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18235024
|
Cone dystrophy with supernormal rod response is strictly associated with mutations in KCNV2. PURPOSE: Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior RESULTS: Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. results. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS: The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.
|
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19779499
|
Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family. Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant disorder, which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. A major disease-causing gene for HypoPP has been identified as CACNA1S, which encodes the skeletal muscle calcium channel alpha-subunit with four transmembrane domains (I-IV), each with six transmembrane segments (S1-S6). To date, all CACNA1S mutations identified in HypoPP patients are located within the voltage-sensor S4 segment. In this study we report a novel CACNA1S mutation in a new region of the protein, the S3 segment of domain III. We characterized a four-generation South American family with HypoPP. Genetic analysis identified a novel V876E mutation in all HypoPP patients in the family, but not in normal family members or 160 control people. Clinical analysis indicates that mutation V876E is associated with a severe outcome as characterized by a very early age of onset, complete penetrance and a severe prognosis including death. These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP.
|
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20801104
|
Association study of polymorphisms in the promoter region of DRD4 with schizophrenia, depression, and heroin addiction. This study investigated the possible association between three functional polymorphisms in the promoter region of the dopamine D4 receptor (DRD4) gene and schizophrenia, depression, and heroin addiction. Genomic DNA was isolated from the venous blood leukocytes of 322 unrelated patients with schizophrenia, 156 patients with depression, 300 patients with heroin addiction, and 300 healthy unrelated individuals. Polymorphisms in the promoter region of DRD4 (-120 bp duplication, -616C/G, and -521C/T) were genotyped using allele-specific polymerase chain reaction analysis. Genotype and allele were analyzed using SPSS 11.5 software. Results of this analysis indicated that there is a strong finding of -120 bp duplication allele frequencies with schizophrenia (p=0.008) and weak finding with -1240 L/S and for paranoid schizophrenia (p=0.022). Interestingly, there is a stronger finding with -521 C/T allele frequencies with heroin dependence (p=0.0002). These observations strongly suggest that the -120-bp duplication polymorphism of DRD4 is associated with schizophrenia and that the -521 C/T polymorphism is associated with heroin addiction.
|
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"0",
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"0",
"5",
"5",
"0",
"0",
"0",
"0",
"2",
"2",
"0"
] |
22836123
|
Late-onset scleroderma renal crisis induced by tacrolimus and prednisolone: a case report. Scleroderma renal crisis (SRC) is a rare complication of systemic sclerosis (SSc) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with SSc. In this article, we report a patient with SRC induced by tacrolimus and corticosteroids. The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc.
|
[
"Late-onset",
"scleroderma",
"renal",
"crisis",
"induced",
"by",
"tacrolimus",
"and",
"prednisolone",
":",
"a",
"case",
"report",
".",
"Scleroderma",
"renal",
"crisis",
"(",
"SRC",
")",
"is",
"a",
"rare",
"complication",
"of",
"systemic",
"sclerosis",
"(",
"SSc",
")",
"but",
"can",
"be",
"severe",
"enough",
"to",
"require",
"temporary",
"or",
"permanent",
"renal",
"replacement",
"therapy",
".",
"Moderate",
"to",
"high",
"dose",
"corticosteroid",
"use",
"is",
"recognized",
"as",
"a",
"major",
"risk",
"factor",
"for",
"SRC",
".",
"Furthermore",
",",
"there",
"have",
"been",
"reports",
"of",
"thrombotic",
"microangiopathy",
"precipitated",
"by",
"cyclosporine",
"in",
"patients",
"with",
"SSc",
".",
"In",
"this",
"article",
",",
"we",
"report",
"a",
"patient",
"with",
"SRC",
"induced",
"by",
"tacrolimus",
"and",
"corticosteroids",
".",
"The",
"aim",
"of",
"this",
"work",
"is",
"to",
"call",
"attention",
"to",
"the",
"risk",
"of",
"tacrolimus",
"use",
"in",
"patients",
"with",
"SSc",
"."
] |
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27184800
|
Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib. BACKGROUND: Sorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking. METHODS: We used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used. RESULTS: We observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival. CONCLUSION: These findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.
|
[
"Metallothionein-1",
"as",
"a",
"biomarker",
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"altered",
"redox",
"metabolism",
"in",
"hepatocellular",
"carcinoma",
"cells",
"exposed",
"to",
"sorafenib",
".",
"BACKGROUND",
":",
"Sorafenib",
",",
"a",
"kinase",
"inhibitor",
"active",
"against",
"various",
"solid",
"tumours",
",",
"induces",
"oxidative",
"stress",
"and",
"ferroptosis",
",",
"a",
"new",
"form",
"of",
"oxidative",
"necrosis",
",",
"in",
"some",
"cancer",
"cells",
".",
"Clinically-applicable",
"biomarkers",
"that",
"reflect",
"the",
"impact",
"of",
"sorafenib",
"on",
"the",
"redox",
"metabolism",
"of",
"cancer",
"cells",
"are",
"lacking",
".",
"METHODS",
":",
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"microarrays",
",",
"real-time",
"PCR",
",",
"immunoblot",
",",
"protein-specific",
"ELISA",
",",
"and",
"gene",
"reporter",
"constructs",
"encoding",
"the",
"enzyme",
"luciferase",
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"the",
"response",
"of",
"a",
"panel",
"of",
"cancer",
"cells",
"to",
"sorafenib",
".",
"Tumour",
"explants",
"prepared",
"from",
"surgical",
"hepatocellular",
"carcinoma",
"(",
"HCC",
")",
"samples",
"and",
"serum",
"samples",
"obtained",
"from",
"HCC",
"patients",
"receiving",
"sorafenib",
"were",
"also",
"used",
".",
"RESULTS",
":",
"We",
"observed",
"that",
"genes",
"of",
"the",
"metallothionein-1",
"(",
"MT1",
")",
"family",
"are",
"induced",
"in",
"the",
"HCC",
"cell",
"line",
"Huh7",
"exposed",
"to",
"sorafenib",
".",
"Sorafenib",
"increased",
"the",
"expression",
"of",
"MT1G",
"mRNA",
"in",
"a",
"panel",
"of",
"human",
"cancer",
"cells",
",",
"an",
"effect",
"that",
"was",
"not",
"observed",
"with",
"eight",
"other",
"clinically-approved",
"kinase",
"inhibitors",
".",
"We",
"identified",
"the",
"minimal",
"region",
"of",
"the",
"MT1G",
"promoter",
"that",
"confers",
"inducibility",
"by",
"sorafenib",
"to",
"a",
"133",
"base",
"pair",
"region",
"containing",
"an",
"Anti-oxidant",
"Response",
"Element",
"(",
"ARE",
")",
"and",
"showed",
"the",
"essential",
"role",
"of",
"the",
"transcription",
"factor",
"NRF2",
"(",
"Nuclear",
"factor",
"erythroid",
"2-Related",
"Factor",
"2",
")",
".",
"We",
"examined",
"the",
"clinical",
"relevance",
"of",
"our",
"findings",
"by",
"analysing",
"the",
"regulation",
"of",
"MT1G",
"in",
"five",
"tumour",
"explants",
"prepared",
"from",
"surgical",
"HCC",
"samples",
".",
"Finally",
",",
"we",
"showed",
"that",
"the",
"protein",
"levels",
"of",
"MT1",
"increase",
"in",
"the",
"serum",
"of",
"some",
"HCC",
"patients",
"receiving",
"sorafenib",
",",
"and",
"found",
"an",
"association",
"with",
"reduced",
"overall",
"survival",
".",
"CONCLUSION",
":",
"These",
"findings",
"indicate",
"that",
"MT1",
"constitute",
"a",
"biomarker",
"adapted",
"for",
"exploring",
"the",
"impact",
"of",
"sorafenib",
"on",
"the",
"redox",
"metabolism",
"of",
"cancer",
"cells",
"."
] |
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16001362
|
An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein with spectrin repeat and Rho guanine-nucleotide exchange-factor domains. Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. By positional cloning, we have identified the gene strongly associated with a form of degenerative ataxia (chromosome 16q22.1-linked ADCA) that clinically shows progressive pure cerebellar ataxia. Detailed examination by use of audiogram suggested that sensorineural hearing impairment may be associated with ataxia in our families. After restricting the candidate region in chromosome 16q22.1 by haplotype analysis, we found that all patients from 52 unrelated Japanese families harbor a heterozygous C-->T single-nucleotide substitution, 16 nt upstream of the putative translation initiation site of the gene for a hypothetical protein DKFZP434I216, which we have called "puratrophin-1" (Purkinje cell atrophy associated protein-1). The full-length puratrophin-1 mRNA had an open reading frame of 3,576 nt, predicted to contain important domains, including the spectrin repeat and the guanine-nucleotide exchange factor (GEF) for Rho GTPases, followed by the Dbl-homologous domain, which indicates the role of puratrophin-1 in intracellular signaling and actin dynamics at the Golgi apparatus. Puratrophin-1--normally expressed in a wide range of cells, including epithelial hair cells in the cochlea--was aggregated in Purkinje cells of the chromosome 16q22.1-linked ADCA brains. Consistent with the protein prediction data of puratrophin-1, the Golgi-apparatus membrane protein and spectrin also formed aggregates in Purkinje cells. The present study highlights the importance of the 5' untranslated region (UTR) in identification of genes of human disease, suggests that a single-nucleotide substitution in the 5' UTR could be associated with protein aggregation, and indicates that the GEF protein is associated with cerebellar degeneration in humans.
|
[
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"and",
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"that",
"the",
"GEF",
"protein",
"is",
"associated",
"with",
"cerebellar",
"degeneration",
"in",
"humans",
"."
] |
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] |
16158428
|
Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families. Recent reports have demonstrated that mutations in the OPHN1 gene were responsible for a syndromic rather than non-specific mental retardation. Abnormalities of the posterior fossa with cerebellar hypoplasia have been demonstrated in all male patients reported to date. We report here a new family with X-linked mental retardation due to mutation in OPHN1 and present unpublished data about two families previously reported, concerning the facial and psychological phenotype of affected males and carrier females. Our study confirms that cerebellar hypoplasia is a hallmark of this syndrome. In addition, affected males display facial similarities that can help the diagnosis. Most carrier females have mild mental retardation and subtle facial changes.
|
[
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"the",
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"phenotype",
"associated",
"with",
"OPHN1",
"mutations",
"based",
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"clinical",
"and",
"neuropsychological",
"evaluation",
"of",
"three",
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".",
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"reports",
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"rather",
"than",
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"retardation",
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"of",
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"posterior",
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"have",
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"date",
".",
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"report",
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"family",
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"cerebellar",
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"a",
"hallmark",
"of",
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".",
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"addition",
",",
"affected",
"males",
"display",
"facial",
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"the",
"diagnosis",
".",
"Most",
"carrier",
"females",
"have",
"mild",
"mental",
"retardation",
"and",
"subtle",
"facial",
"changes",
"."
] |
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16786513
|
McArdle disease: the mutation spectrum of PYGM in a large Italian cohort. Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.
|
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",",
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"that",
"no",
"population-related",
"mutations",
"are",
"clearly",
"identified",
"in",
"Italian",
"patients",
"."
] |
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18672102
|
GATA4 mutations in 486 Chinese patients with congenital heart disease. Recent studies have reported germline mutations in GATA4 gene in some types of congenital heart disease (CHD). However, the prevalence of GATA4 mutations in CHD and the correlation between the GATA4 genotype and CHD phenotype have not been extensively studied. We screened germline mutations in the coding exons and the flanking intron sequences of the GATA4 gene in 486 CHD patients by denaturing high-performance liquid chromatography (DHPLC), and confirmed the mutations by sequencing. Nine distinct mutations including one small deletion mutation (46delS), two small insertion mutations (118-119insA and 125-126insAA), and six non-synonymous mutations (A6V, P163S, E359K, P407Q, S429T and A442V) were identified in 12 of the 486 patients (nine with ventricular septal defect, two with Tetralogy of Fallot, and one with endocardial cushion defect). Of them, two patients carrying E359K mutation were from two generations in one family with ventricular septal defect (VSD). Interestingly, a nucleotide insertion of c.1146+25insA in exon 6 was detected in five VSD patients, but not in 486 normal healthy controls. Our findings are useful in understanding the prevalence of GATA4 mutations and the correlation between the GATA4 genotype and the CHD phenotype in Chinese patients.
|
[
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"Chinese",
"patients",
"."
] |
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"4",
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] |
28512644
|
Analysis of Serum Cytokines and Single-Nucleotide Polymorphisms of SOD1, SOD2, and CAT in Erysipelas Patients. Increased free radical production had been documented in group A (beta-hemolytic) streptococcus infection cases. Comparing 71 erysipelas patients to 55 age-matched healthy individuals, we sought for CAT, SOD1, and SOD2 single polymorphism mutation (SNPs) interactions with erysipelas' predisposition and serum cytokine levels in the acute and recovery phases of erysipelas infection. Whereas female patients had a higher predisposition to erysipelas, male patients were prone to having a facial localization of the infection. The presence of SOD1 G7958, SOD2 T2734, and CAT C262 alleles was linked to erysipelas' predisposition. T and C alleles of SOD2 T2734C individually were linked to patients with bullous and erythematous erysipelas, respectively. G and A alleles of SOD1 G7958A individually were associated with lower limbs and higher body part localizations of the infection, respectively. Serum levels of IL-1beta, CCL11, IL-2Ralpha, CXCL9, TRAIL, PDGF-BB, and CCL4 were associated with symptoms accompanying the infection, while IL-6, IL-9, IL-10, IL-13, IL-15, IL-17, G-CSF, and VEGF were associated with predisposition and recurrence of erysipelas. While variations of IL-1beta, IL-7, IL-8, IL-17, CCL5, and HGF were associated with the SOD2 T2734C SNP, variations of PDFG-BB and CCL2 were associated with the CAT C262T SNP.
|
[
"Analysis",
"of",
"Serum",
"Cytokines",
"and",
"Single-Nucleotide",
"Polymorphisms",
"of",
"SOD1",
",",
"SOD2",
",",
"and",
"CAT",
"in",
"Erysipelas",
"Patients",
".",
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"free",
"radical",
"production",
"had",
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"documented",
"in",
"group",
"A",
"(",
"beta-hemolytic",
")",
"streptococcus",
"infection",
"cases",
".",
"Comparing",
"71",
"erysipelas",
"patients",
"to",
"55",
"age-matched",
"healthy",
"individuals",
",",
"we",
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"for",
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",",
"SOD1",
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"and",
"SOD2",
"single",
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"predisposition",
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"cytokine",
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"and",
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"phases",
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",",
"male",
"patients",
"were",
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"the",
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"SOD1",
"G7958",
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"SOD2",
"T2734",
",",
"and",
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"C262",
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"'",
"predisposition",
".",
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"and",
"C",
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"of",
"SOD2",
"T2734C",
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"were",
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"patients",
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"bullous",
"and",
"erythematous",
"erysipelas",
",",
"respectively",
".",
"G",
"and",
"A",
"alleles",
"of",
"SOD1",
"G7958A",
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"were",
"associated",
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"limbs",
"and",
"higher",
"body",
"part",
"localizations",
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"the",
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",",
"respectively",
".",
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"levels",
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"IL-1beta",
",",
"CCL11",
",",
"IL-2Ralpha",
",",
"CXCL9",
",",
"TRAIL",
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"PDGF-BB",
",",
"and",
"CCL4",
"were",
"associated",
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"the",
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",",
"while",
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",",
"IL-9",
",",
"IL-10",
",",
"IL-13",
",",
"IL-15",
",",
"IL-17",
",",
"G-CSF",
",",
"and",
"VEGF",
"were",
"associated",
"with",
"predisposition",
"and",
"recurrence",
"of",
"erysipelas",
".",
"While",
"variations",
"of",
"IL-1beta",
",",
"IL-7",
",",
"IL-8",
",",
"IL-17",
",",
"CCL5",
",",
"and",
"HGF",
"were",
"associated",
"with",
"the",
"SOD2",
"T2734C",
"SNP",
",",
"variations",
"of",
"PDFG-BB",
"and",
"CCL2",
"were",
"associated",
"with",
"the",
"CAT",
"C262T",
"SNP",
"."
] |
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15122711
|
POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Alpers' syndrome is a fatal neurogenetic disorder first described more than 70 years ago. It is an autosomal recessive, developmental mitochondrial DNA depletion disorder characterized by deficiency in mitochondrial DNA polymerase gamma (POLG) catalytic activity, refractory seizures, neurodegeneration, and liver disease. In two unrelated pedigrees of Alpers' syndrome, each affected child was found to carry a homozygous mutation in exon 17 of the POLG locus that led to a Glu873Stop mutation just upstream of the polymerase domain of the protein. In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein.
|
[
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"the",
"protein",
"."
] |
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17304550
|
Disruption of a synaptotagmin (SYT14) associated with neurodevelopmental abnormalities. We report cytogenetic and molecular studies of a de novo, apparently balanced t(1;3)(q32.1;q25.1) identified in a 12-year-old female (designated DGAP128) with cerebral atrophy, macrocephaly seizures, and developmental delay. A combination of fluorescence in situ hybridization (FISH) and Southern blot analysis demonstrated disruption of a synaptotagmin gene (SYT14) at the 1q32 breakpoint. Expression of SYT14 in human brain was confirmed using Northern analysis. Because members of the synaptotagmin family of proteins function as sensors that link changes in calcium levels with a variety of biological processes, including neurotransmission and hormone-responsiveness, SYT14 is an intriguing candidate gene for the abnormal development in this child. This is the first known constitutional rearrangement of SYT14, and further systematic genetic analysis and clinical studies of DGAP128 may offer unique insights into the role of SYT14 in neurodevelopment.
|
[
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"of",
"a",
"synaptotagmin",
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"SYT14",
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"associated",
"with",
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"abnormalities",
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"was",
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".",
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"function",
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"sensors",
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"calcium",
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"with",
"a",
"variety",
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"processes",
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",",
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"for",
"the",
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"development",
"in",
"this",
"child",
".",
"This",
"is",
"the",
"first",
"known",
"constitutional",
"rearrangement",
"of",
"SYT14",
",",
"and",
"further",
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"analysis",
"and",
"clinical",
"studies",
"of",
"DGAP128",
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"unique",
"insights",
"into",
"the",
"role",
"of",
"SYT14",
"in",
"neurodevelopment",
"."
] |
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20415560
|
Vitamin E reduces cardiovascular disease in individuals with diabetes mellitus and the haptoglobin 2-2 genotype. AIMS: Individuals with both diabetes mellitus (DM) and the Haptoglobin (Hp) 2-2 genotype are at increased risk of cardiovascular disease. As the antioxidant function of the Hp 2-2 protein is impaired, we sought to test the pharmacogenomic hypothesis that antioxidant vitamin E supplementation would provide cardiovascular protection to Hp 2-2 DM individuals. MATERIALS & METHODS: We determined the Hp genotype on DM participants from two trials (HOPE and ICARE) and assessed the effect of vitamin E by Hp genotype on their common prespecified outcome, the composite of stroke, myocardial infarction and cardiovascular death. Data was analyzed with a fixed-effect model. These results were input into a simulation model, the Evidence Based Medicine Integrator, in order to estimate their long-term implications in a real-world population from Kaiser Permanente (CA, USA). RESULTS: Meta-analysis of the two trials demonstrated a significant overall reduction in the composite end point in Hp 2-2 DM individuals with vitamin E (odds ratio: 0.58; 95% CI: 0.40-0.86; p = 0.006). There was a statistically significant interaction between the Hp genotype and vitamin E on the composite end point. In these trials, Hp typing of 69 DM individuals and treating those with the Hp 2-2 with vitamin E prevented one myocardial infarct, stroke or cardiovascular death. Lifelong administration of vitamin E to Hp 2-2 DM individuals in the Kaiser population would increase their life expectancy by 3 years. CONCLUSION: A pharmacogenomic strategy of screening DM individuals for the Hp genotype and treating those with Hp 2-2 with vitamin E appears to be highly clinically effective.
|
[
"Vitamin",
"E",
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"cardiovascular",
"disease",
"in",
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"with",
"diabetes",
"mellitus",
"and",
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"haptoglobin",
"2-2",
"genotype",
".",
"AIMS",
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"mellitus",
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"the",
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"Hp",
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"2-2",
"genotype",
"are",
"at",
"increased",
"risk",
"of",
"cardiovascular",
"disease",
".",
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"the",
"antioxidant",
"function",
"of",
"the",
"Hp",
"2-2",
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"is",
"impaired",
",",
"we",
"sought",
"to",
"test",
"the",
"pharmacogenomic",
"hypothesis",
"that",
"antioxidant",
"vitamin",
"E",
"supplementation",
"would",
"provide",
"cardiovascular",
"protection",
"to",
"Hp",
"2-2",
"DM",
"individuals",
".",
"MATERIALS",
"&",
"METHODS",
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"Hp",
"genotype",
"on",
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"participants",
"from",
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"HOPE",
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",",
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"death",
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] |
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20523265
|
Association study of complement factor H, C2, CFB, and C3 and age-related macular degeneration in a Han Chinese population. PURPOSE: Genes in the complement pathway, including complement factor H (CFH), C2/BF, and C3, have been reported to be associated with age-related macular degeneration (AMD). Genetic variants, single-nucleotide polymorphisms (SNPs), in these genes were geno-typed for a case-control association study in a mainland Han Chinese population. METHODS: One hundred and fifty-eight patients with wet AMD, 80 patients with soft drusen, and 220 matched control subjects were recruited among Han Chinese in mainland China. Seven SNPs in CFH and two SNPs in C2, CFB', and C3 were genotyped using the ABI SNaPshot method. A deletion of 84,682 base pairs covering the CFHR1 and CFHR3 genes was detected by direct polymerase chain reaction and gel electrophoresis. RESULTS: Four SNPs, including rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), in CFH showed a significant association with wet AMD in the cohort of this study. A haplotype containing these four SNPs (CATA) significantly increased protection of wet AMD with a P value of 0.0005 and an odds ratio of 0.29 (95% confidence interval: 0.15-0.60). Unlike in other populations, rs2274700 and rs1410996 did not show a significant association with AMD in the Chinese population of this study. None of the SNPs in CFH showed a significant association with drusen, and none of the SNPs in CFH, C2, CFB, and C3 showed a significant association with either wet AMD or drusen in the cohort of this study. The CFHR1 and CFHR3 deletion was not polymorphic in the Chinese population and was not associated with wet AMD or drusen. CONCLUSION: This study showed that SNPs rs3753394 (P = 0.0276), rs800292 (P = 0.0266), rs1061170 (P = 0.00514), and rs1329428 (P = 0.0089), but not rs7535263, rs1410996, or rs2274700, in CFH were significantly associated with wet AMD in a mainland Han Chinese population. This study showed that CFH was more likely to be AMD susceptibility gene at Chr.1q31 based on the finding that the CFHR1 and CFHR3 deletion was not polymorphic in the cohort of this study, and none of the SNPs that were significantly associated with AMD in a white population in C2, CFB, and C3 genes showed a significant association with AMD.
|
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] |
20949073
|
Alternative splicing at a NAGNAG acceptor site as a novel phenotype modifier. Approximately 30% of alleles causing genetic disorders generate premature termination codons (PTCs), which are usually associated with severe phenotypes. However, bypassing the deleterious stop codon can lead to a mild disease outcome. Splicing at NAGNAG tandem splice sites has been reported to result in insertion or deletion (indel) of three nucleotides. We identified such a mechanism as the origin of the mild to asymptomatic phenotype observed in cystic fibrosis patients homozygous for the E831X mutation (2623G>T) in the CFTR gene. Analyses performed on nasal epithelial cell mRNA detected three distinct isoforms, a considerably more complex situation than expected for a single nucleotide substitution. Structure-function studies and in silico analyses provided the first experimental evidence of an indel of a stop codon by alternative splicing at a NAGNAG acceptor site. In addition to contributing to proteome plasticity, alternative splicing at a NAGNAG tandem site can thus remove a disease-causing UAG stop codon. This molecular study reveals a naturally occurring mechanism where the effect of either modifier genes or epigenetic factors could be suspected. This finding is of importance for genetic counseling as well as for deciding appropriate therapeutic strategies.
|
[
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"at",
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"NAGNAG",
"acceptor",
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"as",
"a",
"novel",
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".",
"Approximately",
"30",
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"bypassing",
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"E831X",
"mutation",
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"2623G",
">",
"T",
")",
"in",
"the",
"CFTR",
"gene",
".",
"Analyses",
"performed",
"on",
"nasal",
"epithelial",
"cell",
"mRNA",
"detected",
"three",
"distinct",
"isoforms",
",",
"a",
"considerably",
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"complex",
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"splicing",
"at",
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"NAGNAG",
"tandem",
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"remove",
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"disease-causing",
"UAG",
"stop",
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".",
"This",
"molecular",
"study",
"reveals",
"a",
"naturally",
"occurring",
"mechanism",
"where",
"the",
"effect",
"of",
"either",
"modifier",
"genes",
"or",
"epigenetic",
"factors",
"could",
"be",
"suspected",
".",
"This",
"finding",
"is",
"of",
"importance",
"for",
"genetic",
"counseling",
"as",
"well",
"as",
"for",
"deciding",
"appropriate",
"therapeutic",
"strategies",
"."
] |
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21533187
|
Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a "second hit," that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome.
|
[
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"sequence",
"analysis",
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"regions",
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"identified",
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"multiple",
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"disorders",
"Ollier",
"disease",
"or",
"Maffucci",
"syndrome",
",",
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"sequence",
"PTPN11",
"mutations",
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"conclude",
"that",
"heterozygous",
"loss-of-function",
"mutations",
"in",
"PTPN11",
"are",
"a",
"frequent",
"cause",
"of",
"MC",
",",
"that",
"lesions",
"in",
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"with",
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"a",
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"second",
"hit",
",",
"''",
"that",
"MC",
"may",
"be",
"locus",
"heterogeneous",
"since",
"1",
"familial",
"and",
"5",
"sporadically",
"occurring",
"cases",
"lacked",
"obvious",
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"and",
"that",
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"mutations",
"are",
"not",
"a",
"common",
"cause",
"of",
"Ollier",
"disease",
"or",
"Maffucci",
"syndrome",
"."
] |
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15686794
|
Acute low back pain during intravenous administration of amiodarone: a report of two cases. Amiodarone represents an effective antiarrhythmic drug for cardioversion of recent-onset atrial fibrillation (AF) and maintenance of sinus rhythm. We briefly describe two patients suffering from recent-onset atrial fibrillation, who experienced an acute devastating low back pain a few minutes after initiation of intravenous amiodarone loading. Notably, this side effect has not been ever reported in the medical literature. Clinicians should be aware of this reaction since prompt termination of parenteral administration leads to complete resolution.
|
[
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"resolution",
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] |
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15755837
|
Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery. BACKGROUND: Folate is critical for cell division, a major feature of in utero development. Dihydrofolate reductase (DHFR) is required to convert the folic acid used in supplements and for food fortification and the dihydrofolate produced by thymidylate synthase during DNA synthesis to the reduced folate forms used by the cell. OBJECTIVE: We aimed to determine whether a common, recently discovered deletion polymorphism in the DHFR gene is a risk factor for preterm delivery or low birth weight. DESIGN: We studied 324 pregnant women from Camden, NJ. Folate intake was computed from folate supplement intake plus the mean of two 24-h recalls completed during the course of pregnancy. Genomic DNA was extracted from the women's leukocytes and genotyped. RESULTS: Women with a deletion allele had a significantly greater risk of preterm delivery [adjusted odds ratio (AOR): 3.0; 95% CI: 1.0, 8.8; P < 0.05] than did those without a deletion allele. Women with both a DHFR deletion allele and low folate intake (<400 microg/d from diet plus supplements) had a significantly greater risk of preterm delivery (AOR: 5.5; 95% CI: 1.5, 20.4; P = 0.01) and a significantly greater risk of having an infant with a low birth weight (AOR: 8.3; 95% CI: 1.8, 38.6; P = 0.01) than did women without a deletion allele and with a folate intake >/=400 microg/d. CONCLUSIONS: The DHFR 19-base pair deletion allele may be a risk factor for preterm delivery. In the presence of low dietary folate, the allele may also be a risk factor for low birth weight. This may be a gene-environment interaction.
|
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"in",
"supplements",
"and",
"for",
"food",
"fortification",
"and",
"the",
"dihydrofolate",
"produced",
"by",
"thymidylate",
"synthase",
"during",
"DNA",
"synthesis",
"to",
"the",
"reduced",
"folate",
"forms",
"used",
"by",
"the",
"cell",
".",
"OBJECTIVE",
":",
"We",
"aimed",
"to",
"determine",
"whether",
"a",
"common",
",",
"recently",
"discovered",
"deletion",
"polymorphism",
"in",
"the",
"DHFR",
"gene",
"is",
"a",
"risk",
"factor",
"for",
"preterm",
"delivery",
"or",
"low",
"birth",
"weight",
".",
"DESIGN",
":",
"We",
"studied",
"324",
"pregnant",
"women",
"from",
"Camden",
",",
"NJ",
".",
"Folate",
"intake",
"was",
"computed",
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"folate",
"supplement",
"intake",
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"mean",
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"24-h",
"recalls",
"completed",
"during",
"the",
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"of",
"pregnancy",
".",
"Genomic",
"DNA",
"was",
"extracted",
"from",
"the",
"women",
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"leukocytes",
"and",
"genotyped",
".",
"RESULTS",
":",
"Women",
"with",
"a",
"deletion",
"allele",
"had",
"a",
"significantly",
"greater",
"risk",
"of",
"preterm",
"delivery",
"[",
"adjusted",
"odds",
"ratio",
"(",
"AOR",
")",
":",
"3.0",
";",
"95",
"%",
"CI",
":",
"1.0",
",",
"8.8",
";",
"P",
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"0.05",
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"than",
"did",
"those",
"without",
"a",
"deletion",
"allele",
".",
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"with",
"both",
"a",
"DHFR",
"deletion",
"allele",
"and",
"low",
"folate",
"intake",
"(",
"<",
"400",
"microg/d",
"from",
"diet",
"plus",
"supplements",
")",
"had",
"a",
"significantly",
"greater",
"risk",
"of",
"preterm",
"delivery",
"(",
"AOR",
":",
"5.5",
";",
"95",
"%",
"CI",
":",
"1.5",
",",
"20.4",
";",
"P",
"=",
"0.01",
")",
"and",
"a",
"significantly",
"greater",
"risk",
"of",
"having",
"an",
"infant",
"with",
"a",
"low",
"birth",
"weight",
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"AOR",
":",
"8.3",
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":",
"1.8",
",",
"38.6",
";",
"P",
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"0.01",
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"without",
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"allele",
"and",
"with",
"a",
"folate",
"intake",
">",
"/=400",
"microg/d",
".",
"CONCLUSIONS",
":",
"The",
"DHFR",
"19-base",
"pair",
"deletion",
"allele",
"may",
"be",
"a",
"risk",
"factor",
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"delivery",
".",
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"the",
"presence",
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"dietary",
"folate",
",",
"the",
"allele",
"may",
"also",
"be",
"a",
"risk",
"factor",
"for",
"low",
"birth",
"weight",
".",
"This",
"may",
"be",
"a",
"gene-environment",
"interaction",
"."
] |
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15851735
|
Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation. BACKGROUND: Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. OBJECTIVE: To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. METHODS: Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. RESULTS: Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c.2607C>A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c.2607C>A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. CONCLUSIONS: The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy.
|
[
"Mild",
"glycine",
"encephalopathy",
"(",
"NKH",
")",
"in",
"a",
"large",
"kindred",
"due",
"to",
"a",
"silent",
"exonic",
"GLDC",
"splice",
"mutation",
".",
"BACKGROUND",
":",
"Classic",
"neonatal-onset",
"glycine",
"encephalopathy",
"(",
"GE",
")",
"is",
"devastating",
"and",
"life",
"threatening",
".",
"Milder",
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"later",
"onset",
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"have",
"been",
"reported",
"but",
"were",
"usually",
"sporadic",
"and",
"incompletely",
"defined",
".",
"OBJECTIVE",
":",
"To",
"determine",
"the",
"clinical",
"and",
"biochemical",
"phenotype",
"and",
"molecular",
"basis",
"of",
"mild",
"GE",
"in",
"nine",
"children",
"from",
"a",
"consanguineous",
"Israeli",
"Bedouin",
"kindred",
".",
"METHODS",
":",
"Genomic",
"DNA",
"was",
"screened",
"for",
"GLDC",
",",
"AMT",
",",
"and",
"GCSH",
"gene",
"mutations",
".",
"GLDC",
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"was",
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"by",
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"blot",
"and",
"reverse",
"transcriptase",
"PCR",
"analysis",
".",
"RESULTS",
":",
"Clinical",
"features",
"included",
"hypotonia",
",",
"abnormal",
"movements",
",",
"convulsions",
",",
"and",
"moderate",
"mental",
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",",
"and",
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"language",
".",
"Aggression",
"and",
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"were",
"prominent",
".",
"CSF-to-plasma",
"glycine",
"ratio",
"was",
"mildly",
"to",
"moderately",
"elevated",
".",
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"nine",
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"were",
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"for",
"a",
"novel",
",",
"translationally",
"silent",
"GLDC",
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"c.2607C",
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"A",
".",
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"GLDC",
"mRNA",
"levels",
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"considerably",
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".",
"Three",
"aberrantly",
"spliced",
"cDNA",
"species",
"were",
"identified",
":",
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"22",
"and",
"exon",
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"to",
"23",
"skipping",
",",
"and",
"insertion",
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"exon",
".",
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">",
"A",
"was",
"also",
"identified",
"in",
"an",
"unrelated",
"but",
"haplotypically",
"identical",
"patient",
"with",
"an",
"unusually",
"favorable",
"outcome",
"despite",
"severe",
"neonatal-onset",
"GE",
".",
"Mutation",
"analysis",
"enabled",
"prenatal",
"diagnosis",
"of",
"three",
"unaffected",
"and",
"one",
"affected",
"pregnancies",
".",
"CONCLUSIONS",
":",
"The",
"mutation",
"in",
"this",
"kindred",
"led",
"to",
"missplicing",
"and",
"reduced",
"GLDC",
"(",
"glycine",
"decarboxylase",
")",
"expression",
".",
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"to",
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"GLDC",
"mRNA",
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"patients",
"may",
"account",
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"relatively",
"favorable",
"clinical",
"outcome",
"compared",
"with",
"patients",
"with",
"classic",
"glycine",
"encephalopathy",
"."
] |
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] |
18262054
|
A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis. We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735-6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease.
|
[
"A",
"family",
"with",
"two",
"consecutive",
"nonsense",
"mutations",
"in",
"BMPR1A",
"causing",
"juvenile",
"polyposis",
".",
"We",
"describe",
"a",
"novel",
"germline",
"mutation",
"of",
"BMPR1A",
"in",
"a",
"family",
"with",
"juvenile",
"polyposis",
"and",
"colon",
"cancer",
".",
"This",
"mutation",
"consists",
"of",
"two",
"consecutive",
"substitutions",
"(",
"735-6",
"TG",
">",
"AT",
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"that",
"cause",
"two",
"nonsense",
"mutations",
"(",
"Y245X",
",",
"G246X",
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",",
"inherited",
"in",
"an",
"autosomal",
"dominant",
"fashion",
",",
"on",
"one",
"parental",
"chromosome",
".",
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"mutation",
"caused",
"protein",
"truncation",
",",
"and",
"represents",
"a",
"novel",
"case",
"of",
"consecutive",
"nonsense",
"mutations",
"in",
"human",
"disease",
"."
] |
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] |
19101703
|
Study of a Taiwanese family with oculopharyngeal muscular dystrophy. BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscle disorder. OPMD is caused by a short trinucleotide repeat expansion encoding an expanded polyalanine tract in the polyadenylate binding-protein nuclear 1 (PABPN1) gene. We identified and characterized a PABPN1 mutation in a Taiwanese family with OPMD. METHODS: The phenotypic and genotypic characteristics of all subjects were evaluated in a Taiwanese OPMD family. Genetic alterations in the PABPN1 gene were identified using PCR and DNA sequencing. RESULTS: Ten subjects with OPMD (6 symptomatic and 4 asymptomatic) within the Taiwanese family carried a novel mutation in the PABPN1 gene. The normal (GCG)6(GCA)3GCG sequence was replaced by (GCG)6(GCA)(GCG)4(GCA)3GCG due to an insertion of (GCG)4GCA into the normal allele in the Taiwanese OPMD subjects. CONCLUSIONS: In contrast to a single GCG expansion in most of OPMD patients in the literature, an insertion of (GCG)4GCA in the PABPN1 gene was found in the Taiwanese OPMD subjects. The identification of this mutation appears to support the molecular mechanism of unequal cross-over of two PABPN1 alleles.
|
[
"Study",
"of",
"a",
"Taiwanese",
"family",
"with",
"oculopharyngeal",
"muscular",
"dystrophy",
".",
"BACKGROUND",
":",
"Oculopharyngeal",
"muscular",
"dystrophy",
"(",
"OPMD",
")",
"is",
"a",
"late",
"onset",
"autosomal",
"dominant",
"muscle",
"disorder",
".",
"OPMD",
"is",
"caused",
"by",
"a",
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] |
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21904390
|
Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients. PURPOSE: Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6 gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6 gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. PATIENTS AND METHODS: Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6 gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. RESULTS: By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6 gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T>C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6 gene and DKFZ p686k1684 gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. CONCLUSION: Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6 gene.
|
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] |
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15241482
|
Paraoxonase 1 polymorphisms and survival. The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, -107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P = 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P = 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.
|
[
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"did",
"not",
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"the",
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".",
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"self-reported",
"data",
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"ischemic",
"heart",
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"the",
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"the",
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"homozygosity",
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"results",
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"indicates",
"that",
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"homozygosity",
"is",
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"with",
"increased",
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"development",
"of",
"CHD",
"."
] |
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17273972
|
Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. Deletion 22q11.2 syndrome is the most frequent known microdeletion syndrome and is associated with a highly variable phenotype, including DiGeorge and Shprintzen (velocardiofacial) syndromes. Although haploinsufficiency of the T-box transcription factor gene TBX1 is thought to cause the phenotype, to date, only four different point mutations in TBX1 have been reported in association with six of the major features of 22q11.2 deletion syndrome. Although, for the two truncating mutations, loss of function was previously shown, the pathomechanism of the missense mutations remains unknown. We report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions.
|
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"conclude",
"that",
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"gain-of-function",
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"spectrum",
"as",
"haploinsufficiency",
"caused",
"by",
"loss-of-function",
"mutations",
"or",
"deletions",
"."
] |
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24588023
|
The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11 529 patients. Because of a lack of contemporary data regarding seizures after cardiac surgery, we undertook a retrospective analysis of prospectively collected data from 11 529 patients in whom cardiopulmonary bypass was used from January 2004 to December 2010. A convulsive seizure was defined as a transient episode of disturbed brain function characterised by abnormal involuntary motor movements. Multivariate regression analysis was performed to identify independent predictors of postoperative seizures. A total of 100 (0.9%) patients developed postoperative convulsive seizures. Generalised and focal seizures were identified in 68 and 32 patients, respectively. The median (IQR [range]) time after surgery when the seizure occurred was 7 (6-12 [1-216]) h and 8 (6-11 [4-18]) h, respectively. Epileptiform findings on electroencephalography were seen in 19 patients. Independent predictors of postoperative seizures included age, female sex, redo cardiac surgery, calcification of ascending aorta, congestive heart failure, deep hypothermic circulatory arrest, duration of aortic cross-clamp and tranexamic acid. When tested in a multivariate regression analysis, tranexamic acid was a strong independent predictor of seizures (OR 14.3, 95% CI 5.5-36.7; p < 0.001). Patients with convulsive seizures had 2.5 times higher in-hospital mortality rates and twice the length of hospital stay compared with patients without convulsive seizures. Mean (IQR [range]) length of stay in the intensive care unit was 115 (49-228 [32-481]) h in patients with convulsive seizures compared with 26 (22-69 [14-1080]) h in patients without seizures (p < 0.001). Convulsive seizures are a serious postoperative complication after cardiac surgery. As tranexamic acid is the only modifiable factor, its administration, particularly in doses exceeding 80 mg.kg(-1), should be weighed against the risk of postoperative seizures.
|
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] |
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15983230
|
Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Impaired insulin secretion is a fundamental defect in type 2 diabetes. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study. With the exception of SLC2A2, other genes were not associated with the risk of type 2 diabetes. All four SNPs of SLC2A2 predicted the conversion to diabetes, and rs5393 (AA genotype) increased the risk of type 2 diabetes in the entire study population by threefold (odds ratio 3.04, 95% CI 1.34-6.88, P = 0.008). The risk for type 2 diabetes in the AA genotype carriers was increased in the control group (5.56 [1.78-17.39], P = 0.003) but not in the intervention group. We conclude that the SNPs of SLC2A2 predict the conversion to diabetes in obese subjects with IGT.
|
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",",
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"HNF-1alpha",
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",",
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"2",
"diabetes",
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"of",
"the",
"Finnish",
"Diabetes",
"Prevention",
"Study",
".",
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"the",
"exception",
"of",
"SLC2A2",
",",
"other",
"genes",
"were",
"not",
"associated",
"with",
"the",
"risk",
"of",
"type",
"2",
"diabetes",
".",
"All",
"four",
"SNPs",
"of",
"SLC2A2",
"predicted",
"the",
"conversion",
"to",
"diabetes",
",",
"and",
"rs5393",
"(",
"AA",
"genotype",
")",
"increased",
"the",
"risk",
"of",
"type",
"2",
"diabetes",
"in",
"the",
"entire",
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"3.04",
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"95",
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"CI",
"1.34-6.88",
",",
"P",
"=",
"0.008",
")",
".",
"The",
"risk",
"for",
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"2",
"diabetes",
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"the",
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"genotype",
"carriers",
"was",
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"group",
"(",
"5.56",
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",",
"P",
"=",
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")",
"but",
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"intervention",
"group",
".",
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"conclude",
"that",
"the",
"SNPs",
"of",
"SLC2A2",
"predict",
"the",
"conversion",
"to",
"diabetes",
"in",
"obese",
"subjects",
"with",
"IGT",
"."
] |
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] |
16412238
|
Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3). BACKGROUND: Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-gamma. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. METHODS: We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. RESULTS: The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. CONCLUSION: Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-gamma deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.
|
[
"Peroxisomal",
"proliferator",
"activated",
"receptor-gamma",
"deficiency",
"in",
"a",
"Canadian",
"kindred",
"with",
"familial",
"partial",
"lipodystrophy",
"type",
"3",
"(",
"FPLD3",
")",
".",
"BACKGROUND",
":",
"Familial",
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"type",
"3",
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"FPLD3",
",",
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"proliferator-activated",
"receptor-gamma",
".",
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"condition",
".",
"METHODS",
":",
"We",
"present",
"a",
"Canadian",
"FPLD3",
"kindred",
"with",
"an",
"affected",
"mother",
"who",
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",",
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"increase",
"in",
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",",
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",",
"suprascapular",
"or",
"abdominal",
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".",
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"had",
"profound",
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"resistance",
",",
"diabetes",
",",
"severe",
"hypertriglyceridemia",
"and",
"relapsing",
"pancreatitis",
",",
"while",
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"pre-pubescent",
"daughter",
"had",
"normal",
"fat",
"distribution",
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"plasma",
"triglycerides",
"and",
"C-peptide",
"and",
"depressed",
"high-density",
"lipoprotein",
"cholesterol",
".",
"RESULTS",
":",
"The",
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"and",
"daughter",
"were",
"each",
"heterozygous",
"for",
"PPARG",
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"mutation",
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"activity",
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".",
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"addition",
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"mutant",
"protein",
"appeared",
"to",
"be",
"markedly",
"unstable",
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"CONCLUSION",
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"together",
"with",
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"studies",
"of",
"human",
"PPARG",
"mutations",
",",
"these",
"findings",
"suggest",
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"due",
"either",
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"haploinsufficiency",
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"activity",
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"due",
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"dominant",
"negative",
"interference",
"of",
"the",
"normal",
"allele",
"product",
"'s",
"function",
"can",
"each",
"contribute",
"to",
"the",
"FPLD3",
"phenotype",
"."
] |
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] |
18487244
|
Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. We investigated clinical and cellular phenotypes of 24 children with mutations in the catalytic (alpha) subunit of the mitochondrial DNA (mtDNA) gamma polymerase (POLG1). Twenty-one had Alpers syndrome, the commonest severe POLG1 autosomal recessive phenotype, comprising hepatoencephalopathy and often mtDNA depletion. The cellular mtDNA content reflected the genotype more closely than did clinical features. Patients with tissue depletion of mtDNA all had at least one allele with either a missense mutation in a catalytic domain or a nonsense mutation. Four out of 12 patients exhibited a progressive, mosaic pattern of mtDNA depletion in cultured fibroblasts. All these patients had mutations in a catalytic domain in both POLG1 alleles, in either the polymerase or exonuclease domain or both. The tissue mtDNA content of patients who had two linker mutations was normal, and their phenotypes the mildest. Epilepsy and/or movement disorder were major features in all 21. Previous studies have implicated replication stalling as a mechanism for mtDNA depletion. The mosaic cellular depletion that we have demonstrated in cell cultures may be a manifestation of severe replication stalling. One patient with a severe cellular and clinical phenotype was a compound heterozygote with POLG1 mutations in the polymerase and exonuclease domain intrans. This suggests that POLG1 requires both polymerase and 3'-5' exonuclease activity in the same molecule. This is consistent with current functional models for eukaryotic DNA polymerases, which alternate between polymerizing and editing modes, as determined by competition between these two active sites for the 3' end of the DNA.
|
[
"Depletion",
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"mitochondrial",
"DNA",
"in",
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"cultures",
"from",
"patients",
"with",
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"mutations",
"is",
"a",
"consequence",
"of",
"catalytic",
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".",
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"and",
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"with",
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".",
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"comprising",
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"a",
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",",
"mosaic",
"pattern",
"of",
"mtDNA",
"depletion",
"in",
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"fibroblasts",
".",
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"these",
"patients",
"had",
"mutations",
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"a",
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"domain",
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"POLG1",
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",",
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"either",
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"or",
"exonuclease",
"domain",
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".",
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"tissue",
"mtDNA",
"content",
"of",
"patients",
"who",
"had",
"two",
"linker",
"mutations",
"was",
"normal",
",",
"and",
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"phenotypes",
"the",
"mildest",
".",
"Epilepsy",
"and/or",
"movement",
"disorder",
"were",
"major",
"features",
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"all",
"21",
".",
"Previous",
"studies",
"have",
"implicated",
"replication",
"stalling",
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"a",
"mechanism",
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"mtDNA",
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".",
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"mosaic",
"cellular",
"depletion",
"that",
"we",
"have",
"demonstrated",
"in",
"cell",
"cultures",
"may",
"be",
"a",
"manifestation",
"of",
"severe",
"replication",
"stalling",
".",
"One",
"patient",
"with",
"a",
"severe",
"cellular",
"and",
"clinical",
"phenotype",
"was",
"a",
"compound",
"heterozygote",
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"POLG1",
"mutations",
"in",
"the",
"polymerase",
"and",
"exonuclease",
"domain",
"intrans",
".",
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"suggests",
"that",
"POLG1",
"requires",
"both",
"polymerase",
"and",
"3'-5",
"'",
"exonuclease",
"activity",
"in",
"the",
"same",
"molecule",
".",
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"is",
"consistent",
"with",
"current",
"functional",
"models",
"for",
"eukaryotic",
"DNA",
"polymerases",
",",
"which",
"alternate",
"between",
"polymerizing",
"and",
"editing",
"modes",
",",
"as",
"determined",
"by",
"competition",
"between",
"these",
"two",
"active",
"sites",
"for",
"the",
"3",
"'",
"end",
"of",
"the",
"DNA",
"."
] |
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] |
19037252
|
Mutations in phospholipase C epsilon 1 are not sufficient to cause diffuse mesangial sclerosis. Diffuse mesangial sclerosis occurs as an isolated abnormality or as a part of a syndrome. Recently, mutations in phospholipase C epsilon 1 (PLCE1) were found to cause a nonsyndromic, autosomal recessive form of this disease. Here we describe three children from one consanguineous kindred of Pakistani origin with diffuse mesangial sclerosis who presented with congenital or infantile nephrotic syndrome. Homozygous mutations in PLCE1 (also known as KIAA1516, PLCE, or NPHS3) were identified following genome-wide mapping of single-nucleotide polymorphisms. All affected children were homozygous for a four-basepair deletion in exon 3, which created a premature translational stop codon. Analysis of the asymptomatic father of two of the children revealed that he was also homozygous for the same mutation. We conclude this nonpenetrance may be due to compensatory mutations at a second locus and that mutation within PLCE1 is not always sufficient to cause diffuse mesangial sclerosis.
|
[
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"in",
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"C",
"epsilon",
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"are",
"not",
"sufficient",
"to",
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"diffuse",
"mesangial",
"sclerosis",
".",
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"mesangial",
"sclerosis",
"occurs",
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"affected",
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"were",
"homozygous",
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",",
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"a",
"premature",
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"stop",
"codon",
".",
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"father",
"of",
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"the",
"children",
"revealed",
"that",
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"was",
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"for",
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"not",
"always",
"sufficient",
"to",
"cause",
"diffuse",
"mesangial",
"sclerosis",
"."
] |
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20129423
|
Fatal carbamazepine induced fulminant eosinophilic (hypersensitivity) myocarditis: emphasis on anatomical and histological characteristics, mechanisms and genetics of drug hypersensitivity and differential diagnosis. The most severe adverse reactions to carbamazepine have been observed in the haemopoietic system, the liver and the cardiovascular system. A frequently fatal, although exceptionally rare side effect of carbamazepine is necrotizing eosinophilic (hypersensitivity) myocarditis. We report a case of hypersensitivity myocarditis secondary to administration of carbamazepine. Acute hypersensitivity myocarditis was not suspected clinically, and the diagnosis was made post-mortem. Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage. Clinically, death was due to cardiogenic shock. To best of our knowledge this is the second case of fatal carbamazepine induced myocarditis reported in English literature.
|
[
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"myocarditis",
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"and",
"histological",
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"mechanisms",
"and",
"genetics",
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"drug",
"hypersensitivity",
"and",
"differential",
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"have",
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".",
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"eosinophils",
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"with",
"myocyte",
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".",
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",",
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"due",
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"induced",
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"reported",
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"English",
"literature",
"."
] |
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21699520
|
PTCH1 gene mutations in exon 17 and loss of heterozygosity on D9S180 microsatellite in sporadic and inherited human basal cell carcinomas. BACKGROUND: Basal cell carcinomas (BCCs) are the most frequent human cancer that results from malignant transformation of basal cells in the epidermis. Gorlin syndrome is a rare inherited autosomal dominant disease that predisposes with multiple BCCs and other birth defects. Both sporadic and inherited BCCs are associated with mutations in the tumor suppressor gene PTCH1, but there is still uncertainty on the role of its homolog PTCH2. OBJECTIVES: To search for mutations and genomic instability in sporadic and inherited BCCs. METHODS: DNA obtained from leukocytes and tumor cells was amplified by polymerase chain reaction regarding five exons of PTCH1 and PTCH2 and neighboring microsatellites. Exons were sequenced and compared with the GenBank database. RESULTS: Only D9S180, of six microsatellites, showed loss of heterozygosity in three BCCs (two sporadic and one inherited). One sporadic BCC presented the mutation g.2885G>C in exon 17 of PTCH1, which predicts the substitution p.R962T in an external domain of the protein. In addition, the leukocytes and tumor cells of one patient with Gorlin syndrome showed the mutation g.2839T>G in the same exon and gene, which predicts a p.E947stop and truncated protein. All control and tumor samples presented IVS9 + 217T in intron 9 of PTCH1. CONCLUSION: Mutations found in the PTCH1 gene and neighboring repetitive sequences may have contributed to the development of the studied BCCs.
|
[
"PTCH1",
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"mutations",
"in",
"exon",
"17",
"and",
"loss",
"of",
"heterozygosity",
"on",
"D9S180",
"microsatellite",
"in",
"sporadic",
"and",
"inherited",
"human",
"basal",
"cell",
"carcinomas",
".",
"BACKGROUND",
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"Basal",
"cell",
"carcinomas",
"(",
"BCCs",
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"are",
"the",
"most",
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"human",
"cancer",
"that",
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".",
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",",
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"uncertainty",
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".",
"OBJECTIVES",
":",
"To",
"search",
"for",
"mutations",
"and",
"genomic",
"instability",
"in",
"sporadic",
"and",
"inherited",
"BCCs",
".",
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":",
"DNA",
"obtained",
"from",
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"cells",
"was",
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"by",
"polymerase",
"chain",
"reaction",
"regarding",
"five",
"exons",
"of",
"PTCH1",
"and",
"PTCH2",
"and",
"neighboring",
"microsatellites",
".",
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"were",
"sequenced",
"and",
"compared",
"with",
"the",
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"database",
".",
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":",
"Only",
"D9S180",
",",
"of",
"six",
"microsatellites",
",",
"showed",
"loss",
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"heterozygosity",
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"two",
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"one",
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".",
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"addition",
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"presented",
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"the",
"PTCH1",
"gene",
"and",
"neighboring",
"repetitive",
"sequences",
"may",
"have",
"contributed",
"to",
"the",
"development",
"of",
"the",
"studied",
"BCCs",
"."
] |
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22104738
|
Novel compound heterozygous mutation of MLYCD in a Chinese patient with malonic aciduria. A 3-year-old Chinese boy presented with prominent clinical features of malonic aciduria, including developmental delay, short stature, brain abnormalities and massive excretion of malonic acid and methylmalonic acid. Molecular characterization by DNA sequencing analysis and multiplex ligation-dependent probe amplification of the MLYCD gene revealed a heterozygous mutation (c.920T>G, p.Leu307Arg) in the patient and his father and a heterozygous deletion comprising exon 1 in the patient and his mother. The missense mutation (c.920T>G) was not found in 100 healthy controls and has not been reported previously. Our findings expand the number of reported cases and add a novel entry to the repertoire of MLYCD mutations.
|
[
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"compound",
"heterozygous",
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"a",
"Chinese",
"patient",
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"malonic",
"aciduria",
".",
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"add",
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"the",
"repertoire",
"of",
"MLYCD",
"mutations",
"."
] |
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15200408
|
Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity. BACKGROUND: Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis. METHODS: To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences. RESULTS: Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P= 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P= 0.036 adjusted for both subsets of cases vs. controls). CONCLUSION: Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.
|
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18000905
|
Regional analysis on the occurrence of oral clefts in South America. The aim of this work was to search for unequal birth prevalence rates (BPRs) of cleft lip +/- cleft palate (CL/P), and cleft palate only (CPO), among different geographic areas in South America, and to analyze phenotypic characteristics and associated risk factors in each identified cluster. Included were 5,128 CL/P cases, 1,745 CPO cases, and 3,712 controls (like-sexed, non-malformed liveborn infant, born immediately after a malformed one, in the same hospital), over 4,199,630 consecutive births. They were ascertained between 1967 and 2004, in 190 maternity hospitals of the ECLAMC (Estudio Colaborativo Latinoamericano de Malformaciones Congenitas) network, in 102 cities of all 10 South American countries. Non-predefined geographical areas with significantly unusual cleft BPRs were identified with Kulldorf and Nagarwalla's spatial scan statistic, employing number of cases and births, and exact location of each hospital. Expected values were cleft BPRs registered for the entire ECLAMC hospital network. Syndromic and non-syndromic clefts were considered for cluster analysis, and phenotypic characterization, while only non-syndromic for risk factor analysis. Seven clusters for CL/P, and four for CPO, with unusual BPRs were identified. CL/P cases in high BPR areas were more severe than elsewhere in the sample, similar to a previous ECLAMC report on microtia. For CL/P, high BPR clusters were associated with high altitude above sea level, Amerindian ancestry, and low socioeconomic strata; low BPR clusters showed association with African Black ancestry. Advanced maternal age, a recognized risk factor for CPO, was also associated with the only identified geographic cluster for CPO.
|
[
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18397285
|
L1503R is a member of group I mutation and has dominant-negative effect on secretion of full-length VWF multimers: an analysis of two patients with type 2A von Willebrand disease. Type 2A von Willebrand disease (VWD) is characterized by decreased platelet-dependent function of von Willebrand factor (VWF); this in turn is associated with an absence of high-molecular-weight multimers. Sequence analysis of the VWF gene from two unrelated type 2A VWD patients showed an identical, novel, heterozygous T-->G transversion at nucleotide 4508, resulting in the substitution of L1503R in the VWF A2 domain. This substitution, which was not found in 60 unrelated normal individuals, was introduced into a full-length VWF cDNA and subsequently expressed in 293T cells. Only trace amount of the mutant VWF protein was secreted but most of the same was retained in 293T cells. Co-transfection experiment of both wild-type and mutant plasmids indicated the dominant-negative mechanism of disease development; as more of mutant DNA was transfected, VWF secretion was impaired in the media, whereas more of VWF was stored in the cell lysates. Molecular dynamic simulations of structural changes induced by L1503R indicated that the mean value of all-atom root-mean-squared-deviation was shifted from those with wild type or another mutation L1503Q that has been reported to be a group II mutation, which is susceptible to ADAMTS13 proteolysis. Protein instability of L1503R may be responsible for its intracellular retention and perhaps the larger VWF multimers, containing more mutant VWF subunits, are likely to be mal-processed and retained within the cell.
|
[
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20588063
|
Permeability, ultrastructural changes, and distribution of novel proteins in the glomerular barrier in early puromycin aminonucleoside nephrosis. BACKGROUND/AIMS: It is still unclear what happens in the glomerulus when proteinuria starts. Using puromycin aminonucleoside nephrosis (PAN) rats, we studied early ultrastructural and permeability changes in relation to the expression of the podocyte-associated molecules nephrin, a-actinin, dendrin, and plekhh2, the last two of which were only recently discovered in podocytes. METHODS: Using immune stainings, semiquantitative measurement was performed under the electron microscope. Permeability was assessed using isolated kidney perfusion with tracers. Possible effects of ACE inhibition were tested. RESULTS: By day 2, some patchy foot process effacement, but no proteinuria, appeared. The amount of nephrin was reduced in both diseased and normal areas. The other proteins showed few changes, which were limited to diseased areas. By day 4, foot process effacement was complete and proteinuria appeared in parallel with signs of size barrier damage. Nephrin decreased further, while dendrin and plekhh2 also decreased but a-actinin remained unchanged. ACE inhibition had no significant protective effect. CONCLUSIONS: PAN glomeruli already showed significant pathology by day 4, despite relatively mild proteinuria. This was preceded by altered nephrin expression, supporting its pivotal role in podocyte morphology. The novel proteins dendrin and plekhh2 were both reduced, suggesting roles in PAN, whereas a-actinin was unchanged.
|
[
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".",
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"whereas",
"a-actinin",
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] |
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24100257
|
Takotsubo syndrome (or apical ballooning syndrome) secondary to Zolmitriptan. Takotsubo syndrome (TS), also known as broken heart syndrome, is characterized by left ventricle apical ballooning with elevated cardiac biomarkers and electrocardiographic changes suggestive of an acute coronary syndrome (ie, ST-segment elevation, T wave inversions, and pathologic Q waves). We report a case of 54-year-old woman with medical history of mitral valve prolapse and migraines, who was admitted to the hospital for substernal chest pain and electrocardiogram demonstrated 1/2 mm ST-segment elevation in leads II, III, aVF, V5, and V6 and positive troponin I. Emergent coronary angiogram revealed normal coronary arteries with moderately reduced left ventricular ejection fraction with wall motion abnormalities consistent with TS. Detailed history obtained retrospectively revealed that the patient took zolmitriptan sparingly only when she had migraines. But before this event, she was taking zolmitriptan 2-3 times daily for several days because of a persistent migraine headache. She otherwise reported that she is quite active, rides horses, and does show jumping without any limitations in her physical activity. There was no evidence of any recent stress or status migrainosus. Extensive literature search revealed multiple cases of coronary artery vasospasm secondary to zolmitriptan, but none of the cases were associated with TS.
|
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",",
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"of",
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"were",
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"with",
"TS",
"."
] |
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25263533
|
CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil. The majority of CXCR5(+) PD1(+) CD4(+) T follicular helper (Tfh) cells ( >90%) are CD25(-) Bcl6(hi) , while a small subpopulation ( <10%) are CD25(+) Bcl6(low) but do not express FoxP3 and are not T regulatory cells. We purified T:B-cell conjugates from tonsils and found they were enriched for the CD25(+) Bcl6(low) Tfh-cell subpopulation. In response to IL-2, these CD25(+) Tfh cells increased expression of costimulatory molecules ICOS or OX40, upregulated transcription factor cMaf, produced cytokines IL-21, IL-17, and IL-10, and raised the levels of antiapoptotic protein Bcl2. Conjugates formed with CD25(+) BCl6(low) Tfh cells included B cells expressing higher levels of activation-induced cytidine deaminase (AID), memory marker CD45RO, surface IgG or IgA, and MHC class II compared to B-cell conjugates including CD25(-) Bcl6(hi) Tfh cells. While IL-2 suppresses early Tfh-cell differentiation, Tfh-cell recognition of antigen-presenting B cells and signaling through the T-cell receptor likely triggers expression of the high-affinity IL-2 receptor and responses to IL-2 including downregulation of Bcl6. CD25 expression on Tfh cells and local production of IL-2 in tonsil or lymph node may support B helper T-cell function during later stages of B-cell maturation and the development of immune memory.
|
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"B-cell",
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"and",
"the",
"development",
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"immune",
"memory",
"."
] |
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16810074
|
Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.
|
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"that",
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"the",
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"does",
"not",
"make",
"a",
"major",
"contribution",
"to",
"this",
"form",
"of",
"hypertension",
"."
] |
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16920333
|
Anticonvulsant effect of eslicarbazepine acetate (BIA 2-093) on seizures induced by microperfusion of picrotoxin in the hippocampus of freely moving rats. Eslicarbazepine acetate (BIA 2-093, S-(-)-10-acetoxy-10,11-dihydro-5H-dibenzo/b,f/azepine-5-carboxamide) is a novel antiepileptic drug, now in Phase III clinical trials, designed with the aim of improving efficacy and safety in comparison with the structurally related drugs carbamazepine (CBZ) and oxcarbazepine (OXC). We have studied the effects of oral treatment with eslicarbazepine acetate on a whole-animal model in which partial seizures can be elicited repeatedly on different days without changes in threshold or seizure patterns. In the animals treated with threshold doses of picrotoxin, the average number of seizures was 2.3+/-1.2, and average seizure duration was 39.5+/-8.4s. Pre-treatment with a dose of 30 mg/kg 2h before picrotoxin microperfusion prevented seizures in the 75% of the rats. Lower doses (3 and 10mg/kg) did not suppress seizures, however, after administration of 10mg/kg, significant reductions in seizures duration (24.3+/-6.8s) and seizure number (1.6+/-0.34) were found. No adverse effects of eslicarbazepine acetate were observed in the behavioral/EEG patterns studied, including sleep/wakefulness cycle, at the doses studied.
|
[
"Anticonvulsant",
"effect",
"of",
"eslicarbazepine",
"acetate",
"(",
"BIA",
"2-093",
")",
"on",
"seizures",
"induced",
"by",
"microperfusion",
"of",
"picrotoxin",
"in",
"the",
"hippocampus",
"of",
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"rats",
".",
"Eslicarbazepine",
"acetate",
"(",
"BIA",
"2-093",
",",
"S-",
"(",
"-",
")",
"-10-acetoxy-10,11-dihydro-5H-dibenzo/b",
",",
"f/azepine-5-carboxamide",
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"a",
"novel",
"antiepileptic",
"drug",
",",
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"III",
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"trials",
",",
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"aim",
"of",
"improving",
"efficacy",
"and",
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"comparison",
"with",
"the",
"structurally",
"related",
"drugs",
"carbamazepine",
"(",
"CBZ",
")",
"and",
"oxcarbazepine",
"(",
"OXC",
")",
".",
"We",
"have",
"studied",
"the",
"effects",
"of",
"oral",
"treatment",
"with",
"eslicarbazepine",
"acetate",
"on",
"a",
"whole-animal",
"model",
"in",
"which",
"partial",
"seizures",
"can",
"be",
"elicited",
"repeatedly",
"on",
"different",
"days",
"without",
"changes",
"in",
"threshold",
"or",
"seizure",
"patterns",
".",
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"the",
"animals",
"treated",
"with",
"threshold",
"doses",
"of",
"picrotoxin",
",",
"the",
"average",
"number",
"of",
"seizures",
"was",
"2.3+/-1.2",
",",
"and",
"average",
"seizure",
"duration",
"was",
"39.5+/-8.4s",
".",
"Pre-treatment",
"with",
"a",
"dose",
"of",
"30",
"mg/kg",
"2h",
"before",
"picrotoxin",
"microperfusion",
"prevented",
"seizures",
"in",
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"%",
"of",
"the",
"rats",
".",
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"doses",
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"3",
"and",
"10mg/kg",
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"did",
"not",
"suppress",
"seizures",
",",
"however",
",",
"after",
"administration",
"of",
"10mg/kg",
",",
"significant",
"reductions",
"in",
"seizures",
"duration",
"(",
"24.3+/-6.8s",
")",
"and",
"seizure",
"number",
"(",
"1.6+/-0.34",
")",
"were",
"found",
".",
"No",
"adverse",
"effects",
"of",
"eslicarbazepine",
"acetate",
"were",
"observed",
"in",
"the",
"behavioral/EEG",
"patterns",
"studied",
",",
"including",
"sleep/wakefulness",
"cycle",
",",
"at",
"the",
"doses",
"studied",
"."
] |
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17615423
|
Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir. OBJECTIVE: To report a case of a severe interaction between simvastatin, amiodarone, and atazanavir resulting in rhabdomyolysis and acute renal failure. BACKGROUND: A 72-year-old white man with underlying human immunodeficiency virus, atrial fibrillation, coronary artery disease, and hyperlipidemia presented with generalized pain, fatigue, and dark orange urine for 3 days. The patient was taking 80 mg simvastatin at bedtime (initiated 27 days earlier); amiodarone at a dose of 400 mg daily for 7 days, then 200 mg daily (initiated 19 days earlier); and 400 mg atazanavir daily (initiated at least 2 years previously). Laboratory evaluation revealed 66,680 U/L creatine kinase, 93 mg/dL blood urea nitrogen, 4.6 mg/dL creatinine, 1579 U/L aspartate aminotransferase, and 738 U/L alanine aminotransferase. Simvastatin, amiodarone, and the patient's human immunodeficiency virus medications were all temporarily discontinued and the patient was given forced alkaline diuresis and started on dialysis. Nine days later the patient's creatine kinase had dropped to 1695 U/L and creatinine was 3.3 mg/dL. The patient was discharged and continued outpatient dialysis for 1 month until his renal function recovered. DISCUSSION: The risk of rhabdomyolysis is increased in the presence of concomitant drugs that inhibit simvastatin metabolism. Simvastatin is metabolized by CYP3A4. Amiodarone and atazanavir are recognized CYP3A4 inhibitors. CONCLUSIONS: Pharmacokinetic differences in statins are an important consideration for assessing the risk of potential drug interactions. In patients requiring the concurrent use of statins and CYP3A4 inhibitors, pravastatin, fluvastatin, and rosuvastatin carry the lowest risk of drug interactions; atorvastatin carries moderate risk, whereas simvastatin and lovastatin have the highest risk and should be avoided in patients taking concomitant CYP3A4 inhibitors.
|
[
"Severe",
"rhabdomyolysis",
"and",
"acute",
"renal",
"failure",
"secondary",
"to",
"concomitant",
"use",
"of",
"simvastatin",
",",
"amiodarone",
",",
"and",
"atazanavir",
".",
"OBJECTIVE",
":",
"To",
"report",
"a",
"case",
"of",
"a",
"severe",
"interaction",
"between",
"simvastatin",
",",
"amiodarone",
",",
"and",
"atazanavir",
"resulting",
"in",
"rhabdomyolysis",
"and",
"acute",
"renal",
"failure",
".",
"BACKGROUND",
":",
"A",
"72-year-old",
"white",
"man",
"with",
"underlying",
"human",
"immunodeficiency",
"virus",
",",
"atrial",
"fibrillation",
",",
"coronary",
"artery",
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",",
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",",
"and",
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"urine",
"for",
"3",
"days",
".",
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"patient",
"was",
"taking",
"80",
"mg",
"simvastatin",
"at",
"bedtime",
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"27",
"days",
"earlier",
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";",
"amiodarone",
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"a",
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"7",
"days",
",",
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"mg",
"atazanavir",
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"initiated",
"at",
"least",
"2",
"years",
"previously",
")",
".",
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"evaluation",
"revealed",
"66,680",
"U/L",
"creatine",
"kinase",
",",
"93",
"mg/dL",
"blood",
"urea",
"nitrogen",
",",
"4.6",
"mg/dL",
"creatinine",
",",
"1579",
"U/L",
"aspartate",
"aminotransferase",
",",
"and",
"738",
"U/L",
"alanine",
"aminotransferase",
".",
"Simvastatin",
",",
"amiodarone",
",",
"and",
"the",
"patient",
"'s",
"human",
"immunodeficiency",
"virus",
"medications",
"were",
"all",
"temporarily",
"discontinued",
"and",
"the",
"patient",
"was",
"given",
"forced",
"alkaline",
"diuresis",
"and",
"started",
"on",
"dialysis",
".",
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"days",
"later",
"the",
"patient",
"'s",
"creatine",
"kinase",
"had",
"dropped",
"to",
"1695",
"U/L",
"and",
"creatinine",
"was",
"3.3",
"mg/dL",
".",
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"patient",
"was",
"discharged",
"and",
"continued",
"outpatient",
"dialysis",
"for",
"1",
"month",
"until",
"his",
"renal",
"function",
"recovered",
".",
"DISCUSSION",
":",
"The",
"risk",
"of",
"rhabdomyolysis",
"is",
"increased",
"in",
"the",
"presence",
"of",
"concomitant",
"drugs",
"that",
"inhibit",
"simvastatin",
"metabolism",
".",
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"is",
"metabolized",
"by",
"CYP3A4",
".",
"Amiodarone",
"and",
"atazanavir",
"are",
"recognized",
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"inhibitors",
".",
"CONCLUSIONS",
":",
"Pharmacokinetic",
"differences",
"in",
"statins",
"are",
"an",
"important",
"consideration",
"for",
"assessing",
"the",
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"potential",
"drug",
"interactions",
".",
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"patients",
"requiring",
"the",
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"of",
"statins",
"and",
"CYP3A4",
"inhibitors",
",",
"pravastatin",
",",
"fluvastatin",
",",
"and",
"rosuvastatin",
"carry",
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"lowest",
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";",
"atorvastatin",
"carries",
"moderate",
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",",
"whereas",
"simvastatin",
"and",
"lovastatin",
"have",
"the",
"highest",
"risk",
"and",
"should",
"be",
"avoided",
"in",
"patients",
"taking",
"concomitant",
"CYP3A4",
"inhibitors",
"."
] |
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18182964
|
Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. OBJECTIVE: To examine the safety and tolerability of clonidine used alone or with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In a 16-week multicenter, double-blind trial, 122 children with ADHD were randomly assigned to clonidine (n = 31), methylphenidate (n = 29), clonidine and methylphenidate (n = 32), or placebo (n = 30). Doses were flexibly titrated up to 0.6 mg/day for clonidine and 60 mg/day for methylphenidate (both with divided dosing). Groups were compared regarding adverse events and changes from baseline to week 16 in electrocardiograms and vital signs. RESULTS: There were more incidents of bradycardia in subjects treated with clonidine compared with those not treated with clonidine (17.5% versus 3.4%; p =.02), but no other significant group differences regarding electrocardiogram and other cardiovascular outcomes. There were no suggestions of interactions between clonidine and methylphenidate regarding cardiovascular outcomes. Moderate or severe adverse events were more common in subjects on clonidine (79.4% versus 49.2%; p =.0006) but not associated with higher rates of early study withdrawal. Drowsiness was common on clonidine, but generally resolved by 6 to 8 weeks. CONCLUSIONS: Clonidine, used alone or with methylphenidate, appears safe and well tolerated in childhood ADHD. Physicians prescribing clonidine should monitor for bradycardia and advise patients about the high likelihood of initial drowsiness.
|
[
"Clonidine",
"for",
"attention-deficit/hyperactivity",
"disorder",
":",
"II",
".",
"ECG",
"changes",
"and",
"adverse",
"events",
"analysis",
".",
"OBJECTIVE",
":",
"To",
"examine",
"the",
"safety",
"and",
"tolerability",
"of",
"clonidine",
"used",
"alone",
"or",
"with",
"methylphenidate",
"in",
"children",
"with",
"attention-deficit/hyperactivity",
"disorder",
"(",
"ADHD",
")",
".",
"METHOD",
":",
"In",
"a",
"16-week",
"multicenter",
",",
"double-blind",
"trial",
",",
"122",
"children",
"with",
"ADHD",
"were",
"randomly",
"assigned",
"to",
"clonidine",
"(",
"n",
"=",
"31",
")",
",",
"methylphenidate",
"(",
"n",
"=",
"29",
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",",
"clonidine",
"and",
"methylphenidate",
"(",
"n",
"=",
"32",
")",
",",
"or",
"placebo",
"(",
"n",
"=",
"30",
")",
".",
"Doses",
"were",
"flexibly",
"titrated",
"up",
"to",
"0.6",
"mg/day",
"for",
"clonidine",
"and",
"60",
"mg/day",
"for",
"methylphenidate",
"(",
"both",
"with",
"divided",
"dosing",
")",
".",
"Groups",
"were",
"compared",
"regarding",
"adverse",
"events",
"and",
"changes",
"from",
"baseline",
"to",
"week",
"16",
"in",
"electrocardiograms",
"and",
"vital",
"signs",
".",
"RESULTS",
":",
"There",
"were",
"more",
"incidents",
"of",
"bradycardia",
"in",
"subjects",
"treated",
"with",
"clonidine",
"compared",
"with",
"those",
"not",
"treated",
"with",
"clonidine",
"(",
"17.5",
"%",
"versus",
"3.4",
"%",
";",
"p",
"=.02",
")",
",",
"but",
"no",
"other",
"significant",
"group",
"differences",
"regarding",
"electrocardiogram",
"and",
"other",
"cardiovascular",
"outcomes",
".",
"There",
"were",
"no",
"suggestions",
"of",
"interactions",
"between",
"clonidine",
"and",
"methylphenidate",
"regarding",
"cardiovascular",
"outcomes",
".",
"Moderate",
"or",
"severe",
"adverse",
"events",
"were",
"more",
"common",
"in",
"subjects",
"on",
"clonidine",
"(",
"79.4",
"%",
"versus",
"49.2",
"%",
";",
"p",
"=.0006",
")",
"but",
"not",
"associated",
"with",
"higher",
"rates",
"of",
"early",
"study",
"withdrawal",
".",
"Drowsiness",
"was",
"common",
"on",
"clonidine",
",",
"but",
"generally",
"resolved",
"by",
"6",
"to",
"8",
"weeks",
".",
"CONCLUSIONS",
":",
"Clonidine",
",",
"used",
"alone",
"or",
"with",
"methylphenidate",
",",
"appears",
"safe",
"and",
"well",
"tolerated",
"in",
"childhood",
"ADHD",
".",
"Physicians",
"prescribing",
"clonidine",
"should",
"monitor",
"for",
"bradycardia",
"and",
"advise",
"patients",
"about",
"the",
"high",
"likelihood",
"of",
"initial",
"drowsiness",
"."
] |
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18422462
|
Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available.
|
[
"Spectrum",
"of",
"adverse",
"events",
"after",
"generic",
"HAART",
"in",
"southern",
"Indian",
"HIV-infected",
"patients",
".",
"To",
"determine",
"the",
"incidence",
"of",
"clinically",
"significant",
"adverse",
"events",
"after",
"long-term",
",",
"fixed-dose",
",",
"generic",
"highly",
"active",
"antiretroviral",
"therapy",
"(",
"HAART",
")",
"use",
"among",
"HIV-infected",
"individuals",
"in",
"South",
"India",
",",
"we",
"examined",
"the",
"experiences",
"of",
"3154",
"HIV-infected",
"individuals",
"who",
"received",
"a",
"minimum",
"of",
"3",
"months",
"of",
"generic",
"HAART",
"between",
"February",
"1996",
"and",
"December",
"2006",
"at",
"a",
"tertiary",
"HIV",
"care",
"referral",
"center",
"in",
"South",
"India",
".",
"The",
"most",
"common",
"regimens",
"were",
"3TC",
"+",
"d4T",
"+",
"nevirapine",
"(",
"NVP",
")",
"(",
"54.8",
"%",
")",
",",
"zidovudine",
"(",
"AZT",
")",
"+",
"3TC",
"+",
"NVP",
"(",
"14.5",
"%",
")",
",",
"3TC",
"+",
"d4T",
"+",
"efavirenz",
"(",
"EFV",
")",
"(",
"20.1",
"%",
")",
",",
"and",
"AZT",
"+",
"3TC",
"+",
"EFV",
"(",
"5.4",
"%",
")",
".",
"The",
"most",
"common",
"adverse",
"events",
"and",
"median",
"CD4",
"at",
"time",
"of",
"event",
"were",
"rash",
"(",
"15.2",
"%",
";",
"CD4",
",",
"285",
"cells/microL",
")",
"and",
"peripheral",
"neuropathy",
"(",
"9.0",
"%",
"and",
"348",
"cells/microL",
")",
".",
"Clinically",
"significant",
"anemia",
"(",
"hemoglobin",
"<",
"7",
"g/dL",
")",
"was",
"observed",
"in",
"5.4",
"%",
"of",
"patients",
"(",
"CD4",
",",
"165",
"cells/microL",
")",
"and",
"hepatitis",
"(",
"clinical",
"jaundice",
"with",
"alanine",
"aminotransferase",
">",
"5",
"times",
"upper",
"limits",
"of",
"normal",
")",
"in",
"3.5",
"%",
"of",
"patients",
"(",
"CD4",
",",
"260",
"cells/microL",
")",
".",
"Women",
"were",
"significantly",
"more",
"likely",
"to",
"experience",
"lactic",
"acidosis",
",",
"while",
"men",
"were",
"significantly",
"more",
"likely",
"to",
"experience",
"immune",
"reconstitution",
"syndrome",
"(",
"p",
"<",
"0.05",
")",
".",
"Among",
"the",
"patients",
"with",
"1",
"year",
"of",
"follow-up",
",",
"NVP",
"therapy",
"was",
"significantly",
"associated",
"with",
"developing",
"rash",
"and",
"d4T",
"therapy",
"with",
"developing",
"peripheral",
"neuropathy",
"(",
"p",
"<",
"0.05",
")",
".",
"Anemia",
"and",
"hepatitis",
"often",
"occur",
"within",
"12",
"weeks",
"of",
"initiating",
"generic",
"HAART",
".",
"Frequent",
"and",
"early",
"monitoring",
"for",
"these",
"toxicities",
"is",
"warranted",
"in",
"developing",
"countries",
"where",
"generic",
"HAART",
"is",
"increasingly",
"available",
"."
] |
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] |
18442015
|
Protective effect of verapamil on gastric hemorrhagic ulcers in severe atherosclerotic rats. Studies concerning with pathogenesis of gastric hemorrhage and mucosal ulceration produced in atherosclerotic rats are lacking. The aim of this study is to examine the role of gastric acid back-diffusion, mast cell histamine release, lipid peroxide (LPO) generation and mucosal microvascular permeability in modulating gastric hemorrhage and ulcer in rats with atherosclerosis induced by coadministration of vitamin D2 and cholesterol. Additionally, the protective effect of verapamil on this ulcer model was evaluated. Male Wistar rats were challenged intragastrically once daily for 9 days with 1.0 ml/kg of corn oil containing vitamin D2 and cholesterol to induce atherosclerosis. Control rats received corn oil only. After gastric surgery, rat stomachs were irrigated for 3 h with either simulated gastric juice or normal saline. Gastric acid back-diffusion, mucosal LPO generation, histamine concentration, microvascular permeability, luminal hemoglobin content and ulcer areas were determined. Elevated atherosclerotic parameters, such as serum calcium, total cholesterol and low-density lipoprotein concentration were obtained in atherosclerotic rats. Severe gastric ulcers accompanied with increased ulcerogenic factors, including gastric acid back-diffusion, histamine release, LPO generation and luminal hemoglobin content were also observed in these rats. Moreover, a positive correlation of histamine to gastric hemorrhage and to ulcer was found in those atherosclerotic rats. This hemorrhagic ulcer and various ulcerogenic parameters were dose-dependently ameliorated by daily intragastric verapamil. Atherosclerosis could produce gastric hemorrhagic ulcer via aggravation of gastric acid back-diffusion, LPO generation, histamine release and microvascular permeability that could be ameliorated by verapamil in rats.
|
[
"Protective",
"effect",
"of",
"verapamil",
"on",
"gastric",
"hemorrhagic",
"ulcers",
"in",
"severe",
"atherosclerotic",
"rats",
".",
"Studies",
"concerning",
"with",
"pathogenesis",
"of",
"gastric",
"hemorrhage",
"and",
"mucosal",
"ulceration",
"produced",
"in",
"atherosclerotic",
"rats",
"are",
"lacking",
".",
"The",
"aim",
"of",
"this",
"study",
"is",
"to",
"examine",
"the",
"role",
"of",
"gastric",
"acid",
"back-diffusion",
",",
"mast",
"cell",
"histamine",
"release",
",",
"lipid",
"peroxide",
"(",
"LPO",
")",
"generation",
"and",
"mucosal",
"microvascular",
"permeability",
"in",
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"gastric",
"hemorrhage",
"and",
"ulcer",
"in",
"rats",
"with",
"atherosclerosis",
"induced",
"by",
"coadministration",
"of",
"vitamin",
"D2",
"and",
"cholesterol",
".",
"Additionally",
",",
"the",
"protective",
"effect",
"of",
"verapamil",
"on",
"this",
"ulcer",
"model",
"was",
"evaluated",
".",
"Male",
"Wistar",
"rats",
"were",
"challenged",
"intragastrically",
"once",
"daily",
"for",
"9",
"days",
"with",
"1.0",
"ml/kg",
"of",
"corn",
"oil",
"containing",
"vitamin",
"D2",
"and",
"cholesterol",
"to",
"induce",
"atherosclerosis",
".",
"Control",
"rats",
"received",
"corn",
"oil",
"only",
".",
"After",
"gastric",
"surgery",
",",
"rat",
"stomachs",
"were",
"irrigated",
"for",
"3",
"h",
"with",
"either",
"simulated",
"gastric",
"juice",
"or",
"normal",
"saline",
".",
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"acid",
"back-diffusion",
",",
"mucosal",
"LPO",
"generation",
",",
"histamine",
"concentration",
",",
"microvascular",
"permeability",
",",
"luminal",
"hemoglobin",
"content",
"and",
"ulcer",
"areas",
"were",
"determined",
".",
"Elevated",
"atherosclerotic",
"parameters",
",",
"such",
"as",
"serum",
"calcium",
",",
"total",
"cholesterol",
"and",
"low-density",
"lipoprotein",
"concentration",
"were",
"obtained",
"in",
"atherosclerotic",
"rats",
".",
"Severe",
"gastric",
"ulcers",
"accompanied",
"with",
"increased",
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"also",
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"positive",
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"histamine",
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"hemorrhage",
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"parameters",
"were",
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".",
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"be",
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"by",
"verapamil",
"in",
"rats",
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] |
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] |
18754075
|
Massive proteinuria and acute renal failure after oral bisphosphonate (alendronate) administration in a patient with focal segmental glomerulosclerosis. A 61-year-old Japanese man with nephrotic syndrome due to focal segmental glomerulosclerosis was initially responding well to steroid therapy. The amount of daily urinary protein decreased from 15.6 to 2.8 g. Within 14 days of the oral bisphosphonate (alendronate sodium) administration, the amount of daily urinary protein increased rapidly up to 12.8 g with acute renal failure. After discontinuing the oral alendronate, the patient underwent six cycles of hemodialysis and four cycles of LDL apheresis. Urinary volume and serum creatinine levels recovered to the normal range, with urinary protein disappearing completely within 40 days. This report demonstrates that not only intravenous, but also oral bisphosphonates can aggravate proteinuria and acute renal failure.
|
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] |
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18945509
|
Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents.
|
[
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] |
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19058010
|
Effect of green tea and vitamin E combination in isoproterenol induced myocardial infarction in rats. The present study was aimed to investigate the combined effects of green tea and vitamin E on heart weight, body weight, serum marker enzymes, lipid peroxidation, endogenous antioxidants and membrane bound ATPases in isoproterenol (ISO)-induced myocardial infarction in rats. Adult male albino rats, treated with ISO (200 mg/kg, s.c.) for 2 days at an interval of 24 h caused a significant (P<0.05) elevation of heart weight, serum marker enzymes, lipid peroxidation and Ca+2 ATPase level whereas there was a significant (P<0.05) decrease in body weight, endogenous antioxidants, Na+/ K+ ATPase and Mg+2 ATPase levels. Administration of green tea (100 mg/kg/day, p.o.) and vitamin E (100 mg/kg/day, p.o.) together for 30 consecutive days and challenged with ISO on the day 29th and 30th, showed a significant (P<0.05) decrease in heart weight, serum marker enzymes, lipid peroxidation, Ca+2 ATPase and a significant increase in the body weight, endogenous antioxidants, Na+/K+ ATPase and Mg+2 ATPase when compared with ISO treated group and green tea or vitamin E alone treated groups. These findings indicate the synergistic protective effect of green tea and vitamin E during ISO induced myocardial infarction in rats.
|
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23949582
|
The cytogenetic action of ifosfamide, mesna, and their combination on peripheral rabbit lymphocytes: an in vivo/in vitro cytogenetic study. Ifosfamide (IFO) is an alkylating nitrogen mustard, administrated as an antineoplasmic agent. It is characterized by its intense urotoxic action, leading to hemorrhagic cystitis. This side effect of IFO raises the requirement for the co-administration with sodium 2-sulfanylethanesulfonate (Mesna) aiming to avoid or minimize this effect. IFO and Mesna were administrated separately on rabbit's lymphocytes in vivo, which were later developed in vitro. Cytogenetic markers for sister chromatid exchanges (SCEs), proliferation rate index (PRI) and Mitotic Index were recorded. Mesna's action, in conjunction with IFO reduces the frequency of SCEs, in comparison with the SCEs recordings obtained when IFO is administered alone. In addition to this, when high concentrations of Mesna were administered alone significant reductions of the PRI were noted, than with IFO acting at the same concentration on the lymphocytes. Mesna significantly reduces IFO's genotoxicity, while when administered in high concentrations it acts in an inhibitory fashion on the cytostatic action of the drug.
|
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