +proteinuric B +( O +190 O ++ O +/ O +- O +80 O +mg O +/ O +24 O +hr O +) O +, O +and O +all O +rats O +were O +given O +colloidal O +carbon O +( O +CC O +) O +intravenously O +. O + +At O +5 O +months O +glomerular B +sclerosis I +was O +found O +in O +7 O +. O +6 O ++ O +/ O +- O +3 O +. O +4 O +% O +of O +the O +glomeruli O +of O +PAN O +rats O +; O +glomeruli O +of O +the O +controls O +were O +normal O +. O + +Glomeruli O +of O +PAN O +rats O +contained O +significantly O +more O +CC O +than O +glomeruli O +of O +controls O +. O + +Glomeruli O +with O +sclerosis B +contained O +significantly O +more O +CC O +than O +non O +- O +sclerotic O +glomeruli O +in O +the O +same O +kidneys O +. O + +CC O +was O +preferentially O +localized O +within O +the O +sclerotic O +areas O +of O +the O +affected O +glomeruli O +. O + +Since O +mesangial O +CC O +clearance O +from O +the O +mesangium O +did O +not O +change O +during O +chronic O +PAN O +treatment O +, O +we O +conclude O +that O +this O +preferential O +CC O +localization O +within O +the O +lesions O +is O +caused O +by O +an O +increased O +CC O +uptake O +shortly O +after O +injection O +in O +apparent O +vulnerable O +areas O +where O +sclerosis B +will O +develop O +subsequently O +. O + +Cluster O +analysis O +showed O +a O +random O +distribution O +of O +lesions O +in O +the O +PAN O +glomeruli O +in O +concordance O +with O +the O +random O +localization O +of O +mesangial O +areas O +with O +dysfunction O +in O +this O +model O +. O + +Similar O +to O +the O +remnant O +kidney O +model O +in O +PAN O +nephrosis B +the O +development O +of O +glomerular B +sclerosis I +may O +be O +related O +to O +" O +mesangial O +overloading O +. O +" O + +Relationship O +between O +nicotine O +- O +induced O +seizures B +and O +hippocampal O +nicotinic O +receptors O +. O + +A O +controversy O +has O +existed O +for O +several O +years O +concerning O +the O +physiological O +relevance O +of O +the O +nicotinic O +receptor O +measured O +by O +alpha O +- O +bungarotoxin O +binding O +. O + +Using O +mice O +derived O +from O +a O +classical O +F2 O +and O +backcross O +genetic O +design O +, O +a O +relationship O +between O +nicotine O +- O +induced O +seizures B +and O +alpha O +- O +bungarotoxin O +nicotinic O +receptor O +concentration O +was O +found O +. O + +Mice O +sensitive O +to O +the O +convulsant O +effects O +of O +nicotine O +had O +greater O +alpha O +- O +bungarotoxin O +binding O +in O +the O +hippocampus O +than O +seizure B +insensitive O +mice O +. O + +The O +binding O +sites O +from O +seizure B +sensitive O +and O +resistant O +mice O +were O +equally O +affected O +by O +treatment O +with O +dithiothreitol O +, O +trypsin O +or O +heat O +. O + +Thus O +it O +appears O +that O +the O +difference O +between O +seizure B +sensitive O +and O +insensitive O +animals O +may O +be O +due O +to O +a O +difference O +in O +hippocampal O +nicotinic O +receptor O +concentration O +as O +measured O +with O +alpha O +- O +bungarotoxin O +binding O +. O + +The O +role O +of O +p O +- O +aminophenol O +in O +acetaminophen O +- O +induced O +nephrotoxicity B +: O +effect O +of O +bis O +( O +p O +- O +nitrophenyl O +) O +phosphate O +on O +acetaminophen O +and O +p O +- O +aminophenol O +nephrotoxicity B +and O +metabolism O +in O +Fischer O +344 O +rats O +. O + +Acetaminophen O +( O +APAP O +) O +produces O +proximal O +tubular I +necrosis I +in O +Fischer O +344 O +( O +F344 O +) O +rats O +. O + +Recently O +, O +p O +- O +aminophenol O +( O +PAP O +) O +, O +a O +known O +potent O +nephrotoxicant O +, O +was O +identified O +as O +a O +metabolite O +of O +APAP O +in O +F344 O +rats O +. O + +The O +purpose O +of O +this O +study O +was O +to O +determine O +if O +PAP O +formation O +is O +a O +requisite O +step O +in O +APAP O +- O +induced O +nephrotoxicity B +. O + +Therefore O +, O +the O +effect O +of O +bis O +( O +p O +- O +nitrophenyl O +) O +phosphate O +( O +BNPP O +) O +, O +an O +acylamidase O +inhibitor O +, O +on O +APAP O +and O +PAP O +nephrotoxicity B +and O +metabolism O +was O +determined O +. O + +BNPP O +( O +1 O +to O +8 O +mM O +) O +reduced O +APAP O +deacetylation O +and O +covalent O +binding O +in O +F344 O +renal O +cortical O +homogenates O +in O +a O +concentration O +- O +dependent O +manner O +. O + +Pretreatment O +of O +animals O +with O +BNPP O +prior O +to O +APAP O +or O +PAP O +administration O +resulted O +in O +marked O +reduction O +of O +APAP O +( O +900 O +mg O +/ O +kg O +) O +nephrotoxicity B +but O +not O +PAP O +nephrotoxicity B +. O + +This O +result O +was O +not O +due O +to O +altered O +disposition O +of O +either O +APAP O +or O +acetylated O +metabolites O +in O +plasma O +or O +renal O +cortical O +and O +hepatic O +tissue O +. O + +Rather O +, O +BNPP O +pretreatment O +reduced O +the O +fraction O +of O +APAP O +excreted O +as O +PAP O +by O +64 O +and O +75 O +% O +after O +APAP O +doses O +of O +750 O +and O +900 O +mg O +/ O +kg O +. O + +BNPP O +did O +not O +alter O +the O +excretion O +of O +APAP O +or O +any O +of O +its O +non O +- O +deacetylated O +metabolites O +nor O +did O +BNPP O +alter O +excretion O +of O +PAP O +or O +its O +metabolites O +after O +PAP O +doses O +of O +150 O +and O +300 O +mg O +/ O +kg O +. O + +Therefore O +, O +the O +BNPP O +- O +induced O +reduction O +in O +APAP O +- O +induced O +nephrotoxicity B +appears O +to O +be O +due O +to O +inhibition O +of O +APAP O +deacetylation O +. O + +It O +is O +concluded O +that O +PAP O +formation O +, O +in O +vivo O +, O +accounts O +, O +at O +least O +in O +part O +, O +for O +APAP O +- O +induced O +renal B +tubular I +necrosis I +. O + +Morphine O +- O +induced O +seizures B +in O +newborn O +infants O +. O + +Two O +neonates O +suffered O +from O +generalized O +seizures B +during O +the O +course O +of O +intravenous O +morphine O +sulfate O +for O +post O +- O +operative O +analgesia O +. O + +They O +received O +morphine O +in O +doses O +of O +32 O +micrograms O +/ O +kg O +/ O +hr O +and O +40 O +micrograms O +/ O +kg O +/ O +hr O +larger O +than O +a O +group O +of O +10 O +neonates O +who O +received O +6 O +- O +24 O +micrograms O +/ O +kg O +/ O +hr O +and O +had O +no O +seizures B +. O + +Plasma O +concentrations O +of O +morphine O +in O +these O +neonates O +was O +excessive O +( O +60 O +and O +90 O +mg O +/ O +ml O +) O +. O + +Other O +known O +reasons O +for O +seizures B +were O +ruled O +out O +and O +the O +convulsions B +stopped O +a O +few O +hours O +after O +cessation O +of O +morphine O +and O +did O +not O +reoccur O +in O +the O +subsequent O +8 O +months O +. O + +It O +is O +suggested O +that O +post O +- O +operative O +intravenous O +morphine O +should O +not O +exceed O +20 O +micrograms O +/ O +kg O +/ O +ml O +in O +neonates O +. O + +Indomethacin O +induced O +hypotension B +in O +sodium O +and O +volume O +depleted O +rats O +. O + +After O +a O +single O +oral O +dose O +of O +4 O +mg O +/ O +kg O +indomethacin O +( O +IDM O +) O +to O +sodium O +and O +volume O +depleted O +rats O +plasma O +renin O +activity O +( O +PRA O +) O +and O +systolic O +blood O +pressure O +fell O +significantly O +within O +four O +hours O +. O + +In O +sodium O +repleted O +animals O +indomethacin O +did O +not O +change O +systolic O +blood O +pressure O +( O +BP O +) O +although O +plasma O +renin O +activity O +was O +decreased O +. O + +Thus O +, O +indomethacin O +by O +inhibition O +of O +prostaglandin O +synthesis O +may O +diminish O +the O +blood O +pressure O +maintaining O +effect O +of O +the O +stimulated O +renin O +- O +angiotensin O +system O +in O +sodium O +and O +volume O +depletion O +. O + +On O +the O +antiarrhythmic O +activity O +of O +one O +N O +- O +substituted O +piperazine O +derivative O +of O +trans O +- O +2 O +- O +amino O +- O +3 O +- O +hydroxy O +- O +1 O +, O +2 O +, O +3 O +, O +4 O +- O +tetrahydroanaphthalene O +. O + +The O +antiarrhythmic O +activity O +of O +the O +compound O +N O +- O +( O +trans O +- O +3 O +- O +hydroxy O +- O +1 O +, O +2 O +, O +3 O +, O +4 O +- O +tetrahydro O +- O +2 O +- O +naphthyl O +) O +- O +N O +- O +( O +3 O +- O +oxo O +- O +3 O +- O +phenyl O +- O +2 O +- O +methylpropyl O +) O +- O +piperazine O +hydrochloride O +, O +referred O +to O +as O +P11 O +, O +is O +studied O +on O +anaesthesized O +cats O +and O +Wistar O +albino O +rats O +, O +as O +well O +as O +on O +non O +- O +anaesthesized O +rabbits O +. O + +Four O +types O +of O +experimental O +arrhythmia B +are O +used O +- O +- O +with O +BaCl2 O +, O +with O +chloroform O +- O +adrenaline O +, O +with O +strophantine O +G O +and O +with O +aconitine O +. O + +The O +compound O +P11 O +is O +introduced O +in O +doses O +of O +0 O +. O +25 O +and O +0 O +. O +50 O +mg O +/ O +kg O +intravenously O +and O +10 O +mg O +/ O +kg O +orally O +. O + +The O +compound O +manifests O +antiarrhythmic O +activity O +in O +all O +models O +of O +experimental O +arrhythmia B +used O +, O +causing O +greatest O +inhibition O +on O +the O +arrhythmia B +induced O +by O +chloroform O +- O +adrenaline O +( O +in O +90 O +per O +cent O +) O +and O +with O +BaCl2 O +( O +in O +84 O +per O +cent O +) O +. O + +The O +results O +obtained O +are O +associated O +with O +the O +beta O +- O +adrenoblocking O +and O +with O +the O +membrane O +- O +stabilizing O +action O +of O +the O +compound O +. O + +Recurrent O +subarachnoid B +hemorrhage I +associated O +with O +aminocaproic O +acid O +therapy O +and O +acute B +renal I +artery I +thrombosis I +. O + +Case O +report O +. O + +Epsilon O +aminocaproic O +acid O +( O +EACA O +) O +has O +been O +used O +to O +prevent O +rebleeding O +in O +patients O +with O +subarachnoid B +hemorrhage I +( O +SAH B +) O +. O + +Although O +this O +agent O +does O +decrease O +the O +frequency O +of O +rebleeding O +, O +several O +reports O +have O +described O +thrombotic B +complications O +of O +EACA O +therapy O +. O + +These O +complications O +have O +included O +clinical O +deterioration O +and O +intracranial O +vascular I +thrombosis B +in O +patients O +with O +SAH B +, O +arteriolar O +and O +capillary O +fibrin O +thrombi B +in O +patients O +with O +fibrinolytic O +syndromes O +treated O +with O +EACA O +, O +or O +other O +thromboembolic B +phenomena O +. O + +Since O +intravascular O +fibrin O +thrombi B +are O +often O +observed O +in O +patients O +with O +fibrinolytic B +disorders I +, O +EACA O +should O +not O +be O +implicated O +in O +the O +pathogenesis O +of O +fibrin O +thrombi B +in O +patients O +with O +disseminated B +intravascular I +coagulation I +or O +other O +" O +consumption B +coagulopathies I +. O +" O +This O +report O +describes O +subtotal O +infarction B +of I +the I +kidney I +due O +to O +thrombosis B +of O +a O +normal O +renal O +artery O +. O + +This O +occlusion O +occurred O +after O +EACA O +therapy O +in O +a O +patient O +with O +SAH B +and O +histopathological O +documentation O +of O +recurrent O +SAH B +. O + +The O +corresponding O +clinical O +event O +was O +characterized O +by O +marked O +hypertension B +and O +abrupt O +neurological B +deterioration I +. O + +Effect O +of O +vincristine O +sulfate O +on O +Pseudomonas B +infections I +in O +monkeys O +. O + +In O +rhesus O +monkeys O +, O +intravenous O +challenge O +with O +0 O +. O +6 O +x O +10 O +( O +10 O +) O +to O +2 O +. O +2 O +x O +10 O +( O +10 O +) O +Pseudomonas O +aeruginosa O +organisms O +caused O +acute O +illness O +of O +4 O +to O +5 O +days O +' O +duration O +with O +spontaneous O +recovery O +in O +13 O +of O +15 O +monkeys O +; O +blood O +cultures O +became O +negative O +3 O +to O +17 O +days O +after O +challenge O +. O + +Leukocytosis B +was O +observed O +in O +all O +monkeys O +. O + +Intravenous O +or O +intratracheal O +inoculation O +of O +2 O +. O +0 O +to O +2 O +. O +5 O +mg O +of O +vincristine O +sulfate O +was O +followed O +by O +leukopenia B +in O +4 O +to O +5 O +days O +. O + +Intravenous O +inoculation O +of O +4 O +. O +2 O +x O +10 O +( O +10 O +) O +to O +7 O +. O +8 O +x O +10 O +( O +10 O +) O +pyocin O +type O +6 O +Pseudomonas O +organisms O +in O +monkeys O +given O +vincristine O +sulfate O +4 O +days O +previously O +resulted O +in O +fatal O +infection B +in O +11 O +of O +14 O +monkeys O +, O +whereas O +none O +of O +four O +receiving O +Pseudomonas O +alone O +died O +. O + +These O +studies O +suggest O +that O +an O +antimetabolite O +- O +induced O +leukopenia B +predisposes O +to O +severe O +Pseudomonas B +sepsis I +and O +that O +such O +monkeys O +may O +serve O +as O +a O +biological O +model O +for O +study O +of O +comparative O +efficacy O +of O +antimicrobial O +agents O +. O + +Modification O +by O +propranolol O +of O +cardiovascular O +effects O +of O +induced O +hypoglycaemia B +. O + +The O +cardiovascular O +effects O +of O +hypoglycaemia B +, O +with O +and O +without O +beta O +- O +blockade O +, O +were O +compared O +in O +fourteen O +healthy O +men O +. O + +Eight O +received O +insulin O +alone O +, O +and O +eight O +, O +including O +two O +of O +the O +original O +insulin O +- O +only O +group O +, O +were O +given O +propranolol O +and O +insulin O +. O + +In O +the O +insulin O +- O +group O +the O +period O +of O +hypoglycaemia B +was O +associated O +with O +an O +increase O +in O +heart O +- O +rate O +and O +a O +fall O +in O +diastolic O +blood O +- O +pressure O +. O + +In O +the O +propranolol O +- O +insulin O +group O +there O +was O +a O +significant O +fall O +in O +heart O +- O +rate O +in O +most O +subjects O +and O +an O +increase O +in O +diastolic O +pressure O +. O + +Typical O +S O +- O +T O +/ O +T O +changes O +occurred O +in O +the O +insulin O +- O +group O +but O +in O +none O +of O +the O +propranolol O +- O +insulin O +group O +. O + +Hypertension B +in O +diabetics B +prone O +to O +hypoglycaemia B +attacks O +should O +not O +be O +treated O +with O +beta O +- O +blockers O +because O +these O +drugs O +may O +cause O +a O +sharp O +rise O +in O +blood O +- O +pressure O +in O +such O +patients O +. O + +Long O +- O +term O +propranolol O +therapy O +in O +pregnancy O +: O +maternal O +and O +fetal O +outcome O +. O + +Propranolol O +, O +a O +beta O +- O +adrenergic O +blocking O +agent O +, O +has O +found O +an O +important O +position O +in O +the O +practice O +of O +medicine O +. O + +Its O +use O +in O +pregnancy O +, O +however O +, O +is O +an O +open O +question O +as O +a O +number O +of O +detrimental O +side O +effects O +have O +been O +reported O +in O +the O +fetus O +and O +neonate O +. O + +Ten O +patients O +and O +12 O +pregnancies O +are O +reported O +where O +chronic O +propranolol O +has O +been O +administered O +. O + +Five O +patients O +with O +serial O +pregnancies O +with O +and O +without O +propranolol O +therapy O +are O +also O +examined O +. O + +Maternal O +, O +fetal O +, O +and O +neonatal O +complications O +are O +examined O +. O + +An O +attempt O +is O +made O +to O +differentiate O +drug O +- O +related O +complications O +from O +maternal O +disease O +- O +- O +related O +complications O +. O + +We O +conclude O +that O +previously O +reported O +hypoglycemia B +, O +hyperbilirubinemia B +, O +polycythemia B +, O +neonatal B +apnea I +, O +and O +bradycardia B +are O +not O +invariable O +and O +cannot O +be O +statistically O +correlated O +with O +chronic O +propranolol O +therapy O +. O + +Growth B +retardation I +, O +however O +, O +appears O +to O +be O +significant O +in O +both O +of O +our O +series O +. O + +Central O +excitatory O +actions O +of O +flurazepam O +. O + +Toxic O +actions O +of O +flurazepam O +( O +FZP O +) O +were O +studied O +in O +cats O +, O +mice O +and O +rats O +. O + +High O +doses O +caused O +an O +apparent O +central O +excitation O +, O +most O +clearly O +seen O +as O +clonic B +convulsions I +, O +superimposed O +on O +general O +depression B +. O + +Following O +a O +lethal O +dose O +, O +death B +was O +always O +associated O +with O +convulsions B +. O + +Comparing O +the O +relative O +sensitivity O +to O +central O +depression B +and O +excitation O +revealed O +that O +rats O +were O +least O +likely O +to O +have O +convulsions B +at O +doses O +that O +did O +not O +first O +cause O +loss B +of I +consciousness I +, O +while O +cats O +most O +clearly O +showed O +marked O +central O +excitatory O +actions O +. O + +Signs O +of O +FZP O +toxocity O +in O +cats O +included O +excessive O +salivation O +, O +extreme O +apprehensive O +behavior O +, O +retching O +, O +muscle B +tremors I +and O +convulsions B +. O + +An O +interaction O +between O +FZP O +and O +pentylenetetrazol O +( O +PTZ O +) O +was O +shown O +by O +pretreating O +mice O +with O +FZP O +before O +PTZ O +challenge O +. O + +As O +a O +function O +of O +dose O +, O +FZP O +first O +protected O +against O +convulsions B +and O +death B +. O + +At O +higher O +doses O +, O +however O +, O +convulsions B +again O +emerged O +. O + +These O +doses O +of O +FZP O +were O +lower O +than O +those O +that O +would O +alone O +cause O +convulsions B +. O + +These O +results O +may O +be O +relevant O +to O +the O +use O +of O +FZP O +in O +clinical O +situations O +in O +which O +there O +is O +increased O +neural O +excitability O +, O +such O +as O +epilepsy B +or O +sedative O +- O +hypnotic O +drug O +withdrawal O +. O + +Use O +of O +propranolol O +in O +the O +treatment O +of O +idiopathic O +orthostatic B +hypotension I +. O + +Five O +patients O +with O +idiopathic O +orthostatic B +hypotension I +who O +had O +physiologic O +and O +biochemical O +evidence O +of O +severe O +autonomic B +dysfunction I +were O +included O +in O +the O +study O +. O + +They O +all O +exhibited O +markedly O +reduced O +plasma O +catecholamines O +and O +plasma O +renin O +activity O +in O +both O +recumbent O +and O +upright O +positions O +and O +had O +marked O +hypersensitivity B +to O +the O +pressor O +effects O +of O +infused O +norepinephrine O +. O + +Treatment O +with O +propanolol O +administered O +intravenously O +( O +1 O +- O +5 O +mg O +) O +produced O +increases B +in I +supine I +and I +upright I +blood I +pressure I +in O +4 O +of O +the O +5 O +individuals O +with O +rises O +ranging O +from O +11 O +/ O +6 O +to O +22 O +/ O +11 O +mmHg O +. O + +Chronic O +oral O +administration O +of O +propranolol O +( O +40 O +- O +160 O +mg O +/ O +day O +) O +also O +elevated O +the O +blood O +pressures O +of O +these O +individuals O +with O +increases O +in O +the O +order O +of O +20 O +- O +35 O +/ O +15 O +- O +25 O +mmg O +being O +observed O +. O + +In O +1 O +patient O +, O +marked O +hypertension B +was O +induced O +by O +propranolol O +and O +the O +drug O +had O +to O +be O +withdrawn O +. O + +It O +otherwise O +was O +well O +tolerated O +and O +no O +important O +side O +effects O +were O +observed O +. O + +Treatment O +has O +been O +continued O +in O +3 O +individuals O +for O +6 O +- O +13 O +months O +with O +persistence O +of O +the O +pressor O +effect O +, O +although O +there O +appears O +to O +have O +been O +some O +decrease O +in O +the O +degree O +of O +response O +with O +time O +. O + +Hemodynamic O +measurements O +in O +1 O +of O +the O +patients O +demonstrated O +an O +increase O +in O +total O +peripheral O +resistance O +and O +essentially O +no O +change O +in O +cardiac O +output O +following O +propranolol O +therapy O +. O + +The O +studies O +suggest O +that O +propranolol O +is O +a O +useful O +drug O +in O +selected O +patients O +with O +severe O +idiopathic O +orthostatic B +hypotension I +. O + +Total O +intravenous O +anesthesia O +with O +etomidate O +. O + +III O +. O + +Some O +observations O +in O +adults O +. O + +An O +investigation O +was O +undertaken O +to O +determine O +the O +dosage O +of O +etomidate O +required O +to O +maintain O +sleep O +in O +adults O +undergoing O +surgery O +under O +regional O +local O +anesthesia O +. O + +Premedication O +of O +diazepam O +10 O +mg O +and O +atropine O +0 O +. O +5 O +mg O +was O +given O +, O +and O +sleep O +was O +induced O +and O +maintained O +by O +intermittent O +intravenous O +injections O +of O +etomidate O +0 O +. O +1 O +/ O +mg O +/ O +kg O +, O +given O +whenever O +the O +patient O +would O +open O +his O +eyes O +on O +request O +. O + +A O +mean O +overall O +dose O +of O +etomidate O +17 O +. O +4 O +microgram O +/ O +kg O +/ O +min O +. O +was O +required O +to O +maintain O +sleep O +, O +but O +great O +individual O +variation O +occurred O +, O +with O +older O +patients O +requiring O +less O +drug O +. O + +The O +investigation O +was O +discontinued O +after O +18 O +patients O +because O +of O +the O +frequency O +and O +intensity O +of O +side O +- O +effects O +, O +particularly O +pain B +and O +myoclonia B +, O +which O +caused O +the O +technique O +to O +be O +abandoned O +in O +two O +cases O +. O + +It O +is O +considered O +unlikely O +that O +etomidate O +will O +prove O +to O +be O +the O +hypnotic O +of O +choice O +for O +a O +totally O +intravenous O +anesthetic O +technique O +in O +adults O +because O +of O +the O +high O +incidence O +of O +myoclonia B +after O +prolonged O +administration O +. O + +In O +several O +patients O +uncontrollable O +muscle O +movements O +persisted O +for O +many O +minutes O +after O +complete O +recovery O +of O +consciousness O +. O + +Evidence O +for O +cardiac O +beta O +2 O +- O +adrenoceptors O +in O +man O +. O + +We O +compared O +the O +effects O +of O +single O +doses O +of O +50 O +mg O +atenolol O +( O +cardioselective O +) O +, O +40 O +mg O +propranolol O +( O +nonselective O +) O +, O +and O +placebo O +on O +both O +exercise O +- O +and O +isoproterenol O +- O +induced O +tachycardia B +in O +two O +experiments O +involving O +nine O +normal O +subjects O +. O + +Maximal O +exercise O +heart O +rate O +was O +reduced O +from O +187 O ++ O +/ O +- O +4 O +( O +SEM O +) O +after O +placebo O +to O +146 O ++ O +/ O +- O +7 O +bpm O +after O +atenolol O +and O +138 O ++ O +/ O +- O +6 O +bpm O +after O +propranolol O +, O +but O +there O +were O +no O +differences O +between O +the O +drugs O +. O + +The O +effects O +on O +isoproterenol O +tachycardia B +were O +determined O +before O +and O +after O +atropine O +( O +0 O +. O +04 O +mg O +/ O +kg O +IV O +) O +. O + +Isoproterenol O +sensitivity O +was O +determined O +as O +the O +intravenous O +dose O +that O +increased O +heart O +rate O +by O +25 O +bpm O +( O +CD25 O +) O +and O +this O +was O +increased O +from O +1 O +. O +8 O ++ O +/ O +- O +0 O +. O +3 O +micrograms O +after O +placebo O +to O +38 O +. O +9 O ++ O +/ O +- O +8 O +. O +3 O +micrograms O +after O +propranolol O +and O +8 O +. O +3 O ++ O +/ O +- O +1 O +. O +7 O +micrograms O +after O +atenolol O +. O + +The O +difference O +in O +the O +effects O +of O +the O +two O +was O +significant O +. O + +After O +atropine O +the O +CD25 O +was O +unchanged O +after O +placebo O +( O +2 O +. O +3 O ++ O +/ O +- O +0 O +. O +3 O +micrograms O +) O +and O +atenolol O +( O +7 O +. O +7 O ++ O +/ O +- O +1 O +. O +3 O +micrograms O +) O +; O +it O +was O +reduced O +after O +propranolol O +( O +24 O +. O +8 O ++ O +/ O +- O +5 O +. O +0 O +micrograms O +) O +, O +but O +remained O +different O +from O +atenolol O +. O + +This O +change O +with O +propranolol O +sensitivity O +was O +calculated O +as O +the O +apparent O +Ka O +, O +this O +was O +unchanged O +by O +atropine O +( O +11 O +. O +7 O ++ O +/ O +- O +2 O +. O +1 O +and O +10 O +. O +1 O ++ O +/ O +- O +2 O +. O +5 O +ml O +/ O +ng O +) O +. O + +These O +data O +are O +consistent O +with O +the O +hypothesis O +that O +exercise O +- O +induced O +tachycardia B +results O +largely O +from O +beta O +1 O +- O +receptor O +activation O +that O +is O +blocked O +by O +both O +cardioselective O +and O +nonselective O +drugs O +, O +whereas O +isoproterenol O +activates O +both O +beta O +1 O +- O +and O +beta O +2 O +- O +receptors O +so O +that O +after O +cardioselective O +blockade O +there O +remains O +a O +beta O +2 O +- O +component O +that O +can O +be O +blocked O +with O +a O +nonselective O +drug O +. O + +While O +there O +appear O +to O +be O +beta O +2 O +- O +receptors O +in O +the O +human O +heart O +, O +their O +physiologic O +or O +pathologic O +roles O +remain O +to O +be O +defined O +. O + +Hormones O +and O +risk O +of O +breast B +cancer I +. O + +This O +paper O +reports O +the O +results O +of O +a O +study O +of O +50 O +menopausal O +women O +receiving O +hormonal O +replacement O +therapy O +. O + +The O +majority O +( O +29 O +) O +had O +surgical O +menopause O +; O +their O +mean O +age O +was O +45 O +. O +7 O +years O +. O + +It O +was O +hypothesized O +that O +progestins O +could O +equilibrate O +the O +effects O +of O +the O +estrogenic O +stimulation O +on O +the O +mammary O +and O +endometrial O +target O +tissues O +of O +women O +on O +hormonal O +replacement O +therapy O +. O + +The O +treatment O +schedule O +consisted O +of O +conjugated O +estrogens O +( O +Premarin O +) O +1 O +. O +25 O +mg O +/ O +day O +for O +21 O +days O +and O +Medroxyprogesterone O +acetate O +10 O +mg O +/ O +day O +for O +10 O +days O +in O +each O +month O +. O + +The O +mean O +treatment O +period O +was O +18 O +months O +. O + +During O +the O +follow O +- O +up O +period O +, O +attention O +was O +paid O +to O +breast O +modifications O +as O +evidenced O +by O +symptomatology O +, O +physical O +examination O +, O +and O +plate O +thermography O +. O + +Mastodynia B +was O +reported O +by O +21 O +patients O +, O +and O +physical O +examination O +revealed O +a O +light O +increase O +in O +breast O +firmness O +in O +12 O +women O +and O +a O +moderate O +increase O +in O +breast O +nodularity O +in O +2 O +women O +. O + +Themography O +confirmed O +the O +existence O +of O +an O +excessive O +breast O +stimulation O +in O +1 O +women O +who O +complained O +of O +moderate O +mastodynia B +and O +in O +5 O +of O +the O +7 O +women O +who O +complained O +of O +severe O +mastodynia B +. O + +Normalization O +was O +obtained O +by O +halving O +the O +estrogen O +dose O +. O + +These O +results O +suggest O +that O +hormonal O +replacement O +therapy O +can O +be O +safely O +prescribed O +if O +the O +following O +criteria O +are O +satisfied O +: O +1 O +) O +preliminary O +evaluation O +of O +patients O +from O +a O +clinical O +, O +metabolic O +, O +cytologic O +, O +and O +mammographic O +perspective O +; O +2 O +) O +cyclic O +treatment O +schedule O +, O +with O +a O +progestative O +phase O +of O +10 O +days O +; O +and O +3 O +) O +periodic O +complete O +follow O +- O +up O +, O +with O +accurate O +thermographic O +evaluation O +of O +the O +breast O +target O +tissues O +. O + +Early O +infections B +in O +kidney O +, O +heart O +, O +and O +liver O +transplant O +recipients O +on O +cyclosporine O +. O + +Eighty O +- O +one O +renal O +, O +seventeen O +heart O +, O +and O +twenty O +- O +four O +liver O +transplant O +patients O +were O +followed O +for O +infection B +. O + +Seventeen O +renal O +patients O +received O +azathioprine O +( O +Aza O +) O +and O +prednisone O +as O +part O +of O +a O +randomized O +trial O +of O +immunosuppression O +with O +21 O +cyclosporine O +- O +and O +- O +prednisone O +- O +treated O +renal O +transplant O +patients O +. O + +All O +others O +received O +cyclosporine O +and O +prednisone O +. O + +The O +randomized O +Aza O +patients O +had O +more O +overall O +infections B +( O +P O +less O +than O +0 O +. O +05 O +) O +and O +more O +nonviral B +infections I +( O +P O +less O +than O +0 O +. O +02 O +) O +than O +the O +randomized O +cyclosporine O +patients O +. O + +Heart O +and O +liver O +patients O +had O +more O +infections B +than O +cyclosporine O +renal O +patients O +but O +fewer O +infections B +than O +the O +Aza O +renal O +patients O +. 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O +4 O +mumol O +/ O +kg O +) O +and O +caerulein O +dose O +range O +0 O +. O +1 O +- O +0 O +. O +8 O +mumol O +/ O +kg O +) O +showed O +bell O +- O +shaped O +dose O +- O +effect O +curves O +, O +with O +the O +greatest O +maximum O +inhibition O +for O +CCK O +- O +8 O +- O +NS O +. O + +The O +peptide O +CCK O +- O +5 O +- O +8 O +had O +weak O +anticonvulsant O +activity O +in O +comparison O +to O +the O +octapeptides O +, O +3 O +. O +2 O +mumol O +/ O +kg O +and O +larger O +doses O +of O +the O +reference O +drug O +, O +diazepam O +, O +totally O +prevented O +picrotoxin O +- O +induced O +seizures B +and O +mortality O +. O + +The O +maximum O +effect O +of O +the O +peptides O +tested O +was O +less O +than O +that O +of O +diazepam O +. O + +Experiments O +with O +analogues O +and O +derivatives O +of O +CCK O +- O +5 O +- O +8 O +demonstrated O +that O +the O +effectiveness O +of O +the O +beta O +- O +alanyl O +derivatives O +of O +CCK O +- O +5 O +- O +8 O +were O +enhanced O +and O +that O +they O +were O +equipotent O +with O +CCK O +- O +8 O +- O +SE O +. O + +Of O +the O +CCK O +- O +2 O +- O +8 O +analogues O +, O +Ser O +( O +SO3H O +) O +7 O +- O +Ac O +- O +CCK O +- O +2 O +- O +8 O +- O +SE O +and O +Thr O +( O +SO3H O +) O +7 O +- O +Ac O +- O +CCK O +- O +2 O +- O +8 O +- O +SE O +and O +Hyp O +( O +SO3H O +) O +- O +Ac O +- O +CCK O +- O +2 O +- O +8 O +- O +SE O +were O +slightly O +more O +active O +than O +CCK O +- O +8 O +- O +SE O +. O + +Vasopressin O +as O +a O +possible O +contributor O +to O +hypertension B +. O + +The O +role O +of O +vasopressin O +as O +a O +pressor O +agent O +to O +the O +hypertensive B +process O +was O +examined O +. 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O + +Increased O +secretion O +of O +vasopressin O +from O +neurohypophysis O +also O +promotes O +the O +function O +of O +the O +hormone O +as O +a O +pathogenetic O +factor O +in O +hypertension B +. O + +An O +unproportional O +release O +of O +vasopressin O +compared O +to O +plasma O +osmolality O +may O +be O +induced O +by O +the O +absence O +of O +an O +adjusting O +control O +of O +angiotensin O +II O +forming O +and O +receptor O +binding O +capacity O +for O +sodium O +balance O +in O +the O +brain O +. O + +However O +, O +the O +role O +of O +vasopressin O +remains O +to O +be O +determined O +in O +human O +essential O +hypertension B +. O + +Toxic B +hepatitis I +induced O +by O +disulfiram O +in O +a O +non O +- O +alcoholic O +. O + +A O +reversible O +toxic O +liver B +damage I +was O +observed O +in O +a O +non O +- O +alcoholic O +woman O +treated O +with O +disulfiram O +. O + +The O +causative O +relationship O +was O +proven O +by O +challenge O +. O + +Atrial B +thrombosis I +involving O +the O +heart O +of O +F O +- O +344 O +rats O +ingesting O +quinacrine O +hydrochloride O +. O + +Quinacrine O +hydrochloride O +is O +toxic O +for O +the O +heart O +of O +F O +- O +344 O +rats O +. O + +Rats O +treated O +with O +500 O +ppm O +quinacrine O +hydrochloride O +in O +the O +diet O +all O +developed O +a O +high O +incidence O +of O +left B +atrial I +thrombosis I +. O + +The O +lesion O +was O +associated O +with O +cardiac B +hypertrophy I +and O +dilatation O +and O +focal O +myocardial B +degeneration I +. O + +Rats O +died O +from O +cardiac B +hypertrophy I +with O +severe O +acute O +and O +chronic O +congestion B +of I +the I +lungs I +, O +liver O +, O +and O +other O +organs O +. O + +Seventy O +percent O +of O +rats O +given O +250 O +ppm O +quinacrine O +hydrochloride O +and O +1 O +, O +000 O +ppm O +sodium O +nitrite O +simultaneously O +in O +the O +diet O +had O +thrombosis B +of I +the I +atria I +of I +the I +heart I +, O +while O +untreated O +control O +rats O +in O +this O +laboratory O +did O +not O +have O +atrial B +thrombosis I +. O + +Sodium O +nitrite O +in O +combination O +with O +quinacrine O +hydrochloride O +appeared O +to O +have O +no O +additional O +effect O +. O + +Alternating O +sinus O +rhythm O +and O +intermittent O +sinoatrial B +block I +induced O +by O +propranolol O +. O + +Alternating O +sinus O +rhythm O +and O +intermittent O +sinoatrial B +( I +S I +- I +A I +) I +block I +was O +observed O +in O +a O +57 O +- O +year O +- O +old O +woman O +, O +under O +treatment O +for O +angina B +with O +80 O +mg O +propranolol O +daily O +. O + +The O +electrocardiogram O +showed O +alternation O +of O +long O +and O +short O +P O +- O +P O +intervals O +and O +occasional O +pauses O +. O + +These O +pauses O +were O +always O +preceded O +by O +the O +short O +P O +- O +P O +intervals O +and O +were O +usually O +followed O +by O +one O +or O +two O +P O +- O +P O +intervals O +of O +0 O +. O +92 O +- O +0 O +. O +95 O +s O +representing O +the O +basic O +sinus O +cycle O +. O + +Following O +these O +basic O +sinus O +cycles O +, O +alternating O +rhythm O +started O +with O +the O +longer O +P O +- O +P O +interval O +. O + +The O +long O +P O +- O +P O +intervals O +ranged O +between O +1 O +. O +04 O +- O +1 O +. O +12 O +s O +and O +the O +short O +P O +- O +P O +intervals O +between O +0 O +. O +80 O +- O +0 O +. O +84 O +s O +, O +respectively O +. O + +The O +duration O +of O +the O +pauses O +were O +equal O +or O +almost O +equal O +to O +one O +short O +plus O +one O +long O +P O +- O +P O +interval O +or O +to O +twice O +the O +basic O +sinus O +cycle O +. O + +In O +one O +recording O +a O +short O +period O +of O +regular O +sinus O +rhythm O +with O +intermittent O +2 O +/ O +1 O +S O +- O +A O +block O +was O +observed O +. O + +This O +short O +period O +of O +sinus O +rhythm O +was O +interrupted O +by O +sudden O +prolongation O +of O +the O +P O +- O +P O +interval O +starting O +the O +alternative O +rhythm O +. O + +There O +were O +small O +changes O +in O +the O +shape O +of O +the O +P O +waves O +and O +P O +- O +R O +intervals O +. O + +S O +- O +A O +conduction O +through O +two O +pathways O +, O +the O +first O +with O +2 O +/ O +1 O +block O +the O +second O +having O +0 O +. O +12 O +- O +0 O +. O +14 O +s O +longer O +conduction O +time O +and O +with O +occasional O +2 O +/ O +1 O +block O +was O +proposed O +for O +the O +explanation O +of O +the O +alternating O +P O +- O +P O +interval O +and O +other O +electrocardiographic O +features O +seen O +. O + +Atropine O +1 O +mg O +given O +intravenously O +resulted O +in O +shortening O +of O +all O +P O +- O +P O +intervals O +without O +changing O +the O +rhythm O +. O + +The O +abnormal O +rhythm O +disappeared O +with O +the O +withdrawal O +of O +propranolol O +and O +when O +the O +drug O +was O +restarted O +a O +2 O +/ O +1 O +S O +- O +A O +block O +was O +seen O +. O + +This O +was O +accepted O +as O +evidence O +for O +propranolol O +being O +the O +cause O +of O +this O +conduction B +disorder I +. O + +Antitumor O +effect O +, O +cardiotoxicity B +, O +and O +nephrotoxicity B +of O +doxorubicin O +in O +the O +IgM O +solid O +immunocytoma B +- O +bearing O +LOU O +/ O +M O +/ O +WSL O +rat O +. O + +Antitumor O +activity O +, O +cardiotoxicity B +, O +and O +nephrotoxicity B +induced O +by O +doxorubicin O +were O +studied O +in O +LOU O +/ O +M O +/ O +WSL O +inbred O +rats O +each O +bearing O +a O +transplantable O +solid O +IgM O +immunocytoma B +. O + +Animals O +with O +a O +tumor B +( O +diameter O +, O +15 O +. O +8 O ++ O +/ O +- O +3 O +. O +3 O +mm O +) O +were O +treated O +with O +iv O +injections O +of O +doxorubicin O +on O +5 O +consecutive O +days O +, O +followed O +by O +1 O +weekly O +injection O +for O +7 O +weeks O +( O +dose O +range O +, O +0 O +. O +015 O +- O +4 O +. O +0 O +mg O +/ O +kg O +body O +wt O +) O +. O + +Tumor B +regression O +was O +observed O +with O +0 O +. O +5 O +mg O +doxorubicin O +/ O +kg O +. O + +Complete O +disappearance O +of O +the O +tumor B +was O +induced O +with O +1 O +. O +0 O +mg O +doxorubicin O +/ O +kg O +. O + +Histologic O +evidence O +of O +cardiotoxicity B +scored O +as O +grade O +III O +was O +only O +observed O +at O +a O +dose O +of O +1 O +. O +0 O +mg O +doxorubicin O +/ O +kg O +. O + +Light O +microscopic O +evidence O +of O +renal B +damage I +was O +seen O +above O +a O +dose O +of O +0 O +. O +5 O +mg O +doxorubicin O +/ O +kg O +, O +which O +resulted O +in O +albuminuria B +and O +very O +low O +serum O +albumin O +levels O +. O + +In O +the O +group O +that O +received O +1 O +. O +0 O +mg O +doxorubicin O +/ O +kg O +, O +the O +serum O +albumin O +level O +decreased O +from O +33 O +. O +6 O ++ O +/ O +- O +4 O +. O +1 O +to O +1 O +. O +5 O ++ O +/ O +- O +0 O +. O +5 O +g O +/ O +liter O +. O + +Ascites B +and O +hydrothorax B +were O +observed O +simultaneously O +. O + +The O +same O +experiments O +were O +performed O +with O +non O +- O +tumor B +- O +bearing O +rats O +, O +in O +which O +no O +major O +differences O +were O +observed O +. O + +In O +conclusion O +, O +antitumor O +activity O +, O +cardiotoxicity B +, O +and O +nephrotoxicity B +were O +studied O +simultaneously O +in O +the O +same O +LOU O +/ O +M O +/ O +WSL O +rat O +. O + +Albuminuria B +due O +to O +renal B +damage I +led O +to O +extremely O +low O +serum O +albumin O +levels O +, O +so O +ascites B +and O +hydrothorax B +were O +not O +necessarily O +a O +consequence O +of O +the O +observed O +cardiomyopathy B +. O + +Intraoperative O +bradycardia B +and O +hypotension B +associated O +with O +timolol O +and O +pilocarpine O +eye O +drops O +. O + +A O +69 O +- O +yr O +- O +old O +man O +, O +who O +was O +concurrently O +being O +treated O +with O +pilocarpine O +nitrate O +and O +timolol O +maleate O +eye O +drops O +, O +developed O +a O +bradycardia B +and O +became O +hypotensive B +during O +halothane O +anaesthesia O +. O + +Both O +timolol O +and O +pilocarpine O +were O +subsequently O +identified O +in O +a O +24 O +- O +h O +collection O +of O +urine O +. O + +Timolol O +( O +but O +not O +pilocarpine O +) O +was O +detected O +in O +a O +sample O +of O +plasma O +removed O +during O +surgery O +; O +the O +plasma O +concentration O +of O +timolol O +( O +2 O +. O +6 O +ng O +ml O +- O +1 O +) O +was O +consistent O +with O +partial O +beta O +- O +adrenoceptor O +blockade O +. O + +It O +is O +postulated O +that O +this O +action O +may O +have O +been O +enhanced O +during O +halothane O +anaesthesia O +with O +resultant O +bradycardia B +and O +hypotension B +. O + +Pilocarpine O +may O +have O +had O +a O +contributory O +effect O +. O + +Succinylcholine O +apnoea B +: O +attempted O +reversal O +with O +anticholinesterases O +. O + +Anticholinesterases O +were O +administered O +in O +an O +attempt O +to O +antagonize O +prolonged O +neuromuscular B +blockade I +following O +the O +administration O +of O +succinylcholine O +in O +a O +patient O +later O +found O +to O +be O +homozygous O +for O +atypical O +plasma O +cholinesterase O +. O + +Edrophonium O +10 O +mg O +, O +given O +74 O +min O +after O +succinylcholine O +, O +when O +train O +- O +of O +- O +four O +stimulation O +was O +characteristic O +of O +phase O +II O +block O +, O +produced O +partial O +antagonism O +which O +was O +not O +sustained O +. O + +Repeated O +doses O +of O +edrophonium O +to O +70 O +mg O +and O +neostigmine O +to O +2 O +. O +5 O +mg O +did O +not O +antagonize O +or O +augment O +the O +block O +. O + +Spontaneous O +respiration O +recommenced O +200 O +min O +after O +succinylcholine O +administration O +. O + +It O +is O +concluded O +that O +anticholinesterases O +are O +only O +partially O +effective O +in O +restoring O +neuromuscular O +function O +in O +succinylcholine O +apnoea B +despite O +muscle O +twitch O +activity O +typical O +of O +phase O +II O +block O +. O + +Effect O +of O +doxorubicin O +on O +[ O +omega O +- O +I O +- O +131 O +] O +heptadecanoic O +acid O +myocardial O +scintigraphy O +and O +echocardiography O +in O +dogs O +. O + +The O +effects O +of O +serial O +treatment O +with O +doxorubicin O +on O +dynamic O +myocardial O +scintigraphy O +with O +[ O +omega O +- O +I O +- O +131 O +] O +heptadecanoic O +acid O +( O +I O +- O +131 O +HA O +) O +, O +and O +on O +global O +left O +- O +ventricular O +function O +determined O +echocardiographically O +, O +were O +studied O +in O +a O +group O +of O +nine O +mongrel O +dogs O +. O + +Total O +extractable O +myocardial O +lipid O +was O +compared O +postmortem O +between O +a O +group O +of O +control O +dogs O +and O +doxorubicin O +- O +treated O +dogs O +. O + +A O +significant O +and O +then O +progressive O +fall O +in O +global O +LV O +function O +was O +observed O +at O +a O +cumulative O +doxorubicin O +dose O +of O +4 O +mg O +/ O +kg O +. O + +A O +significant O +increase O +in O +the O +myocardial O +t1 O +/ O +2 O +of O +the O +I O +- O +131 O +HA O +was O +observed O +only O +at O +a O +higher O +cumulative O +dose O +, O +10 O +mg O +/ O +kg O +. O + +No O +significant O +alteration O +in O +total O +extractable O +myocardial O +lipids O +was O +observed O +between O +control O +dogs O +and O +those O +treated O +with O +doxorubicin O +. O + +Our O +findings O +suggest O +that O +the O +changes O +leading O +to O +an O +alteration O +of O +myocardial O +dynamic O +imaging O +with O +I O +- O +131 O +HA O +are O +not O +the O +initiating O +factor O +in O +doxorubicin O +cardiotoxicity B +. O + +Hemodynamics O +and O +myocardial O +metabolism O +under O +deliberate O +hypotension B +. O + +An O +experimental O +study O +in O +dogs O +. O + +Coronary O +blood O +flow O +, O +cardiac O +work O +and O +metabolism O +were O +studied O +in O +dogs O +under O +sodium O +nitroprusside O +( O +SNP O +) O +and O +trimetaphan O +( O +TMP O +) O +deliberate O +hypotension B +( O +20 O +% O +and O +40 O +% O +mean O +pressure O +decrease O +from O +baseline O +) O +. 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O + +The O +reduction O +of O +amphetamine O +hyperactivity B +induced O +by O +DSP4 O +was O +blocked O +by O +pretreatment O +with O +the O +noradrenaline O +- O +uptake O +blocking O +agent O +, O +desipramine O +, O +which O +prevents O +the O +neurotoxic B +action O +of O +DSP4 O +. O + +The O +present O +results O +suggest O +a O +selective O +involvement O +of O +central O +noradrenergic O +neurones O +in O +the O +locomotor O +stimulant O +effect O +of O +amphetamine O +in O +the O +rat O +. O + +Accelerated O +junctional O +rhythms O +during O +oral O +verapamil O +therapy O +. O + +This O +study O +examined O +the O +frequency O +of O +atrioventricular B +( I +AV I +) I +dissociation I +and O +accelerated O +junctional O +rhythms O +in O +59 O +patients O +receiving O +oral O +verapamil O +. O + +Accelerated O +junctional O +rhythms O +and O +AV O +dissociation I +were O +frequent O +in O +patients O +with O +supraventricular B +tachyarrhythmias I +, O +particularly O +AV B +nodal I +reentry I +. O + +Verapamil O +administration O +to O +these O +patients O +led O +to O +an O +asymptomatic O +increase O +in O +activity O +of O +these O +junctional O +pacemakers O +. O + +In O +patients O +with O +various O +chest B +pain I +syndromes O +, O +verapamil O +neither O +increased O +the O +frequency O +of O +junctional O +rhythms O +nor O +suppressed O +their O +role O +as O +escape O +rhythms O +under O +physiologically O +appropriate O +circumstances O +. O + +Interstrain O +variation O +in O +acute O +toxic O +response O +to O +caffeine O +among O +inbred O +mice O +. 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O + +SNP O +is O +authorized O +for O +clinical O +use O +in O +USA O +and O +UK O +, O +and O +ATP O +is O +clinically O +used O +in O +other O +countries O +such O +as O +Japan O +. O + +We O +investigated O +how O +these O +two O +drugs O +act O +on O +the O +cardiovascular O +systems O +of O +20 O +dogs O +whose O +hearts O +had O +been O +denervated O +by O +a O +procedure O +we O +had O +devised O +. O + +ATP O +( O +10 O +dogs O +) O +or O +SNP O +( O +10 O +dogs O +) O +was O +administered O +to O +reduce O +mean O +arterial O +pressure O +by O +30 O +% O +to O +70 O +% O +of O +control O +. O + +Before O +, O +during O +and O +after O +induced O +hypotension B +, O +we O +measured O +major O +cardiovascular O +parameters O +. O + +Hypotension B +induced O +by O +ATP O +was O +accompanied O +by O +significant O +decreases O +in O +mean O +pulmonary O +arterial O +pressure O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +central O +venous O +pressure O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +left O +ventricular O +end O +- O +diastolic O +pressure O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +total O +peripheral O +resistance O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +rate O +pressure O +product O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +total O +body O +oxygen O +consumption O +( O +p O +less O +than O +0 O +. O +05 O +) O +, O +and O +heart O +rate O +( O +p O +less O +than O +0 O +. O +001 O +) O +; O +all O +these O +variables O +returned O +normal O +within O +30 O +min O +after O +ATP O + +stopped O +. O + +Cardiac O +output O +did O +not O +change O +. O + +During O +hypotension B +produced O +by O +SNP O +similar O +decreases O +were O +observed O +in O +mean O +pulmonary O +arterial O +pressure O +( O +p O +less O +than O +0 O +. O +01 O +) O +, O +central O +venous O +pressure O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +left O +ventricular O +end O +- O +diastolic O +pressure O +( O +p O +less O +than O +0 O +. O +01 O +) O +, O +total O +peripheral O +resistance O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +rate O +pressure O +product O +( O +p O +less O +than O +0 O +. O +001 O +) O +, O +and O +oxygen O +content O +difference O +between O +arterial O +and O +mixed O +venous O +blood O +( O +p O +less O +than O +0 O +. O +05 O +) O +, O +while O +heart O +rate O +( O +p O +less O +than O +0 O +. O +001 O +) O +and O +cardiac O +output O +( O + +less O +than O +0 O +. O +05 O +) O +were O +increased O +. O + +Recoveries O +of O +heart O +rate O +and O +left O +ventricular O +end O +- O +diastolic O +pressure O +were O +not O +shown O +within O +60 O +min O +after O +SNP O +had O +been O +stopped O +. O + +Both O +ATP O +and O +SNP O +should O +act O +on O +the O +pacemaker O +tissue O +of O +the O +heart O +. O + +Comparative O +study O +: O +Endografine O +( O +diatrizoate O +) O +, O +Vasurix O +polyvidone O +( O +acetrizoate O +) O +, O +Dimer O +- O +X O +( O +iocarmate O +) O +and O +Hexabrix O +( O +ioxaglate O +) O +in O +hysterosalpingography O +. O + +Side O +effects O +of O +hysterosalpingography O +with O +Dimer O +- O +X O +, O +Hexabrix O +, O +Vasurix O +polyvidone O +and O +Endografine O +in O +142 O +consecutive O +patients O +, O +receiving O +one O +of O +the O +four O +tested O +media O +were O +evaluated O +from O +replies O +to O +postal O +questionnaires O +. O + +The O +Dimer O +- O +X O +group O +had O +a O +higher O +incidence O +of O +nausea B +and O +dizziness B +. O + +The O +Endografine O +group O +had O +a O +higher O +incidence O +of O +abdominal B +pain I +. O + +These O +differences O +occur O +especially O +in O +the O +age O +groups O +under O +30 O +years O +. O + +Hexabrix O +and O +Vasurix O +polyvidone O +are O +considered O +the O +best O +contrast O +media O +for O +hysterosalpingography O +and O +perhaps O +because O +of O +its O +low O +toxicity O +Hexabrix O +should O +be O +preferred O +. O + +Post O +- O +suxamethonium O +pains B +in O +Nigerian O +surgical O +patients O +. O + +Contrary O +to O +an O +earlier O +report O +by O +Coxon O +, O +scoline O +pain I +occurs O +in O +African O +negroes O +. O + +Its O +incidence O +was O +determined O +in O +a O +prospective O +study O +involving O +a O +total O +of O +100 O +Nigerian O +patients O +( O +50 O +out O +- O +patients O +and O +50 O +in O +- O +patients O +) O +. O + +About O +62 O +% O +of O +the O +out O +- O +patients O +developed O +scoline O +pain B +as O +compared O +with O +about O +26 O +% O +among O +the O +in O +- O +patients O +. O + +The O +abolition O +of O +muscle B +fasciculations I +( O +by O +0 O +. O +075mg O +/ O +kg O +dose O +of O +Fazadinium O +) O +did O +not O +influence O +the O +occurrence O +of O +scoline O +pain B +. O + +Neither O +the O +type O +of O +induction O +agent O +( O +Althesin O +or O +Thiopentone O +) O +nor O +the O +salt O +preparation O +of O +suxamethonium O +used O +( O +chloride O +or O +bromide O +) O +, O +affected O +the O +incidence O +of O +scoline O +pain B +. O + +Invasive B +carcinoma I +of I +the I +renal I +pelvis I +following O +cyclophosphamide O +therapy O +for O +nonmalignant O +disease I +. O + +A O +47 O +- O +year O +- O +old O +woman O +with O +right O +hydroureteronephrosis B +due O +to O +ureterovesical B +junction I +obstruction I +had O +gross O +hematuria B +after O +being O +treated O +for O +five O +years O +wtih O +cyclophosphamide O +for O +cerebral B +vasculitis I +. O + +A O +right O +nephroureterectomy O +was O +required O +for O +control O +of O +bleeding B +. O + +The O +pathology O +specimen O +contained O +clinically O +occult O +invasive B +carcinoma B +of I +the I +renal I +pelvis I +. O + +Although O +the O +ability O +of O +cyclophosphamide O +to O +cause O +hemorrhagic B +cystitis I +and O +urine O +cytologic O +abnormalities O +indistinguishable O +from O +high O +grade O +carcinoma B +is O +well O +known O +, O +it O +is O +less O +widely O +appreciated O +that O +it O +is O +also O +associated O +with O +carcinoma B +of I +the I +urinary I +tract I +. O + +Twenty O +carcinomas B +of I +the I +urinary I +bladder I +and O +one O +carcinoma B +of I +the I +prostate I +have O +been O +reported O +in O +association O +with O +its O +use O +. O + +The O +present O +case O +is O +the O +first O +carcinoma B +of I +the I +renal I +pelvis I +reported O +in O +association O +with O +cyclophosphamide O +treatment O +. O + +It O +is O +the O +third O +urinary B +tract I +cancer I +reported O +in O +association O +with O +cyclophosphamide O +treatment O +for O +nonmalignant O +disease I +. O + +The O +association O +of O +the O +tumor B +with O +preexisting O +hydroureteronephrosis B +suggests O +that O +stasis O +prolonged O +and O +intensified O +exposure O +of O +upper O +urinary O +tract O +epithelium O +to O +cyclophosphamide O +. O + +Patients O +who O +are O +candidates O +for O +long O +- O +term O +cyclophosphamide O +treatment O +should O +be O +routinely O +evaluated O +for O +obstructive B +uropathy I +. O + +Medial O +changes O +in O +arterial O +spasm B +induced O +by O +L O +- O +norepinephrine O +. O + +In O +normal O +rats O +, O +the O +media O +of O +small O +arteries O +( O +0 O +. O +4 O +- O +- O +0 O +. O +2 O +mm O +in O +diameter O +) O +previously O +was O +shown O +to O +contain O +intracellular O +vacuoles O +, O +identified O +ultrastructurally O +as O +herniations O +of O +one O +smooth O +muscle O +cell O +into O +another O +. O + +The O +hypothesis O +that O +intense O +vasoconstriction O +would O +increase O +the O +number O +of O +such O +vacuoles O +has O +been O +tested O +. O + +In O +the O +media O +of O +the O +saphenous O +artery O +and O +its O +distal O +branch O +, O +vasoconstriction O +induced O +by O +L O +- O +norepinephrine O +produced O +many O +cell O +- O +to O +- O +cell O +hernias B +within O +15 O +minutes O +. O + +At O +1 O +day O +their O +number O +was O +reduced O +to O +about O +1 O +/ O +10 O +of O +the O +original O +number O +. O + +By O +7 O +days O +the O +vessel O +was O +almost O +restored O +to O +normal O +. O + +Triple O +stimulation O +over O +1 O +day O +induced O +more O +severe O +changes O +in O +the O +media O +. O + +These O +findings O +suggest O +that O +smooth O +muscle O +cells O +are O +susceptible O +to O +damage O +in O +the O +course O +of O +their O +specific O +function O +. O + +The O +experimental O +data O +are O +discussed O +in O +relation O +to O +medial O +changes O +observed O +in O +other O +instances O +of O +arterial B +spasm I +. O + +Endothelial O +changes O +that O +developed O +in O +the O +same O +experimental O +model O +were O +described O +in O +a O +previous O +paper O +. O + +Bilateral O +retinal B +artery I +and I +choriocapillaris I +occlusion I +following O +the O +injection O +of O +long O +- O +acting O +corticosteroid O +suspensions O +in O +combination O +with O +other O +drugs O +: O +I O +. O + +Clinical O +studies O +. O + +Two O +well O +- O +documented O +cases O +of O +bilateral O +retinal B +artery I +and I +choriocapillaris I +occlusions I +with O +blindness B +following O +head O +and O +neck O +soft O +- O +tissue O +injection O +with O +methylprednisolone O +acetate O +in O +combination O +with O +lidocaine O +, O +epinephrine O +, O +or O +penicillin O +are O +reported O +. O + +One O +case O +had O +only O +a O +unilateral O +injection O +. O + +The O +acute O +observations O +included O +hazy B +sensorium I +, O +superior B +gaze I +palsy I +, O +pupillary B +abnormalities I +, O +and O +conjunctival B +hemorrhages I +with O +edema B +. O + +Follow O +- O +up O +changes O +showed O +marked O +visual B +loss I +, O +constricted B +visual I +fields I +, O +optic O +nerve I +pallor I +, O +vascular O +attenuation O +, O +and O +chorioretinal B +atrophy I +. O + +The O +literature O +is O +reviewed O +, O +and O +possible O +causes O +are O +discussed O +. O + +Abnormalities O +of O +the O +pupil O +and O +visual O +- O +evoked O +potential O +in O +quinine O +amblyopia B +. O + +Total B +blindness I +with O +a O +transient O +tonic O +pupillary O +response O +, O +denervation O +supersensitivity O +, O +and O +abnormal O +visual O +- O +evoked O +potentials O +developed O +in O +a O +54 O +- O +year O +- O +old O +man O +after O +the O +use O +of O +quinine O +sulfate O +for O +leg B +cramps I +. O + +He O +later O +recovered O +normal O +visual O +acuity O +. O + +A O +transient O +tonic O +pupillary O +response O +, O +denervation O +supersensitivity O +, O +and O +abnormal O +visual O +- O +evoked O +potentials O +in O +quinine O +toxicity B +, O +to O +our O +knowledge O +, O +have O +not O +been O +previously O +reported O +. O + +Suxamethonium O +- O +induced O +jaw B +stiffness I +and O +myalgia B +associated O +with O +atypical O +cholinesterase O +: O +case O +report O +. O + +An O +11 O +- O +year O +- O +old O +boy O +was O +given O +halothane O +, O +nitrous O +oxide O +and O +oxygen O +, O +pancuronium O +0 O +. O +4 O +mg O +and O +suxamethonium O +100 O +mg O +for O +induction O +of O +anaesthesia O +. O + +In O +response O +to O +this O +a O +marked O +jaw B +stiffness I +occurred O +which O +lasted O +for O +two O +minutes O +and O +the O +anaesthesia O +were O +terminated O +. O + +Four O +hours O +of O +apnoea B +ensued O +and O +he O +suffered O +generalized O +severe O +myalgia B +lasting O +for O +one O +week O +. O + +He O +was O +found O +to O +have O +atypical O +plasma O +cholinesterase O +with O +a O +dibucaine O +number O +of O +12 O +, O +indicating O +homozygocity O +. O + +This O +was O +verified O +by O +study O +of O +the O +family O +. O + +The O +case O +shows O +that O +prolonged O +jaw B +rigidity I +and O +myalgia B +may O +occur O +after O +suxamethonium O +in O +patients O +with O +atypical O +cholinesterase O +despite O +pretreatment O +with O +pancuronium O +. O + +Indomethacin O +- O +induced O +hyperkalemia B +in O +three O +patients O +with O +gouty B +arthritis I +. O + +We O +describe O +three O +patients O +in O +whom O +severe O +, O +life O +- O +threatening O +hyperkalemia B +and O +renal B +insufficiency I +developed O +after O +treatment O +of O +acute O +gouty B +arthritis I +with O +indomethacin O +. O + +This O +complication O +may O +result O +from O +an O +inhibition O +of O +prostaglandin O +synthesis O +and O +consequent O +hyporeninemic B +hypoaidosteronism I +. O + +Careful O +attention O +to O +renal O +function O +and O +potassium O +balance O +in O +patients O +receiving O +indomethacin O +or O +other O +nonsteroidal O +anti O +- O +inflammatory O +agents O +, O +particularly O +in O +those O +patients O +with O +diabetes B +mellitus I +or O +preexisting O +renal B +disease I +, O +will O +help O +prevent O +this O +potentially O +serious O +complication O +. O + +Etomidate O +: O +a O +foreshortened O +clinical O +trial O +. O + +A O +clinical O +evaluation O +of O +etomidate O +for O +outpatient O +cystoscopy O +was O +embarked O +upon O +. O + +Unpremedicated O +patients O +were O +given O +fentanyl O +1 O +microgram O +/ O +kg O +followed O +by O +etomidate O +0 O +. O +3 O +mg O +/ O +kg O +. O + +Anaesthesia O +was O +maintained O +with O +intermittent O +etomidate O +in O +2 O +- O +4 O +mg O +doses O +. O + +Patients O +were O +interviewed O +personally O +later O +the O +same O +day O +, O +and O +by O +questionnaire O +three O +to O +four O +weeks O +later O +. O + +The O +trial O +was O +discontinued O +after O +20 O +cases O +because O +of O +an O +unacceptable O +incidence O +of O +side O +effects O +. O + +Venous B +pain I +occurred O +in O +68 O +% O +of O +patients O +and O +50 O +% O +had O +redness B +, O +pain B +or O +swelling B +related O +to O +the O +injection O +site O +, O +in O +some O +cases O +lasting O +up O +to O +three O +weeks O +after O +anaesthesia O +. O + +Skeletal O +movements O +occurred O +in O +50 O +% O +of O +patients O +; O +30 O +% O +experienced O +respiratory O +upset I +, O +one O +sufficiently O +severe O +to O +necessitate O +abandoning O +the O +technique O +. O + +Nausea B +and O +vomiting B +occurred O +in O +40 O +% O +and O +25 O +% O +had O +disturbing O +emergence O +psychoses B +. O + +Levodopa O +- O +induced O +dyskinesias B +are O +improved O +by O +fluoxetine O +. O + +We O +evaluated O +the O +severity O +of O +motor B +disability I +and O +dyskinesias B +in O +seven O +levodopa O +- O +responsive O +patients O +with O +Parkinson B +' I +s I +disease I +after O +an O +acute O +challenge O +with O +the O +mixed O +dopamine O +agonist O +, O +apomorphine O +, O +before O +and O +after O +the O +administration O +of O +fluoxetine O +( O +20 O +mg O +twice O +per O +day O +) O +for O +11 O ++ O +/ O +- O +1 O +days O +. O + +After O +fluoxetine O +treatment O +, O +there O +was O +a O +significant O +47 O +% O +improvement O +( O +p O +< O +0 O +. O +05 O +) O +of O +apomorphine O +- O +induced O +dyskinesias B +without O +modification O +of O +parkinsonian B +motor B +disability I +. O + +The O +dyskinesias B +were O +reduced O +predominantly O +in O +the O +lower O +limbs O +during O +the O +onset O +and O +disappearance O +of O +dystonic B +dyskinesias I +( O +onset O +- O +and O +end O +- O +of O +- O +dose O +dyskinesias B +) O +and O +in O +the O +upper O +limbs O +during O +choreic O +mid O +- O +dose O +dyskinesias B +. O + +The O +results O +suggest O +that O +increased O +brain O +serotoninergic O +transmission O +with O +fluoxetine O +may O +reduce O +levodopa O +- O +or O +dopamine O +agonist O +- O +induced O +dyskinesias B +without O +aggravating O +parkinsonian B +motor B +disability I +. O + +A O +large O +population O +- O +based O +follow O +- O +up O +study O +of O +trimethoprim O +- O +sulfamethoxazole O +, O +trimethoprim O +, O +and O +cephalexin O +for O +uncommon O +serious O +drug O +toxicity B +. O + +We O +conducted O +a O +population O +- O +based O +45 O +- O +day O +follow O +- O +up O +study O +of O +232 O +, O +390 O +people O +who O +were O +prescribed O +trimethoprim O +- O +sulfamethoxazole O +( O +TMP O +- O +SMZ O +) O +, O +266 O +, O +951 O +prescribed O +trimethoprim O +alone O +, O +and O +196 O +, O +397 O +prescribed O +cephalexin O +, O +to O +estimate O +the O +risk O +of O +serious O +liver B +, I +blood I +, I +skin I +, I +and I +renal I +disorders I +resulting O +in O +referral O +or O +hospitalization O +associated O +with O +these O +drugs O +. O + +The O +results O +were O +based O +on O +information O +recorded O +on O +office O +computers O +by O +selected O +general O +practitioners O +in O +the O +United O +Kingdom O +, O +together O +with O +a O +review O +of O +clinical O +records O +. O + +The O +risk O +of O +clinically O +important O +idiopathic O +liver B +disease I +was O +similar O +for O +persons O +prescribed O +TMP O +- O +SMZ O +( O +5 O +. O +2 O +/ O +100 O +, O +000 O +) O +and O +those O +prescribed O +trimethoprim O +alone O +( O +3 O +. O +8 O +/ O +100 O +, O +000 O +) O +. O + +The O +risk O +for O +those O +prescribed O +cephalexin O +was O +somewhat O +lower O +( O +2 O +. O +0 O +/ O +100 O +, O +000 O +) O +. O + +Only O +five O +patients O +experienced O +blood B +disorders I +, O +one O +of O +whom O +was O +exposed O +to O +TMP O +- O +SMZ O +; O +of O +seven O +with O +erythema B +multiforme I +and O +Stevens B +- I +Johnson I +syndrome I +, O +four O +were O +exposed O +to O +TMP O +- O +SMZ O +. O + +The O +one O +case O +of O +toxic O +epidermal I +necrolysis I +occurred O +in O +a O +patient O +who O +took O +cephalexin O +. O + +Finally O +, O +only O +five O +cases O +of O +acute B +parenchymal I +renal I +disease I +occurred O +, O +none O +likely O +to O +be O +caused O +by O +a O +study O +drug O +. O + +We O +conclude O +that O +the O +risk O +of O +the O +serious O +diseases O +studied O +is O +small O +for O +the O +three O +agents O +, O +and O +compares O +reasonably O +with O +the O +risk O +for O +many O +other O +antibiotics O +. O + +Clinical O +safety O +of O +lidocaine O +in O +patients O +with O +cocaine O +- O +associated O +myocardial B +infarction I +. O + +STUDY O +OBJECTIVE O +: O +To O +evaluate O +the O +safety O +of O +lidocaine O +in O +the O +setting O +of O +cocaine O +- O +induced O +myocardial B +infarction I +( O +MI B +) O +. O + +DESIGN O +: O +A O +retrospective O +, O +multicenter O +study O +. O + +SETTING O +: O +Twenty O +- O +nine O +university O +, O +university O +- O +affiliated O +, O +or O +community O +hospitals O +during O +a O +6 O +- O +year O +period O +( O +total O +of O +117 O +cumulative O +hospital O +- O +years O +) O +. O + +PARTICIPANTS O +: O +Patients O +with O +cocaine O +- O +associated O +MI B +who O +received O +lidocaine O +in O +the O +emergency O +department O +. O + +RESULTS O +: O +Of O +29 O +patients O +who O +received O +lidocaine O +in O +the O +setting O +of O +cocaine O +- O +associated O +MI B +, O +no O +patient O +died O +; O +exhibited O +bradydysrhythmias B +, O +ventricular B +tachycardia I +, O +or O +ventricular B +fibrillation I +; O +or O +experienced O +seizures B +after O +administration O +of O +lidocaine O +( O +95 O +% O +confidence O +interval O +, O +0 O +% O +to O +11 O +% O +) O +. O + +CONCLUSION O +: O +Despite O +theoretical O +concerns O +that O +lidocaine O +may O +enhance O +cocaine O +toxicity B +, O +the O +use O +of O +lidocaine O +in O +patients O +with O +cocaine O +- O +associated O +MI B +was O +not O +associated O +with O +significant O +cardiovascular B +or I +central I +nervous I +system I +toxicity I +. O + +Experimental O +progressive O +muscular B +dystrophy I +and O +its O +treatment O +with O +high O +doses O +anabolizing O +agents O +. O + +We O +are O +still O +a O +long O +way O +from O +discovering O +an O +unequivocal O +pathogenetic O +interpretation O +of O +progressive O +muscular B +dystrophy I +in O +man O +. O + +Noteworthy O +efforts O +have O +been O +made O +in O +the O +experimental O +field O +; O +a O +recessive O +autosomic O +form O +found O +in O +the O +mouse O +seems O +to O +bear O +the O +closest O +resemblance O +to O +the O +human O +form O +from O +the O +genetic O +point O +of O +view O +. O + +Myopathy B +due O +to O +lack O +of O +vitamin O +E O +and O +myopathy B +induced O +by O +certain O +viruses O +have O +much O +in O +common O +anatomically O +and O +pathologically O +with O +the O +human O +form O +. O + +The O +authors O +induced O +myodystrophy B +in O +the O +rat O +by O +giving O +it O +a O +diet O +lacking O +in O +vitamin O +E O +. O + +The O +pharmacological O +characteristics O +of O +vitamin O +E O +and O +the O +degenerative O +changes O +brought O +about O +by O +its O +deficiency O +, O +especially O +in O +the O +muscles O +, O +are O +illustrated O +. O + +It O +is O +thus O +confirmed O +that O +the O +histological O +characteristics O +of O +myopathic B +rat O +muscle O +induced O +experimentally O +are O +extraordinarily O +similar O +to O +those O +of O +human O +myopathy B +as O +confirmed O +during O +biopsies O +performed O +at O +the O +Orthopaedic O +Traumatological O +Centre O +, O +Florence O +. O + +The O +encouraging O +results O +obtained O +in O +various O +authoratative O +departments O +in O +myopathic B +patients O +by O +using O +anabolizing O +steroids O +have O +encouraged O +the O +authors O +to O +investigate O +the O +beneficial O +effects O +of O +one O +anabolizing O +agent O +( O +Dianabol O +, O +CIBA O +) O +at O +high O +doses O +in O +rats O +rendered O +myopathic B +by O +a O +diet O +deficient O +in O +vitamin O +E O +. O + +In O +this O +way O +they O +obtained O +appreciable O +changes O +in O +body O +weight O +( O +increased O +from O +50 O +to O +70 O +g O +after O +forty O +days O +at O +a O +dose O +of O +5 O +mg O +per O +day O +of O +anabolizing O +agent O +) O +, O +but O +most O +of O +all O +they O +found O +histological O +changes O +due O +to O +" O +regenerative O +" O +changes O +in O +the O +muscle O +tissue O +, O +which O +however O +maintained O +its O +myopathic B +characteristics O +in O +the O +control O +animals O +that O +were O +not O +treated O +with O +the O +anabolizing O +agent O +. O + +The O +authors O +conclude O +by O +affirming O +the O +undoubted O +efficacy O +of O +the O +anabolizing O +steroids O +in O +experimental O +myopathic B +disease I +, O +but O +they O +have O +reservations O +as O +to O +the O +transfer O +of O +the O +results O +into O +the O +human O +field O +, O +where O +high O +dosage O +cannot O +be O +carried O +out O +continuously O +because O +of O +the O +effects O +of O +the O +drug O +on O +virility O +; O +because O +the O +tissue B +injury I +too O +often O +occurs O +at O +an O +irreversible O +stage O +vis O +- O +a O +- O +vis O +the O +" O +regeneration O +" O +of O +the O +muscle O +tissue O +; O +and O +finally O +because O +the O +dystrophic B +injurious O +agent O +is O +certainly O +not O +the O +lack O +of O +vitamin O +E O +but O +something O +as O +yet O +unknown O +. O + +Paclitaxel O +3 O +- O +hour O +infusion O +given O +alone O +and O +combined O +with O +carboplatin O +: O +preliminary O +results O +of O +dose O +- O +escalation O +trials O +. O + +Paclitaxel O +( O +Taxol O +; O +Bristol O +- O +Myers O +Squibb O +Company O +, O +Princeton O +, O +NJ O +) O +by O +3 O +- O +hour O +infusion O +was O +combined O +with O +carboplatin O +in O +a O +phase O +I O +/ O +II O +study O +directed O +to O +patients O +with O +non B +- I +small I +cell I +lung I +cancer I +. O + +Carboplatin O +was O +given O +at O +a O +fixed O +target O +area O +under O +the O +concentration O +- O +time O +curve O +of O +6 O +. O +0 O +by O +the O +Calvert O +formula O +, O +whereas O +paclitaxel O +was O +escalated O +in O +patient O +cohorts O +from O +150 O +mg O +/ O +m2 O +( O +dose O +level O +I O +) O +to O +175 O +, O +200 O +, O +225 O +, O +and O +250 O +mg O +/ O +m2 O +. O + +The O +225 O +mg O +/ O +m2 O +level O +was O +expanded O +for O +the O +phase O +II O +study O +since O +the O +highest O +level O +achieved O +( O +250 O +mg O +/ O +m2 O +) O +required O +modification O +because O +of O +nonhematologic O +toxicities B +( O +arthralgia B +and O +sensory B +neuropathy I +) O +. O + +Therapeutic O +effects O +were O +noted O +at O +all O +dose O +levels O +, O +with O +objective O +responses O +in O +17 O +( O +two O +complete O +and O +15 O +partial O +regressions O +) O +of O +41 O +previously O +untreated O +patients O +. O + +Toxicities B +were O +compared O +with O +a O +cohort O +of O +patients O +in O +a O +phase O +I O +trial O +of O +paclitaxel O +alone O +at O +identical O +dose O +levels O +. O + +Carboplatin O +did O +not O +appear O +to O +add O +to O +the O +hematologic B +toxicities I +observed O +, O +and O +the O +paclitaxel O +/ O +carboplatin O +combination O +could O +be O +dosed O +every O +3 O +weeks O +. O + +The O +dose O +- O +dependent O +effect O +of O +misoprostol O +on O +indomethacin O +- O +induced O +renal B +dysfunction I +in O +well O +compensated O +cirrhosis B +. O + +Misoprostol O +( O +200 O +micrograms O +) O +has O +been O +shown O +to O +acutely O +counteract O +the O +indomethacin O +- O +induced O +renal B +dysfunction I +in O +well O +compensated O +cirrhotic B +patients O +. O + +The O +aim O +of O +this O +study O +was O +to O +determine O +if O +the O +prophylactic O +value O +of O +misoprostol O +was O +dose O +- O +dependent O +. O + +Parameters O +of O +renal O +hemodynamics O +and O +tubular O +sodium O +and O +water O +handling O +were O +assessed O +by O +clearance O +techniques O +in O +26 O +well O +compensated O +cirrhotic B +patients O +before O +and O +after O +an O +oral O +combination O +of O +50 O +mg O +of O +indomethacin O +and O +various O +doses O +of O +misoprostol O +. O + +The O +200 O +- O +micrograms O +dose O +was O +able O +to O +totally O +abolish O +the O +deleterious O +renal O +effects O +of O +indomethacin O +, O +whereas O +the O +800 O +- O +micrograms O +dose O +resulted O +in O +significant O +worsening O +of O +renal O +hemodynamics O +and O +sodium O +retention O +. O + +These O +changes O +were O +maximal O +in O +the O +hour O +immediately O +after O +medications O +and O +slowly O +returned O +toward O +base O +- O +line O +levels O +thereafter O +. O + +These O +results O +suggest O +that O +the O +renal O +protective O +effects O +of O +misoprostol O +is O +dose O +- O +dependent O +. O + +However O +, O +until O +this O +apparent O +ability O +of O +200 O +micrograms O +of O +misoprostol O +to O +prevent O +the O +adverse O +effects O +of O +indomethacin O +on O +renal O +function O +is O +confirmed O +with O +chronic O +frequent O +dosing O +, O +it O +would O +be O +prudent O +to O +avoid O +nonsteroidal O +anti O +- O +inflammatory O +therapy O +in O +patients O +with O +cirrhosis B +. O + +Increased O +frequency O +and O +severity O +of O +angio B +- I +oedema I +related O +to O +long O +- O +term O +therapy O +with O +angiotensin O +- O +converting O +enzyme O +inhibitor O +in O +two O +patients O +. O + +Adverse O +reactions O +to O +drugs O +are O +well O +recognized O +as O +a O +cause O +of O +acute O +or O +chronic O +urticaria B +, O +and O +angio B +- I +oedema I +. O + +Angiotensin O +- O +converting O +enzyme O +( O +ACE O +) O +inhibitors O +, O +used O +to O +treat O +hypertension B +and O +congestive B +heart I +failure I +, O +were O +introduced O +in O +Europe O +in O +the O +middle O +of O +the O +eighties O +, O +and O +the O +use O +of O +these O +drugs O +has O +increased O +progressively O +. O + +Soon O +after O +the O +introduction O +of O +ACE O +inhibitors O +, O +acute O +bouts O +of O +angio B +- I +oedema I +were O +reported O +in O +association O +with O +the O +use O +of O +these O +drugs O +. O + +We O +wish O +to O +draw O +attention O +to O +the O +possibility O +of O +adverse O +reactions O +to O +ACE O +inhibitors O +after O +long O +- O +term O +use O +and O +in O +patients O +with O +pre O +- O +existing O +angio B +- I +oedema I +. O + +Myoclonus B +associated O +with O +lorazepam O +therapy O +in O +very O +- O +low O +- O +birth O +- O +weight O +infants O +. O + +Lorazepam O +is O +being O +used O +with O +increasing O +frequency O +as O +a O +sedative O +in O +the O +newborn O +and O +the O +young O +infant O +. O + +Concern O +has O +been O +raised O +with O +regard O +to O +the O +safety O +of O +lorazepam O +in O +this O +age O +group O +, O +especially O +in O +very O +- O +low O +- O +birth O +- O +weight O +( O +VLBW O +; O +< O +1 O +, O +500 O +g O +) O +infants O +. O + +Three O +young O +infants O +, O +all O +of O +birth O +weight O +< O +1 O +, O +500 O +g O +, O +experienced O +myoclonus B +following O +the O +intravenous O +administration O +of O +lorazepam O +. O + +The O +potential O +neurotoxic B +effects O +of O +the O +drug O +( O +and O +its O +vehicle O +) O +in O +this O +population O +are O +discussed O +. O + +Injectable O +lorazepam O +should O +be O +used O +with O +caution O +in O +VLBW B +infants O +. O + +Transvenous O +right O +ventricular O +pacing O +during O +cardiopulmonary O +resuscitation O +of O +pediatric O +patients O +with O +acute B +cardiomyopathy I +. O + +We O +describe O +the O +cardiopulmonary O +resuscitation O +efforts O +on O +five O +patients O +who O +presented O +in O +acute B +circulatory I +failure I +from O +myocardial B +dysfunction I +. O + +Three O +patients O +had O +acute O +viral B +myocarditis I +, O +one O +had O +a O +carbamazepine O +- O +induced O +acute O +eosinophilic B +myocarditis I +, O +and O +one O +had O +cardiac B +hemosiderosis I +resulting O +in O +acute O +cardiogenic B +shock I +. O + +All O +patients O +were O +continuously O +monitored O +with O +central O +venous O +and O +arterial O +catheters O +in O +addition O +to O +routine O +noninvasive O +monitoring O +. O + +An O +introducer O +sheath O +, O +a O +pacemaker O +, O +and O +sterile O +pacing O +wires O +were O +made O +readily O +available O +for O +the O +patients O +, O +should O +the O +need O +arise O +to O +terminate O +resistant O +cardiac B +dysrhythmias I +. O + +All O +patients O +developed O +cardiocirculatory B +arrest I +associated O +with O +extreme O +hypotension B +and O +dysrhythmias B +within O +the O +first O +48 O +hours O +of O +their O +admission O +to O +the O +pediatric O +intensive O +care O +unit O +( O +PICU O +) O +. O + +Right O +ventricular O +pacemaker O +wires O +were O +inserted O +in O +all O +of O +them O +during O +cardiopulmonary O +resuscitation O +( O +CPR O +) O +. O + +In O +four O +patients O +, O +cardiac O +pacing O +was O +used O +, O +resulting O +in O +a O +temporary O +captured O +rhythm O +and O +restoration O +of O +their O +cardiac O +output O +. O + +These O +patients O +had O +a O +second O +event O +of O +cardiac B +arrest I +, O +resulting O +in O +death B +, O +within O +10 O +to O +60 O +minutes O +. O + +In O +one O +patient O +, O +cardiac O +pacing O +was O +not O +used O +, O +because O +he O +converted O +to O +normal O +sinus O +rhythm O +by O +electrical O +defibrillation O +within O +three O +minutes O +of O +initiating O +CPR O +. O + +We O +conclude O +that O +cardiac O +pacing O +during O +resuscitative O +efforts O +in O +pediatric O +patients O +suffering O +from O +acute B +myocardial I +dysfunction I +may O +not O +have O +long O +- O +term O +value O +in O +and O +of O +itself O +; O +however O +, O +if O +temporary O +hemodynamic O +stability O +is O +achieved O +by O +this O +procedure O +, O +it O +may O +provide O +additional O +time O +needed O +to O +institute O +other O +therapeutic O +modalities O +. O + +Efficacy O +and O +safety O +of O +granisetron O +, O +a O +selective O +5 O +- O +hydroxytryptamine O +- O +3 O +receptor O +antagonist O +, O +in O +the O +prevention O +of O +nausea B +and I +vomiting I +induced O +by O +high O +- O +dose O +cisplatin O +. O + +PURPOSE O +: O +To O +assess O +the O +antiemetic O +effects O +and O +safety O +profile O +of O +four O +different O +doses O +of O +granisetron O +( O +Kytril O +; O +SmithKline O +Beecham O +Pharmaceuticals O +, O +Philadelphia O +, O +PA O +) O +when O +administered O +as O +a O +single O +intravenous O +( O +IV O +) O +dose O +for O +prophylaxis O +of O +cisplatin O +- O +induced O +nausea B +and I +vomiting I +. O + +PATIENTS O +AND O +METHODS O +: O +One O +hundred O +eighty O +- O +four O +chemotherapy O +- O +naive O +patients O +receiving O +high O +- O +dose O +cisplatin O +( O +81 O +to O +120 O +mg O +/ O +m2 O +) O +were O +randomized O +to O +receive O +one O +of O +four O +granisetron O +doses O +( O +5 O +, O +10 O +, O +20 O +, O +or O +40 O +micrograms O +/ O +kg O +) O +administered O +before O +chemotherapy O +. O + +Patients O +were O +observed O +on O +an O +inpatient O +basis O +for O +18 O +to O +24 O +hours O +, O +and O +vital O +signs O +, O +nausea B +, O +vomiting B +, O +retching O +, O +and O +appetite O +were O +assessed O +. O + +Safety O +analyses O +included O +incidence O +of O +adverse O +experiences O +and O +laboratory O +parameter O +changes O +. O + +RESULTS O +: O +After O +granisetron O +doses O +of O +5 O +, O +10 O +, O +20 O +, O +and O +40 O +micrograms O +/ O +kg O +, O +a O +major O +response O +( O +< O +or O += O +two O +vomiting B +or O +retching O +episodes O +, O +and O +no O +antiemetic O +rescue O +) O +was O +recorded O +in O +23 O +% O +, O +57 O +% O +, O +58 O +% O +, O +and O +60 O +% O +of O +patients O +, O +respectively O +, O +and O +a O +complete O +response O +( O +no O +vomiting B +or O +retching O +, O +and O +no O +antiemetic O +rescue O +) O +in O +18 O +% O +, O +41 O +% O +, O +40 O +% O +, O +and O +47 O +% O +of O +patients O +, O +respectively O +. O + +There O +was O +a O +statistically O +longer O +time O +to O +first O +episode O +of O +nausea B +( O +P O += O +. O +0015 O +) O +and O +vomiting B +( O +P O += O +. O +0001 O +) O +, O +and O +fewer O +patients O +were O +administered O +additional O +antiemetic O +medication O +in O +the O +10 O +- O +micrograms O +/ O +kg O +dosing O +groups O +than O +in O +the O +5 O +- O +micrograms O +/ O +kg O +dosing O +group O +. O + +As O +granisetron O +dose O +increased O +, O +appetite O +return O +increased O +( O +P O += O +. O +040 O +) O +. O + +Headache B +was O +the O +most O +frequently O +reported O +adverse O +event O +( O +20 O +% O +) O +. O + +CONCLUSION O +: O +A O +single O +10 O +- O +, O +20 O +- O +, O +or O +40 O +- O +micrograms O +/ O +kg O +dose O +of O +granisetron O +was O +effective O +in O +controlling O +vomiting B +in O +57 O +% O +to O +60 O +% O +of O +patients O +who O +received O +cisplatin O +at O +doses O +greater O +than O +81 O +mg O +/ O +m2 O +and O +totally O +prevented O +vomiting B +in O +40 O +% O +to O +47 O +% O +of O +patients O +. O + +There O +were O +no O +statistically O +significant O +differences O +in O +efficacy O +between O +the O +10 O +- O +micrograms O +/ O +kg O +dose O +and O +the O +20 O +- O +and O +40 O +- O +micrograms O +/ O +kg O +doses O +. O + +Granisetron O +was O +well O +tolerated O +at O +all O +doses O +. O + +Adverse O +interaction O +between O +clonidine O +and O +verapamil O +. O + +OBJECTIVE O +: O +To O +report O +two O +cases O +of O +a O +possible O +adverse O +interaction O +between O +clonidine O +and O +verapamil O +resulting O +in O +atrioventricular B +( I +AV I +) I +block I +in O +both O +patients O +and O +severe O +hypotension B +in O +one O +patient O +. O + +CASE O +SUMMARIES O +: O +A O +54 O +- O +year O +- O +old O +woman O +with O +hyperaldosteronism B +was O +treated O +with O +verapamil O +480 O +mg O +/ O +d O +and O +spironolactone O +100 O +mg O +/ O +d O +. O + +After O +the O +addition O +of O +a O +minimal O +dose O +of O +clonidine O +( O +0 O +. O +15 O +mg O +bid O +) O +, O +she O +developed O +complete O +AV B +block I +and O +severe O +hypotension B +, O +which O +resolved O +upon O +cessation O +of O +all O +medications O +. O + +A O +65 O +- O +year O +- O +old O +woman O +was O +treated O +with O +extended O +- O +release O +verapamil O +240 O +mg O +/ O +d O +. O + +After O +the O +addition O +of O +clonidine O +0 O +. O +15 O +mg O +bid O +she O +developed O +complete O +AV B +block I +, O +which O +resolved O +after O +all O +therapy O +was O +stopped O +. O + +DISCUSSION O +: O +An O +adverse O +interaction O +between O +clonidine O +and O +verapamil O +has O +not O +been O +reported O +previously O +. O + +We O +describe O +two O +such O +cases O +and O +discuss O +the O +various O +mechanisms O +that O +might O +cause O +such O +an O +interaction O +. O + +Clinicians O +should O +be O +acquainted O +with O +this O +possibly O +fatal O +interaction O +between O +two O +commonly O +used O +antihypertensive O +drugs O +. O + +CONCLUSIONS O +: O +Caution O +is O +recommended O +in O +combining O +clonidine O +and O +verapamil O +therapy O +, O +even O +in O +patients O +who O +do O +not O +have O +sinus B +or I +AV I +node I +dysfunction I +. O + +The O +two O +drugs O +may O +act O +synergistically O +on O +both O +the O +AV O +node O +and O +the O +peripheral O +circulation O +. O + +Pharmacological O +studies O +on O +a O +new O +dihydrothienopyridine O +calcium O +antagonist O +, O +S O +- O +312 O +- O +d O +. O + +5th O +communication O +: O +anticonvulsant O +effects O +in O +mice O +. O + +S O +- O +312 O +, O +S O +- O +312 O +- O +d O +, O +but O +not O +S O +- O +312 O +- O +l O +, O +L O +- O +type O +calcium O +channel O +antagonists O +, O +showed O +anticonvulsant O +effects O +on O +the O +audiogenic O +tonic O +convulsions B +in O +DBA O +/ O +2 O +mice O +; O +and O +their O +ED50 O +values O +were O +18 O +. O +4 O +( O +12 O +. O +8 O +- O +27 O +. O +1 O +) O +mg O +/ O +kg O +, O +p O +. O +o O +. O +and O +15 O +. O +0 O +( O +10 O +. O +2 O +- O +23 O +. O +7 O +) O +mg O +/ O +kg O +, O +p O +. O +o O +. O +, O +respectively O +, O +while O +that O +of O +flunarizine O +was O +34 O +. O +0 O +( O +26 O +. O +0 O +- O +44 O +. O +8 O +) O +mg O +/ O +kg O +, O +p O + +. O +o O +. O + +Although O +moderate O +anticonvulsant O +effects O +of O +S O +- O +312 O +- O +d O +in O +higher O +doses O +were O +observed O +against O +the O +clonic B +convulsions I +induced O +by O +pentylenetetrazole O +( O +85 O +mg O +/ O +kg O +, O +s O +. O +c O +. 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O + +In O +group O +4 O +, O +a O +combination O +of O +cocaine O +and O +diazepam O +was O +administered O +simultaneously O +. O + +This O +resulted O +in O +no O +overt O +or O +EEG O +- O +detectable O +seizures B +and O +a O +50 O +% O +incidence O +of O +death B +. O + +Group O +5 O +received O +a O +similar O +combination O +of O +cocaine O +and O +diazepam O +, O +followed O +later O +by O +5 O +mg O +/ O +kg O +flumazenil O +. O + +This O +resulted O +in O +an O +increased O +incidence O +of O +seizures B +, O +90 O +% O +( O +P O +< O +. O +01 O +) O +, O +and O +death B +, O +100 O +% O +( O +P O +< O +or O += O +. O +01 O +) O +, O +compared O +with O +group O +4 O +. O + +Group O +6 O +received O +cocaine O +and O +diazepam O +followed O +by O +10 O +mg O +/ O +kg O +flumazenil O +. O + +This O +also O +resulted O +in O +an O +increased O +incidence O +of O +seizures B +, O +90 O +% O +( O +P O +< O +or O += O +. O +01 O +) O +, O +and O +death B +, O +90 O +% O +( O +P O +< O +or O += O +. O +05 O +) O +, O +compared O +with O +group O +4 O +. O + +CONCLUSION O +: O +Flumazenil O +can O +unmask O +seizures B +and O +increase O +the O +incidence O +of O +death B +in O +a O +model O +of O +combined O +cocaine O +- O +diazepam O +intoxications O +. O + +Mechanisms O +for O +protective O +effects O +of O +free O +radical O +scavengers O +on O +gentamicin O +- O +mediated O +nephropathy B +in O +rats O +. O + +Studies O +were O +performed O +to O +examine O +the O +mechanisms O +for O +the O +protective O +effects O +of O +free O +radical O +scavengers O +on O +gentamicin O +( O +GM O +) O +- O +mediated O +nephropathy B +. 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O + +In O +this O +report O +, O +we O +describe O +a O +patient O +with O +acute O +hyperkinetic B +delirium I +connected O +with O +a O +high O +serum O +total O +fluoxetine O +( O +fluoxetine O +plus O +desmethylfluoxetine O +) O +concentration O +. O + +Pulmonary B +edema I +and O +shock B +after O +high O +- O +dose O +aracytine O +- O +C O +for O +lymphoma B +; O +possible O +role O +of O +TNF O +- O +alpha O +and O +PAF O +. O + +Four O +out O +of O +23 O +consecutive O +patients O +treated O +with O +high O +- O +dose O +Ara O +- O +C O +for O +lymphomas B +in O +our O +institution O +developed O +a O +strikingly O +similar O +syndrome O +during O +the O +perfusion O +. O + +It O +was O +characterized O +by O +the O +onset O +of O +fever B +, O +diarrhea B +, O +shock B +, O +pulmonary B +edema I +, O +acute B +renal I +failure I +, O +metabolic B +acidosis I +, O +weight B +gain I +and O +leukocytosis B +. O + +Thorough O +bacteriological O +screening O +failed O +to O +provide O +evidence O +of O +infection O +. O + +Sequential O +biological O +assays O +of O +IL O +- O +1 O +, O +IL O +- O +2 O +, O +TNF O +and O +PAF O +were O +performed O +during O +Ara O +- O +C O +infusion O +to O +ten O +patients O +, O +including O +the O +four O +who O +developed O +the O +syndrome O +. O + +TNF O +and O +PAF O +activity O +was O +found O +in O +the O +serum O +of O +respectively O +two O +and O +four O +of O +the O +cases O +, O +but O +not O +in O +the O +six O +controls O +. O + +As O +TNF O +and O +PAF O +are O +thought O +to O +be O +involved O +in O +the O +development O +of O +septic B +shock I +and O +adult B +respiratory I +distress I +syndrome I +, O +we O +hypothesize O +that O +high O +- O +dose O +Ara O +- O +C O +may O +be O +associated O +with O +cytokine O +release O +. O + +Protective O +effect O +of O +clentiazem O +against O +epinephrine O +- O +induced O +cardiac B +injury I +in O +rats O +. O + +We O +investigated O +the O +effects O +of O +clentiazem O +, O +a O +1 O +, O +5 O +- O +benzothiazepine O +calcium O +antagonist O +, O +on O +epinephrine O +- O +induced O +cardiomyopathy B +in O +rats O +. O + +With O +2 O +- O +week O +chronic O +epinephrine O +infusion O +, O +16 O +of O +30 O +rats O +died O +within O +4 O +days O +, O +and O +severe O +ischemic B +lesions I +and O +fibrosis B +of O +the O +left O +ventricles O +were O +observed O +. O + +In O +epinephrine O +- O +treated O +rats O +, O +left O +atrial O +and O +left O +ventricular O +papillary O +muscle O +contractile O +responses O +to O +isoproterenol O +were O +reduced O +, O +but O +responses O +to O +calcium O +were O +normal O +or O +enhanced O +compared O +to O +controls O +. O + +Left O +ventricular O +alpha O +and O +beta O +adrenoceptor O +densities O +were O +also O +reduced O +compared O +to O +controls O +. O + +Treatment O +with O +clentiazem O +prevented O +epinephrine O +- O +induced O +death B +( O +P O +< O +. O +05 O +) O +, O +and O +attenuated O +the O +ventricular B +ischemic I +lesions I +and O +fibrosis B +, O +in O +a O +dose O +- O +dependent O +manner O +. O + +Left O +atrial O +and O +left O +ventricular O +papillary O +muscle O +contractile O +responses O +to O +isoproterenol O +were O +reduced O +compared O +to O +controls O +in O +groups O +treated O +with O +clentiazem O +alone O +, O +but O +combined O +with O +epinephrine O +, O +clentiazem O +restored O +left O +atrial O +responses O +and O +enhanced O +left O +ventricular O +papillary O +responses O +to O +isoproterenol O +. O + +On O +the O +other O +hand O +clentiazem O +did O +not O +prevent O +epinephrine O +- O +induced O +down O +- O +regulation O +of O +alpha O +and O +beta O +adrenoceptors O +. O + +Interestingly O +, O +clentiazem O +, O +infused O +alone O +, O +resulted O +in O +decreased O +adrenergic O +receptor O +densities O +in O +the O +left O +ventricle O +. O + +Clentiazem O +also O +did O +not O +prevent O +the O +enhanced O +responses O +to O +calcium O +seen O +in O +the O +epinephrine O +- O +treated O +animals O +, O +although O +the O +high O +dose O +of O +clentiazem O +partially O +attenuated O +the O +maximal O +response O +to O +calcium O +compared O +to O +epinephrine O +- O +treated O +animals O +. O + +In O +conclusion O +, O +clentiazem O +attenuated O +epinephrine O +- O +induced O +cardiac B +injury I +, O +possibly O +through O +its O +effect O +on O +the O +adrenergic O +pathway O +. O + +Kaliuretic O +effect O +of O +L O +- O +dopa O +treatment O +in O +parkinsonian B +patients O +. O + +Hypokalemia B +, O +sometimes O +severe O +, O +was O +observed O +in O +some O +L O +- O +dopa O +- O +treated O +parkinsonian B +patients O +. O + +The O +influence O +of O +L O +- O +dopa O +on O +the O +renal O +excretion O +of O +potassium O +was O +studied O +in O +3 O +patients O +with O +hypokalemia B +and O +in O +5 O +normokalemic O +patients O +by O +determination O +of O +renal O +plasma O +flow O +, O +glomerular O +filtration O +rate O +, O +plasma O +concentration O +of O +potassium O +and O +sodium O +as O +well O +as O +urinary O +excretion O +of O +potassium O +, O +sodium O +and O +aldosterone O +. O + +L O +- O +Dopa O +intake O +was O +found O +to O +cause O +an O +increased O +excretion O +of O +potassium O +, O +and O +sometimes O +also O +of O +sodium O +, O +in O +the O +hypokalemic B +but O +not O +in O +the O +normokalemic O +patients O +. O + +This O +effect O +on O +the O +renal O +function O +could O +be O +prohibited O +by O +the O +administration O +of O +a O +peripheral O +dopa O +decarbodylase O +inhibitor O +. O + +It O +is O +not O +known O +why O +this O +effect O +occurred O +in O +some O +individuals O +but O +not O +in O +others O +, O +but O +our O +results O +indicate O +a O +correlation O +between O +aldosterone O +production O +and O +this O +renal O +effect O +of O +L O +- O +dopa O +. O + +Cocaine O +induced O +myocardial B +ischemia I +. O + +We O +report O +a O +case O +of O +myocardial B +ischemia I +induced O +by O +cocaine O +. O + +The O +ischemia B +probably O +induced O +by O +coronary B +artery I +spasm I +was O +reversed O +by O +nitroglycerin O +and O +calcium O +blocking O +agents O +. O + +Doxorubicin O +- O +induced O +cardiotoxicity B +monitored O +by O +ECG O +in O +freely O +moving O +mice O +. O + +A O +new O +model O +to O +test O +potential O +protectors O +. O + +In O +laboratory O +animals O +, O +histology O +is O +most O +commonly O +used O +to O +study O +doxorubicin O +- O +induced O +cardiotoxicity B +. O + +However O +, O +for O +monitoring O +during O +treatment O +, O +large O +numbers O +of O +animals O +are O +needed O +. O + +Recently O +we O +developed O +a O +new O +method O +to O +measure O +ECG O +values O +in O +freely O +moving O +mice O +by O +telemetry O +. O + +With O +this O +model O +we O +investigated O +the O +effect O +of O +chronic O +doxorubicin O +administration O +on O +the O +ECG O +of O +freely O +moving O +BALB O +/ O +c O +mice O +and O +the O +efficacy O +of O +ICRF O +- O +187 O +as O +a O +protective O +agent O +. O + +The O +ST O +interval O +significantly O +widened O +from O +15 O +. O +0 O ++ O +/ O +- O +1 O +. O +5 O +to O +56 O +. O +8 O ++ O +/ O +- O +11 O +. O +8 O +ms O +in O +week O +10 O +( O +7 O +weekly O +doses O +of O +4 O +mg O +/ O +kg O +doxorubicin O +given O +i O +. O +v O +. O +plus O +3 O +weeks O +of O +observation O +) O +. O + +The O +ECG O +of O +the O +control O +animals O +did O +not O +change O +during O +the O +entire O +study O +. O + +After O +sacrifice O +the O +hearts O +of O +doxorubicin O +- O +treated O +animals O +were O +enlarged O +and O +the O +atria O +were O +hypertrophic B +. O + +As O +this O +schedule O +exerted O +more O +toxicity B +than O +needed O +to O +investigate O +protective O +agents O +, O +the O +protection O +of O +ICRF O +- O +187 O +was O +determined O +using O +a O +dose O +schedule O +with O +lower O +general O +toxicity B +( O +6 O +weekly O +doses O +of O +4 O +mg O +/ O +kg O +doxorubicin O +given O +i O +. O +v O +. O +plus O +2 O +weeks O +of O +observation O +) O +. O + +On O +this O +schedule O +, O +the O +animals O +' O +hearts O +appeared O +normal O +after O +sacrifice O +and O +ICRF O +- O +187 O +( O +50 O +mg O +/ O +kg O +given O +i O +. O +p O +. O +1 O +h O +before O +doxorubicin O +) O +provided O +almost O +full O +protection O +. O + +These O +data O +were O +confirmed O +by O +histology O +. O + +The O +results O +indicate O +that O +this O +new O +model O +is O +very O +sensitive O +and O +enables O +monitoring O +of O +the O +development O +of O +cardiotoxicity B +with O +time O +. O + +These O +findings O +result O +in O +a O +model O +that O +allows O +the O +testing O +of O +protectors O +against O +doxorubicin O +- O +induced O +cardiotoxicity B +as O +demonstrated O +by O +the O +protection O +provided O +by O +ICRF O +- O +187 O +. O + +Epinephrine O +dysrhythmogenicity O +is O +not O +enhanced O +by O +subtoxic O +bupivacaine O +in O +dogs O +. O + +Since O +bupivacaine O +and O +epinephrine O +may O +both O +precipitate O +dysrhythmias B +, O +circulating O +bupivacaine O +during O +regional O +anesthesia O +could O +potentiate O +dysrhythmogenic O +effects O +of O +epinephrine O +. 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O + +Bupivacaine O +antagonizes O +epinephrine O +dysrhythmogenicity O +in O +conscious O +dogs O +susceptible O +to O +VT B +and O +in O +anesthetized O +dogs O +with O +spontaneous O +postinfarct B +dysrhythmias B +. O + +There O +is O +no O +evidence O +that O +systemic O +subtoxic O +bupivacaine O +administration O +enhances O +the O +dysrhythmogenicity O +of O +subsequent O +epinephrine O +. O + +Milk B +- I +alkali I +syndrome I +induced O +by O +1 O +, O +25 O +( O +OH O +) O +2D O +in O +a O +patient O +with O +hypoparathyroidism B +. O + +Milk B +- I +alkali I +syndrome I +was O +first O +described O +70 O +years O +ago O +in O +the O +context O +of O +the O +treatment O +of O +peptic B +ulcer I +disease I +with O +large O +amounts O +of O +calcium O +and O +alkali O +. 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O + +Increased O +expression O +of O +neuronal O +nitric O +oxide O +synthase O +in O +bladder O +afferent O +pathways O +following O +chronic O +bladder O +irritation O +. O + +Immunocytochemical O +techniques O +were O +used O +to O +examine O +alterations O +in O +the O +expression O +of O +neuronal O +nitric O +oxide O +synthase O +( O +NOS O +) O +in O +bladder O +pathways O +following O +acute O +and O +chronic O +irritation O +of O +the O +urinary O +tract O +of O +the O +rat O +. O + +Chemical O +cystitis B +was O +induced O +by O +cyclophosphamide O +( O +CYP O +) O +which O +is O +metabolized O +to O +acrolein O +, O +an O +irritant O +eliminated O +in O +the O +urine O +. O + +Injection O +of O +CYP O +( O +n O += O +10 O +, O +75 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +) O +2 O +hours O +prior O +to O +perfusion O +( O +acute O +treatment O +) O +of O +the O +animals O +increased O +Fos O +- O +immunoreactivity O +( O +IR O +) O +in O +neurons O +in O +the O +dorsal O +commissure O +, O +dorsal O +horn O +, O +and O +autonomic O +regions O +of O +spinal O +segments O +( O +L1 O +- O +L2 O +and O +L6 O +- O +S1 O +) O +which O +receive O +afferent O +inputs O +from O +the O +bladder O +, O +urethra O +, O +and O +ureter O +. O + +Fos O +- O +IR O +in O +the O +spinal O +cord O +was O +not O +changed O +in O +rats O +receiving O +chronic O +CYP O +treatment O +( O +n O += O +15 O +, O +75 O +mg O +/ O +kg O +, O +i O +. O +p O +. O +, O +every O +3rd O +day O +for O +2 O +weeks O +) O +. O + +In O +control O +animals O +and O +in O +animals O +treated O +acutely O +with O +CYP O +, O +only O +small O +numbers O +of O +NOS O +- O +IR O +cells O +( O +0 O +. O +5 O +- O +0 O +. O +7 O +cell O +profiles O +/ O +sections O +) O +were O +detected O +in O +the O +L6 O +- O +S1 O +dorsal O +root O +ganglia O +( O +DRG O +) O +. O + +Chronic O +CYP O +administration O +significantly O +( O +P O +< O +or O += O +. O +002 O +) O +increased O +bladder O +weight O +by O +60 O +% O +and O +increased O +( O +7 O +- O +to O +11 O +- O +fold O +) O +the O +numbers O +of O +NOS O +- O +immunoreactive O +( O +IR O +) O +afferent O +neurons O +in O +the O +L6 O +- O +S1 O +DRG O +. O + +A O +small O +increase O +( O +1 O +. O +5 O +- O +fold O +) O +also O +occurred O +in O +the O +L1 O +DRG O +, O +but O +no O +change O +was O +detected O +in O +the O +L2 O +and O +L5 O +DRG O +. O + +Bladder O +afferent O +cells O +in O +the O +L6 O +- O +S1 O +DRG O +labeled O +by O +Fluorogold O +( O +40 O +microliters O +) O +injected O +into O +the O +bladder O +wall O +did O +not O +exhibit O +NOS O +- O +IR O +in O +control O +animals O +; O +however O +, O +following O +chronic O +CYP O +administration O +, O +a O +significant O +percentage O +of O +bladder O +afferent O +neurons O +were O +NOS O +- O +IR O +: O +L6 O +( O +19 O +. O +8 O ++ O +/ O +- O +4 O +. O +6 O +% O +) O +and O +S1 O +( O +25 O +. O +3 O ++ O +/ O +- O +2 O +. O +9 O +% O +) O +. O + +These O +results O +indicate O +that O +neuronal O +gene O +expression O +in O +visceral O +sensory O +pathways O +can O +be O +upregulated O +by O +chemical O +irritation O +of O +afferent O +receptors O +in O +the O +urinary O +tract O +and O +/ O +or O +that O +pathological O +changes O +in O +the O +urinary O +tract O +can O +initiate O +chemical O +signals O +that O +alter O +the O +chemical O +properties O +of O +visceral O +afferent O +neurons O +. O + +Effects O +of O +a O +new O +calcium O +antagonist O +, O +CD O +- O +832 O +, O +on O +isoproterenol O +- O +induced O +myocardial B +ischemia I +in O +dogs O +with O +partial O +coronary B +stenosis I +. O + +Effects O +of O +CD O +- O +832 O +on O +isoproterenol O +( O +ISO O +) O +- O +induced O +myocardial B +ischemia I +were O +studied O +in O +dogs O +with O +partial O +coronary B +stenosis I +of O +the O +left O +circumflex O +coronary O +artery O +and O +findings O +were O +compared O +with O +those O +for O +nifedipine O +or O +diltiazem O +. O + +In O +the O +presence O +of O +coronary B +artery I +stenosis I +, O +3 O +- O +min O +periods O +of O +intracoronary O +ISO O +infusion O +( O +10 O +ng O +/ O +kg O +/ O +min O +) O +increased O +heart O +rate O +and O +maximal O +rate O +of O +left O +ventricular O +pressure O +rise O +, O +which O +resulted O +in O +a O +decrease O +in O +percentage O +segmental O +shortening O +and O +ST O +- O +segment O +elevation O +of O +the O +epicardial O +electrocardiogram O +. O + +After O +the O +control O +ISO O +infusion O +with O +stenosis O +was O +performed O +, O +equihypotensive O +doses O +of O +CD O +- O +832 O +( O +3 O +and O +10 O +micrograms O +/ O +kg O +/ O +min O +, O +n O += O +7 O +) O +, O +nifedipine O +( O +1 O +and O +3 O +micrograms O +/ O +kg O +/ O +min O +, O +n O += O +9 O +) O +or O +diltiazem O +( O +10 O +and O +30 O +micrograms O +/ O +kg O +/ O +min O +, O +n O += O +7 O +) O +were O +infused O +5 O +min O +before O +and O +during O +the O +second O +and O +third O +ISO O +infusion O +. O + +Both O +CD O +- O +832 O +and O +diltiazem O +, O +but O +not O +nifedipine O +, O +significantly O +reduced O +the O +increase O +in O +heart O +rate O +induced O +by O +ISO O +infusion O +. O + +In O +contrast O +to O +nifedipine O +, O +CD O +- O +832 O +( O +10 O +micrograms O +/ O +kg O +/ O +min O +) O +prevented O +the O +decrease O +in O +percentage O +segmental O +shortening O +from O +32 O ++ O +/ O +- O +12 O +% O +to O +115 O ++ O +/ O +- O +26 O +% O +of O +the O +control O +value O +( O +P O +< O +. O +01 O +) O +and O +ST O +- O +segment O +elevation O +from O +5 O +. O +6 O ++ O +/ O +- O +1 O +. O +0 O +mV O +to O +1 O +. O +6 O ++ O +/ O +- O +1 O +. O +3 O +mV O +( O +P O +< O +. O +01 O +) O +at O +3 O +min O +after O +ISO O +infusion O +with O +stenosis O +. O + +Diltiazem O +( O +30 O +micrograms O +/ O +kg O +/ O +min O +) O +also O +prevented O +the O +decrease O +in O +percentage O +segmental O +shortening O +from O +34 O ++ O +/ O +- O +14 O +% O +to O +63 O ++ O +/ O +- O +18 O +% O +of O +the O +control O +value O +( O +P O +< O +. O +05 O +) O +and O +ST O +- O +segment O +elevation O +from O +4 O +. O +7 O ++ O +/ O +- O +0 O +. O +7 O +mV O +to O +2 O +. O +1 O ++ O +/ O +- O +0 O +. O +7 O +mV O +( O +P O +< O +. O +01 O +) O +at O +3 O +min O +after O +ISO O +infusion O +with O +stenosis O +. O + +These O +data O +show O +that O +CD O +- O +832 O +improves O +myocardial B +ischemia I +during O +ISO O +infusion O +with O +stenosis O +and O +suggest O +that O +the O +negative O +chronotropic O +property O +of O +CD O +- O +832 O +plays O +a O +major O +role O +in O +the O +beneficial O +effects O +of O +CD O +- O +832 O +. O + +The O +effect O +of O +recombinant O +human O +insulin O +- O +like O +growth O +factor O +- O +I O +on O +chronic O +puromycin O +aminonucleoside O +nephropathy B +in O +rats O +. O + +We O +recently O +demonstrated O +that O +recombinant O +hGH O +exacerbates O +renal B +functional I +and I +structural I +injury I +in O +chronic O +puromycin O +aminonucleoside O +( O +PAN O +) O +nephropathy B +, O +an O +experimental O +model O +of O +glomerular B +disease I +. O + +Therefore O +, O +we O +examined O +whether O +recombinant O +human O +( O +rh O +) O +IGF O +- O +I O +is O +a O +safer O +alternative O +for O +the O +treatment O +of O +growth B +failure I +in O +rats O +with O +chronic O +PAN O +nephropathy B +. O + +The O +glomerulopathy B +was O +induced O +by O +seven O +serial O +injections O +of O +PAN O +over O +12 O +wk O +. O + +Experimental O +animals O +( O +n O += O +6 O +) O +received O +rhIGF O +- O +I O +, O +400 O +micrograms O +/ O +d O +, O +whereas O +control O +rats O +( O +n O += O +6 O +) O +received O +the O +vehicle O +. O + +rhIGF O +- O +I O +improved O +weight B +gain I +by O +14 O +% O +( O +p O +< O +0 O +. O +05 O +) O +, O +without O +altering O +hematocrit O +or O +blood O +pressure O +in O +rats O +with O +renal B +disease I +. O + +Urinary O +protein O +excretion O +was O +unaltered O +by O +rhIGF O +- O +I O +treatment O +in O +rats O +with O +chronic O +PAN O +nephropathy B +. O + +After O +12 O +wk O +, O +the O +inulin O +clearance O +was O +higher O +in O +rhIGF O +- O +I O +- O +treated O +rats O +, O +0 O +. O +48 O ++ O +/ O +- O +0 O +. O +08 O +versus O +0 O +. O +24 O ++ O +/ O +- O +0 O +. O +06 O +mL O +/ O +min O +/ O +100 O +g O +of O +body O +weight O +in O +untreated O +PAN O +nephropathy B +animals O +, O +p O +< O +0 O +. O +05 O +. O + +The O +improvement O +in O +GFR O +was O +not O +associated O +with O +enhanced O +glomerular B +hypertrophy I +or O +increased O +segmental O +glomerulosclerosis B +, O +tubulointerstitial B +injury I +, O +or O +renal O +cortical O +malondialdehyde O +content O +. O + +In O +rats O +with O +PAN O +nephropathy B +, O +administration O +of O +rhIGF O +- O +I O +increased O +IGF O +- O +I O +and O +GH O +receptor O +gene O +expression O +, O +without O +altering O +the O +steady O +state O +level O +of O +IGF O +- O +I O +receptor O +mRNA O +. O + +In O +normal O +rats O +with O +intact O +kidneys O +, O +rhIGF O +- O +I O +administration O +( O +n O += O +4 O +) O +did O +not O +alter O +weight B +gain I +, O +blood O +pressure O +, O +proteinuria B +, O +GFR O +, O +glomerular O +planar O +area O +, O +renal O +cortical O +malondialdehyde O +content O +, O +or O +glomerular B +or I +tubulointerstitial I +damage I +, O +compared O +with O +untreated O +animals O +( O +n O += O +4 O +) O +. O + +rhIGF O +- O +I O +treatment O +reduced O +the O +steady O +state O +renal O +IGF O +- O +I O +mRNA O +level O +but O +did O +not O +modify O +gene O +expression O +of O +the O +IGF O +- O +I O +or O +GH O +receptors O +. O + +We O +conclude O +that O +: O +1 O +) O +administration O +of O +rhIGF O +- O +I O +improves O +growth O +and O +GFR O +in O +rats O +with O +chronic O +PAN O +nephropathy B +and O +2 O +) O +unlike O +rhGH O +, O +long O +- O +term O +use O +of O +rhIGF O +- O +I O +does O +not O +worsen O +renal B +functional I +and I +structural I +injury I +in O +this O +disease O +model O +. O + +Nefiracetam O +( O +DM O +- O +9384 O +) O +reverses O +apomorphine O +- O +induced O +amnesia B +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 O +- O +induced O +learning O +and O +post O +- O +training O +consolidation O +deficits O +. O + +Given O +that O +apomorphine O +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 B +induced O +by O +dopaminergic O +agonism O +. 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 O +( 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 O +during O +training O +or O +10h O +thereafter O +produced O +no O +significant O +anti O +- O +amnesic B +effect O +. O + +However O +, O +administration O +of O +nefiracetam O +during O +training O +completely O +reversed O +the O +amnesia B +induced O +by O +apomorphine O +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 O +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 + +Phenytoin O +encephalopathy B +as O +probable O +idiosyncratic O +reaction O +: O +case O +report O +. O + +A O +case O +of O +phenytoin O +( O +DPH O +) O +encephalopathy B +with O +increasing O +seizures B +and O +EEG O +and O +mental O +changes O +is O +described O +. O + +Despite O +adequate O +oral O +dosage O +of O +DPH O +( O +5 O +mg O +/ O +kg O +/ O +daily O +) O +the O +plasma O +level O +was O +very O +low O +( O +2 O +. O +8 O +microgramg O +/ O +ml O +) O +. O + +The O +encephalopathy B +was O +probably O +an O +idiosyncratic O +and O +not O +toxic O +or O +allergic O +reaction O +. O + +In O +fact O +the O +concentration O +of O +free O +DPH O +was O +normal O +, O +the O +patient O +presented O +a O +retarded O +morbilliform B +rash I +during O +DPH O +treatment O +, O +the O +protidogram O +was O +normal O +, O +and O +an O +intradermic O +DPH O +injection O +had O +no O +local O +effect O +. O + +The O +authors O +conclude O +that O +in O +a O +patient O +starting O +DPH O +treatment O +an O +unexpected O +increase O +in O +seizures B +, O +with O +EEG O +and O +mental O +changes O +occurring O +simultaneously O +, O +should O +alert O +the O +physician O +to O +the O +possible O +need O +for O +eliminating O +DPH O +from O +the O +therapeutic O +regimen O +, O +even O +if O +plasma O +concentrations O +are O +low O +. O + +Prevention O +and O +treatment O +of O +endometrial B +disease I +in O +climacteric O +women O +receiving O +oestrogen O +therapy O +. O + +The O +treatment O +regimens O +are O +described O +in O +74 O +patients O +with O +endometrial B +disease I +among O +850 O +climacteric O +women O +receiving O +oestrogen O +therapy O +. O + +Cystic B +hyperplasia I +was O +associated O +with O +unopposed O +oestrogen O +therapy O +without O +progestagen O +. O + +Two O +courses O +of O +21 O +days O +of O +5 O +mg O +norethisterone O +daily O +caused O +reversion O +to O +normal O +in O +all O +57 O +cases O +of O +cystic B +hyperplasia I +and O +6 O +of O +the O +8 O +cases O +of O +atypical O +hyperplasia I +. O + +4 O +cases O +of O +endometrial B +carcinoma I +referred O +from O +elsewhere O +demonstrated O +the O +problems O +of O +inappropriate O +and O +unsupervised O +unopposed O +oestrogen O +therapy O +and O +the O +difficulty O +in O +distinguishing O +severe O +hyperplasia B +from O +malignancy B +. O + +Cyclical O +low O +- O +dose O +oestrogen O +therapy O +with O +7 O +- O +- O +13 O +days O +of O +progestagen O +does O +not O +seem O +to O +increase O +the O +risk O +of O +endometrial B +hyperplasia I +or O +carcinoma B +. O + +Effects O +of O +exercise O +on O +the O +severity O +of O +isoproterenol O +- O +induced O +myocardial B +infarction I +. O + +The O +effect O +of O +exercise O +on O +the O +severity O +of O +isoproterenol O +- O +induced O +myocardial B +infarction I +was O +studied O +in O +male O +rats O +. O + +Ninety O +- O +three O +rats O +were O +randomly O +divided O +into O +three O +groups O +. O + +The O +exercise O +- O +isoproterenol O +( O +E O +- O +1 O +) O +and O +exercise O +control O +( O +EC O +) O +groups O +exercised O +daily O +for O +thirty O +days O +on O +a O +treadmill O +at O +1 O +mph O +, O +2 O +% O +grade O +while O +animals O +of O +the O +sedentary O +- O +isoproterenol O +( O +S O +- O +I O +) O +group O +remained O +sedentary O +. O + +Eight O +animals O +were O +assigned O +to O +the O +sedentary O +control O +( O +SC O +) O +group O +which O +remained O +sedentary O +throughout O +the O +experimental O +period O +. O + +Forty O +- O +eight O +hours O +after O +the O +final O +exercise O +period O +, O +S O +- O +I O +and O +E O +- O +I O +animals O +received O +a O +single O +subcutaneous O +injection O +of O +isoproterenol O +( O +250 O +mg O +/ O +kg O +body O +weight O +) O +. O + +Animals O +of O +the O +S O +- O +I O +group O +exhibited O +significantly O +( O +Pp O +less O +than O +0 O +. O +05 O +) O +greater O +mortality O +from O +the O +effects O +of O +isoproterenol O +than O +animals O +of O +the O +E O +- O +I O +group O +. O + +Serum O +CPK O +activity O +for O +E O +- O +I O +animals O +was O +significantly O +( O +p O +less O +than O +0 O +. O +05 O +) O +greater O +than O +for O +animals O +in O +the O +S O +- O +I O +and O +EC O +groups O +twenty O +hours O +following O +isoproterenol O +injection O +. O + +No O +statistically O +significant O +differences O +were O +observed O +between O +the O +two O +isoproterenol O +treated O +groups O +for O +severity O +of O +the O +induced O +lesions O +, O +changes O +in O +heart O +weight O +, O +or O +heart O +weight O +to O +body O +weight O +ratios O +. O + +The O +results O +indicated O +that O +exercise O +reduced O +the O +mortality O +associated O +with O +the O +effects O +of O +large O +dosages O +of O +isoproterenol O +but O +had O +little O +on O +the O +severity O +of O +the O +infarction B +. O + +Human O +corticotropin O +- O +releasing O +hormone O +and O +thyrotropin O +- O +releasing O +hormone O +modulate O +the O +hypercapnic B +ventilatory O +response O +in O +humans O +. O + +Human O +corticotropin O +- O +releasing O +hormone O +( O +hCRH O +) O +and O +thyrotropin O +- O +releasing O +hormone O +( O +TRH O +) O +are O +known O +to O +stimulate O +ventilation O +after O +i O +. O +v O +. O +administration O +in O +humans O +. O + +In O +a O +placebo O +- O +controlled O +, O +single O +- O +blind O +study O +we O +aimed O +to O +clarify O +if O +both O +peptides O +act O +by O +altering O +central O +chemosensitivity O +. O + +Two O +subsequent O +CO2 O +- O +rebreathing O +tests O +were O +performed O +in O +healthy O +young O +volunteers O +. O + +During O +the O +first O +test O +0 O +. O +9 O +% O +NaCl O +was O +given O +i O +. O +v O +. O +; O +during O +the O +second O +test O +200 O +micrograms O +of O +hCRH O +( O +n O += O +12 O +) O +or O +400 O +micrograms O +of O +TRH O +( O +n O += O +6 O +) O +was O +administered O +i O +. O +v O +. O +Nine O +subjects O +received O +0 O +. O +9 O +% O +NaCl O +i O +. O +v O +. O +during O +both O +rebreathing O +manoeuvres O +. O + +The O +CO2 O +- O +response O +curves O +for O +the O +two O +tests O +were O +compared O +within O +the O +same O +subject O +. O + +In O +the O +hCRH O +group O +a O +marked O +parallel O +shift O +of O +the O +CO2 O +- O +response O +curve O +to O +the O +left O +was O +observed O +after O +hCRH O +( O +P O +< O +0 O +. O +01 O +) O +. O + +The O +same O +effect O +occurred O +following O +TRH O +but O +was O +less O +striking O +( O +P O += O +0 O +. O +05 O +) O +. O + +hCRH O +and O +TRH O +caused O +a O +reduction O +in O +the O +CO2 O +threshold O +. O + +The O +CO2 O +- O +response O +curves O +in O +the O +control O +group O +were O +nearly O +identical O +. O + +The O +results O +indicate O +an O +additive O +effect O +of O +both O +releasing O +hormones O +on O +the O +hypercapnic B +ventilatory O +response O +in O +humans O +, O +presumably O +independent O +of O +central O +chemosensitivity O +. 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O +005 O +) O +, O +it O +still O +induced O +94 O +% O +suppression O +of O +HBV O +DNA O +after O +the O +fourth O +week O +of O +therapy O +. O + +HBV O +DNA O +values O +returned O +to O +pretreatment O +levels O +within O +4 O +weeks O +of O +cessation O +of O +therapy O +. O + +There O +was O +no O +change O +in O +the O +hepatitis O +B O +e O +antigen O +status O +or O +in O +aminotransferase O +levels O +. O + +No O +serious O +adverse O +events O +were O +observed O +. O + +In O +conclusion O +, O +a O +4 O +- O +week O +course O +of O +lamivudine O +was O +safe O +and O +effective O +in O +suppression O +of O +HBV O +DNA O +in O +Chinese O +HBsAg B +carriers O +. O + +The O +suppression O +was O +> O +90 O +% O +but O +reversible O +. O + +Studies O +with O +long O +- O +term O +lamivudine O +administration O +should O +be O +performed O +to O +determine O +if O +prolonged O +suppression O +of O +HBV O +DNA O +can O +be O +achieved O +. O + +Population O +- O +based O +study O +of O +risk O +of O +venous B +thromboembolism I +associated O +with O +various O +oral O +contraceptives O +. O + +BACKGROUND O +: O +Four O +studies O +published O +since O +December O +, O +1995 O +, O +reported O +that O +the O +incidence O +of O +venous B +thromboembolism I +( O +VTE B +) O +was O +higher O +in O +women O +who O +used O +oral O +contraceptives O +( O +OCs O +) O +containing O +the O +third O +- O +generation O +progestagens O +gestodene O +or O +desogestrel O +than O +in O +users O +of O +OCs O +containing O +second O +- O +generation O +progestagens O +. O + +However O +, O +confounding O +and O +bias O +in O +the O +design O +of O +these O +studies O +may O +have O +affected O +the O +findings O +. 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O + +Pronounced O +changes O +in O +the O +surface O +ECG O +( O +cycle O +length O +, O +QT O +, O +and O +QTc O +) O +in O +relation O +to O +the O +dose O +of O +oral O +d O +, O +l O +- O +sotalol O +might O +identify O +a O +subgroup O +of O +patients O +with O +an O +increased O +risk O +for O +torsades B +de I +pointes I +. O + +Other O +ECG O +parameters O +before O +the O +application O +of O +d O +, O +l O +- O +sotalol O +did O +not O +identify O +patients O +at O +increased O +risk O +for O +torsades B +de I +pointes I +. O + +Recurrence O +rates O +of O +ventricular B +tachyarrhythmias I +are O +high O +despite O +complete O +suppression O +of O +the O +arrhythmia B +during O +programmed O +stimulation O +. O + +Therefore O +programmed O +electrical O +stimulation O +in O +the O +case O +of O +d O +, O +l O +- O +sotalol O +seems O +to O +be O +of O +limited O +prognostic O +value O +. O + +Chronic O +hyperprolactinemia B +and O +changes O +in O +dopamine O +neurons O +. O + +The O +tuberoinfundibular O +dopaminergic O +( O +TIDA O +) O +system O +is O +known O +to O +inhibit O +prolactin O +( O +PRL O +) O +secretion O +. O + +In O +young O +animals O +this O +system O +responds O +to O +acute O +elevations O +in O +serum O +PRL O +by O +increasing O +its O +activity O +. O + +However O +, O +this O +responsiveness O +is O +lost O +in O +aging O +rats O +with O +chronically O +high O +serum O +PRL O +levels O +. O + +The O +purpose O +of O +this O +study O +was O +to O +induce O +hyperprolactinemia B +in O +rats O +for O +extended O +periods O +of O +time O +and O +examine O +its O +effects O +on O +dopaminergic O +systems O +in O +the O +brain O +. O + +Hyperprolactinemia B +was O +induced O +by O +treatment O +with O +haloperidol O +, O +a O +dopamine O +receptor O +antagonist O +, O +and O +Palkovits O +' O +microdissection O +technique O +in O +combination O +with O +high O +- O +performance O +liquid O +chromatography O +was O +used O +to O +measure O +neurotransmitter O +concentrations O +in O +several O +areas O +of O +the O +brain O +. O + +After O +6 O +months O +of O +hyperprolactinemia B +, O +dopamine O +( O +DA O +) O +concentrations O +in O +the O +median O +eminence O +( O +ME O +) O +increased O +by O +84 O +% O +over O +the O +control O +group O +. O + +Nine O +months O +of O +hyperprolactinemia B +produced O +a O +50 O +% O +increase O +in O +DA O +concentrations O +in O +the O +ME O +over O +the O +control O +group O +. O + +However O +, O +DA O +response O +was O +lost O +if O +a O +9 O +- O +month O +long O +haloperidol O +- O +induced O +hyperprolactinemia B +was O +followed O +by O +a O +1 O +1 O +/ O +2 O +month O +- O +long O +extremely O +high O +increase O +in O +serum O +PRL O +levels O +produced O +by O +implantation O +of O +MMQ O +cells O +under O +the O +kidney O +capsule O +. O + +There O +was O +no O +change O +in O +the O +levels O +of O +DA O +, O +norepinephrine O +( O +NE O +) O +, O +serotonin O +( O +5 O +- O +HT O +) O +, O +or O +their O +metabolites O +in O +the O +arcuate O +nucleus O +( O +AN O +) O +, O +medial O +preoptic O +area O +( O +MPA O +) O +, O +caudate O +putamen O +( O +CP O +) O +, O +substantia O +nigra O +( O +SN O +) O +, O +and O +zona O +incerta O +( O +ZI O +) O +, O +except O +for O +a O +decrease O +in O +5 O +- O +hydroxyindoleacetic O +acid O +( O +5 O +- O +HIAA O +) O +in O +the O +AN O +after O +6 O +- O +months O +of O +hyperprolactinemia B +and O +an O +increase O + +in O +DA O +concentrations O +in O +the O +AN O +after O +9 O +- O +months O +of O +hyperprolactinemia B +. O + +These O +results O +demonstrate O +that O +hyperprolactinemia B +specifically O +affects O +TIDA O +neurons O +and O +these O +effects O +vary O +, O +depending O +on O +the O +duration O +and O +intensity O +of O +hyperprolactinemia B +. O + +The O +age O +- O +related O +decrease O +in O +hypothalamic O +dopamine O +function O +may O +be O +associated O +with O +increases O +in O +PRL O +secretion O +. O + +Treatment O +- O +related O +disseminated O +necrotizing B +leukoencephalopathy I +with O +characteristic O +contrast O +enhancement O +of O +the O +white O +matter O +. O + +This O +report O +describes O +unique O +contrast O +enhancement O +of O +the O +white O +matter O +on O +T1 O +- O +weighted O +magnetic O +resonance O +images O +of O +two O +patients O +with O +disseminated O +necrotizing I +leukoencephalopathy I +, O +which O +developed O +from O +acute B +lymphoblastic I +leukemia I +treated O +with O +high O +- O +dose O +methotrexate O +. O + +In O +both O +patients O +, O +the O +enhancement O +was O +more O +pronounced O +near O +the O +base O +of O +the O +brain O +than O +at O +the O +vertex O +. O + +Necropsy O +of O +the O +first O +case O +revealed O +loss B +of I +myelination I +and O +necrosis B +of I +the I +white I +matter I +. O + +Possible O +mechanisms O +causing O +such O +a O +leukoencephalopathy B +are O +discussed O +. O + +Thrombotic B +complications I +in O +acute B +promyelocytic I +leukemia I +during O +all O +- O +trans O +- O +retinoic O +acid O +therapy O +. O + +A O +case O +of O +acute B +renal I +failure I +, O +due O +to O +occlusion B +of I +renal I +vessels I +in O +a O +patient O +with O +acute B +promyelocytic I +leukemia I +( O +APL B +) O +treated O +with O +all O +- O +trans O +- O +retinoic O +acid O +( O +ATRA O +) O +and O +tranexamic O +acid O +has O +been O +described O +recently O +. O + +We O +report O +a O +case O +of O +acute B +renal I +failure I +in O +an O +APL B +patient O +treated O +with O +ATRA O +alone O +. O + +This O +case O +further O +supports O +the O +concern O +about O +thromboembolic B +complications I +associated O +with O +ATRA O +therapy O +in O +APL B +patients O +. O + +The O +patients O +, O +a O +43 O +- O +year O +- O +old O +man O +, O +presented O +all O +the O +signs O +and O +symptoms O +of O +APL B +and O +was O +included O +in O +a O +treatment O +protocol O +with O +ATRA O +. O + +After O +10 O +days O +of O +treatment O +, O +he O +developed O +acute B +renal I +failure I +that O +was O +completely O +reversible O +after O +complete O +remission O +of O +APL B +was O +achieved O +and O +therapy O +discontinued O +. O + +We O +conclude O +that O +ATRA O +is O +a O +valid O +therapeutic O +choice O +for O +patients O +with O +APL B +, O +although O +the O +procoagulant O +tendency O +is O +not O +completely O +corrected O +. O + +Thrombotic B +events O +, O +however O +, O +could O +be O +avoided O +by O +using O +low O +- O +dose O +heparin O +. O + +Pupillary O +changes O +associated O +with O +the O +development O +of O +stimulant O +- O +induced O +mania B +: O +a O +case O +report O +. O + +A O +30 O +- O +year O +- O +old O +cocaine O +- O +dependent O +man O +who O +was O +a O +subject O +in O +a O +study O +evaluating O +the O +anticraving O +efficacy O +of O +the O +stimulant O +medication O +diethylpropion O +( O +DEP O +) O +became O +manic B +during O +his O +second O +week O +on O +the O +study O +drug O +. O + +Pupillometric O +changes O +while O +on O +DEP O +, O +especially O +changes O +in O +the O +total O +power O +of O +pupillary O +oscillation O +, O +were O +dramatically O +different O +than O +those O +observed O +in O +the O +eight O +other O +study O +subjects O +who O +did O +not O +become O +manic B +. O + +The O +large O +changes O +in O +total O +power O +of O +pupillary B +oscillation I +occurred O +a O +few O +days O +before O +the O +patient O +became O +fully O +manic B +. O + +Such O +medication O +- O +associated O +changes O +in O +the O +total O +power O +of O +pupillary B +oscillation I +might O +be O +of O +utility O +in O +identifying O +persons O +at O +risk O +for O +manic B +- O +like O +adverse O +effects O +during O +the O +medical O +use O +of O +psychomotor O +stimulants O +or O +sympathomimetic O +agents O +. O + +Fetal O +risks O +due O +to O +warfarin O +therapy O +during O +pregnancy O +. O + +Two O +mothers O +with O +heart O +valve O +prosthesis O +were O +treated O +with O +warfarin O +during O +pregnancy O +. O + +In O +the O +first O +case O +a O +caesarean O +section O +was O +done O +one O +week O +after O +replacement O +of O +warfarin O +with O +heparin O +. O + +The O +baby O +died O +of O +cerebral B +and I +pulmonary I +hemorrhage I +. O + +The O +second O +mother O +had O +a O +male O +infant O +by O +caesarean O +section O +. O + +The O +baby O +showed O +warfarin O +- O +induced O +embryopathy B +with O +nasal B +hypoplasia I +and O +stippled B +epiphyses I +( O +chondrodysplasia B +punctata I +) O +. O + +Nasal B +hypoplasia I +with O +or O +without O +stippled B +epiphyses I +has O +now O +been O +reported O +in O +11 O +infants O +born O +to O +mothers O +treated O +with O +warfarin O +during O +the O +first O +trimester O +, O +and O +a O +causal O +association O +is O +probable O +. O + +In O +view O +of O +the O +risks O +to O +both O +mother O +and O +fetus O +in O +women O +with O +prosthetic O +cardiac O +valves O +it O +is O +recommended O +that O +therapeutic O +abortion O +be O +advised O +as O +the O +first O +alternative O +. O + +The O +negative O +mucosal O +potential O +: O +separating O +central O +and O +peripheral O +effects O +of O +NSAIDs O +in O +man O +. O + +OBJECTIVE O +: O +We O +wanted O +to O +test O +whether O +assessment O +of O +both O +a O +central O +pain B +- O +related O +signal O +( O +chemo O +- O +somatosensory O +evoked O +potential O +, O +CSSEP O +) O +and O +a O +concomitantly O +recorded O +peripheral O +signal O +( O +negative O +mucosal O +potential O +, O +NMP O +) O +allows O +for O +separation O +of O +central O +and O +peripheral O +effects O +of O +NSAIDs O +. O + +For O +this O +purpose O +, O +experimental O +conditions O +were O +created O +in O +which O +NSAIDs O +had O +previously O +been O +observed O +to O +produce O +effects O +on O +phasic O +and O +tonic O +pain B +by O +either O +central O +or O +peripheral O +mechanisms O +. O + +METHODS O +: O +According O +to O +a O +double O +- O +blind O +, O +randomised O +, O +controlled O +, O +threefold O +cross O +- O +over O +design O +, O +18 O +healthy O +subjects O +( O +11 O +males O +, O +7 O +females O +; O +mean O +age O +26 O +years O +) O +received O +either O +placebo O +, O +400 O +mg O +ibuprofen O +, O +or O +800 O +mg O +ibuprofen O +. O + +Phasic O +pain B +was O +applied O +by O +means O +of O +short O +pulses O +of O +CO2 O +to O +the O +nasal O +mucosa O +( O +stimulus O +duration O +500 O +ms O +, O +interval O +approximately O +60 O +s O +) O +, O +and O +tonic O +pain B +was O +induced O +in O +the O +nasal O +cavity O +by O +means O +of O +dry O +air O +of O +controlled O +temperature O +, O +humidity O +and O +flow O +rate O +( O +22 O +degrees O +C O +, O +0 O +% O +relative O +humidity O +, O +145 O +ml O +. O +s O +- O +1 O +) O +. O + +Both O +CSSEPs O +as O +central O +and O +NMPs O +as O +peripheral O +correlates O +of O +pain B +were O +obtained O +in O +response O +to O +the O +CO2 O +stimuli O +. O + +Additionally O +, O +the O +subjects O +rated O +the O +intensity O +of O +both O +phasic O +and O +tonic O +pain B +by O +means O +of O +visual O +analogue O +scales O +. O + +RESULTS O +: O +As O +described O +earlier O +, O +administration O +of O +ibuprofen O +was O +followed O +by O +a O +decrease O +in O +tonic O +pain B +but O +- O +relative O +to O +placebo O +- O +an O +increase O +in O +correlates O +of O +phasic O +pain B +, O +indicating O +a O +specific O +effect O +of O +ibuprofen O +on O +the O +interaction O +between O +the O +pain B +stimuli O +under O +these O +special O +experimental O +conditions O +. O + +Based O +on O +the O +similar O +behaviour O +of O +CSSEP O +and O +NMP O +, O +it O +was O +concluded O +that O +the O +pharmacological O +process O +underlying O +this O +phenomenon O +was O +localised O +in O +the O +periphery O +. O + +By O +means O +of O +the O +simultaneous O +recording O +of O +interrelated O +peripheral O +and O +central O +electrophysiologic O +correlates O +of O +nociception O +, O +it O +was O +possible O +to O +separate O +central O +and O +peripheral O +effects O +of O +an O +NSAID O +. O + +The O +major O +advantage O +of O +this O +pain B +model O +is O +the O +possibility O +of O +obtaining O +peripheral O +pain B +- O +related O +activity O +directly O +using O +a O +non O +- O +invasive O +technique O +in O +humans O +. O + +Effect O +of O +D O +- O +Glucarates O +on O +basic O +antibiotic O +- O +induced O +renal B +damage I +in O +rats O +. O + +Dehydrated O +rats O +regularly O +develop O +acute B +renal I +failure I +following O +single O +injection O +of O +aminoglycoside O +antibiotics O +combined O +with O +dextran O +or O +of O +antibiotics O +only O +. O + +Oral O +administration O +of O +2 O +, O +5 O +- O +di O +- O +O O +- O +acetyl O +- O +D O +- O +glucaro O +- O +1 O +, O +4 O +- O +6 O +, O +3 O +- O +dilactone O +protected O +rats O +against O +renal B +failure I +induced O +by O +kanamycin O +- O +dextran O +. O + +The O +protective O +effect O +was O +prevalent O +among O +D O +- O +glucarates O +, O +and O +also O +to O +other O +saccharic O +acid O +, O +hexauronic O +acids O +and O +hexaaldonic O +acids O +, O +although O +to O +a O +lesser O +degree O +, O +but O +not O +to O +a O +hexaaldose O +, O +sugar O +alcohols O +, O +substances O +inthe O +TCA O +cycle O +and O +other O +acidic O +compounds O +. O + +D O +- O +Glucarates O +were O +effective O +against O +renal B +damage I +induced O +by O +peptide O +antibiotics O +as O +well O +as O +various O +aminoglycoside O +antibitocis O +. O + +Dose O +- O +responses O +were O +observed O +in O +the O +protective O +effect O +of O +D O +- O +Glucarates O +. O + +With O +a O +D O +- O +glucarate O +of O +a O +fixed O +size O +of O +dose O +, O +approximately O +the O +same O +degree O +of O +protection O +was O +obtained O +against O +renal B +damages I +induced O +by O +different O +basic O +antibiotics O +despite O +large O +disparities O +in O +administration O +doses O +of O +different O +antibiotics O +. O + +D O +- O +Glucarates O +had O +the O +ability O +to O +prevent O +renal B +damage I +but O +not O +to O +cure O +it O +. O + +Rats O +excreted O +acidic O +urine O +when O +they O +were O +spared O +from O +renal B +lesions I +by O +monosaccharides O +. O + +The O +reduction O +effect O +of O +D O +- O +glucarates O +against O +nephrotoxicity B +of O +basic O +antibiotics O +was O +discussed O +. O + +Acute O +severe O +depression B +following O +peri O +- O +operative O +ondansetron O +. O + +A O +41 O +- O +year O +- O +old O +woman O +with O +a O +strong O +history O +of O +postoperative B +nausea I +and I +vomiting I +presented O +for O +abdominal O +hysterectomy O +3 O +months O +after O +a O +previous O +anaesthetic O +where O +ondansetron O +prophylaxis O +had O +been O +used O +. O + +She O +had O +developed O +a O +severe O +acute O +major B +depression I +disorder I +almost O +immediately O +thereafter O +, O +possibly O +related O +to O +the O +use O +of O +a O +serotonin O +antagonist O +. O + +Nine O +years O +before O +she O +had O +experienced O +a O +self O +- O +limited O +puerperal O +depressive B +episode I +. O + +Anaesthesia O +with O +a O +propofol O +infusion O +and O +avoidance O +of O +serotonin O +antagonists O +provided O +a O +nausea B +- O +free O +postoperative O +course O +without O +exacerbation O +of O +the O +depression B +disorder I +. O + +Hypertensive B +response O +during O +dobutamine O +stress O +echocardiography O +. O + +Among O +3 O +, O +129 O +dobutamine O +stress O +echocardiographic O +studies O +, O +a O +hypertensive B +response O +, O +defined O +as O +systolic O +blood O +pressure O +( O +BP O +) O +> O +or O += O +220 O +mm O +Hg O +and O +/ O +or O +diastolic O +BP O +> O +or O += O +110 O +mm O +Hg O +, O +occurred O +in O +30 O +patients O +( O +1 O +% O +) O +. O + +Patients O +with O +this O +response O +more O +often O +had O +a O +history O +of O +hypertension B +and O +had O +higher O +resting O +systolic O +and O +diastolic O +BP O +before O +dobutamine O +infusion O +. O + +Continuously O +nebulized O +albuterol O +in O +severe O +exacerbations O +of O +asthma B +in O +adults O +: O +a O +case O +- O +controlled O +study O +. O + +A O +retrospective O +, O +case O +- O +controlled O +analysis O +comparing O +patients O +admitted O +to O +a O +medical O +intensive O +care O +unit O +with O +severe O +exacerbations O +of O +asthma B +who O +received O +continuously O +nebulized O +albuterol O +( O +CNA O +) O +versus O +intermittent O +albuterol O +( O +INA O +) O +treatments O +is O +reported O +. O + +Forty O +matched O +pairs O +of O +patients O +with O +asthma B +are O +compared O +. O + +CNA O +was O +administered O +for O +a O +mean O +of O +11 O ++ O +/ O +- O +10 O +hr O +. O + +The O +incidence O +of O +cardiac B +dysrhythmias I +was O +similar O +between O +groups O +. O + +Symptomatic O +hypokalemia B +did O +not O +occur O +. O + +CNA B +patients O +had O +higher O +heart O +rates O +during O +treatment O +, O +which O +may O +reflect O +severity O +of O +illness O +. O + +The O +incidence O +of O +intubation O +was O +similar O +. O + +We O +conclude O +that O +CNA O +and O +INA O +demonstrated O +similar O +profiles O +with O +regard O +to O +safety O +, O +morbidity O +, O +and O +mortality O +. O + +Paraplegia B +following O +intrathecal O +methotrexate O +: O +report O +of O +a O +case O +and O +review O +of O +the O +literature O +. O + +A O +patient O +who O +developed O +paraplegia B +following O +the O +intrathecal O +instillation O +of O +methotrexate O +is O +discribed O +. O + +The O +ten O +previously O +reported O +cases O +of O +this O +unusual O +complication O +are O +reviewed O +. O + +The O +following O +factors O +appear O +to O +predispose O +to O +the O +development O +of O +this O +complication O +: O +abnormal O +cerebrospinal O +dynamics O +related O +to O +the O +presence O +of O +central B +nervous I +system I +leukemia I +, O +and O +epidural O +cerebrospinal B +leakage I +; O +elevated O +cerebrospinal O +fluid O +methothexate O +concentration O +related O +to O +abnormal O +cerebrospinal O +fluid O +dynamics O +and O +to O +inappropriately O +high O +methotrexate O +doses O +based O +on O +body O +surface O +area O +calculations O +in O +older O +children O +and O +adults O +; O +the O +presence O +of O +neurotoxic B +preservatives O +in O +commercially O +available O +methotrexate O +preparations O +and O +diluents O +; O +and O +the O +use O +of O + +methotrexate O +diluents O +of O +unphysiologic O +pH O +, O +ionic O +content O +and O +osmolarity O +. O + +The O +role O +of O +methotrexate O +contaminants O +, O +local O +folate B +deficiency I +, O +and O +cranial O +irradiation O +in O +the O +pathogenesis O +of O +intrathecal O +methotrexate O +toxicity B +is O +unclear O +. O + +The O +incidence O +of O +neurotoxicity B +may O +be O +reduced O +by O +employing O +lower O +doses O +of O +methotrexate O +in O +the O +presence O +of O +central B +nervous I +system I +leukemia I +, O +in O +older O +children O +and O +adults O +, O +and O +in O +the O +presence O +of O +epidural O +leakage O +. O + +Only O +preservative O +- O +free O +methotrexate O +in O +Elliott O +' O +s O +B O +Solution O +at O +a O +concentration O +of O +not O +more O +than O +1 O +mg O +/ O +ml O +should O +be O +used O +for O +intrathecal O +administration O +. O + +Periodic O +monitoring O +of O +cerebruspinal O +fluid O +methotrexate O +levels O +may O +be O +predictive O +of O +the O +development O +of O +serious O +neurotoxicity B +. O + +Hyperosmolar B +nonketotic I +coma I +precipitated O +by O +lithium O +- O +induced O +nephrogenic B +diabetes I +insipidus I +. O + +A O +45 O +- O +year O +- O +old O +man O +, O +with O +a O +10 O +- O +year O +history O +of O +manic B +depression I +treated O +with O +lithium O +, O +was O +admitted O +with O +hyperosmolar B +, O +nonketotic O +coma B +. O + +He O +gave O +a O +five O +- O +year O +history O +of O +polyuria B +and O +polydipsia B +, O +during O +which O +time O +urinalysis O +had O +been O +negative O +for O +glucose O +. O + +After O +recovery O +from O +hyperglycaemia B +, O +he O +remained O +polyuric B +despite O +normal O +blood O +glucose O +concentrations O +; O +water O +deprivation O +testing O +indicated O +nephrogenic B +diabetes I +insipidus I +, O +likely O +to O +be O +lithium O +- O +induced O +. O + +We O +hypothesize O +that O +when O +this O +man O +developed O +type B +2 I +diabetes I +, O +chronic O +polyuria B +due O +to O +nephrogenic B +diabetes I +insipidus I +was O +sufficient O +to O +precipitate O +hyperosmolar B +dehydration I +. O + +Effects O +of O +the O +intracoronary O +infusion O +of O +cocaine O +on O +left O +ventricular O +systolic O +and O +diastolic O +function O +in O +humans O +. O + +BACKGROUND O +: O +In O +dogs O +, O +a O +large O +amount O +of O +intravenous O +cocaine O +causes O +a O +profound O +deterioration O +of I +left I +ventricular I +( I +LV I +) I +systolic I +function I +and O +an O +increase O +in O +LV O +end O +- O +diastolic O +pressure O +. O + +This O +study O +was O +done O +to O +assess O +the O +influence O +of O +a O +high O +intracoronary O +cocaine O +concentration O +on O +LV O +systolic O +and O +diastolic O +function O +in O +humans O +. O + +METHODS O +AND O +RESULTS O +: O +In O +20 O +patients O +( O +14 O +men O +and O +6 O +women O +aged O +39 O +to O +72 O +years O +) O +referred O +for O +cardiac O +catheterization O +for O +the O +evaluation O +of O +chest B +pain I +, O +we O +measured O +heart O +rate O +, O +systemic O +arterial O +pressure O +, O +LV O +pressure O +and O +its O +first O +derivative O +( O +dP O +/ O +dt O +) O +, O +and O +LV O +volumes O +and O +ejection O +fraction O +before O +and O +during O +the O +final O +2 O +to O +3 O +minutes O +of O +a O +15 O +- O +minute O +intracoronary O +infusion O +of O +saline O +( O +n O += O +10 O +, O +control O +subjects O +) O +or O +cocaine O +hydrochloride O +1 O +mg O +/ O +min O +( O +n O += O +10 O +) O +. O + +No O +variable O +changed O +with O +saline O +. O + +With O +cocaine O +, O +the O +drug O +concentration O +in O +blood O +obtained O +from O +the O +coronary O +sinus O +was O +3 O +. O +0 O ++ O +/ O +- O +0 O +. O +4 O +( O +mean O ++ O +/ O +- O +SD O +) O +mg O +/ O +L O +, O +similar O +in O +magnitude O +to O +the O +blood O +cocaine O +concentration O +reported O +in O +abusers O +dying O +of O +cocaine O +intoxication I +. O + +Cocaine O +induced O +no O +significant O +change O +in O +heart O +rate O +, O +LV O +dP O +/ O +dt O +( O +positive O +or O +negative O +) O +, O +or O +LV O +end O +- O +diastolic O +volume O +, O +but O +it O +caused O +an O +increase O +in O +systolic O +and O +mean O +arterial O +pressures O +, O +LV O +end O +- O +diastolic O +pressure O +, O +and O +LV O +end O +- O +systolic O +volume O +, O +as O +well O +as O +a O +decrease O +in O +LV O +ejection O +fraction O +. O + +CONCLUSIONS O +: O +In O +humans O +, O +the O +intracoronary O +infusion O +of O +cocaine O +sufficient O +in O +amount O +to O +achieve O +a O +high O +drug O +concentration O +in O +coronary O +sinus O +blood O +causes O +a O +deterioration O +of O +LV O +systolic O +and O +diastolic O +performance O +. O + +Ascending O +dose O +tolerance O +study O +of O +intramuscular O +carbetocin O +administered O +after O +normal O +vaginal O +birth O +. O + +OBJECTIVE O +: O +To O +determine O +the O +maximum O +tolerated O +dose O +( O +MTD O +) O +of O +carbetocin O +( O +a O +long O +- O +acting O +synthetic O +analogue O +of O +oxytocin O +) O +, O +when O +administered O +immediately O +after O +vaginal O +delivery O +at O +term O +. O + +MATERIALS O +AND O +METHODS O +: O +Carbetocin O +was O +given O +as O +an O +intramuscular O +injection O +immediately O +after O +the O +birth O +of O +the O +infant O +in O +45 O +healthy O +women O +with O +normal O +singleton O +pregnancies O +who O +delivered O +vaginally O +at O +term O +. O + +Dosage O +groups O +of O +15 O +, O +30 O +, O +50 O +, O +75 O +, O +100 O +, O +125 O +, O +150 O +, O +175 O +or O +200 O +microg O +carbetocin O +were O +assigned O +to O +blocks O +of O +three O +women O +according O +to O +the O +continual O +reassessment O +method O +( O +CRM O +) O +. O + +RESULTS O +: O +All O +dosage O +groups O +consisted O +of O +three O +women O +, O +except O +those O +with O +100 O +microg O +( O +n O += O +6 O +) O +and O +200 O +microg O +( O +n O += O +18 O +) O +. O + +Recorded O +were O +dose O +- O +limiting O +adverse O +events O +: O +hyper B +- I +or I +hypotension B +( O +three O +) O +, O +severe O +abdominal B +pain I +( O +0 O +) O +, O +vomiting B +( O +0 O +) O +and O +retained B +placenta I +( O +four O +) O +. O + +Serious O +adverse O +events O +occurred O +in O +seven O +women O +: O +six O +cases O +with O +blood B +loss O +> O +or O += O +1000 O +ml O +, O +four O +cases O +of O +manual O +placenta O +removal O +, O +five O +cases O +of O +additional O +oxytocics O +administration O +and O +five O +cases O +of O +blood O +transfusion O +. O + +Maximum O +blood B +loss I +was O +greatest O +at O +the O +upper O +and O +lower O +dose O +levels O +, O +and O +lowest O +in O +the O +70 O +- O +125 O +microg O +dose O +range O +. O + +Four O +out O +of O +six O +cases O +with O +blood B +loss I +> O +or O += O +1000 O +ml O +occurred O +in O +the O +200 O +microg O +group O +. O + +The O +majority O +of O +additional O +administration O +of O +oxytocics O +( O +4 O +/ O +5 O +) O +and O +blood O +transfusion O +( O +3 O +/ O +5 O +) O +occurred O +in O +the O +dose O +groups O +of O +200 O +microg O +. O + +All O +retained O +placentae O +were O +found O +in O +the O +group O +of O +200 O +microg O +. O + +CONCLUSION O +: O +The O +MTD O +was O +calculated O +to O +be O +at O +200 O +microg O +carbetocin O +. O + +Heparin O +- O +induced O +thrombocytopenia B +, O +paradoxical O +thromboembolism B +, O +and O +other O +side O +effects O +of O +heparin O +therapy O +. O + +Although O +several O +new O +anticoagulant O +drugs O +are O +in O +development O +, O +heparin O +remains O +the O +drug O +of O +choice O +for O +most O +anticoagulation O +needs O +. O + +The O +clinical O +effects O +of O +heparin O +are O +meritorious O +, O +but O +side O +effects O +do O +exist O +. O + +Important O +untoward O +effects O +of O +heparin O +therapy O +including O +heparin O +- O +induced O +thrombocytopenia B +, O +heparin O +- O +associated O +osteoporosis B +, O +eosinophilia B +, O +skin O +reactions O +, O +allergic B +reactions I +other O +than O +thrombocytopenia B +and O +alopecia B +will O +be O +discussed O +in O +this O +article O +. O + +Nonopaque O +crystal O +deposition O +causing O +ureteric B +obstruction I +in O +patients O +with O +HIV B +undergoing O +indinavir O +therapy O +. O + +OBJECTIVE O +: O +We O +describe O +the O +unique O +CT O +features O +of O +ureteric B +calculi I +in O +six O +HIV B +- I +infected I +patients O +receiving O +indinavir O +, O +the O +most O +commonly O +used O +HIV O +protease O +inhibitor O +, O +which O +is O +associated O +with O +an O +increased O +incidence O +of O +urolithiasis B +. O + +CONCLUSION O +: O +Ureteric B +obstruction I +caused O +by O +precipitated O +indinavir O +crystals O +may O +be O +difficult O +to O +diagnose O +with O +unenhanced O +CT O +. O + +The O +calculi O +are O +not O +opaque O +, O +and O +secondary O +signs O +of O +obstruction O +may O +be O +absent O +or O +minimal O +and O +should O +be O +sought O +carefully O +. O + +Images O +may O +need O +to O +be O +obtained O +using O +i O +. O +v O +. O +contrast O +material O +to O +enable O +diagnosis O +of O +ureteric B +stones I +or O +obstruction O +in O +patients O +with O +HIV B +infection I +who O +receive O +indinavir O +therapy O +. O + +Ischemic B +colitis I +and O +sumatriptan O +use O +. O + +Sumatriptan O +succinate O +, O +a O +serotonin O +- O +1 O +( O +5 O +- O +hydroxytryptamine O +- O +1 O +) O +receptor O +agonist O +, O +is O +an O +antimigraine O +drug O +that O +is O +reported O +to O +act O +by O +selectively O +constricting O +intracranial O +arteries O +. O + +Recently O +, O +vasopressor O +responses O +that O +are O +distinct O +from O +the O +cranial O +circulation O +have O +been O +demonstrated O +to O +occur O +in O +the O +systemic O +, O +pulmonary O +, O +and O +coronary O +circulations O +. O + +Cases O +have O +been O +published O +of O +coronary B +vasospasm I +, O +myocardial B +ischemia I +, O +and O +myocardial B +infarction I +occurring O +after O +sumatriptan O +use O +. O + +We O +report O +on O +the O +development O +of O +8 O +serious O +cases O +of O +ischemic B +colitis I +in O +patients O +with O +migraine B +treated O +with O +sumatriptan O +. O + +Pallidotomy O +with O +the O +gamma O +knife O +: O +a O +positive O +experience O +. O + +51 O +patients O +with O +medically O +refractory O +Parkinson B +' I +s I +disease I +underwent O +stereotactic O +posteromedial O +pallidotomy O +between O +August O +1993 O +and O +February O +1997 O +for O +treatment O +of O +bradykinesia B +, O +rigidity B +, O +and O +L O +- O +DOPA O +- O +induced O +dyskinesias B +. O + +In O +29 O +patients O +, O +the O +pallidotomies O +were O +performed O +with O +the O +Leksell O +Gamma O +Knife O +and O +in O +22 O +they O +were O +performed O +with O +the O +standard O +radiofrequency O +( O +RF O +) O +method O +. O + +Clinical O +assessment O +as O +well O +as O +blinded O +ratings O +of O +Unified O +Parkinson B +' I +s I +Disease I +Rating O +Scale O +( O +UPDRS O +) O +scores O +were O +carried O +out O +pre O +- O +and O +postoperatively O +. O + +Mean O +follow O +- O +up O +time O +is O +20 O +. O +6 O +months O +( O +range O +6 O +- O +48 O +) O +and O +all O +except O +4 O +patients O +have O +been O +followed O +more O +than O +one O +year O +. O + +85 O +percent O +of O +patients O +with O +dyskinesias B +were O +relieved O +of O +symptoms O +, O +regardless O +of O +whether O +the O +pallidotomies O +were O +performed O +with O +the O +Gamma O +Knife O +or O +radiofrequency O +methods O +. O + +About O +2 O +/ O +3 O +of O +the O +patients O +in O +both O +Gamma O +Knife O +and O +radiofrequency O +groups O +showed O +improvements O +in O +bradykinesia B +and O +rigidity B +, O +although O +when O +considered O +as O +a O +group O +neither O +the O +Gamma O +Knife O +nor O +the O +radiofrequency O +group O +showed O +statistically O +significant O +improvements O +in O +UPDRS O +scores O +. O + +One O +patient O +in O +the O +Gamma O +Knife O +group O +( O +3 O +. O +4 O +% O +) O +developed O +a O +homonymous B +hemianopsia I +9 O +months O +following O +treatment O +and O +5 O +patients O +( O +27 O +. O +7 O +% O +) O +in O +the O +radiofrequency O +group O +became O +transiently O +confused O +postoperatively O +. O + +No O +other O +complications O +were O +seen O +. O + +Gamma O +Knife O +pallidotomy O +is O +as O +effective O +as O +radiofrequency O +pallidotomy O +in O +controlling O +certain O +of O +the O +symptoms O +of O +Parkinson B +' I +s I +disease I +. O + +It O +may O +be O +the O +only O +practical O +technique O +available O +in O +certain O +patients O +, O +such O +as O +those O +who O +take O +anticoagulants O +, O +have O +bleeding B +diatheses O +or O +serious O +systemic O +medical B +illnesses O +. O + +It O +is O +a O +viable O +option O +for O +other O +patients O +as O +well O +. O + +Centrally O +mediated O +cardiovascular O +effects O +of O +intracisternal O +application O +of O +carbachol O +in O +anesthetized O +rats O +. O + +The O +pressor O +response O +to O +the O +intracisternal O +( O +i O +. O +c O +. O +) O +injection O +of O +carbachol O +( O +1 O +mug O +) O +in O +anesthetized O +rats O +was O +analyzed O +. O + +This O +response O +was O +significantly O +reduced O +by O +the O +intravenous O +( O +i O +. O +v O +. O +) O +injection O +of O +guanethidine O +( O +5 O +mg O +) O +, O +hexamethonium O +( O +10 O +mg O +) O +or O +phentolamine O +( O +5 O +mg O +) O +, O +and O +conversely O +, O +potentiated O +by O +i O +. O +v O +. O +desmethylimipramine O +( O +0 O +. O +3 O +mg O +) O +, O +while O +propranolol O +( O +0 O +. O +5 O +mg O +) O +i O +. O +v O +. O +selectively O +inhibited O +the O +enlargement O +of O +pulse O +pressure O +and O +the O +tachycardia B +following O +i O +. O +c O +. O +carbachol O +( O +1 O +mug O +) O +. O + +On O +the O +other O +hand O +, O +the O +pressor O +response O +to O +i O +. O +c O +. O +carbachol O +( O +1 O +mug O +) O +was O +almost O +completely O +blocked O +by O +i O +. O +c O +. O +atropine O +( O +3 O +mug O +) O +or O +hexamethonium O +( O +500 O +mug O +) O +, O +and O +significantly O +reduced O +by O +i O +. O +c O +. O +chlorpromazine O +( O +50 O +mug O +) O +but O +significantly O +potentiated O +by O +i O +. O +c O +. O +desmethylimipramine O +( O +30 O +mug O +) O +. O + +The O +pressor O +response O +to O +i O +. O +c O +. O +carbachol O +( O +1 O +mug O +) O +remained O +unchanged O +after O +sectioning O +of O +the O +bilateral O +cervical O +vagal O +nerves O +but O +disappeared O +after O +sectioning O +of O +the O +spinal O +cord O +( O +C7 O +- O +C8 O +) O +. O + +From O +the O +above O +result O +it O +is O +suggested O +that O +the O +pressor O +response O +to O +i O +. O +c O +. O +carbachol O +ortral O +and O +peripheral O +adrenergic O +mechanisms O +, O +and O +that O +the O +sympathetic O +trunk O +is O +the O +main O +pathway O +. O + +Neuroleptic B +malignant I +syndrome I +and O +methylphenidate O +. O + +A O +1 O +- O +year O +- O +old O +female O +presented O +with O +neuroleptic B +malignant I +syndrome I +probably O +caused O +by O +methylphenidate O +. O + +She O +had O +defects O +in O +the O +supratentorial O +brain I +including O +the O +basal O +ganglia I +and O +the O +striatum O +( O +multicystic B +encephalomalacia I +) O +due O +to O +severe O +perinatal O +hypoxic B +- I +ischemic I +encephalopathy I +, O +which O +was O +considered O +to O +be O +a O +possible O +predisposing O +factor O +causing O +neuroleptic B +malignant I +syndrome I +. O + +A O +dopaminergic O +blockade O +mechanism O +generally O +is O +accepted O +as O +the O +pathogenesis O +of O +this O +syndrome O +. O + +However O +, O +methylphenidate O +is O +a O +dopamine O +agonist O +via O +the O +inhibition O +of O +uptake O +of O +dopamine O +, O +and O +therefore O +dopaminergic O +systems O +in O +the O +brainstem O +( O +mainly O +the O +midbrain O +) O +and O +the O +spinal O +cord O +were O +unlikely O +to O +participate O +in O +the O +onset O +of O +this O +syndrome O +. O + +A O +relative O +gamma B +- I +aminobutyric I +acid I +- I +ergic I +deficiency I +might O +occur O +because O +diazepam O +, O +a O +gamma O +- O +aminobutyric O +acid O +- O +mimetic O +agent O +, O +was O +strikingly O +effective O +. O + +This O +is O +the O +first O +reported O +patient O +with O +neuroleptic B +malignant I +syndrome I +probably O +caused O +by O +methylphenidate O +. O + +Differential O +effects O +of O +17alpha O +- O +ethinylestradiol O +on O +the O +neutral O +and O +acidic O +pathways O +of O +bile O +salt O +synthesis O +in O +the O +rat O +. O + +Effects O +of O +17alpha O +- O +ethinylestradiol O +( O +EE O +) O +on O +the O +neutral O +and O +acidic O +biosynthetic O +pathways O +of O +bile O +salt O +( O +BS O +) O +synthesis O +were O +evaluated O +in O +rats O +with O +an O +intact O +enterohepatic O +circulation O +and O +in O +rats O +with O +long O +- O +term O +bile O +diversion O +to O +induce O +BS O +synthesis O +. O + +For O +this O +purpose O +, O +bile O +salt O +pool O +composition O +, O +synthesis O +of O +individual O +BS O +in O +vivo O +, O +hepatic O +activities O +, O +and O +expression O +levels O +of O +cholesterol O +7alpha O +- O +hydroxylase O +( O +CYP7A O +) O +, O +and O +sterol O +27 O +- O +hydroxylase O +( O +CYP27 O +) O +, O +as O +well O +as O +of O +other O +enzymes O +involved O +in O +BS O +synthesis O +, O +were O +analyzed O +in O +rats O +treated O +with O +EE O +( O +5 O +mg O +/ O +kg O +, O +3 O +days O +) O +or O +its O +vehicle O +. O + +BS O +pool O +size O +was O +decreased O +by O +27 O +% O +but O +total O +BS O +synthesis O +was O +not O +affected O +by O +EE O +in O +intact O +rats O +. O + +Synthesis O +of O +cholate O +was O +reduced O +by O +68 O +% O +in O +EE O +- O +treated O +rats O +, O +while O +that O +of O +chenodeoxycholate O +was O +increased O +by O +60 O +% O +. O + +The O +recently O +identified O +Delta22 O +- O +isomer O +of O +beta O +- O +muricholate O +contributed O +for O +5 O +. O +4 O +% O +and O +18 O +. O +3 O +% O +( O +P O +< O +0 O +. O +01 O +) O +to O +the O +pool O +in O +control O +and O +EE O +- O +treated O +rats O +, O +respectively O +, O +but O +could O +not O +be O +detected O +in O +bile O +after O +exhaustion O +of O +the O +pool O +. O + +A O +clear O +reduction O +of O +BS O +synthesis O +was O +found O +in O +bile O +- O +diverted O +rats O +treated O +with O +EE O +, O +yet O +biliary O +BS O +composition O +was O +only O +minimally O +affected O +. O + +Activity O +of O +CYP7A O +was O +decreased O +by O +EE O +in O +both O +intact O +and O +bile O +- O +diverted O +rats O +, O +whereas O +the O +activity O +of O +the O +CYP27 O +was O +not O +affected O +. O + +Hepatic O +mRNA O +levels O +of O +CYP7A O +were O +significantly O +reduced O +by O +EE O +in O +bile O +- O +diverted O +rats O +only O +; O +CYP27 O +mRNA O +levels O +were O +not O +affected O +by O +EE O +. O + +In O +addition O +, O +mRNA O +levels O +of O +sterol O +12alpha O +- O +hydroxylase O +and O +lithocholate O +6beta O +- O +hydroxylase O +were O +increased O +by O +bile O +diversion O +and O +suppressed O +by O +EE O +. O + +This O +study O +shows O +that O +17alpha O +- O +ethinylestradiol O +( O +EE O +) O +- O +induced O +intrahepatic B +cholestasis I +in O +rats O +is O +associated O +with O +selective O +inhibition O +of O +the O +neutral O +pathway O +of O +bile O +salt O +( O +BS O +) O +synthesis O +. O + +Simultaneous O +impairment O +of O +other O +enzymes O +in O +the O +BS O +biosynthetic O +pathways O +may O +contribute O +to O +overall O +effects O +of O +EE O +on O +BS O +synthesis O +. O + +Glibenclamide O +- O +sensitive O +hypotension B +produced O +by O +helodermin O +assessed O +in O +the O +rat O +. O + +The O +effects O +of O +helodermin O +, O +a O +basic O +35 O +- O +amino O +acid O +peptide O +isolated O +from O +the O +venom O +of O +a O +lizard O +salivary O +gland O +, O +on O +arterial O +blood O +pressure O +and O +heart O +rate O +were O +examined O +in O +the O +rat O +, O +focusing O +on O +the O +possibility O +that O +activation O +of O +ATP O +sensitive O +K O ++ O +( O +K O +( O +ATP O +) O +) O +channels O +is O +involved O +in O +the O +responses O +. O + +The O +results O +were O +also O +compared O +with O +those O +of O +vasoactive O +intestinal O +polypeptide O +( O +VIP O +) O +. O + +Helodermin O +produced O +hypotension B +in O +a O +dose O +- O +dependent O +manner O +with O +approximately O +similar O +potency O +and O +duration O +to O +VIP O +. O + +Hypotension B +induced O +by O +both O +peptides O +was O +significantly O +attenuated O +by O +glibenclamide O +, O +which O +abolished O +a O +levcromakalim O +- O +produced O +decrease B +in I +arterial I +blood I +pressure I +. O + +Oxyhemoglobin O +did O +not O +affect O +helodermin O +- O +induced O +hypotension B +, O +whereas O +it O +shortened O +the O +duration O +of O +acetylcholine O +( O +ACh O +) O +- O +produced O +hypotension B +. O + +These O +findings O +suggest O +that O +helodermin O +- O +produced O +hypotension B +is O +partly O +attributable O +to O +the O +activation O +of O +glibenclamide O +- O +sensitive O +K O ++ O +channels O +( O +K O +( O +ATP O +) O +channels O +) O +, O +which O +presumably O +exist O +on O +arterial O +smooth O +muscle O +cells O +. O + +EDRF O +( O +endothelium O +- O +derived O +relaxing O +factor O +) O +/ O +nitric O +oxide O +does O +not O +seem O +to O +play O +an O +important O +role O +in O +the O +peptide O +- O +produced O +hypotension B +. O + +Long O +- O +term O +efficacy O +and O +adverse O +event O +of O +nifedipine O +sustained O +- O +release O +tablets O +for O +cyclosporin O +A O +- O +induced O +hypertension B +in O +patients O +with O +psoriasis B +. O + +Thirteen O +psoriatic B +patients O +with O +hypertension B +during O +the O +course O +of O +cyclosporin O +A O +therapy O +were O +treated O +for O +25 O +months O +with O +a O +calcium O +channel O +blocker O +, O +sustained O +- O +release O +nifedipine O +, O +to O +study O +the O +clinical O +antihypertensive O +effects O +and O +adverse O +events O +during O +treatment O +with O +both O +drugs O +. O + +Seven O +of O +the O +13 O +patients O +had O +exhibited O +a O +subclinical O +hypertensive B +state O +before O +cyclosporin O +A O +therapy O +. O + +Both O +systolic O +and O +diastolic O +blood O +pressures O +of O +these O +13 O +patients O +were O +decreased O +significantly O +after O +4 O +weeks O +of O +nifedipine O +therapy O +, O +and O +blood O +pressure O +was O +maintained O +within O +the O +normal O +range O +thereafter O +for O +25 O +months O +. O + +The O +adverse O +events O +during O +combined O +therapy O +with O +cyclosporin O +A O +and O +nifedipine O +included O +an O +increase O +in O +blood O +urea O +nitrogen O +levels O +in O +9 O +of O +the O +13 O +patients O +and O +development O +of O +gingival B +hyperplasia I +in O +2 O +of O +the O +13 O +patients O +. O + +Our O +findings O +indicate O +that O +sustained O +- O +release O +nifedipine O +is O +useful O +for O +hypertensive B +psoriatic B +patients O +under O +long O +- O +term O +treatment O +with O +cyclosporin O +A O +, O +but O +that O +these O +patients O +should O +be O +monitored O +for O +gingival B +hyperplasia I +. O +