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 . O Thirty O - O two O unrelated O patients O with O features O of O Saethre B - I Chotzen I syndrome I , O a O common O autosomal B dominant I condition I of O craniosynostosis B and O limb B anomalies I , O were O screened O for O mutations O in O TWIST O , O FGFR2 O , O and O FGFR3 O . O Nine O novel O and O three O recurrent O TWIST O mutations O were O found O in O 12 O families O . O Seven O families O were O found O to O have O the O FGFR3 O P250R O mutation O , O and O one O individual O was O found O to O have O an O FGFR2 O VV269 O - O 270 O deletion O . O To O date O , O our O detection O rate O for O TWIST O or O FGFR O mutations O is O 68 O % O in O our O Saethre B - I Chotzen I syndrome I patients O , O including O our O five O patients O elsewhere O reported O with O TWIST O mutations O . 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 . O Germ O - O line O mutations O of O the O tumor B suppressor O APC O are O implicated O in O attenuated B adenomatous I polyposis I coli I ( O AAPC B ) O , O a O variant O of O familial B adenomatous I polyposis I ( O FAP B ) O . O AAPC B is O recognized O by O the O occurrence O of O < O 100 O colonic O adenomas B and O a O later O onset O of O colorectal B cancer I ( O age O > O 40 O years O ) O . O The O aim O of O this O study O was O to O assess O genotype O - O phenotype O correlations O in O AAPC B families O . O By O protein O - O truncation O test O ( O PTT O ) O assay O , O the O entire O coding O region O of O the O APC B gene O was O screened O in O affected O individuals O from O 11 O AAPC B kindreds O , O and O their O phenotypic O differences O were O examined O . 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 . O In O order O to O define O the O types O of O disease O - O causing O ATM O mutations O in O Japanese O A B - I T I patients O as O well O as O to O look O for O possible O mutational O hotspots O , O reverse O - O transcribed O RNA O derived O from O ten O patients O belonging O to O eight O unrelated O Japanese O A B - I T I families O was O analyzed O for O mutations O by O the O restriction O endonuclease O fingerprinting O method O . O As O has O been O reported O by O others O , O mutations O that O lead O to O exon O skipping O or O premature O protein O truncation O were O also O predominant O in O our O mutants O . O Six O different O mutations O were O identified O on O 12 O of O the O 16 O alleles O examined O . O Four O were O deletions O involving O a O loss O of O a O single O exon O exon O 7 O , O exon O 16 O , O exon O 33 O or O exon O 35 O . 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 . O Pubertal O exposure O to O Bisphenol O A O increases O anxiety B - O like O behavior O and O decreases O acetylcholinesterase O activity O of O hippocampus O in O adult O male O mice O . O The O negative O effects O of O Bisphenol O A O ( O BPA O ) O on O neurodevelopment O and O behaviors O have O been O well O established O . O Acetylcholinesterase O ( O AChE O ) O is O a O regulatory O enzyme O which O is O involved O in O anxiety B - O like O behavior O . O This O study O investigated O behavioral O phenotypes O and O AChE O activity O in O male O mice O following O BPA O exposure O during O puberty O . O On O postnatal O day O ( O PND O ) O 35 O , O male O mice O were O exposed O to O 50mg O BPA O / O kg O diet O per O day O for O a O period O of O 35 O days O . O On O PND71 O , O a O behavioral O assay O was O performed O using O the O elevated O plus O maze O ( O EPM O ) O and O the O light O / O dark O test O . O In O addition O , O AChE O activity O was O measured O in O the O prefrontal O cortex O , O hypothalamus O , O cerebellum O and O hippocampus O . O Results O from O our O behavioral O phenotyping O indicated O that O anxiety B - O like O behavior O was O increased O in O mice O exposed O to O BPA O . O AChE O activity O was O significantly O decreased O in O the O hippocampus O of O mice O with O BPA O compared O to O control O mice O , O whereas O no O difference O was O found O in O the O prefrontal O cortex O , O hypothalamus O and O cerebellum O . O Our O findings O showed O that O pubertal O BPA O exposure O increased O anxiety B - O like O behavior O , O which O may O be O associated O with O decreased O AChE O activity O of O the O hippocampus O in O adult O male O mice O . O Further O studies O are O necessary O to O investigate O the O cholinergic O signaling O of O the O hippocampus O in O PBE O induced O anxiety B - I like I behaviors I . O Biochemical O effects O of O Solidago O virgaurea O extract O on O experimental O cardiotoxicity B . O Cardiovascular B diseases I ( O CVDs B ) O are O the O major O health O problem O of O advanced O as O well O as O developing O countries O of O the O world O . O The O aim O of O the O present O study O was O to O investigate O the O protective O effect O of O the O Solidago O virgaurea O extract O on O isoproterenol O - O induced O cardiotoxicity B in O rats O . O The O subcutaneous O injection O of O isoproterenol O ( O 30 O mg O / O kg O ) O into O rats O twice O at O an O interval O of O 24 O h O , O for O two O consecutive O days O , O led O to O a O significant O increase O in O serum O lactate O dehydrogenase O , O creatine O phosphokinase O , O alanine O transaminase O , O aspartate O transaminase O , O and O angiotensin O - O converting O enzyme O activities O , O total O cholesterol O , O triglycerides O , O free O serum O fatty O acid O , O cardiac O tissue O malondialdehyde O ( O MDA O ) O , O and O nitric O oxide O levels O and O a O significant O decrease O in O levels O of O glutathione O and O superoxide O dismutase O in O cardiac O tissue O as O compared O to O the O normal O control O group O ( O P O < O 0 O . O 05 O ) O . O Pretreatment O with O S O . O virgaurea O extract O for O 5 O weeks O at O a O dose O of O 250 O mg O / O kg O followed O by O isoproterenol O injection O significantly O prevented O the O observed O alterations O . O Captopril O ( O 50 O mg O / O kg O / O day O , O given O orally O ) O , O an O inhibitor O of O angiotensin O - O converting O enzyme O used O as O a O standard O cardioprotective O drug O , O was O used O as O a O positive O control O in O this O study O . O The O data O of O the O present O study O suggest O that O S O . O virgaurea O extract O exerts O its O protective O effect O by O decreasing O MDA O level O and O increasing O the O antioxidant O status O in O isoproterenol O - O treated O rats O . O The O study O emphasizes O the O beneficial O action O of O S O . O virgaurea O extract O as O a O cardioprotective O agent O . O " O Real O - O world O " O data O on O the O efficacy O and O safety O of O lenalidomide O and O dexamethasone O in O patients O with O relapsed O / O refractory O multiple B myeloma I who O were O treated O according O to O the O standard O clinical O practice O : O a O study O of O the O Greek O Myeloma I Study O Group O . O Lenalidomide O and O dexamethasone O ( O RD O ) O is O a O standard O of O care O for O relapsed O / O refractory I multiple B myeloma I ( O RRMM B ) O , O but O there O is O limited O published O data O on O its O efficacy O and O safety O in O the O " O real O world O " O ( O RW O ) O , O according O to O the O International O Society O of O Pharmacoeconomics O and O Outcomes O Research O definition O . O We O studied O 212 O RRMM B patients O who O received O RD O in O RW O . O Objective O response O ( O > O PR O ( O partial O response O ) O ) O rate O was O 77 O . O 4 O % O ( O complete O response O ( O CR O ) O , O 20 O . O 2 O % O ) O . O Median O time O to O first O and O best O response O was O 2 O and O 5 O months O , O respectively O . O Median O time O to O CR O when O RD O was O given O as O 2nd O or O > O 2 O ( O nd O ) O - O line O treatment O at O 4 O and O 11 O months O , O respectively O . O Quality O of O response O was O independent O of O previous O lines O of O therapies O or O previous O exposure O to O thalidomide O or O bortezomib O . O Median O duration O of O response O was O 34 O . O 4 O months O , O and O it O was O higher O in O patients O who O received O RD O until O progression O ( O not O reached O versus O 19 O months O , O p O < O 0 O . O 001 O ) O . O Improvement O of O humoral O immunity O occurred O in O 60 O % O of O responders O ( O p O < O 0 O . O 001 O ) O and O in O the O majority O of O patients O who O achieved O stable O disease O . O Adverse O events O were O reported O in O 68 O . O 9 O % O of O patients O ( O myelosuppression B in O 49 O . O 4 O % O ) O and O 12 O . O 7 O % O of O patients O needed O hospitalization O . O Peripheral B neuropathy I was O observed O only O in O 2 O . O 5 O % O of O patients O and O deep B vein I thrombosis I in O 5 O . O 7 O % O . O Dose O reductions O were O needed O in O 31 O % O of O patients O and O permanent O discontinuation O in O 38 O . O 9 O % O . O Median O time O to O treatment O discontinuation O was O 16 O . O 8 O months O . O Performance O status O ( O PS O ) O and O initial O lenalidomide O dose O predicted O for O treatment O discontinuation O . O Extra O - O medullary O relapses O occurred O in O 3 O . O 8 O % O of O patients O . O Our O study O confirms O that O RD O is O effective O and O safe O in O RRMM B in O the O RW O ; O it O produces O durable O responses O especially O in O patients O who O continue O on O treatment O till O progression O and O improves O humoral O immunity O even O in O patients O with O stable O disease O . O The O cytogenetic O action O of O ifosfamide O , O mesna O , O and O their O combination O on O peripheral O rabbit O lymphocytes O : O an O in O vivo O / O in O vitro O cytogenetic O study O . O Ifosfamide O ( O IFO O ) O is O an O alkylating O nitrogen O mustard O , O administrated O as O an O antineoplasmic O agent O . O It O is O characterized O by O its O intense O urotoxic O action O , O leading O to O hemorrhagic B cystitis I . O This O side O effect O of O IFO O raises O the O requirement O for O the O co O - O administration O with O sodium O 2 O - O sulfanylethanesulfonate O ( O Mesna O ) O aiming O to O avoid O or O minimize O this O effect O . O IFO O and O Mesna O were O administrated O separately O on O rabbit O ' O s O lymphocytes O in O vivo O , O which O were O later O developed O in O vitro O . O Cytogenetic O markers O for O sister O chromatid O exchanges O ( O SCEs O ) O , O proliferation O rate O index O ( O PRI O ) O and O Mitotic O Index O were O recorded O . O Mesna O ' O s O action O , O in O conjunction O with O IFO O reduces O the O frequency O of O SCEs O , O in O comparison O with O the O SCEs O recordings O obtained O when O IFO O is O administered O alone O . O In O addition O to O this O , O when O high O concentrations O of O Mesna O were O administered O alone O significant O reductions O of O the O PRI O were O noted O , O than O with O IFO O acting O at O the O same O concentration O on O the O lymphocytes O . O Mesna O significantly O reduces O IFO O ' O s O genotoxicity B , O while O when O administered O in O high O concentrations O it O acts O in O an O inhibitory O fashion O on O the O cytostatic O action O of O the O drug O . O Risk O factors O and O predictors O of O levodopa O - O induced O dyskinesia B among O multiethnic O Malaysians O with O Parkinson B ' I s I disease I . O Chronic O pulsatile O levodopa O therapy O for O Parkinson B ' I s I disease I ( O PD B ) O leads O to O the O development O of O motor O fluctuations O and O dyskinesia B . O We O studied O the O prevalence O and O predictors O of O levodopa O - O induced O dyskinesia B among O multiethnic O Malaysian O patients O with O PD B . O METHODS O : O This O is O a O cross O - O sectional O study O involving O 95 O patients O with O PD B on O uninterrupted O levodopa O therapy O for O at O least O 6 O months O . O The O instrument O used O was O the O UPDRS O questionnaires O . O The O predictors O of O dyskinesia B were O determined O using O multivariate O logistic O regression O analysis O . O RESULTS O : O The O mean O age O was O 65 O . O 6 O + O 8 O . O 5 O years O . O The O mean O onset O age O was O 58 O . O 5 O + O 9 O . O 8 O years O . O The O median O disease O duration O was O 6 O ( O 7 O ) O years O . O Dyskinesia B was O present O in O 44 O % O ( O n O = O 42 O ) O with O median O levodopa O therapy O of O 3 O years O . O There O were O 64 O . O 3 O % O Chinese O , O 31 O % O Malays O , O and O 3 O . O 7 O % O Indians O and O other O ethnic O groups O . O Eighty O - O one O percent O of O patients O with O dyskinesia B had O clinical O fluctuations O . O Patients O with O dyskinesia B had O lower O onset O age O ( O p O < O 0 O . O 001 O ) O , O longer O duration O of O levodopa O therapy O ( O p O < O 0 O . O 001 O ) O , O longer O disease O duration O ( O p O < O 0 O . O 001 O ) O , O higher O total O daily O levodopa O dose O ( O p O < O 0 O . O 001 O ) O , O and O higher O total O UPDRS O scores O ( O p O = O 0 O . O 005 O ) O than O patients O without O dyskinesia B . O The O three O significant O predictors O of O dyskinesia B were O duration O of O levodopa O therapy O , O onset O age O , O and O total O daily O levodopa O dose O . O CONCLUSIONS O : O The O prevalence O of O levodopa O - O induced O dyskinesia B in O our O patients O was O 44 O % O . O The O most O significant O predictors O were O duration O of O levodopa O therapy O , O total O daily O levodopa O dose O , O and O onset O age O . O Dose O - O dependent O neurotoxicity B of O high O - O dose O busulfan O in O children O : O a O clinical O and O pharmacological O study O . O Busulfan O is O known O to O be O neurotoxic B in O animals O and O humans O , O but O its O acute O neurotoxicity B remains O poorly O characterized O in O children O . O We O report O here O a O retrospective O study O of O 123 O children O ( O median O age O , O 6 O . O 5 O years O ) O receiving O high O - O dose O busulfan O in O combined O chemotherapy O before O bone O marrow O transplantation O for O malignant O solid B tumors I , O brain B tumors I excluded O . O Busulfan O was O given O p O . O o O . O , O every O 6 O hours O for O 16 O doses O over O 4 O days O . O Two O total O doses O were O consecutively O used O : O 16 O mg O / O kg O , O then O 600 O mg O / O m2 O . O The O dose O calculation O on O the O basis O of O body O surface O area O results O in O higher O doses O in O young O children O than O in O older O patients O ( O 16 O to O 28 O mg O / O kg O ) O . O Ninety O - O six O patients O were O not O given O anticonvulsive O prophylaxis O ; O 7 O ( O 7 O . O 5 O % O ) O developed O seizures B during O the O 4 O days O of O the O busulfan O course O or O within O 24 O h O after O the O last O dosing O . O When O the O total O busulfan O dose O was O taken O into O account O , O there O was O a O significant O difference O in O terms O of O neurotoxicity B incidence O among O patients O under O 16 O mg O / O kg O ( O 1 O of O 57 O , O 1 O . O 7 O % O ) O and O patients O under O 600 O mg O / O m2 O ( O 6 O of O 39 O , O 15 O . O 4 O % O ) O ( O P O less O than O 0 O . O 02 O ) O . O Twenty O - O seven O patients O were O given O a O 600 O - O mg O / O m2 O busulfan O total O dose O with O continuous O i O . O v O . O infusion O of O clonazepam O ; O none O had O any O neurological O symptoms O . O Busulfan O levels O were O measured O by O a O gas O chromatographic O - O mass O spectrometry O assay O in O the O plasma O and O cerebrospinal O fluid O of O 9 O children O without O central B nervous I system I disease I under O 600 O mg O / O m2 O busulfan O with O clonazepam O : O busulfan O cerebrospinal O fluid O : O plasma O ratio O was O 1 O . O 39 O . O This O was O significantly O different O ( O P O less O than O 0 O . O 02 O ) O from O the O cerebrospinal O fluid O : O plasma O ratio O previously O defined O in O children O receiving O a O 16 O - O mg O / O kg O total O dose O of O busulfan O . O This O study O shows O that O busulfan O neurotoxicity B is O dose O - O dependent O in O children O and O efficiently O prevented O by O clonazepam O . O A O busulfan O dose O calculated O on O the O basis O of O body O surface O area O , O resulting O in O higher O doses O in O young O children O , O was O followed O by O increased O neurotoxicity B , O close O to O neurotoxicity B incidence O observed O in O adults O . O Since O plasma O pharmacokinetic O studies O showed O a O faster O busulfan O clearance O in O children O than O in O adults O , O this O new O dose O may O approximate O more O closely O the O adult O systemic O exposure O obtained O after O the O usual O 16 O - O mg O / O kg O total O dose O , O with O potential O inferences O in O terms O of O anticancer O or O myeloablative O effects O . O The O busulfan O dose O in O children O and O infants O undergoing O bone O marrow O transplantation O should O be O reconsidered O on O the O basis O of O pharmacokinetic O studies O . 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 . O All O - O trans O retinoic O acid O ( O ATRA O ) O , O a O component O of O standard O therapy O for O acute B promyelocytic I leukemia I ( O APL B ) O , O is O associated O with O potentially O serious O but O treatable O adverse O effects O involving O numerous O organ O systems O , O including O rare O skeletal O muscle O involvement O . O Only O a O handful O of O cases O of O ATRA O - O induced O myositis B in O children O have O been O reported O , O and O none O in O the O radiology O literature O . O We O present O such O a O case O in O a O 15 O - O year O - O old O boy O with O APL B , O where O recognition O of O imaging O findings O played O a O crucial O role O in O making O the O diagnosis O and O facilitated O prompt O , O effective O treatment O . O Tolerability O of O lomustine O in O combination O with O cyclophosphamide O in O dogs O with O lymphoma B . O This O retrospective O study O describes O toxicity B associated O with O a O protocol O of O lomustine O ( O CCNU O ) O and O cyclophosphamide O ( O CTX O ) O in O dogs O with O lymphoma B . O CCNU O was O administered O per O os O ( O PO O ) O at O a O targeted O dosage O of O 60 O mg O / O m O ( O 2 O ) O body O surface O area O on O day O 0 O , O CTX O was O administered O PO O at O a O targeted O dosage O of O 250 O mg O / O m O ( O 2 O ) O divided O over O days O 0 O through O 4 O , O and O all O dogs O received O prophylactic O antibiotics O . O Ninety O treatments O were O given O to O the O 57 O dogs O included O in O the O study O . O Neutropenia B was O the O principal O toxic O effect O , O and O the O overall O frequency O of O grade O 4 O neutropenia B after O the O first O treatment O of O CCNU O / O CTX O was O 30 O % O ( O 95 O % O confidence O interval O , O 19 O - O 43 O % O ) O . O The O mean O body O weight O of O dogs O with O grade O 4 O neutropenia B ( O 19 O . O 7 O kg O + O 13 O . O 4 O kg O ) O was O significantly O less O than O the O mean O body O weight O of O dogs O that O did O not O develop O grade O 4 O neutropenia B ( O 31 O . O 7 O kg O + O 12 O . O 4 O kg O ; O P O = O . O 005 O ) O . O One O dog O ( O 3 O % O ) O developed O hematologic O changes O suggestive O of O hepatotoxicity B . O No O dogs O had O evidence O of O either O renal B toxicity I or O hemorrhagic B cystitis I . O Adverse O gastrointestinal O effects O were O uncommon O . O On O the O basis O of O the O findings O reported O herein O , O a O dose O of O 60 O mg O / O m O ( O 2 O ) O of O CCNU O combined O with O 250 O mg O / O m O ( O 2 O ) O of O CTX O ( O divided O over O 5 O days O ) O q O 4 O wk O is O tolerable O in O tumor B - O bearing O dogs O . O Nelarabine O neurotoxicity B with O concurrent O intrathecal O chemotherapy O : O Case O report O and O review O of O literature O . O Severe O nelarabine O neurotoxicity B in O a O patient O who O received O concurrent O intrathecal O ( O IT O ) O chemotherapy O is O reported O . O A O 37 O - O year O - O old O Caucasian O woman O with O a O history O of O T B - I cell I lymphoblastic I lymphoma I was O admitted O for O relapsed O disease O . O She O was O originally O treated O with O induction O chemotherapy O followed O by O an O autologous O transplant O . O She O developed O relapsed O disease O 10 O months O later O with O leukemic B involvement O . O She O was O re O - O induced O with O nelarabine O 1500 O mg O / O m O ( O 2 O ) O on O days O 1 O , O 3 O , O and O 5 O with O 1 O dose O of O IT O cytarabine O 100 O mg O on O day O 2 O as O central O nervous O system O ( O CNS O ) O prophylaxis O . O At O the O time O of O treatment O , O she O was O on O continuous O renal O replacement O therapy O due O to O sequelae O of O tumor B lysis I syndrome I ( O TLS B ) O . O She O tolerated O therapy O well O , O entered O a O complete O remission O , O and O recovered O her O renal O function O . O She O received O a O second O cycle O of O nelarabine O without O additional O IT O prophylaxis O one O month O later O . O A O week O after O this O second O cycle O , O she O noted O numbness B in O her O lower O extremities O . O Predominantly O sensory O , O though O also O motor O and O autonomic O , O peripheral B neuropathy I started O in O her O feet O , O ascended O proximally O to O the O mid O - O thoracic O region O , O and O eventually O included O her O distal O upper O extremities O . O A O magnetic O resonance O imaging O ( O MRI O ) O of O her O spine O demonstrated O changes O from O C2 O to O C6 O consistent O with O subacute O combined O degeneration I . O Nelarabine O was O felt O to O be O the O cause O of O her O symptoms O . O Her O neuropathy B stabilized O and O showed O slight O improvement O and O ultimately O received O an O unrelated O , O reduced O - O intensity O allogeneic O transplant O while O in O complete O remission O , O but O relapsed O disease O 10 O weeks O later O . O She O is O currently O being O treated O with O best O supportive O care O . O To O our O knowledge O , O this O is O the O first O published O case O report O of O severe O neurotoxicity B caused O by O nelarabine O in O a O patient O who O received O concurrent O IT O chemotherapy O . O Valproate O - O induced O hyperammonemic B encephalopathy B in O a O renal O transplanted O patient O . O Neurological B complications I after O renal O transplantation O constitute O an O important O cause O of O morbidity O and O mortality O . O Their O differential O diagnosis O is O difficult O and O essential O for O subsequent O patient O ' O s O management O . O Valproate O - O induced O hyperammonemic B encephalopathy B is O an O uncommon O but O serious O effect O of O valproate O treatment O . O Here O , O we O describe O the O case O of O a O 15 O - O year O - O old O girl O who O was O on O a O long O - O term O therapy O with O valproate O due O to O epilepsy B and O revealed O impaired B consciousness I with O hyperammonemia B 12 O days O after O renal O transplantation O . O After O withdraw O of O valproate O , O patients O ' O symptoms O resolved O within O 24 O h O . O Clinicians O should O increase O their O awareness O for O potential O complication O of O valproate O , O especially O in O transplanted O patients O . O Necrotising B fasciitis I after O bortezomib O and O dexamethasone O - O containing O regimen O in O an O elderly O patient O of O Waldenstrom B macroglobulinaemia I . O Bortezomib O and O high O - O dose O dexamethasone O - O containing O regimens O are O considered O to O be O generally O tolerable O with O few O severe O bacterial B infections I in O patients O with O B B - I cell I malignancies I . O However O , O information O is O limited O concerning O the O safety O of O the O regimen O in O elderly O patients O . O We O report O a O case O of O a O 76 O - O year O - O old O man O with O Waldenstrom B macroglobulinaemia I who O suffered O necrotising B fasciitis I without O neutropenia B after O the O combination O treatment O with O bortezomib O , O high O - O dose O dexamethasone O and O rituximab O . O Despite O immediate O intravenous O antimicrobial O therapy O , O he O succumbed O 23 O h O after O the O onset O . O Physicians O should O recognise O the O possibility O of O fatal O bacterial B infections I related O to O bortezomib O plus O high O - O dose O dexamethasone O in O elderly O patients O , O and O we O believe O this O case O warrants O further O investigation O . O An O integrated O characterization O of O serological O , O pathological O , O and O functional O events O in O doxorubicin O - O induced O cardiotoxicity B . O Many O efficacious O cancer B treatments O cause O significant O cardiac B morbidity I , O yet O biomarkers O or O functional O indices O of O early O damage O , O which O would O allow O monitoring O and O intervention O , O are O lacking O . O In O this O study O , O we O have O utilized O a O rat O model O of O progressive O doxorubicin O ( O DOX O ) O - O induced O cardiomyopathy B , O applying O multiple O approaches O , O including O cardiac O magnetic O resonance O imaging O ( O MRI O ) O , O to O provide O the O most O comprehensive O characterization O to O date O of O the O timecourse O of O serological O , O pathological O , O and O functional O events O underlying O this O toxicity B . O Hannover O Wistar O rats O were O dosed O with O 1 O . O 25 O mg O / O kg O DOX O weekly O for O 8 O weeks O followed O by O a O 4 O week O off O - O dosing O " O recovery O " O period O . O Electron O microscopy O of O the O myocardium O revealed O subcellular O degeneration O and O marked O mitochondrial O changes O after O a O single O dose O . O Histopathological O analysis O revealed O progressive O cardiomyocyte B degeneration I , O hypertrophy B / O cytomegaly B , O and O extensive O vacuolation O after O two O doses O . O Extensive O replacement O fibrosis B ( O quantified O by O Sirius O red O staining O ) O developed O during O the O off O - O dosing O period O . O Functional O indices O assessed O by O cardiac O MRI O ( O including O left O ventricular O ejection O fraction O ( O LVEF O ) O , O cardiac O output O , O and O E O / O A O ratio O ) O declined O progressively O , O reaching O statistical O significance O after O two O doses O and O culminating O in O " O clinical O " O LV B dysfunction I by O 12 O weeks O . O Significant O increases O in O peak O myocardial O contrast O enhancement O and O serological O cardiac O troponin O I O ( O cTnI O ) O emerged O after O eight O doses O , O importantly O preceding O the O LVEF O decline O to O < O 50 O % O . O Troponin O I O levels O positively O correlated O with O delayed O and O peak O gadolinium O contrast O enhancement O , O histopathological O grading O , O and O diastolic B dysfunction I . O In O summary O , O subcellular O cardiomyocyte O degeneration O was O the O earliest O marker O , O followed O by O progressive O functional O decline O and O histopathological O manifestations O . O Myocardial O contrast O enhancement O and O elevations O in O cTnI O occurred O later O . O However O , O all O indices O predated O " O clinical O " O LV B dysfunction I and O thus O warrant O further O evaluation O as O predictive O biomarkers O . O Intradermal O glutamate O and O capsaicin O injections O : O intra O - O and O interindividual O variability O of O provoked O hyperalgesia B and O allodynia B . O Intradermal O injections O of O glutamate O and O capsaicin O are O attractive O to O use O in O human O experimental O pain B models O because O hyperalgesia B and O allodynia B mimic O isolated O aspects O of O clinical O pain B disorders I . O The O aim O of O the O present O study O was O to O investigate O the O reproducibility O of O these O models O . O Twenty O healthy O male O volunteers O ( O mean O age O 24 O years O ; O range O 18 O - O 38 O years O ) O received O intradermal O injections O of O glutamate O and O capsaicin O in O the O volar O forearm O . O Magnitudes O of O secondary O pinprick O hyperalgesia B and O brush O - O evoked O allodynia B were O investigated O using O von O Frey O filaments O ( O gauges O 10 O , O 15 O , O 60 O and O 100 O g O ) O and O brush O strokes O . O Areas O of O secondary O hyperalgesia B and O allodynia B were O quantified O immediately O after O injection O and O after O 15 O , O 30 O and O 60 O min O . O Two O identical O experiments O separated O by O at O least O 7 O days O were O performed O . O Reproducibility O across O and O within O volunteers O ( O inter O - O and O intra O - O individual O variation O , O respectively O ) O was O assessed O using O intraclass O correlation O coefficient O ( O ICC O ) O and O coefficient O of O variation O ( O CV O ) O . O Secondary O pinprick O hyperalgesia I was O observed O as O a O marked O increase O in O the O visual O analogue O scale O ( O VAS O ) O response O to O von O Frey O gauges O 60 O and O 100 O g O ( O P O < O 0 O . O 001 O ) O after O glutamate O injection O . O For O capsaicin O , O secondary O pinprick O hyperalgesia B was O detected O with O all O von O Frey O gauges O ( O P O < O 0 O . O 001 O ) O . O Glutamate O evoked O reproducible O VAS O response O to O all O von O Frey O gauges O ( O ICC O > O 0 O . O 60 O ) O and O brush O strokes O ( O ICC O > O 0 O . O 83 O ) O . O Capsaicin O injection O was O reproducible O for O secondary B hyperalgesia I ( O ICC O > O 0 O . O 70 O ) O and O allodynia B ( O ICC O > O 0 O . O 71 O ) O . O Intra O - O individual O variability O was O generally O lower O for O the O VAS O response O to O von O Frey O and O brush O compared O with O areas O of O secondary O hyperalgesia B and O allodynia B . O In O conclusion O , O glutamate O and O capsaicin O yield O reproducible O hyperalgesic B and O allodynic B responses O , O and O the O present O model O is O well O suited O for O basic O research O , O as O well O as O for O assessing O the O modulation O of O central O phenomena O . O Ocular O - O specific O ER O stress O reduction O rescues O glaucoma B in O murine O glucocorticoid O - O induced O glaucoma B . O Administration O of O glucocorticoids O induces O ocular B hypertension I in O some O patients O . O If O untreated O , O these O patients O can O develop O a O secondary O glaucoma I that O resembles O primary B open I - I angle I glaucoma I ( O POAG B ) O . O The O underlying O pathology O of O glucocorticoid O - O induced O glaucoma B is O not O fully O understood O , O due O in O part O to O lack O of O an O appropriate O animal O model O . O Here O , O we O developed O a O murine O model O of O glucocorticoid O - O induced O glaucoma B that O exhibits O glaucoma B features O that O are O observed O in O patients O . O Treatment O of O WT O mice O with O topical O ocular O 0 O . 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 . O Dexamethasone O induced O the O transcriptional O factor O CHOP O , O a O marker O for O chronic O ER O stress O , O in O the O anterior O segment O tissues O , O and O Chop O deletion O reduced O ER O stress O in O these O tissues O and O prevented O dexamethasone O - O induced O ocular B hypertension I . O Furthermore O , O reduction O of O ER O stress O in O the O TM O with O sodium O 4 O - O phenylbutyrate O prevented O dexamethasone O - O induced O ocular B hypertension I in O WT O mice O . O Our O data O indicate O that O ER O stress O contributes O to O glucocorticoid O - O induced O ocular B hypertension I and O suggest O that O reducing O ER O stress O has O potential O as O a O therapeutic O strategy O for O treating O glucocorticoid O - O induced O glaucoma B . O Effects O of O ginsenosides O on O opioid O - O induced O hyperalgesia B in O mice O . 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 . O The O fetal O kidneys O in O the O PCE O group O displayed O an O enlarged O Bowman O ' O s O space O and O a O shrunken O glomerular O tuft O , O accompanied O by O a O reduced O cortex O width O and O an O increase O in O the O nephrogenic O zone O / O cortical O zone O ratio O . O Observation O by O electronic O microscope O revealed O structural O damage O of O podocytes O ; O the O reduced O expression O level O of O podocyte O marker O genes O , O nephrin O and O podocin O , O was O also O detected O by O q O - O PCR O . O Moreover O , O AT2R O gene O and O protein O expressions O in O fetal O kidneys O were O inhibited O by O PCE O , O associated O with O the O repression O of O the O gene O expression O of O glial O - O cell O - O line O - O derived O neurotrophic O factor O ( O GDNF O ) O / O tyrosine O kinase O receptor O ( O c O - O Ret O ) O signaling O pathway O . O These O results O demonstrated O that O PCE O could O induce O dysplasia B of I fetal I kidneys I as O well O as O glomerulosclerosis B of O adult O offspring O , O and O the O low O functional O programming O of O renal O AT2R O might O mediate O the O developmental O origin O of O adult O glomerulosclerosis B . O 1 O , O 3 O - O Butadiene O , O CML O and O the O t O ( O 9 O : O 22 O ) O translocation O : O A O reality O check O . O UNASSIGNED O : O Epidemiological O studies O of O 1 O , O 3 O - O butadiene O have O suggest O that O exposures O to O humans O are O associated O with O chronic B myeloid I leukemia I ( O CML B ) O . O CML B has O a O well O - O documented O association O with O ionizing O radiation O , O but O reports O of O associations O with O chemical O exposures O have O been O questioned O . O Ionizing O radiation O is O capable O of O inducing O the O requisite O CML B - O associated O t O ( O 9 O : O 22 O ) O translocation O ( O Philadelphia O chromosome O ) O in O appropriate O cells O in O vitro O but O , O thus O far O , O chemicals O have O not O shown O this O capacity O . O We O have O proposed O that O 1 O , O 3 O - O butadiene O metabolites O be O so O tested O as O a O reality O check O on O the O epidemiological O reports O . O In O order O to O conduct O reliable O testing O in O this O regard O , O it O is O essential O that O a O positive O control O for O induction O be O available O . O We O have O used O ionizing O radiation O to O develop O such O a O control O . O Results O described O here O demonstrate O that O this O agent O does O in O fact O induce O pathogenic O t O ( O 9 O : O 22 O ) O translocations O in O a O human O myeloid O cell O line O in O vitro O , O but O does O so O at O low O frequencies O . O Conditions O that O will O be O required O for O studies O of O 1 O , O 3 O - O butadiene O are O discussed O . O Cancer B incidence O and O metolachlor O use O in O the O Agricultural O Health O Study O : O An O update O . O UNASSIGNED O : O Metolachlor O , O a O widely O used O herbicide O , O is O classified O as O a O Group O C O carcinogen O by O the O U O . O S O . O Environmental O Protection O Agency O based O on O increased O liver B neoplasms I in O female O rats O . O Epidemiologic O studies O of O the O health O effects O of O metolachlor O have O been O limited O . O The O Agricultural O Health O Study O ( O AHS O ) O is O a O prospective O cohort O study O including O licensed O private O and O commercial O pesticide O applicators O in O Iowa O and O North O Carolina O enrolled O 1993 O - O 1997 O . O We O evaluated O cancer B incidence O through O 2010 O / O 2011 O ( O NC O / O IA O ) O for O 49 O , O 616 O applicators O , O 53 O % O of O whom O reported O ever O using O metolachlor O . O We O used O Poisson O regression O to O evaluate O relations O between O two O metrics O of O metolachlor O use O ( O lifetime O days O , O intensity O - O weighted O lifetime O days O ) O and O cancer B incidence O . O We O saw O no O association O between O metolachlor O use O and O incidence O of O all O cancers B combined O ( O n O = O 5 O , O 701 O with O a O 5 O - O year O lag O ) O or O most O site O - O specific O cancers B . O For O liver B cancer I , O in O analyses O restricted O to O exposed O workers O , O elevations O observed O at O higher O categories O of O use O were O not O statistically O significant O . O However O , O trends O for O both O lifetime O and O intensity O - O weighted O lifetime O days O of O metolachor O use O were O positive O and O statistically O significant O with O an O unexposed O reference O group O . O A O similar O pattern O was O observed O for O follicular B cell I lymphoma I , O but O no O other O lymphoma B subtypes O . O An O earlier O suggestion O of O increased O lung B cancer I risk O at O high O levels O of O metolachlor O use O in O this O cohort O was O not O confirmed O in O this O update O . O This O suggestion O of O an O association O between O metolachlor O and O liver B cancer I among O pesticide O applicators O is O a O novel O finding O and O echoes O observation O of O increased O liver B neoplasms I in O some O animal O studies O . O However O , O our O findings O for O both O liver B cancer I and O follicular B cell I lymphoma I warrant O follow O - O up O to O better O differentiate O effects O of O metolachlor O use O from O other O factors O . O Mechanisms O Underlying O Latent O Disease O Risk O Associated O with O Early O - O Life O Arsenic O Exposure O : O Current O Research O Trends O and O Scientific O Gaps O . O BACKGROUND O : O Millions O of O individuals O worldwide O , O particularly O those O living O in O rural O and O developing O areas O , O are O exposed O to O harmful O levels O of O inorganic O arsenic O ( O iAs O ) O in O their O drinking O water O . O Inorganic O As O exposure O during O key O developmental O periods O is O associated O with O a O variety O of O adverse O health O effects O including O those O that O are O evident O in O adulthood O . O There O is O considerable O interest O in O identifying O the O molecular O mechanisms O that O relate O early O - O life O iAs O exposure O to O the O development O of O these O latent O diseases O , O particularly O in O relationship O to O cancer B . O OBJECTIVES O : O This O work O summarizes O research O on O the O molecular O mechanisms O that O underlie O the O increased O risk O of O cancer B development O in O adulthood O that O is O associated O with O early O - O life O iAs O exposure O . O DISCUSSION O : O Epigenetic O reprogramming O that O imparts O functional O changes O in O gene O expression O , O the O development O of O cancer B stem O cells O , O and O immunomodulation O are O plausible O underlying O mechanisms O by O which O early O - O life O iAs O exposure O elicits O latent O carcinogenic B effects O . O CONCLUSIONS O : O Evidence O is O mounting O that O relates O early O - O life O iAs O exposure O and O cancer B development O later O in O life O . O Future O research O should O include O animal O studies O that O address O mechanistic O hypotheses O and O studies O of O human O populations O that O integrate O early O - O life O exposure O , O molecular O alterations O , O and O latent O disease O outcomes O . O Nifedipine O induced O bradycardia B in O a O patient O with O autonomic B neuropathy I . O An O 80 O year O old O diabetic B male O with O evidence O of O peripheral B and I autonomic I neuropathy I was O admitted O with O chest B pain I . O He O was O found O to O have O atrial B flutter I at O a O ventricular O rate O of O 70 O / O min O which O slowed O down O to O 30 O - O 40 O / O min O when O nifedipine O ( O 60 O mg O ) O in O 3 O divided O doses O , O during O which O he O was O paced O at O a O rate O of O 70 O / O min O . O This O is O inconsistent O with O the O well O - O established O finding O that O nifedipine O induces O tachycardia B in O normally O innervated O hearts O . O However O , O in O hearts O deprived O of O compensatory O sympathetic O drive O , O it O may O lead O to O bradycardia B . O The O effect O of O haloperidol O in O cocaine O and O amphetamine O intoxication O . O The O effectiveness O of O haloperidol O pretreatment O in O preventing O the O toxic O effects O of O high O doses O of O amphetamine O and O cocaine O was O studied O in O rats O . O In O this O model O , O toxic O effects O were O induced O by O intraperitoneal O ( O i O . O p O . O ) O injection O of O amphetamine O 75 O mg O / O kg O ( O 100 O % O death O rate O ) O or O cocaine O 70 O mg O / O kg O ( O 82 O % O death O rate O ) O . O Haloperidol O failed O to O prevent O amphetamine O - O induced O seizures B , O but O did O lower O the O mortality O rate O at O most O doses O tested O . O Haloperidol O decreased O the O incidence O of O cocaine O - O induced O seizures B at O the O two O highest O doses O , O but O the O lowering O of O the O mortality O rate O did O not O reach O statistical O significance O at O any O dose O . O These O data O suggest O a O protective O role O for O the O central O dopamine O blocker O haloperidol O against O death B from O high O - O dose O amphetamine O exposure O without O reducing O the O incidence O of O seizures B . O In O contrast O , O haloperidol O demonstrated O an O ability O to O reduce O cocaine O - O induced O seizures B without O significantly O reducing O mortality O . O Autoradiographic O evidence O of O estrogen O binding O sites O in O nuclei O of O diethylstilbesterol O induced O hamster O renal B carcinomas I . O Estrogen O binding O sites O were O demonstrated O by O autoradiography O in O one O transplantable O and O five O primary O diethylstilbesterol O induced O renal B carcinomas I in O three O hamsters O . O Radiolabelling O , O following O the O in O vivo O injection O of O 3H O - O 17 O beta O estradiol O , O was O increased O only O over O the O nuclei O of O tumor B cells O ; O stereologic O analysis O revealed O a O 4 O . O 5 O - O to O 6 O . O 7 O - O times O higher O concentration O of O reduced O silver O grains O over O nuclei O than O cytoplasm O of O these O cells O . O Despite O rapid O tubular O excretion O of O estradiol O which O peaked O in O less O than O 1 O h O , O the O normal O cells O did O not O appear O to O bind O the O ligand O . O This O is O the O first O published O report O documenting O the O preferential O in O vivo O binding O of O estrogen O to O nuclei O of O cells O in O estrogen O induced O hamster O renal B carcinomas I . O Bradycardia B due O to O biperiden O . O In O a O 38 O - O year O - O old O male O patient O suffering O from O a O severe O postzosteric O trigeminal B neuralgia I , O intravenous O application O of O 10 O mg O biperiden O lactate O led O to O a O long O - O lasting O paradoxical O reaction O characterized O by O considerable O bradycardia B , O dysarthria B , O and O dysphagia B . O The O heart O rate O was O back O to O normal O within O 12 O hours O upon O administration O of O orciprenaline O under O cardiac O monitoring O in O an O intensive O care O unit O . O Bradycardia B induced O by O biperiden O is O attributed O to O the O speed O of O injection O and O to O a O dose O - O related O dual O effect O of O atropine O - O like O drugs O on O muscarine O receptors O . O Deliberate O hypotension B induced O by O labetalol O with O halothane O , O enflurane O or O isoflurane O for O middle O - O ear O surgery O . O The O feasibility O of O using O labetalol O , O an O alpha O - O and O beta O - O adrenergic O blocking O agent O , O as O a O hypotensive B agent O in O combination O with O inhalation O anaesthetics O ( O halothane O , O enflurane O or O isoflurane O ) O was O studied O in O 23 O adult O patients O undergoing O middle O - O ear O surgery O . O The O mean O arterial O pressure O was O decreased O from O 86 O + O / O - O 5 O ( O s O . O e O . O mean O ) O mmHg O to O 52 O + O / O - O 1 O mmHg O ( O 11 O . O 5 O + O / O - O 0 O . O 7 O to O 6 O . O 9 O + O / O - O 0 O . O 1 O kPa O ) O for O 98 O + O / O - O 10 O min O in O the O halothane O ( O H O ) O group O , O from O 79 O + O / O - O 5 O to O 53 O + O / O - O 1 O mmHg O ( O 10 O . O 5 O + O / O - O 0 O . O 7 O to O 7 O . O 1 O + O / O - O 0 O . O 1 O kPa O ) O for O 129 O + O / O - O 11 O min O in O the O enflurane O ( O E O ) O group O , O and O from O 80 O + O / O - O 4 O to O 49 O + O / O - O 1 O mmHg O ( O 10 O . O 7 O + O / O - O 0 O . O 5 O to O 6 O . O 5 O + O / O - O 0 O . O 1 O kPa O ) O for O 135 O + O / O - O 15 O min O in O the O isoflurane O ( O I O ) O group O . O The O mean O H O concentration O during O hypotension B in O the O inspiratory O gas O was O 0 O . O 7 O + O / O - O 0 O . O 1 O vol O % O , O the O mean O E O concentration O 1 O . O 6 O + O / O - O 0 O . O 2 O vol O % O , O and O the O mean O I O concentration O 1 O . O 0 O + O / O - O 0 O . O 1 O vol O % O . O In O addition O , O the O patients O received O fentanyl O and O d O - O tubocurarine O . O The O initial O dose O of O labetalol O for O lowering O blood O pressure O was O similar O , O 0 O . O 52 O - O 0 O . O 59 O mg O / O kg O , O in O all O the O groups O . O During O hypotension B , O the O heart O rate O was O stable O without O tachy B - O or O bradycardia B . O The O operating O conditions O regarding O bleeding B were O estimated O in O a O double O - O blind O manner O , O and O did O not O differ O significantly O between O the O groups O . O During O hypotension B , O the O serum O creatinine O concentration O rose O significantly O in O all O groups O from O the O values O before O hypotension B and O returned O postoperatively O to O the O initial O level O in O the O other O groups O , O except O the O isoflurane O group O . O After O hypotension B there O was O no O rebound O phenomenon O in O either O blood O pressure O or O heart O rate O . O These O results O indicate O that O labetalol O induces O easily O adjustable O hypotension B without O compensatory O tachycardia B and O rebound O hypertension B . O Convulsion B following O intravenous O fluorescein O angiography O . O Tonic B - I clonic I seizures I followed O intravenous O fluorescein O injection O for O fundus O angiography O in O a O 47 O - O year O - O old O male O . O Despite O precautions O this O adverse O reaction O recurred O on O re O - O exposure O to O intravenous O fluorescein O . O Pharmacology O of O ACC O - O 9653 O ( O phenytoin O prodrug O ) O . O ACC O - O 9653 O , O the O disodium O phosphate O ester O of O 3 O - O hydroxymethyl O - O 5 O , O 5 O - O diphenylhydantoin O , O is O a O prodrug O of O phenytoin O with O advantageous O physicochemical O properties O . O ACC O - O 9653 O is O rapidly O converted O enzymatically O to O phenytoin O in O vivo O . O ACC O - O 9653 O and O phenytoin O sodium O have O equivalent O anticonvulsant O activity O against O seizures B induced O by O maximal O electroshock O ( O MES O ) O in O mice O following O i O . O p O . O , O oral O , O or O i O . O v O . O administration O . O The O ED50 O doses O were O 16 O mg O / O kg O for O i O . O v O . O ACC O - O 9653 O and O 8 O mg O / O kg O for O i O . O v O . O phenytoin O sodium O . O ACC O - O 9653 O and O phenytoin O sodium O have O similar O antiarrhythmic O activity O against O ouabain O - O induced O ventricular B tachycardia I in O anesthetized O dogs O . O The O total O doses O of O ACC O - O 9653 O or O phenytoin O sodium O necessary O to O convert O the O arrhythmia B to O a O normal O sinus O rhythm O were O 24 O + O / O - O 6 O and O 14 O + O / O - O 3 O mg O / O kg O , O respectively O . O Only O phenytoin O sodium O displayed O in O vitro O antiarrhythmic O activity O against O strophanthidin O - O induced O arrhythmias B in O guinea O pig O right O atria O . O In O anesthetized O dogs O , O a O high O dose O of O ACC O - O 9653 O ( O 31 O mg O / O kg O ) O was O infused O over O 15 O , O 20 O , O and O 30 O min O and O the O responses O were O compared O to O an O equimolar O dose O of O phenytoin O sodium O ( O 21 O mg O / O kg O ) O . O The O ACC O - O 9653 O and O phenytoin O sodium O treatments O produced O similar O marked O reductions O in I diastolic I blood I pressure I and O contractile O force O ( O LVdP O / O dt O ) O . O The O maximum O effects O of O each O treatment O occurred O at O the O time O of O maximum O phenytoin O sodium O levels O . O Acute O toxicity B studies O of O ACC O - O 9653 O and O phenytoin O sodium O were O carried O out O in O mice O , O rats O , O rabbits O , O and O dogs O by O i O . O v O . O , O i O . O m O . O , O and O i O . O p O . O routes O of O administration O . O The O systemic O toxic B signs O of O both O agents O were O similar O and O occurred O at O approximately O equivalent O doses O . O Importantly O , O the O local O irritation B of O ACC O - O 9653 O was O markedly O less O than O phenytoin O sodium O following O i O . O m O . O administration O . O ( O ABSTRACT O TRUNCATED O AT O 250 O WORDS O ) O Tachyphylaxis B to O systemic O but O not O to O airway O responses O during O prolonged O therapy O with O high O dose O inhaled O salbutamol O in O asthmatics B . O High O doses O of O inhaled O salbutamol O produce O substantial O improvements O in O airway O response O in O patients O with O asthma B , O and O are O associated O with O dose O - O dependent O systemic O beta O - O adrenoceptor O responses O . O The O purpose O of O the O present O study O was O to O investigate O whether O tachyphylaxis B occurs O during O prolonged O treatment O with O high O dose O inhaled O salbutamol O . O Twelve O asthmatic B patients O ( O FEV1 O , O 81 O + O / O - O 4 O % O predicted O ) O , O requiring O only O occasional O inhaled O beta O - O agonists O as O their O sole O therapy O , O were O given O a O 14 O - O day O treatment O with O high O dose O inhaled O salbutamol O ( O HDS O ) O , O 4 O , O 000 O micrograms O daily O , O low O dose O inhaled O salbutamol O ( O LDS O ) O , O 800 O micrograms O daily O , O or O placebo O ( O PI O ) O by O metered O - O dose O inhaler O in O a O double O - O blind O , O randomized O crossover O design O . O During O the O 14 O - O day O run O - O in O and O during O washout O periods O , O inhaled O beta O - O agonists O were O withheld O and O ipratropium O bromide O was O substituted O for O rescue O purposes O . O At O the O end O of O each O 14 O - O day O treatment O , O a O dose O - O response O curve O ( O DRC O ) O was O performed O , O and O airway O ( O FEV1 O , O FEF25 O - O 75 O ) O chronotropic O ( O HR O ) O , O tremor B , O and O metabolic O ( O K O , O Glu O ) O responses O were O measured O at O each O step O ( O from O 100 O to O 4 O , O 000 O micrograms O ) O . O Treatment O had O no O significant O effect O on O baseline O values O . O There O were O dose O - O dependent O increases O in O FEV1 O and O FEF25 O - O 75 O ( O p O less O than O 0 O . O 001 O ) O , O and O pretreatment O with O HDS O did O not O displace O the O DRC O to O the O right O . O DRC O for O HR O ( O p O less O than O 0 O . O 001 O ) O , O K O ( O p O less O than O 0 O . O 001 O ) O , O and O Glu O ( O p O less O than O 0 O . O 005 O ) O were O attenuated O after O treatment O with O HDS O compared O with O PI O . O There O were O also O differences O between O HDS O and O LDS O for O HR O ( O p O less O than O 0 O . O 001 O ) O and O Glu O ( O p O less O than O 0 O . O 05 O ) O responses O . O Frequency O and O severity O of O subjective O adverse O effects O were O also O reduced O after O HDS O : O tremor B ( O p O less O than O 0 O . O 001 O ) O , O palpitations B ( O p O less O than O 0 O . O 001 O ) O . O ( O ABSTRACT O TRUNCATED O AT O 250 O WORDS O ) O Phenytoin O induced O fatal O hepatic B injury I . 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 . O Without O treatment O , O 73 O of O 92 O animals O ( O 80 O % O ) O died O after O injection O of O bovine O serum O albumin O ( O BSA O ) O on O day O + O 7 O of O pertussis O immunization O . O After O pretreatment O with O 3 O mg O of O cyproheptadine O , O 2 O mg O mianserin O , O or O 2 O mg O chlorpheniramine O , O only O 5 O of O 105 O animals O ( O 5 O % O ) O died O after O receiving O BSA O on O day O + O 7 O ( O p O less O than O 0 O . O 001 O ) O . O Blockade O of O histamine O H1 O receptors O may O reduce O mortality O in O pertussis O immunization O - O induced O encephalopathy B in O mice O . O Support O for O adrenaline O - O hypertension B hypothesis O : O 18 O hour O pressor O effect O after O 6 O hours O adrenaline O infusion O . 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 . O Over O the O total O postinfusion O period O systolic O and O diastolic O arterial O pressure O were O 6 O ( O SEM O 2 O ) O % O and O 7 O ( O 2 O ) O % O , O respectively O , O higher O than O after O dextrose O infusion O ( O ANOVA O , O p O less O than O 0 O . O 001 O ) O . O Thus O , O " O stress O " O levels O of O adrenaline O ( O 230 O pg O / O ml O ) O for O 6 O h O cause O a O delayed O and O protracted O pressor O effect O . O These O findings O are O strong O support O for O the O adrenaline O - O hypertension B hypothesis O in O man O . O Effect O of O alkylxanthines O on O gentamicin O - O induced O acute B renal I failure I in O the O rat O . O Adenosine O antagonists O have O been O previously O shown O to O be O of O benefit O in O some O ischaemic B and O nephrotoxic B models O of O acute B renal I failure I ( O ARF B ) O . 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 . O In O the O patients O , O but O not O the O healthy O subjects O , O these O symptoms O were O significantly O correlated O with O plasma O caffeine O levels O . O Seventy O - O one O percent O of O the O patients O reported O that O the O behavioral O effects O of O caffeine O were O similar O to O those O experienced O during O panic B attacks I . O Caffeine O did O not O alter O plasma O MHPG O levels O in O either O the O healthy O subjects O or O patients O . O Caffeine O increased O plasma O cortisol O levels O equally O in O the O patient O and O healthy O groups O . O Because O caffeine O is O an O adenosine O receptor O antagonist O , O these O results O suggest O that O some O panic B disorder I patients O may O have O abnormalities O in O neuronal O systems O involving O adenosine O . 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 . O Morning O dipping O , O assessed O by O the O fall O in O peak O flow O overnight O , O was O significantly O reduced O in O the O periods O when O either O active O drug O was O taken O , O whereas O no O difference O was O noticed O during O the O placebo O administration O . O No O significant O difference O was O noticed O between O results O obtained O with O either O active O drug O , O as O well O as O with O either O dosage O of O oxitropium O . O No O subject O reported O side O effects O of O oxitropium O , O as O compared O to O three O subjects O reporting O nausea B , O vomiting B and O tremors B after O theophylline O . O Oxitropium O proves O to O be O a O valuable O alternative O to O theophylline O in O nocturnal B asthma I , O since O it O is O equally O potent O , O safer O and O does O not O require O the O titration O of O dosage O . O Penicillin O anaphylaxis B . O A O case O of O oral O penicillin O anaphylaxis B is O described O , O and O the O terminology O , O occurrence O , O clinical O manifestations O , O pathogenesis O , O prevention O , O and O treatment O of O anaphylaxis B are O reviewed O . O Emergency O physicians O should O be O aware O of O oral O penicillin O anaphylaxis B in O order O to O prevent O its O occurrence O by O prescribing O the O antibiotic O judiciously O and O knowledgeably O and O to O offer O optimal O medical O therapy O once O this O life O - O threatening O reaction O has O begun O . O Reversible O valproic O acid O - O induced O dementia B : O a O case O report O . O Reversible O valproic O acid O - O induced O dementia B was O documented O in O a O 21 O - O year O - O old O man O with O epilepsy B who O had O a O 3 O - O year O history O of O insidious O progressive O decline B in O global O cognitive I abilities O documented O by O serial O neuropsychological O studies O . O Repeat O neuropsychological O testing O 7 O weeks O after O discontinuation O of O the O drug O revealed O dramatic O improvement O in O IQ O , O memory O , O naming O , O and O other O tasks O commensurate O with O clinical O recovery O in O his O intellectual O capacity O . O Possible O pathophysiological O mechanisms O which O may O have O been O operative O in O this O case O include O : O a O direct O central O nervous O system O ( O CNS O ) O toxic O effect O of O valproic O acid O ; O a O paradoxical O epileptogenic O effect O secondary O to O the O drug O ; O and O an O indirect O CNS O toxic O effect O mediated O through O valproic O acid O - O induced O hyperammonemia B . O Reversal O of O scopolamine O - O induced O amnesia B of O passive O avoidance O by O pre O - O and O post O - O training O naloxone O . O In O a O series O of O five O experiments O , O the O modulating O role O of O naloxone O on O a O scopolamine O - O induced O retention O deficit O in O a O passive O avoidance O paradigm O was O investigated O in O mice O . O Scopolamine O , O but O not O methyl O scopolamine O ( O 1 O and O 3 O mg O / O kg O ) O , O induced O an O amnesia B as O measured O by O latency O and O duration O parameters O . O Naloxone O ( O 0 O . O 3 O , O 1 O , O 3 O , O and O 10 O mg O / O kg O ) O injected O prior O to O training O attenuated O the O retention O deficit O with O a O peak O of O activity O at O 3 O mg O / O kg O . O The O effect O of O naloxone O could O be O antagonized O with O morphine O ( O 1 O , O 3 O , O and O 10 O mg O / O kg O ) O , O demonstrating O the O opioid O specificity O of O the O naloxone O effect O . O Post O - O training O administration O of O naloxone O ( O 3 O mg O / O kg O ) O as O a O single O or O as O a O split O dose O also O attenuated O the O scopolamine O - O induced O amnesia B . O Control O experiments O indicated O that O neither O an O increase O in O pain B sensitivity O ( O pre O - O training O naloxone O ) O nor O an O induced O aversive O state O ( O post O - O training O naloxone O ) O appear O to O be O responsible O for O the O influence O of O naloxone O on O the O scopolamine O - O induced O retention O deficit O . O These O results O extend O previous O findings O implicating O a O cholinergic O - O opioid O interaction O in O memory O processes O . O A O possible O mechanism O for O this O interaction O involving O the O septo O - O hippocampal O cholinergic O pathway O is O discussed O . O Electron O microscopic O investigations O of O the O cyclophosphamide O - O induced O lesions B of I the I urinary I bladder I of O the O rat O and O their O prevention O by O mesna O . O Fully O developed O cyclophosphamide O - O induced O cystitis B is O characterized O by O nearly O complete O detachment O of O the O urothelium O , O severe O submucosal O edema B owing O to O damage O to O the O microvascular O bed O and O focal O muscle B necroses I . O The O initial O response O to O the O primary O attack O by O the O cyclophosphamide O metabolites O seems O to O be O fragmentation O of O the O luminal O membrane O . O This O damages O the O cellular O barrier O against O the O hypertonic O urine O . O Subsequent O breaks O in O the O lateral O cell O membranes O of O the O superficial O cells O and O in O all O the O plasma O membranes O of O the O intermediate O and O basal O cells O , O intercellular O and O intracellular O edema B and O disintegration O of O the O desmosomes O and O hemidesmosomes O lead O to O progressive O degeneration O and O detachment O of O the O epithelial O cells O with O exposure O and O splitting O of O the O basal O membrane O . O The O morphological O changes O of O the O endothelial O cells O , O which O become O more O pronounced O in O the O later O stages O of O the O experiment O , O the O involvement O of O blood O vessels O regardless O of O their O diameter O and O the O location O - O dependent O extent O of O the O damage O indicate O a O direct O type O of O damage O which O is O preceded O by O a O mediator O - O induced O increase O in O permeability O , O the O morphological O correlate O of O which O is O the O formation O of O gaps O in O the O interendothelial O cell O connections O on O the O venules O . O These O changes O can O be O effectively O prevented O by O mesna O . O The O only O sign O of O a O possible O involvement O is O the O increase O in O the O number O of O specific O granules O with O a O presumed O lysosomal O function O in O the O superficial O cells O . O Increase O in O intragastric O pressure O during O suxamethonium O - O induced O muscle B fasciculations I in O children O : O inhibition O by O alfentanil O . O Changes O in O intragastric O pressure O after O the O administration O of O suxamethonium O 1 O . O 5 O mg O kg O - O 1 O i O . O v O . O were O studied O in O 32 O children O ( O mean O age O 6 O . O 9 O yr O ) O pretreated O with O either O physiological O saline O or O alfentanil O 50 O micrograms O kg O - O 1 O . O Anaesthesia O was O induced O with O thiopentone O 5 O mg O kg O - O 1 O . O The O incidence O and O intensity O of O muscle B fasciculations I caused O by O suxamethonium O were O significantly O greater O in O the O control O than O in O the O alfentanil O group O . O The O intragastric O pressure O during O muscle B fasciculations I was O significantly O higher O in O the O control O group O ( O 16 O + O / O - O 0 O . O 7 O ( O SEM O ) O cm O H2O O ) O than O in O the O alfentanil O group O ( O 7 O . O 7 O + O / O - O 1 O . O 5 O ( O SEM O ) O cm O H2O O ) O . O The O increase O in O intragastric O pressure O was O directly O related O to O the O intensity O of O muscle B fasciculations I ( O regression O line O : O y O = O 0 O . O 5 O + O 4 O . O 78x O with O r O of O 0 O . O 78 O ) O . O It O is O concluded O that O intragastric O pressure O increases O significantly O during O muscle B fasciculations I caused O by O suxamethonium O in O healthy O children O . O Alfentanil O 50 O micrograms O kg O - O 1 O effectively O inhibits O the O incidence O and O intensity O of O suxamethonium O - O induced O muscle B fasciculations I ; O moreover O , O intragastric O pressure O remains O at O its O control O value O . O Acute O insulin O treatment O normalizes O the O resistance O to O the O cardiotoxic B effect O of O isoproterenol O in O streptozotocin O diabetic B rats O . O A O morphometric O study O of O isoproterenol O induced O myocardial B fibrosis I . O The O acute O effect O of O insulin O treatment O on O the O earlier O reported O protective O effect O of O streptozotocin O diabetes B against O the O cardiotoxic B effect O of O high O doses O of O isoproterenol O ( O ISO O ) O was O investigated O in O rats O . O Thirty O to O 135 O min O after O the O injection O of O crystalline O insulin O , O ISO O was O given O subcutaneously O and O when O ISO O induced O fibrosis B in O the O myocardium O was O morphometrically O analyzed O 7 O days O later O , O a O highly O significant O correlation O ( O r O = O 0 O . O 83 O , O 2 O p O = O 0 O . O 006 O ) O to O the O slope O of O the O fall O in O blood O glucose O after O insulin O treatment O appeared O . O The O myocardial O content O of O catecholamines O was O estimated O in O these O 8 O day O diabetic B rats O . O The O norepinephrine O content O was O significantly O increased O while O epinephrine O remained O unchanged O . O An O enhanced O sympathetic O nervous O system O activity O with O a O consequent O down O regulation O of O the O myocardial O beta O - O adrenergic O receptors O could O , O therefore O , O explain O this O catecholamine O resistance O . O The O rapid O reversion O after O insulin O treatment O excludes O the O possibility O that O streptozotocin O in O itself O causes O the O ISO O resistance O and O points O towards O a O direct O insulin O effect O on O myocardial O catecholamine O sensitivity O in O diabetic B rats O . O The O phenomenon O described O might O elucidate O pathogenetic O mechanisms O behind O toxic O myocardial B cell I degeneration I and O may O possibly O have O relevance O for O acute O cardiovascular I complications I in O diabetic B patients O . O Differential O effects O of O non O - O steroidal O anti O - O inflammatory O drugs O on O seizures B produced O by O pilocarpine O in O rats O . O The O muscarinic O cholinergic O agonist O pilocarpine O induces O in O rats O seizures B and O status B epilepticus I followed O by O widespread O damage O to O the O forebrain O . O The O present O study O was O designed O to O investigate O the O effect O of O 5 O non O - O steroidal O anti O - O inflammatory O drugs O , O sodium O salicylate O , O phenylbutazone O , O indomethacin O , O ibuprofen O and O mefenamic O acid O , O on O seizures B produced O by O pilocarpine O . O Pretreatment O of O rats O with O sodium O salicylate O , O ED50 O 103 O mg O / O kg O ( O 60 O - O 174 O ) O , O and O phenylbutazone O , O 59 O mg O / O kg O ( O 50 O - O 70 O ) O converted O the O non O - O convulsant O dose O of O pilocarpine O , O 200 O mg O / O kg O , O to O a O convulsant O one O . O Indomethacin O , O 1 O - O 10 O mg O / O kg O , O and O ibuprofen O , O 10 O - O 100 O mg O / O kg O , O failed O to O modulate O seizures B produced O by O pilocarpine O . O Mefenamic O acid O , O 26 O ( O 22 O - O 30 O ) O mg O / O kg O , O prevented O seizures B and O protected O rats O from O seizure B - O related O brain B damage I induced O by O pilocarpine O , O 380 O mg O / O kg O . O These O results O indicate O that O non O - O steroidal O anti O - O inflammatory O drugs O differentially O modulate O the O threshold O for O pilocarpine O - O induced O seizures B . O Acute O neurologic B dysfunction I after O high O - O dose O etoposide O therapy O for O malignant B glioma I . O Etoposide O ( O VP O - O 16 O - O 213 O ) O has O been O used O in O the O treatment O of O many O solid O tumors B and O hematologic B malignancies I . O When O used O in O high O doses O and O in O conjunction O with O autologous O bone O marrow O transplantation O , O this O agent O has O activity O against O several O treatment O - I resistant I cancers B including O malignant B glioma I . O In O six O of O eight O patients O ( O 75 O % O ) O who O we O treated O for O recurrent O or O resistant O glioma B , O sudden O severe O neurologic B deterioration I occurred O . O This O developed O a O median O of O 9 O days O after O initiation O of O high O - O dose O etoposide O therapy O . O Significant O clinical O manifestations O have O included O confusion B , O papilledema B , O somnolence B , O exacerbation O of O motor B deficits I , O and O sharp O increase O in O seizure B activity O . O These O abnormalities O resolved O rapidly O after O initiation O of O high O - O dose O intravenous O dexamethasone O therapy O . O In O all O patients O , O computerized O tomographic O ( O CT O ) O brain O scans O demonstrated O stability O in O tumor B size O and O peritumor O edema B when O compared O with O pretransplant O scans O . O This O complication O appears O to O represent O a O significant O new O toxicity B of O high O - O dose O etoposide O therapy O for O malignant B glioma I . O Progressive O bile B duct I injury I after O thiabendazole O administration O . O A O 27 O - O yr O - O old O man O developed O jaundice B 2 O wk O after O exposure O to O thiabendazole O . O Cholestasis B persisted O for O 3 O yr O , O at O which O time O a O liver O transplant O was O performed O . O Two O liver O biopsy O specimens O and O the O hepatectomy O specimen O were O remarkable O for O almost O complete O disappearance O of O interlobular O bile O ducts O . O Prominent O fibrosis B and O hepatocellular O regeneration O were O also O present O ; O however O , O the O lobular O architecture O was O preserved O . O This O case O represents O an O example O of O " O idiosyncratic O " O drug O - O induced O liver B damage I in O which O the O primary O target O of O injury O is O the O bile O duct O . O An O autoimmune O pathogenesis O of O the O bile B duct I destruction I is O suggested O . O Differential O effects O of O 1 O , O 4 O - O dihydropyridine O calcium O channel O blockers O : O therapeutic O implications O . O Increasing O recognition O of O the O importance O of O calcium O in O the O pathogenesis O of O cardiovascular B disease I has O stimulated O research O into O the O use O of O calcium O channel O blocking O agents O for O treatment O of O a O variety O of O cardiovascular B diseases I . O The O favorable O efficacy O and O tolerability O profiles O of O these O agents O make O them O attractive O therapeutic O modalities O . O Clinical O applications O of O calcium O channel O blockers O parallel O their O tissue O selectivity O . O In O contrast O to O verapamil O and O diltiazem O , O which O are O roughly O equipotent O in O their O actions O on O the O heart O and O vascular O smooth O muscle O , O the O dihydropyridine O calcium O channel O blockers O are O a O group O of O potent O peripheral O vasodilator O agents O that O exert O minimal O electrophysiologic O effects O on O cardiac O nodal O or O conduction O tissue O . O As O the O first O dihydropyridine O available O for O use O in O the O United O States O , O nifedipine O controls O angina B and O hypertension B with O minimal O depression B of I cardiac I function I . O Additional O members O of O this O group O of O calcium O channel O blockers O have O been O studied O for O a O variety O of O indications O for O which O they O may O offer O advantages O over O current O therapy O . O Once O or O twice O daily O dosage O possible O with O nitrendipine O and O nisoldipine O offers O a O convenient O administration O schedule O , O which O encourages O patient O compliance O in O long O - O term O therapy O of O hypertension B . O The O coronary O vasodilating O properties O of O nisoldipine O have O led O to O the O investigation O of O this O agent O for O use O in O angina B . O Selectivity O for O the O cerebrovascular O bed O makes O nimodipine O potentially O useful O in O the O treatment O of O subarachnoid B hemorrhage I , O migraine B headache I , O dementia B , O and O stroke B . O In O general O , O the O dihydropyridine O calcium O channel O blockers O are O usually O well O tolerated O , O with O headache B , O facial B flushing I , O palpitations B , O edema B , O nausea B , O anorexia B , O and O dizziness B being O the O more O common O adverse O effects O . O The O enhancement O of O aminonucleoside O nephrosis B by O the O co O - O administration O of O protamine O . O An O experimental O model O of O focal O segmental O glomerular B sclerosis I ( O FSGS B ) O was O developed O in O rats O by O the O combined O administration O of O puromycin O - O aminonucleoside O ( O AMNS O ) O and O protamine O sulfate O ( O PS O ) O . 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 . O There O were O no O infectious B deaths O in O renal O transplant O patients O on O cyclosporine O or O Aza O , O but O infection B played O a O major O role O in O 3 O out O of O 6 O cardiac O transplant O deaths O and O in O 8 O out O of O 9 O liver O transplant O deaths O . O Renal O patients O on O cyclosporine O had O the O fewest O bacteremias B . O Analysis O of O site O of O infection B showed O a O preponderance O of O abdominal B infections I in O liver O patients O , O intrathoracic B infections I in O heart O patients O , O and O urinary B tract I infections I in O renal O patients O . O Pulmonary B infections I were O less O common O in O cyclosporine O - O treated O renal O patients O than O in O Aza O - O treated O patients O ( O P O less O than O 0 O . O 05 O ) O . O Aza O patients O had O significantly O more O staphylococcal B infections I than O all O other O transplant O groups O ( O P O less O than O 0 O . O 005 O ) O , O and O systemic O fungal B infections I occurred O only O in O the O liver O transplant O group O . O Cytomegalovirus B ( O CMV O ) O shedding O or O serological O rises O in O antibody O titer O , O or O both O occurred O in O 78 O % O of O cyclosporine O patients O and O 76 O % O of O Aza O patients O . O Of O the O cyclosporine O patients O , O 15 O % O had O symptoms O related O to O CMV B infection I . O Serological O evidence O for O Epstein B Barr I Virus I infection I was O found O in O 20 O % O of O 65 O cyclosporine O patients O studied O . O Three O had O associated O symptoms O , O and O one O developed O a O lymphoma B . O Structure O - O activity O and O dose O - O effect O relationships O of O the O antagonism O of O picrotoxin O - O induced O seizures B by O cholecystokinin O , O fragments O and O analogues O of O cholecystokinin O in O mice O . O Intraperitoneal O administration O of O cholecystokinin O octapeptide O sulphate O ester O ( O CCK O - O 8 O - O SE O ) O and O nonsulphated O cholecystokinin O octapeptide O ( O CCK O - O 8 O - O NS O ) O enhanced O the O latency O of O seizures B induced O by O picrotoxin O in O mice O . O Experiments O with O N O - O and O C O - O terminal O fragments O revealed O that O the O C O - O terminal O tetrapeptide O ( O CCK O - O 5 O - O 8 O ) O was O the O active O centre O of O the O CCK O octapeptide O molecule O . O The O analogues O CCK O - O 8 O - O SE O and O CCK O - O 8 O - O NS O ( O dose O range O 0 O . O 2 O - O 6 O . 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 . O Vasopressin O plays O a O major O role O in O the O pathogenesis O of O DOCA O - O salt O hypertension B , O since O the O elevation O of O blood O pressure O was O not O substantial O in O the O rats O with O lithium O - O treated O diabetes B insipidus I after O DOCA O - O salt O treatment O . O Administration O of O DDAVP O which O has O antidiuretic O action O but O minimal O vasopressor O effect O failed O to O increase O blood O pressure O to O the O levels O observed O after O administration O of O AVP O . O Furthermore O , O the O pressor O action O of O vasopressin O appears O to O be O important O in O the O development O of O this O model O of O hypertension B , O since O the O enhanced O pressor O responsiveness O to O the O hormone O was O observed O in O the O initial O stage O of O hypertension B . 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 . O Regarding O the O effects O of O drug O - O induced O hypotension B on O coronary O blood O flow O , O aortic O and O coronary O sinus O metabolic O data O ( O pH O , O pO2 O , O pCO2 O ) O we O could O confirm O that O nitroprusside O hypotension B could O be O safely O used O to O 30 O % O mean O blood O pressure O decrease O from O control O , O trimetaphan O hypotension B to O 20 O % O mean O blood O pressure O decrease O . O Cardiac O work O was O significantly O reduced O during O SNP O hypotension B . O Myocardial O O2 O consumption O and O O2 O availability O were O directly O dependent O on O the O coronary O perfusion O . O Careful O invasive O monitoring O of O the O blood O pressure O , O blood O gases O and O of O the O ECG O ST O - O T O segment O is O mandatory O . O Evidence O for O a O selective O brain O noradrenergic O involvement O in O the O locomotor O stimulant O effects O of O amphetamine O in O the O rat O . O Male O rats O received O the O noradrenaline O neurotoxin O DSP4 O ( O 50 O mg O / O kg O ) O 7 O days O prior O to O injection O of O D O - O amphetamine O ( O 10 O or O 40 O mumol O / O kg O i O . O p O . O ) O . O The O hyperactivity B induced O by O D O - O amphetamine O ( O 10 O mumol O / O kg O ) O was O significantly O reduced O by O DSP4 O pretreatment O . O However O , O the O increased O rearings O and O the O amphetamine O - O induced O stereotypies O were O not O blocked O by O pretreatment O with O DSP4 O . 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 . O Acute O toxic O dosage O - O dependent O behavioral O effects O of O caffeine O were O compared O in O adult O males O from O seven O inbred O mouse O strains O ( O A O / O J O , O BALB O / O cJ O , O CBA O / O J O , O C3H O / O HeJ O , O C57BL O / O 6J O , O DBA O / O 2J O , O SWR O / O J O ) O . O C57BL O / O 6J O , O chosen O as O a O " O prototypic O " O mouse O strain O , O was O used O to O determine O behavioral O responses O to O a O broad O range O ( O 5 O - O 500 O mg O / O kg O ) O of O caffeine O doses O . O Five O phenotypic O characteristics O - O - O locomotor O activity O , O righting O ability O , O clonic O seizure B induction O , O stress O - O induced O lethality O , O death B without O external O stress O - O - O were O scored O at O various O caffeine O doses O in O drug O - O naive O animals O under O empirically O optimized O , O rigidly O constant O experimental O conditions O . O Mice O ( O n O = O 12 O for O each O point O ) O received O single O IP O injections O of O a O fixed O volume O / O g O body O weight O of O physiological O saline O carrier O with O or O without O caffeine O in O doses O ranging O from O 125 O - O 500 O mg O / O kg O . O Loss O of O righting O ability O was O scored O at O 1 O , O 3 O , O 5 O min O post O dosing O and O at O 5 O min O intervals O thereafter O for O 20 O min O . O In O the O same O animals O the O occurrence O of O clonic B seizures I was O scored O as O to O time O of O onset O and O severity O for O 20 O min O after O drug O administration O . O When O these O proceeded O to O tonic O seizures B , O death B occurred O in O less O than O 20 O min O . O Animals O surviving O for O 20 O min O were O immediately O stressed O by O a O swim O test O in O 25 O degrees O C O water O , O and O death B - O producing O tonic O seizures B were O scored O for O 2 O min O . O In O other O animals O locomotor O activity O was O measured O 15 O or O 60 O min O after O caffeine O administration O . O By O any O single O behavioral O criterion O or O a O combination O of O these O criteria O , O marked O differences O in O response O to O toxic O caffeine O doses O were O observed O between O strains O . O These O results O indicate O that O behavioral O toxicity B testing O of O alkylxanthines O in O a O single O mouse O strain O may O be O misleading O and O suggest O that O toxic O responses O of O the O central O nervous O system O to O this O class O of O compounds O are O genetically O influenced O in O mammals O . O Treatment O of O ovarian B cancer I with O a O combination O of O cis O - O platinum O , O adriamycin O , O cyclophosphamide O and O hexamethylmelamine O . O During O the O last O 2 O 1 O / O 2 O years O , O 38 O patients O with O ovarian B cancer I were O treated O with O a O combination O of O cisplatinum O ( O CPDD O ) O , O 50 O mg O / O m2 O , O adriamycin O , O 30 O mg O / O m2 O , O cyclophosphamide O , O 300 O mg O / O m2 O , O on O day O 1 O ; O and O hexamethylmelamine O ( O HMM O ) O , O 6 O mg O / O kg O daily O , O for O 14 O days O . O Each O course O was O repeated O monthly O . O 2 O patients O had O stage O II O , O 14 O stage O III O and O 22 O stage O IV O disease O . O 14 O of O the O 38 O patients O were O previously O treated O with O chemotherapy O , O 1 O with O radiation O , O 6 O with O both O chemotherapy O and O radiation O , O and O 17 O did O not O have O any O treatment O before O CPDD O combination O . O 31 O of O the O 38 O cases O ( O 81 O . O 5 O % O ) O demonstrated O objective O responses O lasting O for O 2 O months O or O more O . O These O responses O were O partial O in O 19 O and O complete O in O 12 O cases O . O Hematologic O toxicity B was O moderate O and O with O reversible O anemia B developing O in O 71 O % O of O patients O . O Gastrointestinal O side O effects O from O CPDD O were O universal O . O HMM O gastrointestinal B toxicity I necessitated O discontinuation O of O the O drug O in O 5 O patients O . O Severe O nephrotoxicity B was O observed O in O 2 O patients O but O was O reversible O . O There O were O no O drug O - O related O deaths O . O Nontraumatic O dissecting B aneurysm I of I the I basilar I artery I . O A O case O of O nontraumatic O dissecting B aneurysm I of I the I basilar I artery I in O association O with O hypertension B , O smoke O , O and O oral O contraceptives O is O reported O in O a O young O female O patient O with O a O locked B - I in I syndrome I . O A O method O for O the O measurement O of O tremor B , O and O a O comparison O of O the O effects O of O tocolytic O beta O - O mimetics O . O A O method O permitting O measurement O of O finger O tremor B as O a O displacement O - O time O curve O is O described O , O using O a O test O system O with O simple O amplitude O calibration O . O The O coordinates O of O the O inversion O points O of O the O displacement O - O time O curves O were O transferred O through O graphical O input O equipment O to O punched O tape O . O By O means O of O a O computer O program O , O periods O and O amplitudes O of O tremor B oscillations O were O calculated O and O classified O . O The O event O frequency O for O each O class O of O periods O and O amplitudes O was O determined O . O The O actions O of O fenoterol O - O hydrobromide O , O ritodrin O - O HCl O and O placebo O given O to O 10 O healthy O subjects O by O intravenous O infusion O in O a O double O - O blind O crossover O study O were O tested O by O this O method O . O At O therapeutic O doses O both O substances O raised O the O mean O tremor B amplitude O to O about O three O times O the O control O level O . O At O the O same O time O , O the O mean O period O within O each O class O of O amplitudes O shortened O by O 10 O - O - O 20 O ms O , O whereas O the O mean O periods O calculated O from O all O oscillations O together O did O not O change O significantly O . O After O the O end O of O fenoterol O - O hydrobromide O infusion O , O tremor B amplitudes O decreased O significantly O faster O than O those O following O ritodrin O - O HCl O infusion O . O Propylthiouracil O - O induced O hepatic B damage I . O Two O cases O of O propylthiouracil O - O induced O liver B damage I have O been O observed O . O The O first O case O is O of O an O acute O type O of O damage O , O proven O by O rechallenge O ; O the O second O presents O a O clinical O and O histologic O picture O resembling O chronic B active I hepatitis I , O with O spontaneous O remission O . O Studies O on O the O bradycardia B induced O by O bepridil O . O Bepridil O , O a O novel O active O compound O for O prophylactic O treatment O of O anginal B attacks O , O induced O persistent O bradycardia B and O a O non O - O specific O anti O - O tachycardial B effect O , O the O mechanisms O of O which O were O investigated O in O vitro O and O in O vivo O . O In O vitro O perfusion O of O bepridil O in O the O life O - O support O medium O for O isolated O sino O - O atrial O tissue O from O rabbit O heart O , O caused O a O reduction O in O action O potential O ( O AP O ) O spike O frequency O ( O recorded O by O KCl O microelectrodes O ) O starting O at O doses O of O 5 O X O 10 O ( O - O 6 O ) O M O . O This O effect O was O dose O - O dependent O up O to O concentrations O of O 5 O X O 10 O ( O - O 5 O ) O M O , O whereupon O blockade O of O sinus O activity O set O in O . O Bepridil O at O a O dose O of O 5 O X O 10 O ( O - O 6 O ) O M O , O induced O a O concomitant O reduction O in O AP B amplitude O ( O falling O from O 71 O + O / O - O 8 O mV O to O 47 O + O / O - O 6 O mV O ) O , O maximum O systolic O depolarization O velocity O ( O phase O 0 O ) O which O fell O from O 1 O . O 85 O + O / O - O 0 O . O 35 O V O / O s O to O 0 O . O 84 O + O / O - O 0 O . O 28 O V O / O s O , O together O with O maximum O diastolic O depolarization O velocity O ( O phase O 4 O ) O which O fell O from O 38 O + O / O - O 3 O mV O / O s O to O 24 O + O / O - O 5 O mV O s O . O In O vivo O injection O of O bepridil O at O a O dose O of O 5 O mg O / O kg O ( O i O . O v O . O ) O into O 6 O anaesthetized O dogs O which O had O undergone O ablation O of O all O the O extrinsic O cardiac O afferent O nerve O supply O , O together O with O a O bilateral O medullo O - O adrenalectomy O , O caused O a O marked O reduction O in O heart O rate O which O fell O from O 98 O . O 7 O + O / O - O 4 O . O 2 O beats O / O min O to O 76 O + O / O - O 5 O . O 3 O beats O / O min O sustained O for O more O than O 45 O min O . O It O is O concluded O that O bepridil O reduces O heart O rate O by O acting O directly O on O the O sinus O node O . O This O effect O , O which O results O in O a O flattening O of O the O phase O 0 O and O phase O 4 O slope O , O together O with O a O longer O AP B duration O , O may O be O due O to O an O increase O in O the O time O constants O of O slow O inward O ionic O currents O ( O already O demonstrated O elsewhere O ) O , O but O also O to O an O increased O time O constant O for O deactivation O of O the O outward O potassium O current O ( O Ip O ) O . O Hepatitis B and O renal B tubular I acidosis I after O anesthesia O with O methoxyflurane O . O A O 69 O - O year O - O old O man O operated O for O acute O cholecystitis B under O methoxyflurane O anesthesia O developed O postoperatively O a O hepatic B insufficiency I syndrome I and O renal B tubular I acidosis I . O Massive O bleeding B appeared O during O surgery O which O lasted O for O six O hours O . O Postoperative O evolution O under O supportive O therapy O was O favourable O . O Complete O recovery O was O confirmed O by O repeated O controls O performed O over O a O period O of O one O year O after O surgery O . O Pituitary O response O to O luteinizing O hormone O - O releasing O hormone O during O haloperidol O - O induced O hyperprolactinemia B . O The O effects O of O a O 6 O - O hour O infusion O with O haloperidol O on O serum O prolactin O and O luteinizing O hormone O ( O LH O ) O levels O was O studied O in O a O group O of O male O subjects O . O Five O hours O after O starting O the O infusions O , O a O study O of O the O pituitary O responses O to O LH O - O releasing O hormone O ( O LH O - O RH O ) O was O carried O out O . O Control O patients O received O infusions O of O 0 O . O 9 O % O NaCl O solution O . O During O the O course O of O haloperidol O infusions O , O significant O hyperprolactinemia B was O found O , O together O with O an O abolished O pituitary O response O to O LH O - O RH O , O as O compared O with O responses O of O control O subjects O . O Antirifampicin O antibodies O in O acute O rifampicin O - O associated O renal B failure I . O 5 O patients O with O acute B renal I failure I ( O 3 O with O thrombopenia B and O hemolysis B ) O induced O by O the O reintroduction O of O rifampicin O are O described O . O No O correlation O was O found O between O the O severity O of O clinical O manifestations O and O the O total O dose O taken O by O the O patients O . O In O all O but O 1 O patient O , O antirifampicin O antibodies O were O detected O . O Antibodies O suggested O to O be O of O the O IgM O class O were O detected O in O all O 3 O patients O with O hematological B disorders I . O The O pattern O of O non O - O specific O acute B tubular I necrosis I found O in O the O 2 O biopsied O patients O , O indistinguishable O from O that O of O ischemic B origin O , O raised O the O possibility O of O a O vascular O - O mediated O damage O . O In O 3 O patients O , O the O possibility O of O a O triggering O immunoallergic O mechanism O is O discussed O . O Cardiovascular O effects O of O hypotension B induced O by O adenosine O triphosphate O and O sodium O nitroprusside O on O dogs O with O denervated O hearts O . O Adenosine O triphosphate O ( O ATP O ) O and O sodium O nitroprusside O ( O SNP O ) O are O administered O to O patients O to O induce O and O control O hypotension B during O anesthesia O . 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 . O ) O or O bemegride O ( O 40 O mg O / O kg O , O s O . O c O . O ) O , O no O effects O were O observed O in O convulsions B induced O by O N O - O methyl O - O D O - O aspartate O , O picrotoxin O , O or O electroshock O in O Slc O : O ddY O mice O . O S O - O 312 O - O d O may O be O useful O in O the O therapy O of O certain O types O of O human O epilepsy B . O Transmural O myocardial B infarction I with O sumatriptan O . O For O sumatriptan O , O tightness B in I the I chest I caused O by O an O unknown O mechanism O has O been O reported O in O 3 O - O 5 O % O of O users O . O We O describe O a O 47 O - O year O - O old O woman O with O an O acute O myocardial B infarction I after O administration O of O sumatriptan O 6 O mg O subcutaneously O for O cluster B headache I . O The O patient O had O no O history O of O underlying O ischaemic B heart I disease I or O Prinzmetal B ' I s I angina I . O She O recovered O without O complications O . O Flumazenil O induces O seizures B and O death B in O mixed O cocaine O - O diazepam O intoxications O . O STUDY O HYPOTHESIS O : O Administration O of O the O benzodiazepine O antagonist O flumazenil O may O unmask O seizures B in O mixed O cocaine O - O benzodiazepine O intoxication O . O DESIGN O : O Male O Sprague O - O Dawley O rats O received O 100 O mg O / O kg O cocaine O IP O alone O , O 5 O mg O / O kg O diazepam O alone O , O or O a O combination O of O diazepam O and O cocaine O . O Three O minutes O later O , O groups O were O challenged O with O vehicle O or O flumazenil O 5 O or O 10 O mg O / O kg O IP O . O Animal O behavior O , O seizures B ( O time O to O and O incidence O ) O , O death B ( O time O to O and O incidence O ) O , O and O cortical O EEG O tracings O were O recorded O . O INTERVENTIONS O : O Administration O of O flumazenil O to O animals O after O they O had O received O a O combination O dose O of O cocaine O and O diazepam O . O RESULTS O : O In O group O 1 O , O animals O received O cocaine O followed O by O vehicle O . O This O resulted O in O 100 O % O developing O seizures B and O death B . O Group O 2 O received O diazepam O alone O followed O by O vehicle O . O Animals O became O somnolent O and O none O died O . O Group O 3 O received O diazepam O followed O by O 5 O mg O / O kg O flumazenil O . O Animals O became O somnolent O after O diazepam O and O then O active O after O flumazenil O administration O . 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 . O Administration O of O GM O at O 40 O mg O / O kg O sc O for O 13 O days O to O rats O induced O a O significant O reduction B in I renal I blood I flow I ( O RBF O ) O and O inulin O clearance O ( O CIn O ) O as O well O as O marked O tubular O damage O . O A O significant O reduction O in O urinary O guanosine O 3 O ' O , O 5 O ' O - O cyclic O monophosphate O ( O cGMP O ) O excretion O and O a O significant O increase O in O renal O cortical O renin O and O endothelin O - O 1 O contents O were O also O observed O in O GM O - O mediated O nephropathy B . O Superoxide O dismutase O ( O SOD O ) O or O dimethylthiourea O ( O DMTU O ) O significantly O lessened O the O GM O - O induced O decrement O in O CIn O . O The O SOD O - O induced O increase O in O glomerular O filtration O rate O was O associated O with O a O marked O improvement O in O RBF O , O an O increase O in O urinary O cGMP O excretion O , O and O a O decrease O in O renal O renin O and O endothelin O - O 1 O content O . O SOD O did O not O attenuate O the O tubular O damage O . O In O contrast O , O DMTU O significantly O reduced O the O tubular O damage O and O lipid O peroxidation O , O but O it O did O not O affect O renal O hemodynamics O and O vasoactive O substances O . O Neither O SOD O nor O DMTU O affected O the O renal O cortical O GM O content O in O GM O - O treated O rats O . O These O results O suggest O that O 1 O ) O both O SOD O and O DMTU O have O protective O effects O on O GM O - O mediated O nephropathy B , O 2 O ) O the O mechanisms O for O the O protective O effects O differ O for O SOD O and O DMTU O , O and O 3 O ) O superoxide O anions O play O a O critical O role O in O GM O - O induced O renal O vasoconstriction O . O Cephalothin O - O induced O immune O hemolytic B anemia I . O A O patient O with O renal B disease I developed O Coombs O - O positive O hemolytic B anemia I while O receiving O cephalothin O therapy O . O An O anti O - O cephalothin O IgG O antibody O was O detected O in O the O patient O ' O s O serum O and O in O the O eluates O from O her O erythrocytes O . O In O addition O , O nonimmunologic O binding O of O normal O and O patient O ' O s O serum O proteins O to O her O own O and O cephalothin O - O coated O normal O red O cells O was O demonstrated O . O Skin O tests O and O in O vitro O lymphocyte O stimulation O revealed O that O the O patient O was O sensitized O to O cephalothin O and O also O to O ampicillin O . O Careful O investigation O of O drug O - O induced O hemolytic B anemias I reveals O the O complexity O of O the O immune O mechanisms O involved O . O Assessment O of O cardiomyocyte O DNA O synthesis O during O hypertrophy B in O adult O mice O . O The O ability O of O cardiomyocytes O to O synthesize O DNA O in O response O to O experimentally O induced O cardiac B hypertrophy I was O assessed O in O adult O mice O . O Isoproterenol O delivered O by O osmotic O minipump O implantation O in O adult O C3Heb O / O FeJ O mice O resulted O in O a O 46 O % O increase O in O heart O weight O and O a O 19 O . O 3 O % O increase O in O cardiomyocyte O area O . O No O DNA O synthesis O , O as O assessed O by O autoradiographic O analysis O of O isolated O cardiomyocytes O , O was O observed O in O control O or O hypertrophic B hearts O . O A O survey O of O 15 O independent O inbred O strains O of O mice O revealed O that O ventricular O cardiomyocyte O nuclear O number O ranged O from O 3 O to O 13 O % O mononucleate O , O suggesting O that O cardiomyocyte O terminal O differentiation O is O influenced O directly O or O indirectly O by O genetic O background O . O To O determine O whether O the O capacity O for O reactive O DNA O synthesis O was O also O subject O to O genetic O regulation O , O cardiac B hypertrophy I was O induced O in O the O strains O of O mice O comprising O the O extremes O of O the O nuclear O number O survey O . O These O data O indicate O that O adult O mouse O atrial O and O ventricular O cardiomyocytes O do O not O synthesize O DNA O in O response O to O isoproterenol O - O induced O cardiac B hypertrophy I . O Central O cardiovascular O effects O of O AVP O and O ANP O in O normotensive O and O spontaneously O hypertensive B rats O . O The O purpose O of O the O present O study O was O to O compare O influence O of O central O arginine O vasopressin O ( O AVP O ) O and O of O atrial O natriuretic O peptide O ( O ANP O ) O on O control O of O arterial O blood O pressure O ( O MAP O ) O and O heart O rate O ( O HR O ) O in O normotensive O ( O WKY O ) O and O spontaneously O hypertensive B ( O SHR O ) O rats O . O Three O series O of O experiments O were O performed O on O 30 O WKY O and O 30 O SHR O , O chronically O instrumented O with O guide O tubes O in O the O lateral O ventricle O ( O LV O ) O and O arterial O and O venous O catheters O . O MAP O and O HR O were O monitored O before O and O after O i O . O v O . O injections O of O either O vehicle O or O 1 O , O 10 O and O 50 O ng O of O AVP O and O 25 O , O 125 O and O 500 O ng O of O ANP O . O Sensitivity O of O cardiac O component O of O baroreflex O ( O CCB O ) O , O expressed O as O a O slope O of O the O regression O line O was O determined O from O relationships O between O systolic O arterial O pressure O ( O SAP O ) O and O HR O period O ( O HRp O ) O during O phenylephrine O ( O Phe O ) O - O induced O hypertension B and O sodium O nitroprusside O ( O SN O ) O - O induced O hypotension B . O CCB O was O measured O before O and O after O administration O of O either O vehicle O , O AVP O , O ANP O , O or O both O peptides O together O . O Increases O of O MAP O occurred O after O LV O administration O of O 1 O , O 10 O and O 50 O ng O of O AVP O in O WKY O and O of O 10 O and O 50 O ng O in O SHR O . O ANP O did O not O cause O significant O changes O in O MAP O in O both O strains O as O compared O to O vehicle O , O but O it O abolished O AVP O - O induced O MAP O increase O in O WKY O and O SHR O . O CCB O was O reduced O in O WKY O and O SHR O after O LV O administration O of O AVP O during O SN O - O induced O hypotension B . O In O SHR O but O not O in O WKY O administration O of O ANP O , O AVP O and O ANP O + O AVP O decreased O CCB O during O Phe O - O induced O MAP O elevation O . O The O results O indicate O that O centrally O applied O AVP O and O ANP O exert O differential O effects O on O blood O pressure O and O baroreflex O control O of O heart O rate O in O WKY O and O SHR O and O suggest O interaction O of O these O two O peptides O in O blood O pressure O regulation O at O the O level O of O central O nervous O system O . O Cutaneous O exposure O to O warfarin O - O like O anticoagulant O causing O an O intracerebral B hemorrhage I : O a O case O report O . O A O case O of O intercerebral B hematoma I due O to O warfarin O - O induced O coagulopathy B is O presented O . O The O 39 O - O year O - O old O woman O had O spread O a O warfarin O - O type O rat O poison O around O her O house O weekly O using O her O bare O hands O , O with O no O washing O post O application O . O Percutaneous O absorption O of O warfarin O causing O coagulopathy B , O reported O three O times O in O the O past O , O is O a O significant O risk O if O protective O measures O , O such O as O gloves O , O are O not O used O . O An O adverse O drug O interaction O with O piroxicam O , O which O she O took O occasionally O , O may O have O exacerbated O the O coagulopathy B . O Pediatric O heart O transplantation O without O chronic O maintenance O steroids O . O From O 1986 O to O February O 1993 O , O 40 O children O aged O 2 O months O to O 18 O years O ( O average O age O 10 O . O 4 O + O / O - O 5 O . O 8 O years O ) O underwent O heart O transplantation O . O Indications O for O transplantation O were O idiopathic B cardiomyopathy B ( O 52 O % O ) O , O congenital B heart I disease I ( O 35 O % O ) O with O and O without O prior O repair O ( O 71 O % O and O 29 O % O , O respectively O ) O , O hypertrophic B cardiomyopathy I ( O 5 O % O ) O , O valvular B heart I disease I ( O 3 O % O ) O , O and O doxorubicin O cardiomyopathy B ( O 5 O % O ) O . O Patients O were O managed O with O cyclosporine O and O azathioprine O . O No O prophylaxis O with O antilymphocyte O globulin O was O used O . O Steroids O were O given O to O 39 O % O of O patients O for O refractory O rejection O , O but O weaning O was O always O attempted O and O generally O successful O ( O 64 O % O ) O . O Five O patients O ( O 14 O % O ) O received O maintenance O steroids O . O Four O patients O died O in O the O perioperative O period O and O one O died O 4 O months O later O . O There O have O been O no O deaths O related O to O rejection O or O infection B . O Average O follow O - O up O was O 36 O + O / O - O 19 O months O ( O range O 1 O to O 65 O months O ) O . O Cumulative O survival O is O 88 O % O at O 5 O years O . O In O patients O less O than O 7 O years O of O age O , O rejection O was O monitored O noninvasively O . O In O the O first O postoperative O month O , O 89 O % O of O patients O were O treated O for O rejection O . O Freedom O from O serious O infections B was O 83 O % O at O 1 O month O and O 65 O % O at O 1 O year O . O Cytomegalovirus B infections I were O treated O successfully O with O ganciclovir O in O 11 O patients O . O No O impairment B of I growth I was O observed O in O children O who O underwent O transplantation O compared O with O a O control O population O . O Twenty O - O one O patients O ( O 60 O % O ) O have O undergone O annual O catheterizations O and O no O sign O of O graft O atherosclerosis B has O been O observed O . O Seizures B occurred O in O five O patients O ( O 14 O % O ) O and O hypertension B was O treated O in O 10 O patients O ( O 28 O % O ) O . O No O patient O was O disabled O and O no O lymphoproliferative B disorder I was O observed O . O ( O ABSTRACT O TRUNCATED O AT O 250 O WORDS O ) O Delirium B during O fluoxetine O treatment O . O A O case O report O . O The O correlation O between O high O serum O tricyclic O antidepressant O concentrations O and O central O nervous O system O side O effects O has O been O well O established O . O Only O a O few O reports O exist O , O however O , O on O the O relationship O between O the O serum O concentrations O of O selective O serotonin O reuptake O inhibitors O ( O SSRIs O ) O and O their O toxic O effects O . O In O some O cases O , O a O high O serum O concentration O of O citalopram O ( O > O 600 O nmol O / O L O ) O in O elderly O patients O has O been O associated O with O increased O somnolence B and O movement B difficulties I . O Widespread O cognitive B disorders I , O such O as O delirium B , O have O not O been O previously O linked O with O high O blood O levels O of O SSRIs O . 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 . O We O therefore O examined O whether O bupivacaine O alters O the O dysrhythmogenicity O of O subsequent O administration O of O epinephrine O in O conscious O , O healthy O dogs O and O in O anesthetized O dogs O with O myocardial B infarction I . O Forty O - O one O conscious O dogs O received O 10 O micrograms O . O kg O - O 1 O . O min O - O 1 O epinephrine O . O Seventeen O animals O responded O with O ventricular B tachycardia I ( O VT B ) O within O 3 O min O . O After O 3 O h O , O these O responders O randomly O received O 1 O or O 2 O mg O / O kg O bupivacaine O or O saline O over O 5 O min O , O followed O by O 10 O micrograms O . O kg O - O 1 O . O min O - O 1 O epinephrine O . O In O the O bupivacaine O groups O , O epinephrine O caused O fewer O prodysrhythmic O effects O than O without O bupivacaine O . O VT B appeared O in O fewer O dogs O and O at O a O later O time O , O and O there O were O more O sinoatrial O beats O and O less O ectopies O . O Epinephrine O shortened O QT O less O after O bupivacaine O than O in O control O animals O . O One O day O after O experimental O myocardial B infarction I , O six O additional O halothane O - O anesthetized O dogs O received O 4 O micrograms O . O kg O - O 1 O . O min O - O 1 O epinephrine O until O VT B appeared O . O After O 45 O min O , O 1 O mg O / O kg O bupivacaine O was O injected O over O 5 O min O , O again O followed O by O 4 O micrograms O . O kg O - O 1 O . O min O - O 1 O epinephrine O . O In O these O dogs O , O the O prodysrhythmic O response O to O epinephrine O was O also O mitigated O by O preceding O bupivacaine O . 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 . O Although O with O current O ulcer B therapy O ( O H O - O 2 O blockers O , O omeprazole O , O and O sucralfate O ) O , O the O frequency O of O milk B - I alkali I syndrome I has O decreased O significantly O , O the O classic O triad O of O hypercalcemia B , O alkalosis B , O and O renal B impairment I remains O the O hallmark O of O the O syndrome O . O Milk B - I alkali I syndrome I can O present O serious O and O occasionally O life O - O threatening O illness O unless O diagnosed O and O treated O appropriately O . O This O article O presents O a O patient O with O hypoparathyroidism B who O was O treated O with O calcium O carbonate O and O calcitriol O resulting O in O two O admissions O to O the O hospital O for O milk B - I alkali I syndrome I . O The O patient O was O successfully O treated O with O intravenous O pamidronate O on O his O first O admission O and O with O hydrocortisone O on O the O second O . O This O illustrates O intravenous O pamidronate O as O a O valuable O therapeutic O tool O when O milk B - I alkali I syndrome I presents O as O hypercalcemic B emergency O . O Famotidine O - O associated O delirium B . O A O series O of O six O cases O . O Famotidine O is O a O histamine O H2 O - O receptor O antagonist O used O in O inpatient O settings O for O prevention O of O stress B ulcers B and O is O showing O increasing O popularity O because O of O its O low O cost O . O Although O all O of O the O currently O available O H2 O - O receptor O antagonists O have O shown O the O propensity O to O cause O delirium B , O only O two O previously O reported O cases O have O been O associated O with O famotidine O . O The O authors O report O on O six O cases O of O famotidine O - O associated O delirium B in O hospitalized O patients O who O cleared O completely O upon O removal O of O famotidine O . O The O pharmacokinetics O of O famotidine O are O reviewed O , O with O no O change O in O its O metabolism O in O the O elderly O population O seen O . O The O implications O of O using O famotidine O in O elderly O persons O are O discussed O . O Encephalopathy B during O amitriptyline O therapy O : O are O neuroleptic B malignant I syndrome I and O serotonin B syndrome I spectrum I disorders I ? O This O report O describes O a O case O of O encephalopathy B developed O in O the O course O of O amitriptyline O therapy O , O during O a O remission O of O unipolar B depression I . O This O patient O could O have O been O diagnosed O as O having O either O neuroleptic B malignant I syndrome I ( O NMS B ) O or O serotonin B syndrome I ( O SS B ) O . O The O major O determinant O of O the O symptoms O may O have O been O dopamine O / O serotonin O imbalance O in O the O central O nervous O system O . O The O NMS B - O like O encephalopathy B that O develops O in O association O with O the O use O of O antidepressants O indicates O that O NMS B and O SS B are O spectrum B disorders I induced O by O drugs O with O both O antidopaminergic O and O serotonergic O effects O . O Genetic O separation O of O tumor B growth O and O hemorrhagic O phenotypes O in O an O estrogen O - O induced O tumor B . O Chronic O administration O of O estrogen O to O the O Fischer O 344 O ( O F344 O ) O rat O induces O growth O of O large O , O hemorrhagic B pituitary I tumors I . O Ten O weeks O of O diethylstilbestrol O ( O DES O ) O treatment O caused O female O F344 O rat O pituitaries O to O grow O to O an O average O of O 109 O . O 2 O + O / O - O 6 O . O 3 O mg O ( O mean O + O / O - O SE O ) O versus O 11 O . O 3 O + O / O - O 1 O . O 4 O mg O for O untreated O rats O , O and O to O become O highly O hemorrhagic B . O The O same O DES O treatment O produced O no O significant O growth O ( O 8 O . O 9 O + O / O - O 0 O . O 5 O mg O for O treated O females O versus O 8 O . O 7 O + O / O - O 1 O . O 1 O for O untreated O females O ) O or O morphological O changes O in O Brown O Norway O ( O BN O ) O rat O pituitaries O . O An O F1 O hybrid O of O F344 O and O BN O exhibited O significant O pituitary O growth O after O 10 O weeks O of O DES O treatment O with O an O average O mass O of O 26 O . O 3 O + O / O - O 0 O . O 7 O mg O compared O with O 8 O . O 6 O + O / O - O 0 O . O 9 O mg O for O untreated O rats O . O Surprisingly O , O the O F1 O hybrid O tumors B were O not O hemorrhagic O and O had O hemoglobin O content O and O outward O appearance O identical O to O that O of O BN O . O Expression O of O both O growth O and O morphological O changes O is O due O to O multiple O genes O . O However O , O while O DES O - O induced O pituitary O growth O exhibited O quantitative O , O additive O inheritance O , O the O hemorrhagic B phenotype O exhibited O recessive O , O epistatic O inheritance O . O Only O 5 O of O the O 160 O F2 O pituitaries O exhibited O the O hemorrhagic B phenotype O ; O 36 O of O the O 160 O F2 O pituitaries O were O in O the O F344 O range O of O mass O , O but O 31 O of O these O were O not O hemorrhagic B , O indicating O that O the O hemorrhagic B phenotype O is O not O merely O a O consequence O of O extensive O growth O . O The O hemorrhagic B F2 O pituitaries O were O all O among O the O most O massive O , O indicating O that O some O of O the O genes O regulate O both O phenotypes O . 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 . O Lamivudine O is O effective O in O suppressing O hepatitis B B I virus O DNA O in O Chinese O hepatitis O B O surface O antigen O carriers O : O a O placebo O - O controlled O trial O . O Lamivudine O is O a O novel O 2 O ' O , O 3 O ' O - O dideoxy O cytosine O analogue O that O has O potent O inhibitory O effects O on O hepatitis B B I virus O replication O in O vitro O and O in O vivo O . O We O performed O a O single O - O blind O , O placebo O - O controlled O study O to O assess O its O effectiveness O and O safety O in O Chinese O hepatitis O B O surface O antigen O ( O HBsAg O ) O carriers O . O Forty O - O two O Chinese O HBsAg B carriers O were O randomized O to O receive O placebo O ( O 6 O patients O ) O or O lamivudine O orally O in O dosages O of O 25 O mg O , O 100 O mg O , O or O 300 O mg O daily O ( O 12 O patients O for O each O dosage O ) O . O The O drug O was O given O for O 4 O weeks O . O The O patients O were O closely O monitored O clinically O , O biochemically O , O and O serologically O up O to O 4 O weeks O after O drug O treatment O . O All O 36 O patients O receiving O lamivudine O had O a O decrease O in O hepatitis O B O virus O ( O HBV O ) O DNA O values O of O > O 90 O % O ( O P O < O . O 001 O compared O with O placebo O ) O . O Although O 25 O mg O of O lamivudine O was O slightly O less O effective O than O 100 O mg O ( O P O = O . O 011 O ) O and O 300 O mg O ( O P O = O . 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 . O The O aim O of O our O study O was O to O re O - O examine O the O association O between O risk O of O VTE B and O OC O use O with O a O different O study O design O and O analysis O to O avoid O some O of O the O bias O and O confounding O of O the O earlier O studies O . O METHODS O : O We O used O computer O records O of O patients O from O 143 O general O practices O in O the O UK O . O The O study O was O based O on O the O medical O records O of O about O 540 O , O 000 O women O born O between O 1941 O and O 1981 O . O All O women O who O had O a O recorded O diagnosis O of O deep B - I vein I thrombosis I , O venous B thrombosis I not I otherwise O specified O , O or O pulmonary B embolus I during O the O study O period O , O and O who O had O been O treated O with O an O anticoagulant O were O identified O as O potential O cases O of O VTE B . O We O did O a O cohort O analysis O to O estimate O and O compare O incidence O of O VTE B in O users O of O the O main O OC O preparations O , O and O a O nested O case O - O control O study O to O calculate O the O odds O ratios O of O VTE B associated O with O use O of O different O types O of O OC O , O after O adjustment O for O potential O confounding O factors O . O In O the O case O - O control O study O , O we O matched O cases O to O controls O by O exact O year O of O birth O , O practice O , O and O current O use O of O OCs O . O We O used O a O multiple O logistic O regression O model O that O included O body O - O mass O index O , O number O of O cycles O , O change O in O type O of O OC O prescribed O within O 3 O months O of O the O event O , O previous O pregnancy O , O and O concurrent O disease O . O FINDINGS O : O 85 O women O met O the O inclusion O criteria O for O VTE O , O two O of O whom O were O users O of O progestagen O - O only O OCs O . O Of O the O 83 O cases O of O VTE B associated O with O use O of O combined O OCs O , O 43 O were O recorded O as O deep B - I vein I thrombosis I , O 35 O as O pulmonary B thrombosis I , O and O five O as O venous B thrombosis I not I otherwise O specified O . O The O crude O rate O of O VTE B per O 10 O , O 000 O woman O - O years O was O 4 O . O 10 O in O current O users O of O any O OC O , O 3 O . O 10 O in O users O of O second O - O generation O OCs O , O and O 4 O . O 96 O in O users O of O third O - O generation O preparations O . O After O adjustment O for O age O , O the O rate O ratio O of O VTE B in O users O of O third O - O generation O relative O to O second O - O generation O OCs O was O 1 O . O 68 O ( O 95 O % O CI O 1 O . O 04 O - O 2 O . O 75 O ) O . O Logistic O regression O showed O no O significant O difference O in O the O risk O of O VTE B between O users O of O third O - O generation O and O second O - O generation O OCs O . O Among O users O of O third O - O generation O progestagens O , O the O risk O of O VTE B was O higher O in O users O of O desogestrel O with O 20 O g O ethinyloestradiol O than O in O users O of O gestodene O or O desogestrel O with O 30 O g O ethinyloestradiol O . O With O all O second O - O generation O OCs O as O the O reference O , O the O odds O ratios O for O VTE B were O 3 O . O 49 O ( O 1 O . O 21 O - O 10 O . O 12 O ) O for O desogestrel O plus O 20 O g O ethinyloestradiol O and O 1 O . O 18 O ( O 0 O . O 66 O - O 2 O . O 17 O ) O for O the O other O third O - O generation O progestagens O . O INTERPRETATION O : O The O previously O reported O increase O in O odds O ratio O associated O with O third O - O generation O OCs O when O compared O with O second O - O generation O products O is O likely O to O have O been O the O result O of O residual O confounding O by O age O . O The O increased O odds O ratio O associated O with O products O containing O 20 O micrograms O ethinyloestradiol O and O desogestrel O compared O with O the O 30 O micrograms O product O is O biologically O implausible O , O and O is O likely O to O be O the O result O of O preferential O prescribing O and O , O thus O , O confounding O . O MK O - O 801 O augments O pilocarpine O - O induced O electrographic O seizure B but O protects O against O brain B damage I in O rats O . O 1 O . O The O authors O examined O the O anticonvulsant O effects O of O MK O - O 801 O on O the O pilocarpine O - O induced O seizure B model O . O Intraperitoneal O injection O of O pilocarpine O ( O 400 O mg O / O kg O ) O induced O tonic B and I clonic I seizure B . O Scopolamine O ( O 10 O mg O / O kg O ) O and O pentobarbital O ( O 5 O mg O / O kg O ) O prevented O development O of O pilocarpine O - O induced O behavioral O seizure B but O MK O - O 801 O ( O 0 O . O 5 O mg O / O kg O ) O did O not O . O 2 O . O An O electrical O seizure B measured O with O hippocampal O EEG O appeared O in O the O pilocarpine O - O treated O group O . O Scopolamine O and O pentobarbital O blocked O the O pilocarpine O - O induced O electrographic O seizure B , O MK O - O 801 O treatment O augmented O the O electrographic O seizure B induced O by O pilocarpine O . O 3 O . O Brain B damage I was O assessed O by O examining O the O hippocampus O microscopically O . O Pilocarpine O produced O neuronal B death I in O the O hippocampus O , O which O showed O pyknotic O changes O . O Pentobarbital O , O scopolamine O and O MK O - O 801 O protected O the O brain B damage I by O pilocarpine O , O though O in O the O MK O - O 801 O - O treated O group O , O the O pyramidal O cells O of O hippocampus O appeared O darker O than O normal O . O In O all O treatments O , O granule O cells O of O the O dentate O gyrus O were O not O affected O . O 4 O . O These O results O indicate O that O status B epilepticus I induced O by O pilocarpine O is O initiated O by O cholinergic O overstimulation O and O propagated O by O glutamatergic O transmission O , O the O elevation O of O which O may O cause O brain B damage I through O an O excitatory O NMDA O receptor O - O mediated O mechanism O . O Paclitaxel O , O 5 O - O fluorouracil O , O and O folinic O acid O in O metastatic O breast B cancer I : O BRE O - O 26 O , O a O phase O II O trial O . O 5 O - O Fluorouracil O plus O folinic O acid O and O paclitaxel O ( O Taxol O ; O Bristol O - O Myers O Squibb O Company O , O Princeton O , O NJ O ) O are O effective O salvage O therapies O for O metastatic O breast B cancer I patients O . O Paclitaxel O and O 5 O - O fluorouracil O have O additive O cytotoxicity B in O MCF O - O 7 O cell O lines O . O We O performed O a O phase O II O trial O of O paclitaxel O 175 O mg O / O m2 O over O 3 O hours O on O day O I O followed O by O folinic O acid O 300 O mg O over O 1 O hour O before O 5 O - O fluorouracil O 350 O mg O / O m2 O on O days O 1 O to O 3 O every O 28 O days O ( O TFL O ) O in O women O with O metastatic O breast B cancer I . O Analysis O is O reported O on O 37 O patients O with O a O minimum O of O 6 O months O follow O - O up O who O received O a O total O of O 192 O cycles O of O TFL O : O nine O cycles O ( O 5 O % O ) O were O associated O with O grade O 3 O / O 4 O neutropenia B requiring O hospitalization O ; O seven O ( O 4 O % O ) O cycles O in O two O patients O required O granulocyte O colony O - O stimulating O factor O due O to O neutropenia B ; O no O patient O required O platelet O transfusions O . O Grade O 3 O / O 4 O nonhematologic O toxicities B were O uncommon O . O Among O the O 34 O patients O evaluable O for O response O , O there O were O three O complete O responses O ( O 9 O % O ) O and O 18 O partial O responses O ( O 53 O % O ) O for O an O overall O response O rate O of O 62 O % O . O Of O the O 19 O evaluable O patients O with O prior O doxorubicin O exposure O , O 11 O ( O 58 O % O ) O responded O compared O with O nine O of O 15 O ( O 60 O % O ) O without O prior O doxorubicin O . O Plasma O paclitaxel O concentrations O were O measured O at O the O completion O of O paclitaxel O infusion O and O at O 24 O hours O in O 19 O patients O . O TFL O is O an O active O , O well O - O tolerated O regimen O in O metastatic O breast B cancer I . O Efficacy O and O proarrhythmia O with O the O use O of O d O , O l O - O sotalol O for O sustained O ventricular B tachyarrhythmias I . O This O study O prospectively O evaluated O the O clinical O efficacy O , O the O incidence O of O torsades B de I pointes I , O and O the O presumable O risk O factors O for O torsades B de I pointes I in O patients O treated O with O d O , O l O - O sotalol O for O sustained O ventricular B tachyarrhythmias I . O Eighty O - O one O consecutive O patients O ( O 54 O with O coronary B artery I disease I , O and O 20 O with O dilated B cardiomyopathy I ) O with O inducible O sustained O ventricular B tachycardia I or O ventricular B fibrillation I received O oral O d O , O l O - O sotalol O to O prevent O induction O of O the O ventricular B tachyarrhythmia I . O During O oral O loading O with O d O , O l O - O sotalol O , O continuous O electrocardiographic O ( O ECG O ) O monitoring O was O performed O . O Those O patients O in O whom O d O , O l O - O sotalol O prevented O induction O of O ventricular B tachycardia I or O ventricular B fibrillation I were O discharged O with O the O drug O and O followed O up O on O an O outpatient O basis O for O 21 O + O / O - O 18 O months O . O Induction O of O the O ventricular B tachyarrhythmia I was O prevented O by O oral O d O , O l O - O sotalol O in O 35 O ( O 43 O % O ) O patients O ; O the O ventricular B tachyarrhythmia I remained O inducible O in O 40 O ( O 49 O % O ) O patients O ; O and O two O ( O 2 O . O 5 O % O ) O patients O did O not O tolerate O even O 40 O mg O of O d O , O l O - O sotalol O once O daily O . O Four O ( O 5 O % O ) O patients O had O from O torsades B de I pointes I during O the O initial O oral O treatment O with O d O , O l O - O sotalol O . O Neither O ECG O [ O sinus O - O cycle O length O ( O SCL O ) O , O QT O or O QTc O interval O , O or O U O wave O ] O nor O clinical O parameters O identified O patients O at O risk O for O torsades B de I pointes I . O However O , O the O oral O dose O of O d O , O l O - O sotalol O was O significantly O lower O in O patients O with O torsades B de I pointes I ( O 200 O + O / O - O 46 O vs O . O 328 O + O / O - O 53 O mg O / O day O ; O p O = O 0 O . O 0017 O ) O . O Risk O factors O associated O with O the O development O of O torsades B de I pointes I were O the O appearance O of O an O U O wave O ( O p O = O 0 O . O 049 O ) O , O female O gender O ( O p O = O 0 O . O 015 O ) O , O and O significant O dose O - O corrected O changes O of O SCL O , O QT O interval O , O and O QTc O interval O ( O p O < O 0 O . O 05 O ) O . O During O follow O - O up O , O seven O ( O 20 O % O ) O patients O had O a O nonfatal O ventricular B tachycardia I recurrence O , O and O two O ( O 6 O % O ) O patients O died O suddenly O . O One O female O patient O with O stable O cardiac B disease I had O recurrent O torsades B de I pointes I after O 2 O years O of O successful O treatment O with O d O , O l O - O sotalol O . O Torsades B de I pointes I occurred O early O during O treatment O even O with O low O doses O of O oral O d O , O l O - O sotalol O . 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