interacts_with DB06144?
Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 -3B , P01160 , and P36382 from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = .0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF . Natriuretic peptides induce weak P50552 phosphorylation at DB00133 239 in platelets . Cyclic guanosine-3',5'-monophoshate ( cGMP ) is the common second messenger for the cardiovascular effects of nitric oxide ( NO ) and natriuretic peptides ( NP ; e.g. atrial NP [ P01160 ] ) , which activate soluble and particulate guanylyl cyclases , respectively . The role of NO in regulating cGMP and platelet function is well documented , whereas there is little evidence supporting a role for NPs in regulating platelet reactivity . By studying platelet aggregation and secretion in response to a P25116 peptide , collagen and ADP , and phosphorylation of the cGMP-dependent protein kinase ( PKG ) substrate vasodilator-stimulated phosphoprotein ( P50552 ) at serine 239 , we evaluated the effects of NPs in the absence or presence of the non-selective cGMP and DB02527 phosphodiesterase ( PDE ) inhibitor , DB07954 ( DB07954 ) . Our results show that NPs , possibly through the clearance receptor ( natriuretic peptide receptor-C ) expressed on platelet membranes , increase P50552 phosphorylation but only following PDE inhibition , indicating a small , localised cGMP synthesis . As platelet aggregation and secretion measured under the same conditions were not affected , we conclude that the magnitude of PKG activation achieved by NPs in platelets per se is not sufficient to exert functional inhibition of platelet involvement in haemostasis . Biological characterization of DB05037 , a small-molecule inhibitor of cyclin-dependent kinases , in human tumor cell lines . P12004 -dependent kinases ( CDK ) , and their regulatory cyclin partners , play a central role in eukaryotic cell growth , division , and death . This key role in cell cycle progression , as well as their deregulation in several human cancers , makes them attractive therapeutic targets in oncology . A series of CDK inhibitors was developed using Astex 's fragment-based medicinal chemistry approach , linked to high-throughput X-ray crystallography . A compound from this series , designated DB05037 , is currently in early-phase clinical development . We describe here the biological characterization of DB05037 , a potent inhibitor of several CDK family members . DB05037 showed potent antiproliferative activity ( 40-940 nmol/L ) in a panel of human tumor cell lines , and the mechanism of action was shown here to be consistent with the inhibition of P06493 and P24941 in solid tumor cell lines . DB05037 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models . Tumor regression was observed following twice daily dosing of DB05037 in the HCT116 and HT29 colon cancer xenograft models . We show that these biological effects are linked to inhibition of CDKs in vivo and that DB05037 induces tumor cell apoptosis in these xenograft models . DB05037 has an attractive biological profile for development as a clinical candidate , and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development . Studies described here formed the biological rationale for investigating the potential therapeutic benefit of DB05037 in cancer patients . DB09030 : first global approval . DB09030 [ DB09030 (®) ( US ) ] , an orally active protease-activated receptor-1 ( P25116 ) receptor antagonist , has been developed by Merck & Co for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction ( MI ) or peripheral arterial disease ( PAD ) . DB09030 has received its first global approval for this indication in the US . This article summarizes the milestones in the development of vorapaxar leading to this first approval for the reduction of thrombotic cardiovascular events in patients with a prior MI or PAD . DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side-effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single-nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty-eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p=0.0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p=0.041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p=0.0277 ) . The side-effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects . Vasopeptidase-activated latent ligands of the histamine receptor-1 . Whether peptidases present in vascular cells can activate prodrugs active on vascular cells has been tested with 2 potential latent ligands of the histamine H1 receptor ( P35367 ) . First , a peptide consisting of the antihistamine cetirizine ( CTZ ) condensed at the N-terminus of ε-aminocaproyl-bradykinin ( εACA-BK ) was evaluated for an antihistamine activity that could be revealed by degradation of the peptide part of the molecule . CTZ-εACA-BK had a submicromolar affinity for the BK B2 receptor ( P30411 ; IC50 of 590 nM , [(3)H]BK binding competition ) , but a non-negligible affinity for the human H1 receptor ( P35367 ; IC50 of 11 μM for [(3)H] DB06691 binding ) . In the human isolated umbilical vein , a system where both endogenous P30411 and P35367 mediate strong contractions , CTZ-εACA-BK exerted mild antagonist effects on histamine-induced contraction that were not modified by omapatrilat or by a P30411 antagonist that prevents endocytosis of the BK conjugate . Cells expressing recombinant P12821 or P30411 incubated with CTZ-εACA-BK did not release a competitor of [(3)H] DB06691 binding to H1Rs . Thus , there is no evidence that CTZ-εACA-BK can release free cetirizine in biological environments . The second prodrug was a blocked agonist , L-alanyl-histamine , potentially activated by aminopeptidase N ( P15144 ) . This compound did not compete for [(3)H] DB06691 binding to H1Rs . The human umbilical vein contractility assay responded to L-alanyl-histamine ( EC50 54.7 μM ) , but the P15144 inhibitor amastatin massively ( 17-fold ) reduced its apparent potency . Amastatin did not influence the potency of histamine as a contractile agent . One of the 2 tested latent P35367 ligands , L-alanyl-histamine , supported the feasibility of pro-drug activation by vascular ectopeptidases . Protein indicators for HaCaT cell damage induced by UVB irradiation . UVB ( 290-320 nm ) is one major risk factor of skin diseases in human . In order to provide potential protein molecules in skin cell damage and skin diseases induced by UVB irradiation , the differentially expressed proteins in human keratinocytes cell HaCaT by UVB irradiation were screened by two-dimensional difference in-gel electrophoresis ( 2D DIGE ) combined to high performance liquid chromatography-nano-electrospray ionization tandem mass spectrometry ( HPLC-nESI-MS/MS ) . 31 protein spots were found differentially expressed with statistical significance ( p < 0.05 ) . Sixteen and 15 protein spots were observed up-regulated and down-regulated in UVB-irradiated HaCaT , respectively . Twenty-eight unique proteins were identified by searching the MS/MS data against NCBInr database through TurboSequest Bioworks software . Among the identified 28 UVB irradiation responding protein indicators , only laminin receptor 1 ( P08865 ) , calmodulin ( P62158 ) , cathepsin D ( P07339 ) and peroxiredoxin ( Q06830 ) proteins have been reported associated with skin burn and wound healing , keratinocytes proliferation and migration and epidermal barrier repairing . Most of these targets were for the first time revealed to be associated with skin cell damage induced by UVB irradiation . Function and bioinformatics analyses of the identified protein candidates were also performed using PANTHER analysis with the aid of DAVID platform . The current work provides potential protein indicators for skin cell damage from UVB irradiation . Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( DB06144 ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4(3)-based assays were found to be the most economical but had high false-hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color-quenching problems but was expensive and still gave false hits . The nonradioactive Rb+ efflux assay was the most sensitive of all the assays evaluated and had the lowest false-hit rate . Lasting controversy on ranibizumab and bevacizumab . Vascular endothelial growth factor ( P15692 ) , an important angiogenic factor that is able to stimulate the proliferation and migration of endothelial cells , is the best-studied hallmark of angiogenesis . Neovascularization is a major cause of age-related macular degeneration ( AMD ) which is a leading cause of blindness in the elderly population . Specific molecular inhibitors of P15692 have been proved to be useful in the treatment of AMD . DB01270 and DB00112 are structurally similar to anti- P15692 drugs in the treatment of AMD . Many studies have indicated that DB01270 and DB00112 are of roughly equal short-term efficacy and safety , DB00112 is an attractive alternative to DB01270 due to its lower cost . However , only DB01270 has received Food and Drug Administration ( FDA ) approval for the treatment of macular degeneration . More multicenter clinical trials are required to compare the relative efficacy and safety of these two drugs and some progress has been achieved . This review discusses the clinical effectiveness , safety , cost and other practical implications of DB01270 and DB00112 . Contribution of the 37-kDa laminin receptor precursor in the anti-metastatic P08118 -derived peptide DB04985 cell surface binding . PURPOSE : DB04985 is an anti-metastatic synthetic peptide with promising therapeutic efficacy against hormone-refractory prostate cancer . The characterization of the DB04985 peptide cell surface binding/internalization mechanisms and of the receptors involved remained to be explored . RESULTS : [(14)C] DB04985 cell surface binding assays showed rapid and transient kinetic profile , that was inhibited by RGD peptides , laminin , hyaluronan , and type-I collagen . RGD peptides were however unable to inhibit DB04985 intracellular uptake . Far-Western ligand binding studies enabled the identification of the 37-kDa laminin receptor precursor ( P08865 ) as a potential ligand for DB04985 . Overexpression of the recombinant P08865 indeed led to an increase in DB04985 binding but unexpectedly not to its uptake . CONCLUSIONS : Our data support the implication of laminin receptors in cell surface binding and in transducing DB04985 anti-metastatic effects , and provide a rational for targeting cancers that express high levels of such laminin receptors . Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia . Gastric cancer is the second leading cause of cancer death worldwide . Predisposing factors include achlorhydria , Helicobacter pylori infection , oxyntic atrophy and Q03403 -expressing metaplasia . In parietal cells , apical potassium channels comprising the P51787 alpha subunit and the Q9Y6J6 beta subunit provide a K(+) efflux current to facilitate gastric acid secretion by the apical H(+)K(+)ATPase . Accordingly , genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion . Other evidence has suggested a role for Q9Y6J6 in human gastric cancer cell proliferation , independent of its role in gastric acidification . Here , we demonstrate that 1-year-old Kcne2(-/-) mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda , 6-fold increased stomach mass , increased Ki67 and nuclear P12004 D1 expression , and Q03403 - and cytokeratin 7-expressing metaplasia . Some Kcne2(-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum , and neoplastic invasion of thin walled vessels in the sub-mucosa . Finally , analysis of human gastric cancer tissue indicated reduced parietal cell Q9Y6J6 expression . Together with previous findings , the results suggest Q9Y6J6 disruption as a possible risk factor for gastric neoplasia . Changes in urinary proximal tubule parameters in neonatal rats exposed to cadmium chloride during pregnancy . Pregnant Sprague-Dawley rats were injected intraperitoneally with physiological saline solution ( vehicle ) or cadmium chloride ( CdCl2 ) at 2.0 or 2.5 mg kg-1 on days 8 , 10 , 12 and 14 of gestation . On postnatal day ( P01160 ) 3 , 12 or 49 , the offspring were examined for 8- or 24-h urinary excretion of beta 2-microglobulin ( beta 2-m ) , metallothionein ( MT ) and urinary activity of three proximal tubular enzymes : gammaglutamyl transferase ( P19440 ) , alkaline phosphatase ( ALP ) and O60502 ( NAG ) . Treatment with CdCl2 did not affect growth or survival of offspring . Significant decreases in the urinary excretion of P19440 , ALP and NAG were observed on P01160 3 , at both doses . Exposure to 4 x 2.5 mg kg-1 resulted in functional deficit of the proximal tubule on P01160 3 , as evidenced by the significant increase in beta 2-m . Except for a slight but significant increase of beta 2-m in 49-day-old males , all the other urinary parameters returned to control values on P01160 12 . There was no effect on MT . Results from this study show that prenatal exposure to CdCl2 can induce significant changes in the kidney biochemistry of rats in the early postnatal period . DB00160 aminotransferase homologs catalyze the glutamate:glyoxylate aminotransferase reaction in peroxisomes of Arabidopsis . Plant peroxisomal glyoxylate aminotransferases play central roles within the photorespiratory pathway . Genes encoding glyoxylate aminotransferases have been isolated from several animals and microbes , but only recently have plant homologs been identified . Three Arabidopsis homologs of alanine (Ala):glyoxylate aminotransferase 2 ( Q9BYV1 ) contain a putative type 1 peroxisomal targeting signal ( PTS1 ) , but the metabolic significance of these Q9BYV1 homologs is unknown . P19440 and P36268 are Ala aminotransferase ( AlaAT ) homologs from Arabidopsis that represent another type of glyoxylate aminotransferase . These proteins are class I aminotransferases , each containing a putative PTS1 . P19440 and P36268 are members of a small family of AlaATs in Arabidopsis . When expressed as recombinant proteins in Escherichia coli , P19440 and P36268 displayed biochemical characteristics very similar to one another , and to the Arabidopsis protein purified from leaves . Four aminotransferase activities were specifically associated with P19440 and P36268 , using the substrate pairs glutamate ( DB00142 ):glyoxylate , Ala:glyoxylate , DB00142 :pyruvate , and Ala:2-oxoglutarate . P19440 and P36268 may have partially redundant functions ; transcripts of both genes were detected in many of the same tissues . Although DB00142 :glyoxylate aminotransferase ( P19440 ) activity has been observed in several locations in different plants and algae , including the cytoplasm and mitochondria , our subcellular fractionation data indicate that P19440 activity was exclusively peroxisomal in Arabidopsis . Thus , glyoxylate aminotransferase reactions in plant peroxisomes appear to be catalyzed by at least two distinct types of aminotransferases : an AGT1 homolog with serine:glyoxylate aminotransferase activity ( A.H. Liepman , L.J. Olsen [ 2001 ] Plant J 25 : 487-498 ) , and a pair of closely related , potentially redundant AlaAT homologs with P19440 activity . Structure-activity relationship studies of CNS agents -- XVII . Spiro[piperidine-4',1-(1,2,3,4-tetrahydro-beta-carboline)] as a probe defining the extended topographic model of P08908 receptors . Spiro[piperidine-4',1-(1,2,3,4-tetrahydro-beta-carboline)] ( 10 ) , its derivatives 11-15 and its analogs 16 and 17 were examined as ligands of serotonin P08908 receptors . It was shown that compounds 12 and 14 had essentially the same P08908 affinity as 1-phenylpiperazine and its rigid analog 7 , whereas there were substantial differences in the steric arrangement of their crucial pharmacophores , i.e. aromatic and protonation centers . On the basis of the existing models and using the DB04829 structure as a template , a new , extended three-point topographic model of P08908 receptors has been proposed . Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8-hydroxy-DPAT ( 8-OH-DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3-10 , 10-17 or 17-24 ) were injected daily with 1 mg/kg 8-OH-DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye-opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10-17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17-24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin 's influence in brain development . Platelet-associated anti- P08514 -IIIa autoantibodies in chronic immune thrombocytopenic purpura recognizing epitopes close to the ligand-binding site of glycoprotein ( GP ) IIb . Localization of epitopes for platelet-associated ( PA ) anti- P08514 -IIIa ( alpha(IIb)beta(3) ) autoantibodies in chronic immune thrombocytopenic purpura remains elusive . Previous studies suggest that PA antibodies recognize the tertiary structure of intact glycoprotein ( GP ) IIb-IIIa . To localize their epitopes using antigen-capture enzyme-linked immunosorbent assay ( ELISA ) , the reactivity of 34 PA anti- P08514 -IIIa antibodies was examined with recombinant P08514 -IIIa having a defect in ligand-binding sites in either P08514 or P05106 , and no major conformational change was induced : KO variant P08514 -IIIa was attributed to a 2-amino acid insertion between residues 160 and 161 in the W3 4-1 loop in P08514 , and P62158 variant P08514 -IIIa was attributed to D119Y in P05106 . In one third ( 11 of 34 ) of the patients , PA antibodies showed a marked decrease ( less than 50 % ) in reactivity with KO compared with wild-type P08514 -IIIa . Their reactivity was also impaired against GPIIbD163A-IIIa . In sharp contrast , they reacted normally with P62158 P08514 -IIIa . OP-G2 , a ligand-mimetic monoclonal antibody , markedly inhibited their binding to P08514 -IIIa in patients with impaired binding to KO P08514 -IIIa , but small P08514 -IIIa antagonists did not . In addition , a newly developed sensitive ELISA indicated that autoantibodies showing impaired binding to KO are more potent inhibitors for fibrinogen binding . The present data suggest that certain PA anti- P08514 -IIIa autoantibodies recognize epitopes close to the ligand-binding site in P08514 , but not in P05106 . Pharmacogenomics of methadone maintenance treatment . DB00333 is the major opioid substitution therapy for opioid dependence . Dosage is highly variable and is often controlled by the patient and prescriber according to local and national policy and guidelines . Nevertheless many genetic factors have been investigated including those affecting its metabolism ( P20813 -consistent results ) , efflux transport ( P-gp-inconsistent results ) , target μ-opioid receptor ( μ-opioid receptor-inconsistent results ) and a host of other receptors ( P14416 ) and signaling elements ( P48051 and P32121 ; not replicated ) . None by themselves have been able to substantially explain dosage variation ( the major but not sole end point ) . When multiple genes have been combined such as P08183 , P20813 , P35372 and P14416 a greater contribution to dosage variation was found but not as yet replicated . As stabilization of dosage needs to be made rapidly , it is imperative that larger internationally based studies be instigated so that genetic contribution to dosage can be properly assessed , which may or may not tailor to different ethnic groups and each country 's policy towards an outcome that benefits all . Contribution of platelets and the vessel wall to the antithrombotic effects of a single bolus injection of Fab fragments of the antiplatelet P08514 /IIIa antibody 7E3 in a canine arterial eversion graft preparation . The contribution of platelets and the vessel wall to the antithrombotic effects of a single intravenous bolus injection of 0.8 mg/kg Fab fragments of the monoclonal antiplatelet glycoprotein IIb/IIIa receptor antibody DB00054 ( 7E3-Fab ) , combined with continuous heparin anticoagulation ( 100 U/kg bolus and 50 U/kg per hour ) , was studied in a canine preparation consisting of an everted ( inside out ) carotid arterial segment that had been inserted into a transected femoral artery . In all 6 control dogs without antibody , persistent or transient eversion graft occlusion occurred during an initial 2-hour observation period , and 5 of the 6 grafts were occluded at 24 hours . In 6 dogs given 7E3-Fab 24 hours before receiving an everted carotid artery segment from a donor dog , cyclic occlusion and reflow occurred in all dogs , whereas the grafts were patent at the end of a 2-hour observation period in 5 of the 6 dogs ( P = .056 versus control ) . When transferred back to the donor dogs , the patient eversion segments showed brief periods of cyclic occlusion and reflow within 2 hours in 3 of 5 dogs ( P = .034 versus control ) , whereas all of the 5 eversion segments were patent at 24 hours ( P < .005 versus control ) . ( ABSTRACT TRUNCATED AT 250 WORDS ) Interactions between bradykinin ( BK ) and cell adhesion molecule ( P62158 ) expression in peptidoglycan-polysaccharide ( PG-PS ) -induced arthritis . Bradykinin ( BK ) , a vasoactive , proinflammatory nonapeptide , promotes cell adhesion molecule ( P62158 ) expression , leukocyte sequestration , inter-endothelial gap formation , and protein extravasation in postcapillary venules . These effects are mediated by bradykinin-1 ( P46663 ) and-2 ( P30411 ) receptors . We delineated some of the mechanisms by which BK could influence chronic inflammation by altering P62158 expression on leukocytes , endothelium , and synovium in joint sections of peptidoglycan-polysaccharide-injected Lewis rats . Blocking P46663 results in significantly increased joint inflammation . Immunohistochemistry of the P46663 antagonist group revealed increased leukocyte and synovial CD11b and CD54 expression and increased CD11b and P16070 endothelial expression . P30411 antagonism decreased leukocyte and synovial P16070 and CD54 and endothelial CD11b expression . Although these findings implicate P30411 involvement in the acute phase of inflammation by facilitating leukocyte activation ( CD11b ) , homing ( P16070 ) , and transmigration ( CD54 ) . Treatment with a P30411 antagonist did not affect the disease evolution in this model . In contrast , when both BK receptors are blocked , the aggravation of inflammation by P46663 blockade is neutralized and there is no difference from the disease-untreated model . Our findings suggest that P46663 and P30411 signaling show physiologic antagonism . P46663 signaling suggests involvement in down-regulation of leukocyte activation , transmigration , and homing . Further studies are needed to evaluate the B1 receptor agonist 's role in this model . Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44.1 ± 72.1 days ) were genetically analyzed for P51787 , Q12809 , P15382 -5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high-performance liquid chromatography and direct sequencing . Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p.N1774D , p.T290fsX53 , p.F1486del and p.N406K ) in Q14524 , and 1 mutation ( p.G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin-sensitive persistent late Na(+) currents . By contrast , Q14524 -T290fsX53 was nonfunctional . Q12809 -G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation . DB00741 response to stress is associated with myocardial remodeling in salmonid fishes . Cardiac disease is frequently reported in farmed animals , and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing . DB00741 is a major stress hormone in teleosts , and this hormone has adverse effects on the myocardium . Strains of rainbow trout ( Oncorhynchus mykiss ) selected for divergent post-stress cortisol levels [ high responsive ( HR ) and low responsive ( LR ) ] have been established as a comparative model to examine how fish with contrasting stress-coping styles differ in their physiological and behavioral profiles . We show that the mean cardiosomatic index ( CSI ) of adult HR fish was 34 % higher than in LR fish , mainly because of hypertrophy of the compact myocardium . To characterize the hypertrophy as physiological or pathological , we investigated specific cardiac markers at the transcriptional level . HR hearts had higher mRNA levels of cortisol receptors ( MR , GR1 and GR2 ) , increased P53805 levels [ suggesting enhanced pro-hypertrophic nuclear factor of activated T-cell ( NFAT ) signaling ] and increased P15692 gene expression ( reflecting increased angiogenesis ) . Elevated collagen ( Col1a2 ) expression and deposition in HR hearts supported enhanced fibrosis , whereas the heart failure markers P01160 and DB04899 were not upregulated in HR hearts . To confirm our results outside the selection model , we investigated the effect of acute confinement stress in wild-type European brown trout , Salmo trutta . A positive correlation between post-stress cortisol levels and CSI was observed , supporting an association between enhanced cortisol response and myocardial remodeling . In conclusion , post-stress cortisol production correlates with myocardial remodeling , and coincides with several indicators of heart pathology , well-known from mammalian cardiology .