SHS/biored_tokenized · Datasets at Hugging Face

pmid stringclasses 30 values	passage stringclasses 30 values	tokens sequence	ner_tags sequence
19394258	The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.	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2491010	Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene. Eighty unrelated individuals with Duchenne muscular dystrophy (DMD)or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5 ' end of the gene.	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21405999	Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy. Background: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. Material and Methods: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. Results: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. Conclusion: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans.	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21684788	Large contiguous gene deletions in Sjogren-Larsson syndrome. Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.	[ "Large", "contiguous", "gene", "deletions", "in", "Sjogren-Larsson", "syndrome", ".", "Sjogren-Larsson", "syndrome", "(", "SLS", ")", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "ichthyosis", ",", "mental", "retardation", ",", "spasticity", "and", "mutations", "in", "the", "ALDH3A2", "gene", "for", "fatty", "aldehyde", "dehydrogenase", ",", "an", "enzyme", "that", "catalyzes", "the", "oxidation", "of", "fatty", "aldehyde", "to", "fatty", "acid", ".", "More", "than", "70", "mutations", "have", "been", "identified", "in", "SLS", "patients", ",", "including", "small", "deletions", "or", "insertions", ",", "missense", "mutations", ",", "splicing", "defects", "and", "complex", "nucleotide", "changes", ".", "We", "now", "describe", "2", "SLS", "patients", "whose", "disease", "is", "caused", "by", "large", "contiguous", "gene", "deletions", "of", "the", "ALDH3A2", "locus", "on", "17p11.2", ".", "The", "deletions", "were", "defined", "using", "long", "distance", "inverse", "PCR", "and", "microarray-based", "comparative", "genomic", "hybridization", ".", "A", "24-year-old", "SLS", "female", "was", "homozygous", "for", "a", "352-kb", "deletion", "involving", "ALDH3A2", "and", "4", "contiguous", "genes", "including", "ALDH3A1", ",", "which", "codes", "for", "the", "major", "soluble", "protein", "in", "cornea", ".", "Although", "lacking", "corneal", "disease", ",", "she", "showed", "severe", "symptoms", "of", "SLS", "with", "uncommon", "deterioration", "in", "oral", "motor", "function", "and", "loss", "of", "ambulation", ".", "The", "other", "19-month-old", "female", "patient", "was", "a", "compound", "heterozygote", "for", "a", "1.44-Mb", "contiguous", "gene", "deletion", "and", "a", "missense", "mutation", "(", "c.407C", ">", "T", ",", "P136L", ")", "in", "ALDH3A2", ".", "These", "studies", "suggest", "that", "large", "gene", "deletions", "may", "account", "for", "up", "to", "5", "%", "of", "the", "mutant", "alleles", "in", "SLS", ".", "Geneticists", "should", "consider", "the", "possibility", "of", "compound", "heterozygosity", "for", "large", "deletions", "in", "patients", "with", "SLS", "and", "other", "inborn", "errors", "of", "metabolism", ",", "which", "has", "implications", "for", "carrier", "testing", "and", "prenatal", "diagnosis", "." ]	[ "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "0", "2", "0", "0", "0", "2", "2", "2", "0", "0", "2", "0", "2", "2", "0", "2", "0", "0", "0", "0", "1", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "5", "5", "0", "1", "1", "1", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "5", "5", "5", "0", "5", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
16840830	Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.	[ "Two", "novel", "mutations", "in", "the", "MEN1", "gene", "in", "subjects", "with", "multiple", "endocrine", "neoplasia-1", ".", "Multiple", "endocrine", "neoplasia", "type", "1", "(", "MEN1", ")", "is", "characterized", "by", "parathyroid", ",", "enteropancreatic", "endocrine", "and", "pituitary", "adenomas", "as", "well", "as", "germline", "mutation", "of", "the", "MEN1", "gene", ".", "We", "describe", "2", "families", "with", "MEN1", "with", "novel", "mutations", "in", "the", "MEN1", "gene", ".", "One", "family", "was", "of", "Turkish", "origin", ",", "and", "the", "index", "patient", "had", "primary", "hyperparathyroidism", "(", "PHPT", ")", "plus", "a", "prolactinoma", ";", "three", "relatives", "had", "PHPT", "only", ".", "The", "index", "patient", "in", "the", "second", "family", "was", "a", "46-yr-old", "woman", "of", "Chinese", "origin", "living", "in", "Taiwan", ".", "This", "patient", "presented", "with", "a", "complaint", "of", "epigastric", "pain", "and", "watery", "diarrhea", "over", "the", "past", "3", "months", ",", "and", "had", "undergone", "subtotal", "parathyroidectomy", "and", "enucleation", "of", "pancreatic", "islet", "cell", "tumor", "about", "10", "yr", "before", ".", "There", "was", "also", "a", "prolactinoma", ".", "Sequence", "analysis", "of", "the", "MEN1", "gene", "from", "leukocyte", "genomic", "DNA", "revealed", "heterozygous", "mutations", "in", "both", "probands", ".", "The", "Turkish", "patient", "and", "her", "affected", "relatives", "all", "had", "a", "heterozygous", "A", "to", "G", "transition", "at", "codon", "557", "(", "AAG", "--", ">", "GAG", ")", "of", "exon", "10", "of", "MEN1", "that", "results", "in", "a", "replacement", "of", "lysine", "by", "glutamic", "acid", ".", "The", "Chinese", "index", "patient", "and", "one", "of", "her", "siblings", "had", "a", "heterozygous", "mutation", "at", "codon", "418", "of", "exon", "9", "(", "GAC", "--", ">", "TAT", ")", "that", "results", "in", "a", "substitution", "of", "aspartic", "acid", "by", "tyrosine", ".", "In", "conclusion", ",", "we", "have", "identified", "2", "novel", "missense", "mutations", "in", "the", "MEN1", "gene", "." ]	[ "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "2", "2", "2", "0", "2", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "0", "2", "0", "0", "0", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0" ]
15668505	Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers. The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.	[ "Common", "BRCA2", "variants", "and", "modification", "of", "breast", "and", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "HH", "genotype", "of", "the", "nonconservative", "amino", "acid", "substitution", "polymorphism", "N372H", "in", "the", "BRCA2", "gene", "was", "reported", "to", "be", "associated", "with", "a", "1.3-", "to", "1.5-fold", "increase", "in", "risk", "of", "both", "breast", "and", "ovarian", "cancer", ".", "As", "these", "studies", "concerned", "sporadic", "cancer", "cases", ",", "we", "investigated", "whether", "N372H", "and", "another", "common", "variant", "located", "in", "the", "5'-untranslated", "region", "(", "203G", ">", "A", ")", "of", "the", "BRCA2", "gene", "modify", "breast", "or", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "study", "includes", "778", "women", "carrying", "a", "BRCA1", "germ-line", "mutation", "belonging", "to", "403", "families", ".", "The", "two", "BRCA2", "variants", "were", "analyzed", "by", "the", "TaqMan", "allelic", "discrimination", "technique", ".", "Genotypes", "were", "analyzed", "by", "disease-free", "survival", "analysis", "using", "a", "Cox", "proportional", "hazards", "model", ".", "We", "found", "no", "evidence", "of", "a", "significant", "modification", "of", "breast", "cancer", "penetrance", "in", "BRCA1", "mutation", "carriers", "by", "either", "polymorphism", ".", "In", "respect", "of", "ovarian", "cancer", "risk", ",", "we", "also", "saw", "no", "effect", "with", "the", "N372H", "variant", "but", "we", "did", "observe", "a", "borderline", "association", "with", "the", "5'-untranslated", "region", "203A", "allele", "(", "hazard", "ratio", ",", "1.43", ";", "CI", ",", "1.01-2.00", ")", ".", "In", "contrast", "to", "the", "result", "of", "Healey", "et", "al", ".", "on", "newborn", "females", "and", "adult", "female", "controls", ",", "we", "found", "no", "departure", "from", "Hardy-Weinberg", "equilibrium", "in", "the", "distribution", "of", "N372H", "alleles", "for", "our", "female", "BRCA1", "carriers", ".", "We", "conclude", "that", "if", "these", "single-nucleotide", "polymorphisms", "do", "modify", "the", "risk", "of", "cancer", "in", "BRCA1", "mutation", "carriers", ",", "their", "effects", "are", "not", "significantly", "larger", "than", "that", "of", "N372H", "previously", "observed", "in", "the", "general", "population", "." ]	[ "0", "1", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "1", "0", "0", "2", "2", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0" ]
15130900	Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.	[ "Urinary", "bladder", "cancer", "in", "Wegener", "'s", "granulomatosis", ":", "risks", "and", "relation", "to", "cyclophosphamide", ".", "OBJECTIVE", ":", "To", "assess", "and", "characterise", "the", "risk", "of", "bladder", "cancer", ",", "and", "its", "relation", "to", "cyclophosphamide", ",", "in", "patients", "with", "Wegener", "'s", "granulomatosis", ".", "METHODS", ":", "In", "the", "population", "based", ",", "nationwide", "Swedish", "Inpatient", "Register", "a", "cohort", "of", "1065", "patients", "with", "Wegener", "'s", "granulomatosis", ",", "1969-95", ",", "was", "identified", ".", "Through", "linkage", "with", "the", "Swedish", "Cancer", "Register", ",", "all", "subjects", "in", "this", "cohort", "diagnosed", "with", "bladder", "cancer", "were", "identified", ".", "Nested", "within", "the", "cohort", ",", "a", "matched", "case-control", "study", "was", "performed", "to", "estimate", "the", "association", "between", "cyclophosphamide", "and", "bladder", "cancer", "using", "odds", "ratios", "(", "ORs", ")", "as", "relative", "risk", ".", "In", "the", "cohort", "the", "cumulative", "risk", "of", "bladder", "cancer", "after", "Wegener", "'s", "granulomatosis", ",", "and", "the", "relative", "prevalence", "of", "a", "history", "of", "bladder", "cancer", "at", "the", "time", "of", "diagnosis", "of", "Wegener", "'s", "granulomatosis", ",", "were", "also", "estimated", ".", "RESULTS", ":", "The", "median", "cumulative", "doses", "of", "cyclophosphamide", "among", "cases", "(", "n", "=", "11", ")", "and", "controls", "(", "n", "=", "25", ")", "were", "113", "g", "and", "25", "g", ",", "respectively", ".", "The", "risk", "of", "bladder", "cancer", "doubled", "for", "every", "10", "g", "increment", "in", "cyclophosphamide", "(", "OR", "=", "2.0", ",", "95", "%", "confidence", "interval", "(", "CI", ")", "0.8", "to", "4.9", ")", ".", "Treatment", "duration", "longer", "than", "1", "year", "was", "associated", "with", "an", "eightfold", "increased", "risk", "(", "OR", "=", "7.7", ",", "95", "%", "CI", "0.9", "to", "69", ")", ".", "The", "absolute", "risk", "for", "bladder", "cancer", "in", "the", "cohort", "reached", "10", "%", "16", "years", "after", "diagnosis", "of", "Wegener", "'s", "granulomatosis", ",", "and", "a", "history", "of", "bladder", "cancer", "was", "(", "non-significantly", ")", "twice", "as", "common", "as", "expected", "at", "the", "time", "of", "diagnosis", "of", "Wegener", "'s", "granulomatosis", ".", "CONCLUSION", ":", "The", "results", "indicate", "a", "dose-response", "relationship", "between", "cyclophosphamide", "and", "the", "risk", "of", "bladder", "cancer", ",", "high", "cumulative", "risks", "in", "the", "entire", "cohort", ",", "and", "also", "the", "possibility", "of", "risk", "factors", "operating", "even", "before", "Wegener", "'s", "granulomatosis", "." ]	[ "2", "2", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "3", "0", "0", "4", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "4", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0" ]
18257781	Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.	[ "Co-inheritance", "of", "a", "PKD1", "mutation", "and", "homozygous", "PKD2", "variant", ":", "a", "potential", "modifier", "in", "autosomal", "dominant", "polycystic", "kidney", "disease", ".", "BACKGROUND", ":", "Autosomal", "dominant", "polycystic", "kidney", "disease", "(", "ADPKD", ")", ",", "which", "is", "caused", "by", "mutations", "in", "polycystins", "1", "(", "PC1", ")", "and", "2", "(", "PC2", ")", ",", "is", "one", "of", "the", "most", "commonly", "inherited", "renal", "diseases", ",", "affecting", "~1", ":", "1000", "Caucasians", ".", "MATERIALS", "AND", "METHODS", ":", "We", "screened", "Greek", "ADPKD", "patients", "with", "the", "denaturing", "gradient", "gel", "electrophoresis", "(", "DGGE", ")", "assay", "and", "direct", "sequencing", ".", "RESULTS", ":", "We", "identified", "a", "patient", "homozygous", "for", "a", "nucleotide", "change", "c.1445T", ">", "G", ",", "resulting", "in", "a", "novel", "homozygous", "substitution", "of", "the", "non-polar", "hydrophobic", "phenylalanine", "to", "the", "polar", "hydrophilic", "cysteine", "in", "exon", "6", "at", "codon", "482", "(", "p.F482C", ")", "of", "the", "PKD2", "gene", "and", "a", "de-novo", "PKD1", "splice-site", "variant", "IVS21-2delAG", ".", "We", "did", "not", "find", "this", "PKD2", "variant", "in", "a", "screen", "of", "280", "chromosomes", "of", "healthy", "subjects", ",", "supporting", "its", "pathogenicity", ".", "The", "proband", "'s", "parents", "did", "not", "have", "the", "PKD1", "mutation", ".", "Real-time", "PCR", "of", "the", "PKD2", "transcript", "from", "a", "skin", "biopsy", "revealed", "20-fold", "higher", "expression", "in", "the", "patient", "than", "in", "a", "healthy", "subject", "and", "was", "higher", "in", "the", "patient", "'s", "peripheral", "blood", "mononuclear", "cells", "(", "PBMCs", ")", "than", "in", "those", "of", "her", "heterozygote", "daughter", "and", "a", "healthy", "subject", ".", "The", "greater", "gene", "expression", "was", "also", "supported", "by", "Western", "blotting", ".", "Inner", "medullar", "collecting", "duct", "(", "IMCD", ")", "cells", "transfected", "with", "the", "mutant", "PKD2", "mouse", "gene", "presented", "a", "perinuclear", "and", "diffuse", "cytoplasmic", "localization", "compared", "with", "the", "wild", "type", "ER", "localization", ".", "Patch-clamping", "of", "PBMCs", "from", "the", "p.F482C", "homozygous", "and", "heterozygous", "subjects", "revealed", "lower", "polycystin-2", "channel", "function", "than", "in", "controls", ".", "CONCLUSIONS", ":", "We", "report", "for", "the", "first", "time", "a", "patient", "with", "ADPKD", "who", "is", "heterozygous", "for", "a", "de", "novo", "PKD1", "variant", "and", "homozygous", "for", "a", "novel", "PKD2", "mutation", "." ]	[ "0", "0", "0", "1", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "2", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "5", "0", "0", "0", "1", "0", "0", "0", "0", "1", "0", "0", "5", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "1", "0", "0" ]
16970763	Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. BACKGROUND: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP). METHODS: A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing. RESULTS: Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation. CONCLUSION: Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome.	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19276632	Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate. In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the L beck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G>A substitution in the 3'-untranslated region. Two patients carried a c.262G>A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C>T (Ser424Ser) and c.1284T>C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development.	[ "Mutation", "analysis", "of", "FOXF2", "in", "patients", "with", "disorders", "of", "sex", "development", "(", "DSD", ")", "in", "combination", "with", "cleft", "palate", ".", "In", "contrast", "to", "disorders", "of", "sexual", "differentiation", "caused", "by", "lack", "of", "androgen", "production", "or", "inhibited", "androgen", "action", ",", "defects", "affecting", "development", "of", "the", "bipotent", "genital", "anlagen", "have", "rarely", "been", "investigated", "in", "humans", ".", "We", "have", "previously", "documented", "that", "the", "transcription", "factor", "FOXF2", "is", "highly", "expressed", "in", "human", "foreskin", ".", "Moreover", ",", "Foxf2", "knockout", "mice", "present", "with", "cleft", "palate", "in", "combination", "with", "hypoplasia", "of", "the", "genital", "tubercle", ".", "We", "hypothesized", "that", "humans", "with", "disorders", "of", "sex", "development", "(", "DSD", ")", "in", "combination", "with", "cleft", "palate", "could", "have", "mutations", "in", "the", "FOXF2", "gene", ".", "Eighteen", "children", "with", "DSD", "and", "cleft", "palate", "were", "identified", "in", "the", "L", "beck", "DSD", "database", "(", "about", "1,500", "entries", ")", ".", "Genomic", "DNA", "sequence", "analysis", "of", "the", "FOXF2", "gene", "was", "performed", "and", "compared", "with", "10", "normal", "female", "and", "10", "normal", "male", "controls", ",", "respectively", ".", "Two", "heterozygous", "DNA", "sequence", "variations", "were", "solely", "present", "in", "one", "single", "patient", "each", "but", "in", "none", "of", "the", "20", "normal", "controls", ":", "a", "duplication", "of", "GCC", "(", "c.97GCC", "[", "9", "]", "+", "[", "10", "]", ")", "resulting", "in", "an", "extra", "alanine", "within", "exon", "1", "and", "a", "25", "*", "G", ">", "A", "substitution", "in", "the", "3'-untranslated", "region", ".", "Two", "patients", "carried", "a", "c.262G", ">", "A", "sequence", "variation", "predicting", "for", "an", "Ala88Thr", "exchange", "which", "was", "also", "detected", "in", "2", "normal", "controls", ".", "Two", "silent", "mutations", ",", "c.1272C", ">", "T", "(", "Ser424Ser", ")", "and", "c.1284T", ">", "C", "(", "Tyr428Tyr", ")", ",", "respectively", ",", "occurred", "in", "the", "coding", "region", "of", "exon", "2", ",", "again", "in", "both", "patients", "and", "normal", "controls", ".", "In", "conclusion", ",", "the", "majority", "of", "the", "detected", "sequence", "alterations", "were", "polymorphisms", "without", "obvious", "functional", "relevance", ".", "However", ",", "it", "can", "not", "be", "excluded", "that", "the", "2", "unique", "DNA", "sequence", "alterations", "could", "have", "affected", "FOXF2", "on", "the", "mRNA", "or", "protein", "level", "thus", "contributing", "to", "the", "observed", "disturbances", "in", "genital", "and", "palate", "development", "." ]	[ "0", "0", "0", "1", "0", "4", "0", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "3", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "4", "0", "0", "0", "0", "1", "0", "4", "0", "0", "2", "2", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "0", "4", "0", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "5", "0", "0", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
15459975	Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis. Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.	[ "Fine", "mapping", "and", "identification", "of", "a", "candidate", "gene", "SSH1", "in", "disseminated", "superficial", "actinic", "porokeratosis", ".", "Disseminated", "superficial", "actinic", "porokeratosis", "(", "DSAP", ")", "is", "an", "uncommon", "autosomal", "dominant", "chronic", "keratinization", "disorder", ",", "characterized", "by", "multiple", "superficial", "keratotic", "lesions", "surrounded", "by", "a", "slightly", "raised", "keratotic", "border", ".", "Thus", "far", ",", "although", "two", "loci", "for", "DSAP", "have", "been", "identified", ",", "the", "genetic", "basis", "and", "pathogenesis", "of", "this", "disorder", "have", "not", "been", "elucidated", "yet", ".", "In", "this", "study", ",", "we", "performed", "a", "genome-wide", "linkage", "analysis", "in", "three", "Chinese", "affected", "families", "and", "localized", "the", "gene", "in", "an", "8.0", "cM", "interval", "defined", "by", "D12S330", "and", "D12S354", "on", "chromosome", "12", ".", "Upon", "screening", "30", "candidate", "genes", ",", "we", "identified", "a", "missense", "mutation", ",", "p.Ser63Asn", "in", "SSH1", "in", "one", "family", ",", "a", "frameshift", "mutation", ",", "p.Ser19CysfsX24", "in", "an", "alternative", "variant", "(", "isoform", "f", ")", "of", "SSH1", "in", "another", "family", ",", "and", "a", "frameshift", "mutation", ",", "p.Pro27ProfsX54", "in", "the", "same", "alternative", "variant", "in", "one", "non-familial", "case", "with", "DSAP", ".", "SSH1", "encodes", "a", "phosphatase", "that", "plays", "a", "pivotal", "role", "in", "actin", "dynamics", ".", "Our", "data", "suggested", "that", "cytoskeleton", "disorganization", "in", "epidermal", "cells", "is", "likely", "associated", "with", "the", "pathogenesis", "of", "DSAP", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "2", "2", "2", "2", "0", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
16330669	Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. PURPOSE: To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). PATIENTS AND METHODS: Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. RESULTS: The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. CONCLUSION: Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.	[ "Array-based", "comparative", "genomic", "hybridization", "analysis", "reveals", "recurrent", "chromosomal", "alterations", "and", "prognostic", "parameters", "in", "primary", "cutaneous", "large", "B-cell", "lymphoma", ".", "PURPOSE", ":", "To", "evaluate", "the", "clinical", "relevance", "of", "genomic", "aberrations", "in", "primary", "cutaneous", "large", "B-cell", "lymphoma", "(", "PCLBCL", ")", ".", "PATIENTS", "AND", "METHODS", ":", "Skin", "biopsy", "samples", "of", "31", "patients", "with", "a", "PCLBCL", "classified", "as", "either", "primary", "cutaneous", "follicle", "center", "lymphoma", "(", "PCFCL", ";", "n", "=", "19", ")", "or", "PCLBCL", ",", "leg", "type", "(", "n", "=", "12", ")", ",", "according", "to", "the", "WHO-European", "Organisation", "for", "Research", "and", "Treatment", "of", "Cancer", "(", "EORTC", ")", "classification", ",", "were", "investigated", "using", "array-based", "comparative", "genomic", "hybridization", ",", "fluorescence", "in", "situ", "hybridization", "(", "FISH", ")", ",", "and", "examination", "of", "promoter", "hypermethylation", ".", "RESULTS", ":", "The", "most", "recurrent", "alterations", "in", "PCFCL", "were", "high-level", "DNA", "amplifications", "at", "2p16.1", "(", "63", "%", ")", "and", "deletion", "of", "chromosome", "14q32.33", "(", "68", "%", ")", ".", "FISH", "analysis", "confirmed", "c-REL", "amplification", "in", "patients", "with", "gains", "at", "2p16.1", ".", "In", "PCLBCL", ",", "leg", "type", ",", "most", "prominent", "aberrations", "were", "a", "high-level", "DNA", "amplification", "of", "18q21.31-q21.33", "(", "67", "%", ")", ",", "including", "the", "BCL-2", "and", "MALT1", "genes", "as", "confirmed", "by", "FISH", ",", "and", "deletions", "of", "a", "small", "region", "within", "9p21.3", "containing", "the", "CDKN2A", ",", "CDKN2B", ",", "and", "NSG-x", "genes", ".", "Homozygous", "deletion", "of", "9p21.3", "was", "detected", "in", "five", "of", "12", "patients", "with", "PCLBCL", ",", "leg", "type", ",", "but", "in", "zero", "of", "19", "patients", "with", "PCFCL", ".", "Complete", "methylation", "of", "the", "promoter", "region", "of", "the", "CDKN2A", "gene", "was", "demonstrated", "in", "one", "PCLBCL", ",", "leg", "type", ",", "patient", "with", "hemizygous", "deletion", ",", "in", "one", "patient", "without", "deletion", ",", "but", "in", "zero", "of", "19", "patients", "with", "PCFCL", ".", "Seven", "of", "seven", "PCLBCL", ",", "leg", "type", ",", "patients", "with", "deletion", "of", "9p21.3", "and/or", "complete", "methylation", "of", "CDKN2A", "died", "as", "a", "result", "of", "their", "lymphoma", ".", "CONCLUSION", ":", "Our", "results", "demonstrate", "prominent", "differences", "in", "chromosomal", "alterations", "between", "PCFCL", "and", "PCLBCL", ",", "leg", "type", ",", "that", "support", "their", "classification", "as", "separate", "entities", "within", "the", "WHO-EORTC", "scheme", ".", "Inactivation", "of", "CDKN2A", "by", "either", "deletion", "or", "methylation", "of", "its", "promoter", "could", "be", "an", "important", "prognostic", "parameter", "for", "the", "group", "of", "PCLBCL", ",", "leg", "type", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "2", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "0", "0", "0", "2", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0" ]
19208385	Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2. Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by fractures with minimal trauma. Intracranial hemorrhage has been reported in a small number of OI patients. Here we describe three patients, a boy (aged 15 years) and two girls (aged 17 and 7 years) with OI type III who suffered intracranial hemorrhage and in addition had brachydactyly and nail hypoplasia. In all of these patients, OI was caused by glycine mutations affecting exon 49 of the COL1A2 gene, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen type I alpha 2 chain. These observations suggest that mutations in this region of the collagen type I alpha 2 chain carry a high risk of abnormal limb development and intracranial bleeding.	[ "Osteogenesis", "imperfecta", "type", "III", "with", "intracranial", "hemorrhage", "and", "brachydactyly", "associated", "with", "mutations", "in", "exon", "49", "of", "COL1A2", ".", "Osteogenesis", "imperfecta", "(", "OI", ")", "is", "a", "heritable", "bone", "disorder", "characterized", "by", "fractures", "with", "minimal", "trauma", ".", "Intracranial", "hemorrhage", "has", "been", "reported", "in", "a", "small", "number", "of", "OI", "patients", ".", "Here", "we", "describe", "three", "patients", ",", "a", "boy", "(", "aged", "15", "years", ")", "and", "two", "girls", "(", "aged", "17", "and", "7", "years", ")", "with", "OI", "type", "III", "who", "suffered", "intracranial", "hemorrhage", "and", "in", "addition", "had", "brachydactyly", "and", "nail", "hypoplasia", ".", "In", "all", "of", "these", "patients", ",", "OI", "was", "caused", "by", "glycine", "mutations", "affecting", "exon", "49", "of", "the", "COL1A2", "gene", ",", "which", "codes", "for", "the", "most", "carboxy-terminal", "part", "of", "the", "triple-helical", "domain", "of", "the", "collagen", "type", "I", "alpha", "2", "chain", ".", "These", "observations", "suggest", "that", "mutations", "in", "this", "region", "of", "the", "collagen", "type", "I", "alpha", "2", "chain", "carry", "a", "high", "risk", "of", "abnormal", "limb", "development", "and", "intracranial", "bleeding", "." ]	[ "2", "2", "2", "2", "0", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "2", "2", "0", "2", "0", "0", "0", "0", "2", "2", "0", "0", "2", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "2", "2", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "2", "2", "0" ]
19681452	Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication. Cocaine is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use. Drug-related globus pallidus infarctions are most often associated with heroin. Bilateral basal ganglia infarcts after the use of cocaine, without concurrent heroin use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to cocaine and/or ethanol use were the most likely causes of cerebral hypoperfusion.	[ "Bilateral", "haemorrhagic", "infarction", "of", "the", "globus", "pallidus", "after", "cocaine", "and", "alcohol", "intoxication", ".", "Cocaine", "is", "a", "risk", "factor", "for", "both", "ischemic", "and", "haemorrhagic", "stroke", ".", "We", "present", "the", "case", "of", "a", "31-year-old", "man", "with", "bilateral", "ischemia", "of", "the", "globus", "pallidus", "after", "excessive", "alcohol", "and", "intranasal", "cocaine", "use", ".", "Drug-related", "globus", "pallidus", "infarctions", "are", "most", "often", "associated", "with", "heroin", ".", "Bilateral", "basal", "ganglia", "infarcts", "after", "the", "use", "of", "cocaine", ",", "without", "concurrent", "heroin", "use", ",", "have", "never", "been", "reported", ".", "In", "our", "patient", ",", "transient", "cardiac", "arrhythmia", "or", "respiratory", "dysfunction", "related", "to", "cocaine", "and/or", "ethanol", "use", "were", "the", "most", "likely", "causes", "of", "cerebral", "hypoperfusion", "." ]	[ "0", "2", "2", "2", "2", "2", "2", "0", "3", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "2", "2", "2", "2", "0", "0", "3", "0", "0", "3", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "3", "0", "0", "2", "2", "2", "0", "0", "0", "0", "3", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "2", "0", "2", "2", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0" ]
20709368	The fibrinogen gamma 10034C>T polymorphism is not associated with Peripheral Arterial Disease. Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case-control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD.	[ "The", "fibrinogen", "gamma", "10034C", ">", "T", "polymorphism", "is", "not", "associated", "with", "Peripheral", "Arterial", "Disease", ".", "Conversion", "of", "fibrinogen", "to", "fibrin", "plays", "an", "essential", "role", "in", "hemostasis", "and", "results", "in", "stabilization", "of", "the", "fibrin", "clot", ".", "Fibrinogen", "consists", "of", "three", "pairs", "of", "non-identical", "polypeptide", "chains", ",", "encoded", "by", "different", "genes", "(", "fibrinogen", "alpha", "[", "FGA", "]", ",", "fibrinogen", "beta", "[", "FGB", "]", "and", "fibrinogen", "gamma", "[", "FGG", "]", ")", ".", "A", "functional", "single", "nucleotide", "polymorphism", "(", "SNP", ")", "in", "the", "3", "'", "untranslated", "region", "of", "the", "FGG", "gene", "(", "FGG", "10034C", ">", "T", ",", "rs2066865", ")", "has", "been", "associated", "with", "deep", "venous", "thrombosis", "and", "myocardial", "infarction", ".", "Aim", "of", "the", "present", "study", "was", "to", "analyze", "the", "role", "of", "this", "polymorphism", "in", "peripheral", "arterial", "disease", "(", "PAD", ")", ".", "The", "study", "was", "designed", "as", "case-control", "study", "including", "891", "patients", "with", "documented", "PAD", "and", "777", "control", "subjects", ".", "FGG", "genotypes", "were", "determined", "by", "exonuclease", "(", "TaqMan", ")", "assays", ".", "FGG", "genotype", "frequencies", "were", "not", "significantly", "different", "between", "PAD", "patients", "(", "CC", ":", "57.3", "%", ",", "CT", ":", "36.7", "%", ",", "TT", ":", "5.8", "%", ")", "and", "control", "subjects", "(", "CC", ":", "60.9", "%", ",", "CT", ":", "33.5", "%", ",", "TT", "5.6", "%", ";", "p=0.35", ")", ".", "In", "a", "multivariate", "logistic", "regression", "analysis", "including", "age", ",", "sex", ",", "smoking", ",", "diabetes", ",", "arterial", "hypertension", "and", "hypercholesterolemia", ",", "the", "FGG", "10034", "T", "variant", "was", "not", "significantly", "associated", "with", "the", "presence", "of", "PAD", "(", "Odds", "ratio", "1.07", ",", "95", "%", "confidence", "interval", "0.84", "-", "1.37", ";", "p", "=", "0.60", ")", ".", "The", "FGG", "10034C", ">", "T", "polymorphism", "was", "furthermore", "not", "associated", "with", "age", "at", "onset", "of", "PAD", ".", "We", "conclude", "that", "the", "thrombophilic", "FGG", "10034", "T", "gene", "variant", "does", "not", "contribute", "to", "the", "genetic", "susceptibility", "to", "PAD", "." ]	[ "0", "1", "1", "5", "5", "5", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "1", "1", "0", "1", "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "1", "5", "5", "5", "0", "5", "0", "0", "0", "0", "0", "2", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "2", "0", "2", "0", "0", "1", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "1", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0" ]
27798239	Phosphatidylinositol 4-kinase IIb negatively regulates invadopodia formation and suppresses an invasive cellular phenotype. The type II phosphatidylinositol 4-kinase (PI4KII) enzymes synthesize the lipid phosphatidylinositol 4-phosphate (PI(4)P), which has been detected at the Golgi complex and endosomal compartments and recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear. We found that depletion of PI4KIIa and PI4KIIb using small interfering RNA led to actin remodeling. Depletion of PI4KIIb also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP). Depletion of PI4KII isoforms also differentially affected trans-Golgi network (TGN) pools of PI(4)P and post-TGN traffic. PI4KIIb depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalization of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7 but increased localization with the exocytic Rab8. Depletion of PI4KIIb was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIb mRNA are associated with human cancers. This finding supports the cell data and suggests that PI4KIIb may be a clinically significant suppressor of invasion. We propose that PI4KIIb synthesizes a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia.	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15111599	CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype. PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene.	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15820770	Vitamin D-binding protein gene polymorphism association with IA-2 autoantibodies in type 1 diabetes. BACKGROUND: Vitamin D-binding protein (DBP) is the main systemic transporter of 1.25(OH)2D3 and is essential for its cellular endocytosis. There are two known polymorphisms in exon 11 of the DBP gene resulting in amino acid variants: GAT-->GAG substitution replaces aspartic acid by glutamic acid in codon 416; and ACG-->AAG substitution in codon 420 leads to an exchange of threonine for lysine. These DBP variants lead to differences in the affinity for 1.25(OH)2D3. Correlations between DBP alleles and type 1 diabetes have been described in different populations. Therefore, we investigated the polymorphism in codon 416 of the DBP gene for an association with autoimmune markers of type 1 diabetes. DESIGN AND METHODS: The present analysis was a case control study. 110 patients, 68 controls, and 115 first-degree relatives were genotyped for the DBP polymorphism in codon 416. DNA typing of DBP locus was performed by the PCR-restriction fragment length polymorphism method (RFLP). RESULTS: The frequencies of the Asp/Glu and Glu/Glu were significantly increased in diabetic subjects with detectable IA-2 antibodies (P < 0.01). On the contrary, the DBP Glu-containing genotype was not accompanied by differences in the prevalence of GAD65 antibodies. These finding supports a role of the vitamin D endocrine system in the autoimmune process of type 1 diabetes.	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16186368	Characterization of Bietti crystalline dystrophy patients with CYP4V2 mutations. PURPOSE: Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. METHODS: Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). RESULTS: Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3' splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. CONCLUSIONS: This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity.	[ "Characterization", "of", "Bietti", "crystalline", "dystrophy", "patients", "with", "CYP4V2", "mutations", ".", "PURPOSE", ":", "Mutations", "of", "the", "CYP4V2", "gene", ",", "a", "novel", "family", "member", "of", "the", "cytochrome", "P450", "genes", "on", "chromosome", "4q35", ",", "have", "recently", "been", "identified", "in", "patients", "with", "Bietti", "crystalline", "dystrophy", "(", "BCD", ")", ".", "The", "aim", "of", "this", "study", "was", "to", "investigate", "the", "spectrum", "of", "mutations", "in", "this", "gene", "in", "BCD", "patients", "from", "Singapore", ",", "and", "to", "characterize", "their", "phenotype", ".", "METHODS", ":", "Nine", "patients", "with", "BCD", "from", "six", "families", "were", "recruited", "into", "the", "study", ".", "The", "11", "exons", "of", "the", "CYP4V2", "gene", "were", "amplified", "from", "genomic", "DNA", "of", "patients", "by", "polymerase", "chain", "reaction", "and", "then", "sequenced", ".", "Detailed", "characterization", "of", "the", "patients", "'", "phenotype", "was", "performed", "with", "fundal", "photography", ",", "visual", "field", "testing", ",", "fundal", "fluorescein", "angiography", ",", "and", "electroretinography", "(", "ERG", ")", ".", "RESULTS", ":", "Three", "pathogenic", "mutations", "were", "identified", ";", "two", "mutations", ",", "S482X", "and", "K386T", ",", "were", "novel", "and", "found", "in", "three", "patients", ".", "The", "third", "mutation", ",", "a", "previously", "identified", "15-bp", "deletion", "that", "included", "the", "3", "'", "splice", "site", "for", "exon", "7", ",", "was", "found", "in", "all", "nine", "patients", ",", "with", "six", "patients", "carrying", "the", "deletion", "in", "the", "homozygous", "state", ".", "Haplotype", "analysis", "in", "patients", "and", "controls", "indicated", "a", "founder", "effect", "for", "this", "deletion", "mutation", "in", "exon", "7", ".", "Clinical", "heterogeneity", "was", "present", "in", "the", "patients", ".", "Compound", "heterozygotes", "for", "the", "deletion", "in", "exon", "7", "seemed", "to", "have", "more", "severe", "disease", "compared", "to", "patients", "homozygous", "for", "the", "deletion", ".", "There", "was", "good", "correlation", "between", "clinical", "stage", "of", "disease", "and", "ERG", "changes", ",", "but", "age", "did", "not", "correlate", "with", "disease", "severity", ".", "CONCLUSIONS", ":", "This", "study", "identified", "novel", "mutations", "in", "the", "CYP4V2", "gene", "as", "a", "cause", "of", "BCD", ".", "A", "high", "carrier", "frequency", "for", "the", "15-bp", "deletion", "in", "exon", "7", "may", "exist", "in", "the", "Singapore", "population", ".", "Phenotype", "characterization", "showed", "clinical", "heterogeneity", ",", "and", "age", "did", "not", "correlate", "with", "disease", "severity", "." ]	[ "0", "0", "2", "2", "2", "4", "0", "1", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
17511042	An extremely rare case of delusional parasitosis in a chronic hepatitis C patient during pegylated interferon alpha-2b and ribavirin treatment. During treatment of chronic hepatitis C patients with interferon and ribavirin, a lot of side effects are described. Twenty-three percent to 44% of patients develop depression. A minority of patients evolve to psychosis. To the best of our knowledge, no cases of psychogenic parasitosis occurring during interferon therapy have been described in the literature. We present a 49-year-old woman who developed a delusional parasitosis during treatment with pegylated interferon alpha-2b weekly and ribavirin. She complained of seeing parasites and the larvae of fleas in her stools. This could not be confirmed by any technical examination. All the complaints disappeared after stopping pegylated interferon alpha-2b and reappeared after restarting it. She had a complete sustained viral response.	[ "An", "extremely", "rare", "case", "of", "delusional", "parasitosis", "in", "a", "chronic", "hepatitis", "C", "patient", "during", "pegylated", "interferon", "alpha-2b", "and", "ribavirin", "treatment", ".", "During", "treatment", "of", "chronic", "hepatitis", "C", "patients", "with", "interferon", "and", "ribavirin", ",", "a", "lot", "of", "side", "effects", "are", "described", ".", "Twenty-three", "percent", "to", "44", "%", "of", "patients", "develop", "depression", ".", "A", "minority", "of", "patients", "evolve", "to", "psychosis", ".", "To", "the", "best", "of", "our", "knowledge", ",", "no", "cases", "of", "psychogenic", "parasitosis", "occurring", "during", "interferon", "therapy", "have", "been", "described", "in", "the", "literature", ".", "We", "present", "a", "49-year-old", "woman", "who", "developed", "a", "delusional", "parasitosis", "during", "treatment", "with", "pegylated", "interferon", "alpha-2b", "weekly", "and", "ribavirin", ".", "She", "complained", "of", "seeing", "parasites", "and", "the", "larvae", "of", "fleas", "in", "her", "stools", ".", "This", "could", "not", "be", "confirmed", "by", "any", "technical", "examination", ".", "All", "the", "complaints", "disappeared", "after", "stopping", "pegylated", "interferon", "alpha-2b", "and", "reappeared", "after", "restarting", "it", ".", "She", "had", "a", "complete", "sustained", "viral", "response", "." ]	[ "0", "0", "0", "0", "0", "2", "2", "0", "0", "2", "2", "2", "4", "0", "1", "1", "1", "0", "3", "0", "0", "0", "0", "0", "2", "2", "2", "4", "0", "1", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "0", "0", "0", "0", "4", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "2", "2", "0", "0", "0", "1", "1", "1", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
19353688	Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1). Insertional translocations (IT) are rare structural rearrangements. Offspring of IT balanced carriers are at high risk to have either pure partial trisomy or monosomy for the inserted segment as manifested by "pure" phenotypes. We describe an IT between chromosomes 3 and 13 segregating in a three-generation pedigree. Short tandem repeat (STR) segregation analysis and array-comparative genomic hybridization were used to define the IT as a 25.1 Mb segment spanning 13q21.2-q31.1. The phenotype of pure monosomy included deafness, duodenal stenosis, developmental and growth delay, vertebral anomalies, and facial dysmorphisms; the trisomy was manifested by only minor dysmorphisms. As the AUNA1 deafness locus on 13q14-21 overlaps the IT in the PCDH9 (protocadherin-9) gene region, PCDH9 was investigated as a candidate gene for deafness in both families. Genotyping of STRs and single nucleotide polymorphisms defined the AUNA1 breakpoint as 35 kb 5' to PCDH9, with a 2.4 Mb area of overlap with the IT. DNA sequencing of coding regions in the AUNA1 family and in the retained homologue chromosome in the monosomic patient revealed no mutations. We conclude that AUNA1 deafness does not share a common etiology with deafness associated with monosomy 13q21.2-q31.3; deafness may result from monosomy of PCHD9 or another gene in the IT, as has been demonstrated in contiguous gene deletion syndromes. Precise characterization of the breakpoints of the translocated region is useful to identify which genes may be contributing to the phenotype, either through haploinsufficiency or extra dosage effects, in order to define genotype-phenotype correlations.	[ "Pure", "monosomy", "and", "pure", "trisomy", "of", "13q21.2-31.1", "consequent", "to", "a", "familial", "insertional", "translocation", ":", "exclusion", "of", "PCDH9", "as", "the", "responsible", "gene", "for", "autosomal", "dominant", "auditory", "neuropathy", "(", "AUNA1", ")", ".", "Insertional", "translocations", "(", "IT", ")", "are", "rare", "structural", "rearrangements", ".", "Offspring", "of", "IT", "balanced", "carriers", "are", "at", "high", "risk", "to", "have", "either", "pure", "partial", "trisomy", "or", "monosomy", "for", "the", "inserted", "segment", "as", "manifested", "by", "``", "pure", "''", "phenotypes", ".", "We", "describe", "an", "IT", "between", "chromosomes", "3", "and", "13", "segregating", "in", "a", "three-generation", "pedigree", ".", "Short", "tandem", "repeat", "(", "STR", ")", "segregation", "analysis", "and", "array-comparative", "genomic", "hybridization", "were", "used", "to", "define", "the", "IT", "as", "a", "25.1", "Mb", "segment", "spanning", "13q21.2-q31.1", ".", "The", "phenotype", "of", "pure", "monosomy", "included", "deafness", ",", "duodenal", "stenosis", ",", "developmental", "and", "growth", "delay", ",", "vertebral", "anomalies", ",", "and", "facial", "dysmorphisms", ";", "the", "trisomy", "was", "manifested", "by", "only", "minor", "dysmorphisms", ".", "As", "the", "AUNA1", "deafness", "locus", "on", "13q14-21", "overlaps", "the", "IT", "in", "the", "PCDH9", "(", "protocadherin-9", ")", "gene", "region", ",", "PCDH9", "was", "investigated", "as", "a", "candidate", "gene", "for", "deafness", "in", "both", "families", ".", "Genotyping", "of", "STRs", "and", "single", "nucleotide", "polymorphisms", "defined", "the", "AUNA1", "breakpoint", "as", "35", "kb", "5", "'", "to", "PCDH9", ",", "with", "a", "2.4", "Mb", "area", "of", "overlap", "with", "the", "IT", ".", "DNA", "sequencing", "of", "coding", "regions", "in", "the", "AUNA1", "family", "and", "in", "the", "retained", "homologue", "chromosome", "in", "the", "monosomic", "patient", "revealed", "no", "mutations", ".", "We", "conclude", "that", "AUNA1", "deafness", "does", "not", "share", "a", "common", "etiology", "with", "deafness", "associated", "with", "monosomy", "13q21.2-q31.3", ";", "deafness", "may", "result", "from", "monosomy", "of", "PCHD9", "or", "another", "gene", "in", "the", "IT", ",", "as", "has", "been", "demonstrated", "in", "contiguous", "gene", "deletion", "syndromes", ".", "Precise", "characterization", "of", "the", "breakpoints", "of", "the", "translocated", "region", "is", "useful", "to", "identify", "which", "genes", "may", "be", "contributing", "to", "the", "phenotype", ",", "either", "through", "haploinsufficiency", "or", "extra", "dosage", "effects", ",", "in", "order", "to", "define", "genotype-phenotype", "correlations", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "2", "2", "2", "2", "0", "2", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
21126715	A Taiwanese boy with congenital generalized lipodystrophy caused by homozygous Ile262fs mutation in the BSCL2 gene. Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG (Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian.	[ "A", "Taiwanese", "boy", "with", "congenital", "generalized", "lipodystrophy", "caused", "by", "homozygous", "Ile262fs", "mutation", "in", "the", "BSCL2", "gene", ".", "Congenital", "generalized", "lipodystrophy", "(", "CGL", ")", "is", "a", "rare", "autosomal", "recessive", "disease", "that", "is", "characterized", "by", "a", "near-complete", "absence", "of", "adipose", "tissue", "from", "birth", "or", "early", "infancy", ".", "Mutations", "in", "the", "BSCL2", "gene", "are", "known", "to", "result", "in", "CGL2", ",", "a", "more", "severe", "phenotype", "than", "CGL1", ",", "with", "earlier", "onset", ",", "more", "extensive", "fat", "loss", "and", "biochemical", "changes", ",", "more", "severe", "intellectual", "impairment", ",", "and", "more", "severe", "cardiomyopathy", ".", "We", "report", "a", "3-month-old", "Taiwanese", "boy", "with", "initial", "presentation", "of", "a", "lack", "of", "subcutaneous", "fat", ",", "prominent", "musculature", ",", "generalized", "eruptive", "xanthomas", ",", "and", "extreme", "hypertriglyceridemia", ".", "Absence", "of", "mechanical", "adipose", "tissue", "in", "the", "orbits", "and", "scalp", "was", "revealed", "by", "head", "magnetic", "resonance", "imaging", ".", "Hepatomegaly", "was", "noticed", ",", "and", "histological", "examination", "of", "a", "liver", "biopsy", "specimen", "suggested", "severe", "hepatic", "steatosis", "and", "periportal", "necrosis", ".", "However", ",", "echocardiography", "indicated", "no", "sign", "of", "cardiomyopathy", "and", "he", "showed", "no", "distinct", "intellectual", "impairment", "that", "interfered", "with", "daily", "life", ".", "About", "1", "year", "later", ",", "abdominal", "computed", "tomography", "revealed", "enlargement", "of", "kidneys", ".", "He", "had", "a", "homozygous", "insertion", "of", "a", "nucleotide", ",", "783insG", "(", "Ile262fs", "mutation", ")", ",", "in", "exon", "7", "of", "the", "BSCL2", "gene", ".", "We", "reviewed", "the", "genotype", "of", "CGL", "cases", "from", "Japan", ",", "India", ",", "China", "and", "Taiwan", ",", "and", "found", "that", "BSCL2", "is", "a", "major", "causative", "gene", "for", "CGL", "in", "Asian", "." ]	[ "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "5", "0", "0", "0", "1", "0", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0" ]
16252083	Polymorphisms of the DNA mismatch repair gene HMSH2 in breast cancer occurence and progression. The response of the cell to DNA damage and its ability to maintain genomic stability by DNA repair are crucial in preventing cancer initiation and progression. Therefore, polymorphism of DNA repair genes may affect the process of carcinogenesis. The importance of genetic variability of the components of mismatch repair (MMR) genes is well documented in colorectal cancer, but little is known about its role in breast cancer. hMSH2 is one of the crucial proteins of MMR. We performed a case-control study to test the association between two polymorphisms in the hMSH2 gene: an A --> G transition at 127 position producing an Asn --> Ser substitution at codon 127 (the Asn127Ser polymorphism) and a G --> A transition at 1032 position resulting in a Gly --> Asp change at codon 322 (the Gly322Asp polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 age-matched women (controls) by restriction fragment length polymorphism and allele-specific PCR. We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom-Richardson grading. A strong association between breast cancer occurrence and the Gly/Gly phenotype of the Gly322Asp polymorphism (odds ratio 8.39; 95% confidence interval 1.44-48.8) was found. Therefore, MMR may play a role in the breast carcinogenesis and the Gly322Asp polymorphism of the hMSH2 gene may be considered as a potential marker in breast cancer.	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18507837	Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort. INTRODUCTION: Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division. METHODS: We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis. RESULTS: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding. CONCLUSION: It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.	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26615423	Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma. Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and b-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC.	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15000256	Single-strand conformation polymorphism analysis of the FMR1 gene in autistic and mentally retarded children in Japan. Fragile X syndrome is one of the most common causes of mental retardation in males, and patients with fragile X syndrome occasionally develop autism. It is usually caused by an expansion of the trinucleotide repeat in the 5'-untranslated region of the FMR1 gene, but in a small number of patients deletions and point mutations have been identified. We screened all 17 exons of the FMR1 gene for mutations in 90 autistic or mentally retarded children using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations were found in 76 male patients. However, one female patient was heterozygous for a normal allele and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This mutation was not found in 50 controls. Reverse transcription-PCR revealed that a large proportion of the mutant transcripts were spliced aberrantly, causing premature termination of the protein synthesis. Although uncommon, point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients.	[ "Single-strand", "conformation", "polymorphism", "analysis", "of", "the", "FMR1", "gene", "in", "autistic", "and", "mentally", "retarded", "children", "in", "Japan", ".", "Fragile", "X", "syndrome", "is", "one", "of", "the", "most", "common", "causes", "of", "mental", "retardation", "in", "males", ",", "and", "patients", "with", "fragile", "X", "syndrome", "occasionally", "develop", "autism", ".", "It", "is", "usually", "caused", "by", "an", "expansion", "of", "the", "trinucleotide", "repeat", "in", "the", "5'-untranslated", "region", "of", "the", "FMR1", "gene", ",", "but", "in", "a", "small", "number", "of", "patients", "deletions", "and", "point", "mutations", "have", "been", "identified", ".", "We", "screened", "all", "17", "exons", "of", "the", "FMR1", "gene", "for", "mutations", "in", "90", "autistic", "or", "mentally", "retarded", "children", "using", "polymerase", "chain", "reaction", "(", "PCR", ")", "-single", "strand", "conformation", "polymorphism", "(", "SSCP", ")", "analysis", ".", "No", "mutations", "were", "found", "in", "76", "male", "patients", ".", "However", ",", "one", "female", "patient", "was", "heterozygous", "for", "a", "normal", "allele", "and", "a", "mutant", "allele", "with", "an", "A", "to", "C", "substitution", "at", "nucleotide", "879", "in", "exon", "9", ".", "This", "mutation", "was", "not", "found", "in", "50", "controls", ".", "Reverse", "transcription-PCR", "revealed", "that", "a", "large", "proportion", "of", "the", "mutant", "transcripts", "were", "spliced", "aberrantly", ",", "causing", "premature", "termination", "of", "the", "protein", "synthesis", ".", "Although", "uncommon", ",", "point", "mutations", "in", "the", "FMR1", "gene", "may", "be", "a", "cause", "of", "autism", "and", "mental", "retardation", "in", "Japanese", "patients", "." ]	[ "0", "0", "0", "0", "0", "0", "1", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "4", "0", "2", "2", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "4", "0" ]
19957053	Phenylephrine but not ephedrine reduces frontal lobe oxygenation following anesthesia-induced hypotension. BACKGROUND: Vasopressor agents are used to correct anesthesia-induced hypotension. We describe the effect of phenylephrine and ephedrine on frontal lobe oxygenation (S(c)O(2)) following anesthesia-induced hypotension. METHODS: Following induction of anesthesia by fentanyl (0.15 mg kg(-1)) and propofol (2.0 mg kg(-1)), 13 patients received phenylephrine (0.1 mg iv) and 12 patients received ephedrine (10 mg iv) to restore mean arterial pressure (MAP). Heart rate (HR), MAP, stroke volume (SV), cardiac output (CO), and frontal lobe oxygenation (S(c)O(2)) were registered. RESULTS: Induction of anesthesia was followed by a decrease in MAP, HR, SV, and CO concomitant with an elevation in S(c)O(2). After administration of phenylephrine, MAP increased (51 +/- 12 to 81 +/- 13 mmHg; P < 0.001; mean +/- SD). However, a 14% (from 70 +/- 8% to 60 +/- 7%) reduction in S(c)O(2) (P < 0.05) followed with no change in CO (3.7 +/- 1.1 to 3.4 +/- 0.9 l min(-1)). The administration of ephedrine led to a similar increase in MAP (53 +/- 9 to 79 +/- 8 mmHg; P < 0.001), restored CO (3.2 +/- 1.2 to 5.0 +/- 1.3 l min(-1)), and preserved S(c)O(2). CONCLUSIONS: The utilization of phenylephrine to correct hypotension induced by anesthesia has a negative impact on S(c)O(2) while ephedrine maintains frontal lobe oxygenation potentially related to an increase in CO.	[ "Phenylephrine", "but", "not", "ephedrine", "reduces", "frontal", "lobe", "oxygenation", "following", "anesthesia-induced", "hypotension", ".", "BACKGROUND", ":", "Vasopressor", "agents", "are", "used", "to", "correct", "anesthesia-induced", "hypotension", ".", "We", "describe", "the", "effect", "of", "phenylephrine", "and", "ephedrine", "on", "frontal", "lobe", "oxygenation", "(", "S", "(", "c", ")", "O", "(", "2", ")", ")", "following", "anesthesia-induced", "hypotension", ".", "METHODS", ":", "Following", "induction", "of", "anesthesia", "by", "fentanyl", "(", "0.15", "mg", "kg", "(", "-1", ")", ")", "and", "propofol", "(", "2.0", "mg", "kg", "(", "-1", ")", ")", ",", "13", "patients", "received", "phenylephrine", "(", "0.1", "mg", "iv", ")", "and", "12", "patients", "received", "ephedrine", "(", "10", "mg", "iv", ")", "to", "restore", "mean", "arterial", "pressure", "(", "MAP", ")", ".", "Heart", "rate", "(", "HR", ")", ",", "MAP", ",", "stroke", "volume", "(", "SV", ")", ",", "cardiac", "output", "(", "CO", ")", ",", "and", "frontal", "lobe", "oxygenation", "(", "S", "(", "c", ")", "O", "(", "2", ")", ")", "were", "registered", ".", "RESULTS", ":", "Induction", "of", "anesthesia", "was", "followed", "by", "a", "decrease", "in", "MAP", ",", "HR", ",", "SV", ",", "and", "CO", "concomitant", "with", "an", "elevation", "in", "S", "(", "c", ")", "O", "(", "2", ")", ".", "After", "administration", "of", "phenylephrine", ",", "MAP", "increased", "(", "51", "+/-", "12", "to", "81", "+/-", "13", "mmHg", ";", "P", "<", "0.001", ";", "mean", "+/-", "SD", ")", ".", "However", ",", "a", "14", "%", "(", "from", "70", "+/-", "8", "%", "to", "60", "+/-", "7", "%", ")", "reduction", "in", "S", "(", "c", ")", "O", "(", "2", ")", "(", "P", "<", "0.05", ")", "followed", "with", "no", "change", "in", "CO", "(", "3.7", "+/-", "1.1", "to", "3.4", "+/-", "0.9", "l", "min", "(", "-1", ")", ")", ".", "The", "administration", "of", "ephedrine", "led", "to", "a", "similar", "increase", "in", "MAP", "(", "53", "+/-", "9", "to", "79", "+/-", "8", "mmHg", ";", "P", "<", "0.001", ")", ",", "restored", "CO", "(", "3.2", "+/-", "1.2", "to", "5.0", "+/-", "1.3", "l", "min", "(", "-1", ")", ")", ",", "and", "preserved", "S", "(", "c", ")", "O", "(", "2", ")", ".", "CONCLUSIONS", ":", "The", "utilization", "of", "phenylephrine", "to", "correct", "hypotension", "induced", "by", "anesthesia", "has", "a", "negative", "impact", "on", "S", "(", "c", ")", "O", "(", "2", ")", "while", "ephedrine", "maintains", "frontal", "lobe", "oxygenation", "potentially", "related", "to", "an", "increase", "in", "CO", "." ]	[ "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "3", "0", "0", "0", "0", "0", "0", "0", "4", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
18441470	Complete atrioventricular block secondary to lithium therapy. Sinus node dysfunction has been reported most frequently among the adverse cardiovascular effects of lithium. In the present case, complete atrioventricular (AV) block with syncopal attacks developed secondary to lithium therapy, necessitating permanent pacemaker implantation. Serum lithium levels remained under or within the therapeutic range during the syncopal attacks. Lithium should be used with extreme caution, especially in patients with mild disturbance of AV conduction.	[ "Complete", "atrioventricular", "block", "secondary", "to", "lithium", "therapy", ".", "Sinus", "node", "dysfunction", "has", "been", "reported", "most", "frequently", "among", "the", "adverse", "cardiovascular", "effects", "of", "lithium", ".", "In", "the", "present", "case", ",", "complete", "atrioventricular", "(", "AV", ")", "block", "with", "syncopal", "attacks", "developed", "secondary", "to", "lithium", "therapy", ",", "necessitating", "permanent", "pacemaker", "implantation", ".", "Serum", "lithium", "levels", "remained", "under", "or", "within", "the", "therapeutic", "range", "during", "the", "syncopal", "attacks", ".", "Lithium", "should", "be", "used", "with", "extreme", "caution", ",", "especially", "in", "patients", "with", "mild", "disturbance", "of", "AV", "conduction", "." ]	[ "2", "2", "2", "0", "0", "3", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "2", "0", "2", "2", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0" ]
18399341	Clinical comparison of cardiorespiratory effects during unilateral and conventional spinal anaesthesia. BACKGROUND: Spinal anaesthesia is widely employed in clinical practice but has the main drawback of post-spinal block hypotension. Efforts must therefore continue to be made to obviate this setback OBJECTIVE: To evaluate the cardiovascular and respiratory changes during unilateral and conventional spinal anaesthesia. METHODS: With ethical approval, we studied 74 American Society of Anesthesiologists (ASA), physical status class 1 and 2 patients scheduled for elective unilateral lower limb surgery. Patients were randomly allocated into one of two groups: lateral and conventional spinal anaesthesia groups. In the lateral position with operative side down, patients recived 10 mg (2mls) of 0.5% hyperbaric bupivacaine through a 25-gauge spinal needle. Patients in the unilateral group were maintained in the lateral position for 15 minutes following spinal injection while those in the conventional group were turned supine immediately after injection. Blood pressure, heart rate, respiratory rate and oxygen saturation were monitored over 1 hour. RESULTS: Three patients (8.1%) in the unilateral group and 5 (13.5%) in the conventional group developed hypotension, P= 0.71. Four (10.8%) patients in the conventional group and 1 (2.7%) in the unilateral group, P= 0.17 required epinephrine infusion to treat hypotension. Patients in the conventional group had statistically significant greater fall in the systolic blood pressures at 15, 30 and 45 minutes when compared to the baseline (P= 0.003, 0.001 and 0.004). The mean respiratory rate and oxygen saturations in the two groups were similar. CONCLUSION: Compared to conventional spinal anaesthesia, unilateral spinal anaesthesia was associated with fewer cardiovascular perturbations. Also, the type of spinal block instituted affected neither the respiratory rate nor the arterial oxygen saturation.	[ "Clinical", "comparison", "of", "cardiorespiratory", "effects", "during", "unilateral", "and", "conventional", "spinal", "anaesthesia", ".", "BACKGROUND", ":", "Spinal", "anaesthesia", "is", "widely", "employed", "in", "clinical", "practice", "but", "has", "the", "main", "drawback", "of", "post-spinal", "block", "hypotension", ".", "Efforts", "must", "therefore", "continue", "to", "be", "made", "to", "obviate", "this", "setback", "OBJECTIVE", ":", "To", "evaluate", "the", "cardiovascular", "and", "respiratory", "changes", "during", "unilateral", "and", "conventional", "spinal", "anaesthesia", ".", "METHODS", ":", "With", "ethical", "approval", ",", "we", "studied", "74", "American", "Society", "of", "Anesthesiologists", "(", "ASA", ")", ",", "physical", "status", "class", "1", "and", "2", "patients", "scheduled", "for", "elective", "unilateral", "lower", "limb", "surgery", ".", "Patients", "were", "randomly", "allocated", "into", "one", "of", "two", "groups", ":", "lateral", "and", "conventional", "spinal", "anaesthesia", "groups", ".", "In", "the", "lateral", "position", "with", "operative", "side", "down", ",", "patients", "recived", "10", "mg", "(", "2mls", ")", "of", "0.5", "%", "hyperbaric", "bupivacaine", "through", "a", "25-gauge", "spinal", "needle", ".", "Patients", "in", "the", "unilateral", "group", "were", "maintained", "in", "the", "lateral", "position", "for", "15", "minutes", "following", "spinal", "injection", "while", "those", "in", "the", "conventional", "group", "were", "turned", "supine", "immediately", "after", "injection", ".", "Blood", "pressure", ",", "heart", "rate", ",", "respiratory", "rate", "and", "oxygen", "saturation", "were", "monitored", "over", "1", "hour", ".", "RESULTS", ":", "Three", "patients", "(", "8.1", "%", ")", "in", "the", "unilateral", "group", "and", "5", "(", "13.5", "%", ")", "in", "the", "conventional", "group", "developed", "hypotension", ",", "P=", "0.71", ".", "Four", "(", "10.8", "%", ")", "patients", "in", "the", "conventional", "group", "and", "1", "(", "2.7", "%", ")", "in", "the", "unilateral", "group", ",", "P=", "0.17", "required", "epinephrine", "infusion", "to", "treat", "hypotension", ".", "Patients", "in", "the", "conventional", "group", "had", "statistically", "significant", "greater", "fall", "in", "the", "systolic", "blood", "pressures", "at", "15", ",", "30", "and", "45", "minutes", "when", "compared", "to", "the", "baseline", "(", "P=", "0.003", ",", "0.001", "and", "0.004", ")", ".", "The", "mean", "respiratory", "rate", "and", "oxygen", "saturations", "in", "the", "two", "groups", "were", "similar", ".", "CONCLUSION", ":", "Compared", "to", "conventional", "spinal", "anaesthesia", ",", "unilateral", "spinal", "anaesthesia", "was", "associated", "with", "fewer", "cardiovascular", "perturbations", ".", "Also", ",", "the", "type", "of", "spinal", "block", "instituted", "affected", "neither", "the", "respiratory", "rate", "nor", "the", "arterial", "oxygen", "saturation", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "2", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0" ]
24717468	A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients. OBJECTIVE: Dexmedetomidine and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and propofol. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with dexmedetomidine or propofol. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 dexmedetomidine and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or bradycardia in either the unmatched or matched cohorts. CONCLUSIONS: Severe hypotension and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or propofol. Providers should similarly consider the likelihood of hypotension or bradycardia before starting either sedative.	[ "A", "comparison", "of", "severe", "hemodynamic", "disturbances", "between", "dexmedetomidine", "and", "propofol", "for", "sedation", "in", "neurocritical", "care", "patients", ".", "OBJECTIVE", ":", "Dexmedetomidine", "and", "propofol", "are", "commonly", "used", "sedatives", "in", "neurocritical", "care", "as", "they", "allow", "for", "frequent", "neurologic", "examinations", ".", "However", ",", "both", "agents", "are", "associated", "with", "significant", "hemodynamic", "side", "effects", ".", "The", "primary", "objective", "of", "this", "study", "is", "to", "compare", "the", "prevalence", "of", "severe", "hemodynamic", "effects", "in", "neurocritical", "care", "patients", "receiving", "dexmedetomidine", "and", "propofol", ".", "DESIGN", ":", "Multicenter", ",", "retrospective", ",", "propensity-matched", "cohort", "study", ".", "SETTING", ":", "Neurocritical", "care", "units", "at", "two", "academic", "medical", "centers", "with", "dedicated", "neurocritical", "care", "teams", "and", "board-certified", "neurointensivists", ".", "PATIENTS", ":", "Neurocritical", "care", "patients", "admitted", "between", "July", "2009", "and", "September", "2012", "were", "evaluated", "and", "then", "matched", "1:1", "based", "on", "propensity", "scoring", "of", "baseline", "characteristics", ".", "INTERVENTIONS", ":", "Continuous", "sedation", "with", "dexmedetomidine", "or", "propofol", ".", "MEASUREMENTS", "AND", "MAIN", "RESULTS", ":", "A", "total", "of", "342", "patients", "(", "105", "dexmedetomidine", "and", "237", "propofol", ")", "were", "included", "in", "the", "analysis", ",", "with", "190", "matched", "(", "95", "in", "each", "group", ")", "by", "propensity", "score", ".", "The", "primary", "outcome", "of", "this", "study", "was", "a", "composite", "of", "severe", "hypotension", "(", "mean", "arterial", "pressure", "<", "60", "mm", "Hg", ")", "and", "bradycardia", "(", "heart", "rate", "<", "50", "beats/min", ")", "during", "sedative", "infusion", ".", "No", "difference", "in", "the", "primary", "composite", "outcome", "in", "both", "the", "unmatched", "(", "30", "%", "vs", "30", "%", ",", "p", "=", "0.94", ")", "or", "matched", "cohorts", "(", "28", "%", "vs", "34", "%", ",", "p", "=", "0.35", ")", "could", "be", "found", ".", "When", "analyzed", "separately", ",", "no", "differences", "could", "be", "found", "in", "the", "prevalence", "of", "severe", "hypotension", "or", "bradycardia", "in", "either", "the", "unmatched", "or", "matched", "cohorts", ".", "CONCLUSIONS", ":", "Severe", "hypotension", "and", "bradycardia", "occur", "at", "similar", "prevalence", "in", "neurocritical", "care", "patients", "who", "receive", "dexmedetomidine", "or", "propofol", ".", "Providers", "should", "similarly", "consider", "the", "likelihood", "of", "hypotension", "or", "bradycardia", "before", "starting", "either", "sedative", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "4", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0" ]

19394258

The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.

[ "The", "first", "founder", "DGUOK", "mutation", "associated", "with", "hepatocerebral", "mitochondrial", "DNA", "depletion", "syndrome", ".", "Deoxyguanosine", "kinase", "(", "dGK", ")", "deficiency", "is", "a", "frequent", "cause", "of", "mitochondrial", "DNA", "depletion", "associated", "with", "a", "hepatocerebral", "phenotype", ".", "In", "this", "study", ",", "we", "describe", "a", "new", "splice", "site", "mutation", "in", "the", "DGUOK", "gene", "and", "the", "clinical", ",", "radiologic", ",", "and", "genetic", "features", "of", "these", "DGUOK", "patients", ".", "This", "new", "DGUOK", "homozygous", "mutation", "(", "c.444-62C", ">", "A", ")", "was", "identified", "in", "three", "patients", "from", "two", "North-African", "consanguineous", "families", "with", "combined", "respiratory", "chain", "deficiencies", "and", "mitochondrial", "DNA", "depletion", "in", "the", "liver", ".", "Brain", "MRIs", "are", "normal", "in", "DGUOK", "patients", "in", "the", "literature", ".", "Interestingly", ",", "we", "found", "subtentorial", "abnormal", "myelination", "and", "moderate", "hyperintensity", "in", "the", "bilateral", "pallidi", "in", "our", "patients", ".", "This", "new", "mutation", "creates", "a", "cryptic", "splice", "site", "in", "intron", "3", "(", "in", "position", "-62", ")", "and", "is", "predicted", "to", "result", "in", "a", "larger", "protein", "with", "an", "in-frame", "insertion", "of", "20", "amino", "acids", ".", "In", "silico", "analysis", "of", "the", "putative", "impact", "of", "the", "insertion", "shows", "serious", "clashes", "in", "protein", "conformation", ":", "this", "insertion", "disrupts", "the", "alpha5", "helix", "of", "the", "dGK", "kinase", "domain", ",", "rendering", "the", "protein", "unable", "to", "bind", "purine", "deoxyribonucleosides", ".", "In", "addition", ",", "a", "common", "haplotype", "that", "segregated", "with", "the", "disease", "in", "both", "families", "was", "detected", "by", "haplotype", "reconstruction", "with", "10", "markers", "(", "microsatellites", "and", "SNPs", ")", ",", "which", "span", "4.6", "Mb", "of", "DNA", "covering", "the", "DGUOK", "locus", ".", "In", "conclusion", ",", "we", "report", "a", "new", "DGUOK", "splice", "site", "mutation", "that", "provide", "insight", "into", "a", "critical", "protein", "domain", "(", "dGK", "kinase", "domain", ")", "and", "the", "first", "founder", "mutation", "in", "a", "North-African", "population", "." ]

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2491010

Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene. Eighty unrelated individuals with Duchenne muscular dystrophy (DMD)or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5 ' end of the gene.

[ "Molecular", "and", "phenotypic", "analysis", "of", "patients", "with", "deletions", "within", "the", "deletion-rich", "region", "of", "the", "Duchenne", "muscular", "dystrophy", "(", "DMD", ")", "gene", ".", "Eighty", "unrelated", "individuals", "with", "Duchenne", "muscular", "dystrophy", "(", "DMD", ")", "or", "Becker", "muscular", "dystrophy", "(", "BMD", ")", "were", "found", "to", "have", "deletions", "in", "the", "major", "deletion-rich", "region", "of", "the", "DMD", "locus", ".", "This", "region", "includes", "the", "last", "five", "exons", "detected", "by", "cDNA5b-7", ",", "all", "exons", "detected", "by", "cDNA8", ",", "and", "the", "first", "two", "exons", "detected", "by", "cDNA9", ".", "These", "80", "individuals", "account", "for", "approximately", "75", "%", "of", "109", "deletions", "of", "the", "gene", ",", "detected", "among", "181", "patients", "analyzed", "with", "the", "entire", "dystrophin", "cDNA", ".", "Endpoints", "for", "many", "of", "these", "deletions", "were", "further", "characterized", "using", "two", "genomic", "probes", ",", "p20", "(", "DXS269", ";", "Wapenaar", "et", "al", ".", ")", "and", "GMGX11", "(", "DXS239", ";", "present", "paper", ")", ".", "Clinical", "findings", "are", "presented", "for", "all", "80", "patients", "allowing", "a", "correlation", "of", "phenotypic", "severity", "with", "the", "genotype", ".", "Thirty-eight", "independent", "patients", "were", "old", "enough", "to", "be", "classified", "as", "DMD", ",", "BMD", ",", "or", "intermediate", "phenotype", "and", "had", "deletions", "of", "exons", "with", "sequenced", "intron/exon", "boundaries", ".", "Of", "these", ",", "eight", "BMD", "patients", "and", "one", "intermediate", "patient", "had", "gene", "deletions", "predicted", "to", "leave", "the", "reading", "frame", "intact", ",", "while", "21", "DMD", "patients", ",", "7", "intermediate", "patients", ",", "and", "1", "BMD", "patient", "had", "gene", "deletions", "predicted", "to", "disrupt", "the", "reading", "frame", ".", "Thus", ",", "with", "two", "exceptions", ",", "frameshift", "deletions", "of", "the", "gene", "resulted", "in", "more", "severe", "phenotype", "than", "did", "in-frame", "deletions", ".", "This", "is", "in", "agreement", "with", "recent", "findings", "by", "Baumbach", "et", "al", ".", "and", "Koenig", "et", "al", ".", "but", "is", "in", "contrast", "to", "findings", ",", "by", "Malhotra", "et", "al", ".", "at", "the", "5", "'", "end", "of", "the", "gene", "." ]

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21405999

Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy. Background: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. Material and Methods: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. Results: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. Conclusion: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans.

[ "Mutation", "screening", "of", "the", "GUCA1B", "gene", "in", "patients", "with", "autosomal", "dominant", "cone", "and", "cone", "rod", "dystrophy", ".", "Background", ":", "Heterozygous", "mutations", "in", "GUCA1A", "(", "MIM", "#", "600364", ")", "have", "been", "identified", "to", "cause", "autosomal", "dominantly", "inherited", "cone", "dystrophy", ",", "cone", "rod", "dystrophy", "and", "macular", "dystrophy", ".", "However", ",", "the", "role", "of", "GUCA1B", "gene", "mutations", "in", "inherited", "retinal", "disease", "has", "been", "controversial", ".", "We", "therefore", "performed", "a", "mutation", "analysis", "of", "the", "GUCA1B", "gene", "in", "a", "clinically", "well", "characterized", "group", "of", "patients", "of", "European", "and", "North-American", "geographical", "origin", "with", "autosomal", "dominantly", "inherited", "cone", "dystrophy", "and", "cone", "rod", "dystrophy", ".", "Material", "and", "Methods", ":", "Twenty-four", "unrelated", "patients", "diagnosed", "with", "cone", "dystrophy", "or", "cone", "rod", "dystrophy", "according", "to", "standard", "diagnostic", "criteria", "and", "a", "family", "history", "consistent", "with", "an", "autosomal", "dominant", "mode", "of", "inheritance", "were", "included", "in", "the", "study", ".", "Mutation", "analysis", "of", "all", "coding", "exons", "of", "the", "GUCA1B", "gene", "was", "performed", "by", "polymerase", "chain", "reaction", "amplification", "of", "genomic", "DNA", "and", "subsequent", "DNA", "sequencing", ".", "Results", ":", "Three", "different", "sequence", "variants", ",", "c.-17T", ">", "C", ",", "c.171T", ">", "C", ",", "c.465G", ">", "T", "were", "identified", ".", "The", "sequence", "variant", "c.465G", ">", "T", "encodes", "a", "conservative", "amino", "acid", "substitution", ",", "p.Glu155Asp", ",", "located", "in", "EF-hand", "4", ",", "the", "calcium", "binding", "site", "of", "GCAP2", "protein", ".", "All", "sequence", "variants", "were", "previously", "reported", "in", "healthy", "subjects", ".", "Conclusion", ":", "The", "absence", "of", "clearly", "pathogenic", "mutations", "in", "the", "selected", "patient", "group", "suggests", "that", "the", "GUCA1B", "gene", "is", "a", "minor", "cause", "for", "retinal", "degenerations", "in", "Europeans", "or", "North-Americans", "." ]

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21684788

Large contiguous gene deletions in Sjogren-Larsson syndrome. Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.

[ "Large", "contiguous", "gene", "deletions", "in", "Sjogren-Larsson", "syndrome", ".", "Sjogren-Larsson", "syndrome", "(", "SLS", ")", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "ichthyosis", ",", "mental", "retardation", ",", "spasticity", "and", "mutations", "in", "the", "ALDH3A2", "gene", "for", "fatty", "aldehyde", "dehydrogenase", ",", "an", "enzyme", "that", "catalyzes", "the", "oxidation", "of", "fatty", "aldehyde", "to", "fatty", "acid", ".", "More", "than", "70", "mutations", "have", "been", "identified", "in", "SLS", "patients", ",", "including", "small", "deletions", "or", "insertions", ",", "missense", "mutations", ",", "splicing", "defects", "and", "complex", "nucleotide", "changes", ".", "We", "now", "describe", "2", "SLS", "patients", "whose", "disease", "is", "caused", "by", "large", "contiguous", "gene", "deletions", "of", "the", "ALDH3A2", "locus", "on", "17p11.2", ".", "The", "deletions", "were", "defined", "using", "long", "distance", "inverse", "PCR", "and", "microarray-based", "comparative", "genomic", "hybridization", ".", "A", "24-year-old", "SLS", "female", "was", "homozygous", "for", "a", "352-kb", "deletion", "involving", "ALDH3A2", "and", "4", "contiguous", "genes", "including", "ALDH3A1", ",", "which", "codes", "for", "the", "major", "soluble", "protein", "in", "cornea", ".", "Although", "lacking", "corneal", "disease", ",", "she", "showed", "severe", "symptoms", "of", "SLS", "with", "uncommon", "deterioration", "in", "oral", "motor", "function", "and", "loss", "of", "ambulation", ".", "The", "other", "19-month-old", "female", "patient", "was", "a", "compound", "heterozygote", "for", "a", "1.44-Mb", "contiguous", "gene", "deletion", "and", "a", "missense", "mutation", "(", "c.407C", ">", "T", ",", "P136L", ")", "in", "ALDH3A2", ".", "These", "studies", "suggest", "that", "large", "gene", "deletions", "may", "account", "for", "up", "to", "5", "%", "of", "the", "mutant", "alleles", "in", "SLS", ".", "Geneticists", "should", "consider", "the", "possibility", "of", "compound", "heterozygosity", "for", "large", "deletions", "in", "patients", "with", "SLS", "and", "other", "inborn", "errors", "of", "metabolism", ",", "which", "has", "implications", "for", "carrier", "testing", "and", "prenatal", "diagnosis", "." ]

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16840830

Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.

[ "Two", "novel", "mutations", "in", "the", "MEN1", "gene", "in", "subjects", "with", "multiple", "endocrine", "neoplasia-1", ".", "Multiple", "endocrine", "neoplasia", "type", "1", "(", "MEN1", ")", "is", "characterized", "by", "parathyroid", ",", "enteropancreatic", "endocrine", "and", "pituitary", "adenomas", "as", "well", "as", "germline", "mutation", "of", "the", "MEN1", "gene", ".", "We", "describe", "2", "families", "with", "MEN1", "with", "novel", "mutations", "in", "the", "MEN1", "gene", ".", "One", "family", "was", "of", "Turkish", "origin", ",", "and", "the", "index", "patient", "had", "primary", "hyperparathyroidism", "(", "PHPT", ")", "plus", "a", "prolactinoma", ";", "three", "relatives", "had", "PHPT", "only", ".", "The", "index", "patient", "in", "the", "second", "family", "was", "a", "46-yr-old", "woman", "of", "Chinese", "origin", "living", "in", "Taiwan", ".", "This", "patient", "presented", "with", "a", "complaint", "of", "epigastric", "pain", "and", "watery", "diarrhea", "over", "the", "past", "3", "months", ",", "and", "had", "undergone", "subtotal", "parathyroidectomy", "and", "enucleation", "of", "pancreatic", "islet", "cell", "tumor", "about", "10", "yr", "before", ".", "There", "was", "also", "a", "prolactinoma", ".", "Sequence", "analysis", "of", "the", "MEN1", "gene", "from", "leukocyte", "genomic", "DNA", "revealed", "heterozygous", "mutations", "in", "both", "probands", ".", "The", "Turkish", "patient", "and", "her", "affected", "relatives", "all", "had", "a", "heterozygous", "A", "to", "G", "transition", "at", "codon", "557", "(", "AAG", "--", ">", "GAG", ")", "of", "exon", "10", "of", "MEN1", "that", "results", "in", "a", "replacement", "of", "lysine", "by", "glutamic", "acid", ".", "The", "Chinese", "index", "patient", "and", "one", "of", "her", "siblings", "had", "a", "heterozygous", "mutation", "at", "codon", "418", "of", "exon", "9", "(", "GAC", "--", ">", "TAT", ")", "that", "results", "in", "a", "substitution", "of", "aspartic", "acid", "by", "tyrosine", ".", "In", "conclusion", ",", "we", "have", "identified", "2", "novel", "missense", "mutations", "in", "the", "MEN1", "gene", "." ]

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15668505

Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers. The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.

[ "Common", "BRCA2", "variants", "and", "modification", "of", "breast", "and", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "HH", "genotype", "of", "the", "nonconservative", "amino", "acid", "substitution", "polymorphism", "N372H", "in", "the", "BRCA2", "gene", "was", "reported", "to", "be", "associated", "with", "a", "1.3-", "to", "1.5-fold", "increase", "in", "risk", "of", "both", "breast", "and", "ovarian", "cancer", ".", "As", "these", "studies", "concerned", "sporadic", "cancer", "cases", ",", "we", "investigated", "whether", "N372H", "and", "another", "common", "variant", "located", "in", "the", "5'-untranslated", "region", "(", "203G", ">", "A", ")", "of", "the", "BRCA2", "gene", "modify", "breast", "or", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "study", "includes", "778", "women", "carrying", "a", "BRCA1", "germ-line", "mutation", "belonging", "to", "403", "families", ".", "The", "two", "BRCA2", "variants", "were", "analyzed", "by", "the", "TaqMan", "allelic", "discrimination", "technique", ".", "Genotypes", "were", "analyzed", "by", "disease-free", "survival", "analysis", "using", "a", "Cox", "proportional", "hazards", "model", ".", "We", "found", "no", "evidence", "of", "a", "significant", "modification", "of", "breast", "cancer", "penetrance", "in", "BRCA1", "mutation", "carriers", "by", "either", "polymorphism", ".", "In", "respect", "of", "ovarian", "cancer", "risk", ",", "we", "also", "saw", "no", "effect", "with", "the", "N372H", "variant", "but", "we", "did", "observe", "a", "borderline", "association", "with", "the", "5'-untranslated", "region", "203A", "allele", "(", "hazard", "ratio", ",", "1.43", ";", "CI", ",", "1.01-2.00", ")", ".", "In", "contrast", "to", "the", "result", "of", "Healey", "et", "al", ".", "on", "newborn", "females", "and", "adult", "female", "controls", ",", "we", "found", "no", "departure", "from", "Hardy-Weinberg", "equilibrium", "in", "the", "distribution", "of", "N372H", "alleles", "for", "our", "female", "BRCA1", "carriers", ".", "We", "conclude", "that", "if", "these", "single-nucleotide", "polymorphisms", "do", "modify", "the", "risk", "of", "cancer", "in", "BRCA1", "mutation", "carriers", ",", "their", "effects", "are", "not", "significantly", "larger", "than", "that", "of", "N372H", "previously", "observed", "in", "the", "general", "population", "." ]

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15130900

Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.

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18257781

Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.

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16970763

Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. BACKGROUND: To examine the contribution of mutations within the Norrie disease (NDP) gene to the clinically similar retinal diseases Norrie disease, X-linked familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity (ROP). METHODS: A dataset comprising 13 Norrie-FEVR, one Coat's disease, 31 ROP patients and 90 ex-premature babies of <32 weeks' gestation underwent an ophthalmologic examination and were screened for mutations within the NDP gene by direct DNA sequencing, denaturing high-performance liquid chromatography or gel electrophoresis. Controls were only screened using denaturing high-performance liquid chromatography and gel electrophoresis. Confirmation of mutations identified was obtained by DNA sequencing. RESULTS: Evidence for two novel mutations in the NDP gene was presented: Leu103Val in one FEVR patient and His43Arg in monozygotic twin Norrie disease patients. Furthermore, a previously described 14-bp deletion located in the 5' unstranslated region of the NDP gene was detected in three cases of regressed ROP. A second heterozygotic 14-bp deletion was detected in an unaffected ex-premature girl. Only two of the 13 Norrie-FEVR index cases had the full features of Norrie disease with deafness and mental retardation. CONCLUSION: Two novel mutations within the coding region of the NDP gene were found, one associated with a severe disease phenotypes of Norrie disease and the other with FEVR. A deletion within the non-coding region was associated with only mild-regressed ROP, despite the presence of low birthweight, prematurity and exposure to oxygen. In full-term children with retinal detachment only 15% appear to have the full features of Norrie disease and this is important for counselling parents on the possible long-term outcome.

[ "Mutations", "in", "the", "NDP", "gene", ":", "contribution", "to", "Norrie", "disease", ",", "familial", "exudative", "vitreoretinopathy", "and", "retinopathy", "of", "prematurity", ".", "BACKGROUND", ":", "To", "examine", "the", "contribution", "of", "mutations", "within", "the", "Norrie", "disease", "(", "NDP", ")", "gene", "to", "the", "clinically", "similar", "retinal", "diseases", "Norrie", "disease", ",", "X-linked", "familial", "exudative", "vitreoretinopathy", "(", "FEVR", ")", ",", "Coat", "'s", "disease", "and", "retinopathy", "of", "prematurity", "(", "ROP", ")", ".", "METHODS", ":", "A", "dataset", "comprising", "13", "Norrie-FEVR", ",", "one", "Coat", "'s", "disease", ",", "31", "ROP", "patients", "and", "90", "ex-premature", "babies", "of", "<", "32", "weeks", "'", "gestation", "underwent", "an", "ophthalmologic", "examination", "and", "were", "screened", "for", "mutations", "within", "the", "NDP", "gene", "by", "direct", "DNA", "sequencing", ",", "denaturing", "high-performance", "liquid", "chromatography", "or", "gel", "electrophoresis", ".", "Controls", "were", "only", "screened", "using", "denaturing", "high-performance", "liquid", "chromatography", "and", "gel", "electrophoresis", ".", "Confirmation", "of", "mutations", "identified", "was", "obtained", "by", "DNA", "sequencing", ".", "RESULTS", ":", "Evidence", "for", "two", "novel", "mutations", "in", "the", "NDP", "gene", "was", "presented", ":", "Leu103Val", "in", "one", "FEVR", "patient", "and", "His43Arg", "in", "monozygotic", "twin", "Norrie", "disease", "patients", ".", "Furthermore", ",", "a", "previously", "described", "14-bp", "deletion", "located", "in", "the", "5", "'", "unstranslated", "region", "of", "the", "NDP", "gene", "was", "detected", "in", "three", "cases", "of", "regressed", "ROP", ".", "A", "second", "heterozygotic", "14-bp", "deletion", "was", "detected", "in", "an", "unaffected", "ex-premature", "girl", ".", "Only", "two", "of", "the", "13", "Norrie-FEVR", "index", "cases", "had", "the", "full", "features", "of", "Norrie", "disease", "with", "deafness", "and", "mental", "retardation", ".", "CONCLUSION", ":", "Two", "novel", "mutations", "within", "the", "coding", "region", "of", "the", "NDP", "gene", "were", "found", ",", "one", "associated", "with", "a", "severe", "disease", "phenotypes", "of", "Norrie", "disease", "and", "the", "other", "with", "FEVR", ".", "A", "deletion", "within", "the", "non-coding", "region", "was", "associated", "with", "only", "mild-regressed", "ROP", ",", "despite", "the", "presence", "of", "low", "birthweight", ",", "prematurity", "and", "exposure", "to", "oxygen", ".", "In", "full-term", "children", "with", "retinal", "detachment", "only", "15", "%", "appear", "to", "have", "the", "full", "features", "of", "Norrie", "disease", "and", "this", "is", "important", "for", "counselling", "parents", "on", "the", "possible", "long-term", "outcome", "." ]

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19276632

Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate. In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the L beck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G>A substitution in the 3'-untranslated region. Two patients carried a c.262G>A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C>T (Ser424Ser) and c.1284T>C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development.

[ "Mutation", "analysis", "of", "FOXF2", "in", "patients", "with", "disorders", "of", "sex", "development", "(", "DSD", ")", "in", "combination", "with", "cleft", "palate", ".", "In", "contrast", "to", "disorders", "of", "sexual", "differentiation", "caused", "by", "lack", "of", "androgen", "production", "or", "inhibited", "androgen", "action", ",", "defects", "affecting", "development", "of", "the", "bipotent", "genital", "anlagen", "have", "rarely", "been", "investigated", "in", "humans", ".", "We", "have", "previously", "documented", "that", "the", "transcription", "factor", "FOXF2", "is", "highly", "expressed", "in", "human", "foreskin", ".", "Moreover", ",", "Foxf2", "knockout", "mice", "present", "with", "cleft", "palate", "in", "combination", "with", "hypoplasia", "of", "the", "genital", "tubercle", ".", "We", "hypothesized", "that", "humans", "with", "disorders", "of", "sex", "development", "(", "DSD", ")", "in", "combination", "with", "cleft", "palate", "could", "have", "mutations", "in", "the", "FOXF2", "gene", ".", "Eighteen", "children", "with", "DSD", "and", "cleft", "palate", "were", "identified", "in", "the", "L", "beck", "DSD", "database", "(", "about", "1,500", "entries", ")", ".", "Genomic", "DNA", "sequence", "analysis", "of", "the", "FOXF2", "gene", "was", "performed", "and", "compared", "with", "10", "normal", "female", "and", "10", "normal", "male", "controls", ",", "respectively", ".", "Two", "heterozygous", "DNA", "sequence", "variations", "were", "solely", "present", "in", "one", "single", "patient", "each", "but", "in", "none", "of", "the", "20", "normal", "controls", ":", "a", "duplication", "of", "GCC", "(", "c.97GCC", "[", "9", "]", "+", "[", "10", "]", ")", "resulting", "in", "an", "extra", "alanine", "within", "exon", "1", "and", "a", "25", "*", "G", ">", "A", "substitution", "in", "the", "3'-untranslated", "region", ".", "Two", "patients", "carried", "a", "c.262G", ">", "A", "sequence", "variation", "predicting", "for", "an", "Ala88Thr", "exchange", "which", "was", "also", "detected", "in", "2", "normal", "controls", ".", "Two", "silent", "mutations", ",", "c.1272C", ">", "T", "(", "Ser424Ser", ")", "and", "c.1284T", ">", "C", "(", "Tyr428Tyr", ")", ",", "respectively", ",", "occurred", "in", "the", "coding", "region", "of", "exon", "2", ",", "again", "in", "both", "patients", "and", "normal", "controls", ".", "In", "conclusion", ",", "the", "majority", "of", "the", "detected", "sequence", "alterations", "were", "polymorphisms", "without", "obvious", "functional", "relevance", ".", "However", ",", "it", "can", "not", "be", "excluded", "that", "the", "2", "unique", "DNA", "sequence", "alterations", "could", "have", "affected", "FOXF2", "on", "the", "mRNA", "or", "protein", "level", "thus", "contributing", "to", "the", "observed", "disturbances", "in", "genital", "and", "palate", "development", "." ]

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15459975

Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis. Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.

[ "Fine", "mapping", "and", "identification", "of", "a", "candidate", "gene", "SSH1", "in", "disseminated", "superficial", "actinic", "porokeratosis", ".", "Disseminated", "superficial", "actinic", "porokeratosis", "(", "DSAP", ")", "is", "an", "uncommon", "autosomal", "dominant", "chronic", "keratinization", "disorder", ",", "characterized", "by", "multiple", "superficial", "keratotic", "lesions", "surrounded", "by", "a", "slightly", "raised", "keratotic", "border", ".", "Thus", "far", ",", "although", "two", "loci", "for", "DSAP", "have", "been", "identified", ",", "the", "genetic", "basis", "and", "pathogenesis", "of", "this", "disorder", "have", "not", "been", "elucidated", "yet", ".", "In", "this", "study", ",", "we", "performed", "a", "genome-wide", "linkage", "analysis", "in", "three", "Chinese", "affected", "families", "and", "localized", "the", "gene", "in", "an", "8.0", "cM", "interval", "defined", "by", "D12S330", "and", "D12S354", "on", "chromosome", "12", ".", "Upon", "screening", "30", "candidate", "genes", ",", "we", "identified", "a", "missense", "mutation", ",", "p.Ser63Asn", "in", "SSH1", "in", "one", "family", ",", "a", "frameshift", "mutation", ",", "p.Ser19CysfsX24", "in", "an", "alternative", "variant", "(", "isoform", "f", ")", "of", "SSH1", "in", "another", "family", ",", "and", "a", "frameshift", "mutation", ",", "p.Pro27ProfsX54", "in", "the", "same", "alternative", "variant", "in", "one", "non-familial", "case", "with", "DSAP", ".", "SSH1", "encodes", "a", "phosphatase", "that", "plays", "a", "pivotal", "role", "in", "actin", "dynamics", ".", "Our", "data", "suggested", "that", "cytoskeleton", "disorganization", "in", "epidermal", "cells", "is", "likely", "associated", "with", "the", "pathogenesis", "of", "DSAP", "." ]

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16330669

Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. PURPOSE: To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). PATIENTS AND METHODS: Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. RESULTS: The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. CONCLUSION: Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.

[ "Array-based", "comparative", "genomic", "hybridization", "analysis", "reveals", "recurrent", "chromosomal", "alterations", "and", "prognostic", "parameters", "in", "primary", "cutaneous", "large", "B-cell", "lymphoma", ".", "PURPOSE", ":", "To", "evaluate", "the", "clinical", "relevance", "of", "genomic", "aberrations", "in", "primary", "cutaneous", "large", "B-cell", "lymphoma", "(", "PCLBCL", ")", ".", "PATIENTS", "AND", "METHODS", ":", "Skin", "biopsy", "samples", "of", "31", "patients", "with", "a", "PCLBCL", "classified", "as", "either", "primary", "cutaneous", "follicle", "center", "lymphoma", "(", "PCFCL", ";", "n", "=", "19", ")", "or", "PCLBCL", ",", "leg", "type", "(", "n", "=", "12", ")", ",", "according", "to", "the", "WHO-European", "Organisation", "for", "Research", "and", "Treatment", "of", "Cancer", "(", "EORTC", ")", "classification", ",", "were", "investigated", "using", "array-based", "comparative", "genomic", "hybridization", ",", "fluorescence", "in", "situ", "hybridization", "(", "FISH", ")", ",", "and", "examination", "of", "promoter", "hypermethylation", ".", "RESULTS", ":", "The", "most", "recurrent", "alterations", "in", "PCFCL", "were", "high-level", "DNA", "amplifications", "at", "2p16.1", "(", "63", "%", ")", "and", "deletion", "of", "chromosome", "14q32.33", "(", "68", "%", ")", ".", "FISH", "analysis", "confirmed", "c-REL", "amplification", "in", "patients", "with", "gains", "at", "2p16.1", ".", "In", "PCLBCL", ",", "leg", "type", ",", "most", "prominent", "aberrations", "were", "a", "high-level", "DNA", "amplification", "of", "18q21.31-q21.33", "(", "67", "%", ")", ",", "including", "the", "BCL-2", "and", "MALT1", "genes", "as", "confirmed", "by", "FISH", ",", "and", "deletions", "of", "a", "small", "region", "within", "9p21.3", "containing", "the", "CDKN2A", ",", "CDKN2B", ",", "and", "NSG-x", "genes", ".", "Homozygous", "deletion", "of", "9p21.3", "was", "detected", "in", "five", "of", "12", "patients", "with", "PCLBCL", ",", "leg", "type", ",", "but", "in", "zero", "of", "19", "patients", "with", "PCFCL", ".", "Complete", "methylation", "of", "the", "promoter", "region", "of", "the", "CDKN2A", "gene", "was", "demonstrated", "in", "one", "PCLBCL", ",", "leg", "type", ",", "patient", "with", "hemizygous", "deletion", ",", "in", "one", "patient", "without", "deletion", ",", "but", "in", "zero", "of", "19", "patients", "with", "PCFCL", ".", "Seven", "of", "seven", "PCLBCL", ",", "leg", "type", ",", "patients", "with", "deletion", "of", "9p21.3", "and/or", "complete", "methylation", "of", "CDKN2A", "died", "as", "a", "result", "of", "their", "lymphoma", ".", "CONCLUSION", ":", "Our", "results", "demonstrate", "prominent", "differences", "in", "chromosomal", "alterations", "between", "PCFCL", "and", "PCLBCL", ",", "leg", "type", ",", "that", "support", "their", "classification", "as", "separate", "entities", "within", "the", "WHO-EORTC", "scheme", ".", "Inactivation", "of", "CDKN2A", "by", "either", "deletion", "or", "methylation", "of", "its", "promoter", "could", "be", "an", "important", "prognostic", "parameter", "for", "the", "group", "of", "PCLBCL", ",", "leg", "type", "." ]

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19208385

Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2. Osteogenesis imperfecta (OI) is a heritable bone disorder characterized by fractures with minimal trauma. Intracranial hemorrhage has been reported in a small number of OI patients. Here we describe three patients, a boy (aged 15 years) and two girls (aged 17 and 7 years) with OI type III who suffered intracranial hemorrhage and in addition had brachydactyly and nail hypoplasia. In all of these patients, OI was caused by glycine mutations affecting exon 49 of the COL1A2 gene, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen type I alpha 2 chain. These observations suggest that mutations in this region of the collagen type I alpha 2 chain carry a high risk of abnormal limb development and intracranial bleeding.

[ "Osteogenesis", "imperfecta", "type", "III", "with", "intracranial", "hemorrhage", "and", "brachydactyly", "associated", "with", "mutations", "in", "exon", "49", "of", "COL1A2", ".", "Osteogenesis", "imperfecta", "(", "OI", ")", "is", "a", "heritable", "bone", "disorder", "characterized", "by", "fractures", "with", "minimal", "trauma", ".", "Intracranial", "hemorrhage", "has", "been", "reported", "in", "a", "small", "number", "of", "OI", "patients", ".", "Here", "we", "describe", "three", "patients", ",", "a", "boy", "(", "aged", "15", "years", ")", "and", "two", "girls", "(", "aged", "17", "and", "7", "years", ")", "with", "OI", "type", "III", "who", "suffered", "intracranial", "hemorrhage", "and", "in", "addition", "had", "brachydactyly", "and", "nail", "hypoplasia", ".", "In", "all", "of", "these", "patients", ",", "OI", "was", "caused", "by", "glycine", "mutations", "affecting", "exon", "49", "of", "the", "COL1A2", "gene", ",", "which", "codes", "for", "the", "most", "carboxy-terminal", "part", "of", "the", "triple-helical", "domain", "of", "the", "collagen", "type", "I", "alpha", "2", "chain", ".", "These", "observations", "suggest", "that", "mutations", "in", "this", "region", "of", "the", "collagen", "type", "I", "alpha", "2", "chain", "carry", "a", "high", "risk", "of", "abnormal", "limb", "development", "and", "intracranial", "bleeding", "." ]

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19681452

Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication. Cocaine is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use. Drug-related globus pallidus infarctions are most often associated with heroin. Bilateral basal ganglia infarcts after the use of cocaine, without concurrent heroin use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to cocaine and/or ethanol use were the most likely causes of cerebral hypoperfusion.

[ "Bilateral", "haemorrhagic", "infarction", "of", "the", "globus", "pallidus", "after", "cocaine", "and", "alcohol", "intoxication", ".", "Cocaine", "is", "a", "risk", "factor", "for", "both", "ischemic", "and", "haemorrhagic", "stroke", ".", "We", "present", "the", "case", "of", "a", "31-year-old", "man", "with", "bilateral", "ischemia", "of", "the", "globus", "pallidus", "after", "excessive", "alcohol", "and", "intranasal", "cocaine", "use", ".", "Drug-related", "globus", "pallidus", "infarctions", "are", "most", "often", "associated", "with", "heroin", ".", "Bilateral", "basal", "ganglia", "infarcts", "after", "the", "use", "of", "cocaine", ",", "without", "concurrent", "heroin", "use", ",", "have", "never", "been", "reported", ".", "In", "our", "patient", ",", "transient", "cardiac", "arrhythmia", "or", "respiratory", "dysfunction", "related", "to", "cocaine", "and/or", "ethanol", "use", "were", "the", "most", "likely", "causes", "of", "cerebral", "hypoperfusion", "." ]

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20709368

The fibrinogen gamma 10034C>T polymorphism is not associated with Peripheral Arterial Disease. Conversion of fibrinogen to fibrin plays an essential role in hemostasis and results in stabilization of the fibrin clot. Fibrinogen consists of three pairs of non-identical polypeptide chains, encoded by different genes (fibrinogen alpha [FGA], fibrinogen beta [FGB] and fibrinogen gamma [FGG]). A functional single nucleotide polymorphism (SNP) in the 3' untranslated region of the FGG gene (FGG 10034C>T, rs2066865) has been associated with deep venous thrombosis and myocardial infarction. Aim of the present study was to analyze the role of this polymorphism in peripheral arterial disease (PAD). The study was designed as case-control study including 891 patients with documented PAD and 777 control subjects. FGG genotypes were determined by exonuclease (TaqMan) assays. FGG genotype frequencies were not significantly different between PAD patients (CC: 57.3%, CT: 36.7%, TT: 5.8%) and control subjects (CC: 60.9%, CT: 33.5%, TT 5.6%; p=0.35). In a multivariate logistic regression analysis including age, sex, smoking, diabetes, arterial hypertension and hypercholesterolemia, the FGG 10034 T variant was not significantly associated with the presence of PAD (Odds ratio 1.07, 95% confidence interval 0.84 - 1.37; p = 0.60). The FGG 10034C>T polymorphism was furthermore not associated with age at onset of PAD. We conclude that the thrombophilic FGG 10034 T gene variant does not contribute to the genetic susceptibility to PAD.

[ "The", "fibrinogen", "gamma", "10034C", ">", "T", "polymorphism", "is", "not", "associated", "with", "Peripheral", "Arterial", "Disease", ".", "Conversion", "of", "fibrinogen", "to", "fibrin", "plays", "an", "essential", "role", "in", "hemostasis", "and", "results", "in", "stabilization", "of", "the", "fibrin", "clot", ".", "Fibrinogen", "consists", "of", "three", "pairs", "of", "non-identical", "polypeptide", "chains", ",", "encoded", "by", "different", "genes", "(", "fibrinogen", "alpha", "[", "FGA", "]", ",", "fibrinogen", "beta", "[", "FGB", "]", "and", "fibrinogen", "gamma", "[", "FGG", "]", ")", ".", "A", "functional", "single", "nucleotide", "polymorphism", "(", "SNP", ")", "in", "the", "3", "'", "untranslated", "region", "of", "the", "FGG", "gene", "(", "FGG", "10034C", ">", "T", ",", "rs2066865", ")", "has", "been", "associated", "with", "deep", "venous", "thrombosis", "and", "myocardial", "infarction", ".", "Aim", "of", "the", "present", "study", "was", "to", "analyze", "the", "role", "of", "this", "polymorphism", "in", "peripheral", "arterial", "disease", "(", "PAD", ")", ".", "The", "study", "was", "designed", "as", "case-control", "study", "including", "891", "patients", "with", "documented", "PAD", "and", "777", "control", "subjects", ".", "FGG", "genotypes", "were", "determined", "by", "exonuclease", "(", "TaqMan", ")", "assays", ".", "FGG", "genotype", "frequencies", "were", "not", "significantly", "different", "between", "PAD", "patients", "(", "CC", ":", "57.3", "%", ",", "CT", ":", "36.7", "%", ",", "TT", ":", "5.8", "%", ")", "and", "control", "subjects", "(", "CC", ":", "60.9", "%", ",", "CT", ":", "33.5", "%", ",", "TT", "5.6", "%", ";", "p=0.35", ")", ".", "In", "a", "multivariate", "logistic", "regression", "analysis", "including", "age", ",", "sex", ",", "smoking", ",", "diabetes", ",", "arterial", "hypertension", "and", "hypercholesterolemia", ",", "the", "FGG", "10034", "T", "variant", "was", "not", "significantly", "associated", "with", "the", "presence", "of", "PAD", "(", "Odds", "ratio", "1.07", ",", "95", "%", "confidence", "interval", "0.84", "-", "1.37", ";", "p", "=", "0.60", ")", ".", "The", "FGG", "10034C", ">", "T", "polymorphism", "was", "furthermore", "not", "associated", "with", "age", "at", "onset", "of", "PAD", ".", "We", "conclude", "that", "the", "thrombophilic", "FGG", "10034", "T", "gene", "variant", "does", "not", "contribute", "to", "the", "genetic", "susceptibility", "to", "PAD", "." ]

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27798239

Phosphatidylinositol 4-kinase IIb negatively regulates invadopodia formation and suppresses an invasive cellular phenotype. The type II phosphatidylinositol 4-kinase (PI4KII) enzymes synthesize the lipid phosphatidylinositol 4-phosphate (PI(4)P), which has been detected at the Golgi complex and endosomal compartments and recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear. We found that depletion of PI4KIIa and PI4KIIb using small interfering RNA led to actin remodeling. Depletion of PI4KIIb also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP). Depletion of PI4KII isoforms also differentially affected trans-Golgi network (TGN) pools of PI(4)P and post-TGN traffic. PI4KIIb depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalization of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7 but increased localization with the exocytic Rab8. Depletion of PI4KIIb was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIb mRNA are associated with human cancers. This finding supports the cell data and suggests that PI4KIIb may be a clinically significant suppressor of invasion. We propose that PI4KIIb synthesizes a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia.

[ "Phosphatidylinositol", "4-kinase", "IIb", "negatively", "regulates", "invadopodia", "formation", "and", "suppresses", "an", "invasive", "cellular", "phenotype", ".", "The", "type", "II", "phosphatidylinositol", "4-kinase", "(", "PI4KII", ")", "enzymes", "synthesize", "the", "lipid", "phosphatidylinositol", "4-phosphate", "(", "PI", "(", "4", ")", "P", ")", ",", "which", "has", "been", "detected", "at", "the", "Golgi", "complex", "and", "endosomal", "compartments", "and", "recruits", "clathrin", "adaptors", ".", "Despite", "common", "mechanistic", "similarities", "between", "the", "isoforms", ",", "the", "extent", "of", "their", "redundancy", "is", "unclear", ".", "We", "found", "that", "depletion", "of", "PI4KIIa", "and", "PI4KIIb", "using", "small", "interfering", "RNA", "led", "to", "actin", "remodeling", ".", "Depletion", "of", "PI4KIIb", "also", "induced", "the", "formation", "of", "invadopodia", "containing", "membrane", "type", "I", "matrix", "metalloproteinase", "(", "MT1-MMP", ")", ".", "Depletion", "of", "PI4KII", "isoforms", "also", "differentially", "affected", "trans-Golgi", "network", "(", "TGN", ")", "pools", "of", "PI", "(", "4", ")", "P", "and", "post-TGN", "traffic", ".", "PI4KIIb", "depletion", "caused", "increased", "MT1-MMP", "trafficking", "to", "invasive", "structures", "at", "the", "plasma", "membrane", "and", "was", "accompanied", "by", "reduced", "colocalization", "of", "MT1-MMP", "with", "membranes", "containing", "the", "endosomal", "markers", "Rab5", "and", "Rab7", "but", "increased", "localization", "with", "the", "exocytic", "Rab8", ".", "Depletion", "of", "PI4KIIb", "was", "sufficient", "to", "confer", "an", "aggressive", "invasive", "phenotype", "on", "minimally", "invasive", "HeLa", "and", "MCF-7", "cell", "lines", ".", "Mining", "oncogenomic", "databases", "revealed", "that", "loss", "of", "the", "PI4K2B", "allele", "and", "underexpression", "of", "PI4KIIb", "mRNA", "are", "associated", "with", "human", "cancers", ".", "This", "finding", "supports", "the", "cell", "data", "and", "suggests", "that", "PI4KIIb", "may", "be", "a", "clinically", "significant", "suppressor", "of", "invasion", ".", "We", "propose", "that", "PI4KIIb", "synthesizes", "a", "pool", "of", "PI", "(", "4", ")", "P", "that", "maintains", "MT1-MMP", "traffic", "in", "the", "degradative", "pathway", "and", "suppresses", "the", "formation", "of", "invadopodia", "." ]

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15111599

CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype. PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene.

[ "CRYBA3/A1", "gene", "mutation", "associated", "with", "suture-sparing", "autosomal", "dominant", "congenital", "nuclear", "cataract", ":", "a", "novel", "phenotype", ".", "PURPOSE", ":", "To", "identify", "the", "genetic", "defect", "leading", "to", "the", "congenital", "nuclear", "cataract", "affecting", "a", "large", "five-generation", "Swiss", "family", ".", "METHODS", ":", "Family", "history", "and", "clinical", "data", "were", "recorded", ".", "The", "phenotype", "was", "documented", "by", "both", "slit", "lamp", "and", "Scheimpflug", "photography", ".", "One", "cortical", "lens", "was", "evaluated", "by", "electron", "microscopy", "after", "cataract", "extraction", ".", "Lenticular", "phenotyping", "and", "genotyping", "were", "performed", "independently", "with", "short", "tandem", "repeat", "polymorphism", ".", "Linkage", "analysis", "was", "performed", ",", "and", "candidate", "genes", "were", "PCR", "amplified", "and", "screened", "for", "mutations", "on", "both", "strands", "using", "direct", "sequencing", ".", "RESULTS", ":", "Affected", "individuals", "had", "a", "congenital", "nuclear", "lactescent", "cataract", "in", "both", "eyes", ".", "Linkage", "was", "observed", "on", "chromosome", "17", "for", "DNA", "marker", "D17S1857", "(", "lod", "score", ":", "3.44", "at", "theta", "=", "0", ")", ".", "Direct", "sequencing", "of", "CRYBA3/A1", ",", "which", "maps", "to", "the", "vicinity", ",", "revealed", "an", "in-frame", "3-bp", "deletion", "in", "exon", "4", "(", "279delGAG", ")", ".", "This", "mutation", "involved", "a", "deletion", "of", "glycine-91", ",", "cosegregated", "in", "all", "affected", "individuals", ",", "and", "was", "not", "observed", "in", "unaffected", "individuals", "or", "in", "250", "normal", "control", "subjects", "from", "the", "same", "ethnic", "background", ".", "Electron", "microscopy", "showed", "that", "cortical", "lens", "fiber", "morphology", "was", "normal", ".", "CONCLUSIONS", ":", "The", "DeltaG91", "mutation", "in", "CRYBA3/A1", "is", "associated", "with", "an", "autosomal", "dominant", "congenital", "nuclear", "lactescent", "cataract", ".", "A", "splice", "mutation", "(", "IVS3+1G/A", ")", "in", "this", "gene", "has", "been", "reported", "in", "a", "zonular", "cataract", "with", "sutural", "opacities", ".", "These", "results", "indicate", "phenotypic", "heterogeneity", "related", "to", "mutations", "in", "this", "gene", "." ]

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15820770

Vitamin D-binding protein gene polymorphism association with IA-2 autoantibodies in type 1 diabetes. BACKGROUND: Vitamin D-binding protein (DBP) is the main systemic transporter of 1.25(OH)2D3 and is essential for its cellular endocytosis. There are two known polymorphisms in exon 11 of the DBP gene resulting in amino acid variants: GAT-->GAG substitution replaces aspartic acid by glutamic acid in codon 416; and ACG-->AAG substitution in codon 420 leads to an exchange of threonine for lysine. These DBP variants lead to differences in the affinity for 1.25(OH)2D3. Correlations between DBP alleles and type 1 diabetes have been described in different populations. Therefore, we investigated the polymorphism in codon 416 of the DBP gene for an association with autoimmune markers of type 1 diabetes. DESIGN AND METHODS: The present analysis was a case control study. 110 patients, 68 controls, and 115 first-degree relatives were genotyped for the DBP polymorphism in codon 416. DNA typing of DBP locus was performed by the PCR-restriction fragment length polymorphism method (RFLP). RESULTS: The frequencies of the Asp/Glu and Glu/Glu were significantly increased in diabetic subjects with detectable IA-2 antibodies (P < 0.01). On the contrary, the DBP Glu-containing genotype was not accompanied by differences in the prevalence of GAD65 antibodies. These finding supports a role of the vitamin D endocrine system in the autoimmune process of type 1 diabetes.

[ "Vitamin", "D-binding", "protein", "gene", "polymorphism", "association", "with", "IA-2", "autoantibodies", "in", "type", "1", "diabetes", ".", "BACKGROUND", ":", "Vitamin", "D-binding", "protein", "(", "DBP", ")", "is", "the", "main", "systemic", "transporter", "of", "1.25", "(", "OH", ")", "2D3", "and", "is", "essential", "for", "its", "cellular", "endocytosis", ".", "There", "are", "two", "known", "polymorphisms", "in", "exon", "11", "of", "the", "DBP", "gene", "resulting", "in", "amino", "acid", "variants", ":", "GAT", "--", ">", "GAG", "substitution", "replaces", "aspartic", "acid", "by", "glutamic", "acid", "in", "codon", "416", ";", "and", "ACG", "--", ">", "AAG", "substitution", "in", "codon", "420", "leads", "to", "an", "exchange", "of", "threonine", "for", "lysine", ".", "These", "DBP", "variants", "lead", "to", "differences", "in", "the", "affinity", "for", "1.25", "(", "OH", ")", "2D3", ".", "Correlations", "between", "DBP", "alleles", "and", "type", "1", "diabetes", "have", "been", "described", "in", "different", "populations", ".", "Therefore", ",", "we", "investigated", "the", "polymorphism", "in", "codon", "416", "of", "the", "DBP", "gene", "for", "an", "association", "with", "autoimmune", "markers", "of", "type", "1", "diabetes", ".", "DESIGN", "AND", "METHODS", ":", "The", "present", "analysis", "was", "a", "case", "control", "study", ".", "110", "patients", ",", "68", "controls", ",", "and", "115", "first-degree", "relatives", "were", "genotyped", "for", "the", "DBP", "polymorphism", "in", "codon", "416", ".", "DNA", "typing", "of", "DBP", "locus", "was", "performed", "by", "the", "PCR-restriction", "fragment", "length", "polymorphism", "method", "(", "RFLP", ")", ".", "RESULTS", ":", "The", "frequencies", "of", "the", "Asp/Glu", "and", "Glu/Glu", "were", "significantly", "increased", "in", "diabetic", "subjects", "with", "detectable", "IA-2", "antibodies", "(", "P", "<", "0.01", ")", ".", "On", "the", "contrary", ",", "the", "DBP", "Glu-containing", "genotype", "was", "not", "accompanied", "by", "differences", "in", "the", "prevalence", "of", "GAD65", "antibodies", ".", "These", "finding", "supports", "a", "role", "of", "the", "vitamin", "D", "endocrine", "system", "in", "the", "autoimmune", "process", "of", "type", "1", "diabetes", "." ]

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16186368

Characterization of Bietti crystalline dystrophy patients with CYP4V2 mutations. PURPOSE: Mutations of the CYP4V2 gene, a novel family member of the cytochrome P450 genes on chromosome 4q35, have recently been identified in patients with Bietti crystalline dystrophy (BCD). The aim of this study was to investigate the spectrum of mutations in this gene in BCD patients from Singapore, and to characterize their phenotype. METHODS: Nine patients with BCD from six families were recruited into the study. The 11 exons of the CYP4V2 gene were amplified from genomic DNA of patients by polymerase chain reaction and then sequenced. Detailed characterization of the patients' phenotype was performed with fundal photography, visual field testing, fundal fluorescein angiography, and electroretinography (ERG). RESULTS: Three pathogenic mutations were identified; two mutations, S482X and K386T, were novel and found in three patients. The third mutation, a previously identified 15-bp deletion that included the 3' splice site for exon 7, was found in all nine patients, with six patients carrying the deletion in the homozygous state. Haplotype analysis in patients and controls indicated a founder effect for this deletion mutation in exon 7. Clinical heterogeneity was present in the patients. Compound heterozygotes for the deletion in exon 7 seemed to have more severe disease compared to patients homozygous for the deletion. There was good correlation between clinical stage of disease and ERG changes, but age did not correlate with disease severity. CONCLUSIONS: This study identified novel mutations in the CYP4V2 gene as a cause of BCD. A high carrier frequency for the 15-bp deletion in exon 7 may exist in the Singapore population. Phenotype characterization showed clinical heterogeneity, and age did not correlate with disease severity.

[ "Characterization", "of", "Bietti", "crystalline", "dystrophy", "patients", "with", "CYP4V2", "mutations", ".", "PURPOSE", ":", "Mutations", "of", "the", "CYP4V2", "gene", ",", "a", "novel", "family", "member", "of", "the", "cytochrome", "P450", "genes", "on", "chromosome", "4q35", ",", "have", "recently", "been", "identified", "in", "patients", "with", "Bietti", "crystalline", "dystrophy", "(", "BCD", ")", ".", "The", "aim", "of", "this", "study", "was", "to", "investigate", "the", "spectrum", "of", "mutations", "in", "this", "gene", "in", "BCD", "patients", "from", "Singapore", ",", "and", "to", "characterize", "their", "phenotype", ".", "METHODS", ":", "Nine", "patients", "with", "BCD", "from", "six", "families", "were", "recruited", "into", "the", "study", ".", "The", "11", "exons", "of", "the", "CYP4V2", "gene", "were", "amplified", "from", "genomic", "DNA", "of", "patients", "by", "polymerase", "chain", "reaction", "and", "then", "sequenced", ".", "Detailed", "characterization", "of", "the", "patients", "'", "phenotype", "was", "performed", "with", "fundal", "photography", ",", "visual", "field", "testing", ",", "fundal", "fluorescein", "angiography", ",", "and", "electroretinography", "(", "ERG", ")", ".", "RESULTS", ":", "Three", "pathogenic", "mutations", "were", "identified", ";", "two", "mutations", ",", "S482X", "and", "K386T", ",", "were", "novel", "and", "found", "in", "three", "patients", ".", "The", "third", "mutation", ",", "a", "previously", "identified", "15-bp", "deletion", "that", "included", "the", "3", "'", "splice", "site", "for", "exon", "7", ",", "was", "found", "in", "all", "nine", "patients", ",", "with", "six", "patients", "carrying", "the", "deletion", "in", "the", "homozygous", "state", ".", "Haplotype", "analysis", "in", "patients", "and", "controls", "indicated", "a", "founder", "effect", "for", "this", "deletion", "mutation", "in", "exon", "7", ".", "Clinical", "heterogeneity", "was", "present", "in", "the", "patients", ".", "Compound", "heterozygotes", "for", "the", "deletion", "in", "exon", "7", "seemed", "to", "have", "more", "severe", "disease", "compared", "to", "patients", "homozygous", "for", "the", "deletion", ".", "There", "was", "good", "correlation", "between", "clinical", "stage", "of", "disease", "and", "ERG", "changes", ",", "but", "age", "did", "not", "correlate", "with", "disease", "severity", ".", "CONCLUSIONS", ":", "This", "study", "identified", "novel", "mutations", "in", "the", "CYP4V2", "gene", "as", "a", "cause", "of", "BCD", ".", "A", "high", "carrier", "frequency", "for", "the", "15-bp", "deletion", "in", "exon", "7", "may", "exist", "in", "the", "Singapore", "population", ".", "Phenotype", "characterization", "showed", "clinical", "heterogeneity", ",", "and", "age", "did", "not", "correlate", "with", "disease", "severity", "." ]

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17511042

An extremely rare case of delusional parasitosis in a chronic hepatitis C patient during pegylated interferon alpha-2b and ribavirin treatment. During treatment of chronic hepatitis C patients with interferon and ribavirin, a lot of side effects are described. Twenty-three percent to 44% of patients develop depression. A minority of patients evolve to psychosis. To the best of our knowledge, no cases of psychogenic parasitosis occurring during interferon therapy have been described in the literature. We present a 49-year-old woman who developed a delusional parasitosis during treatment with pegylated interferon alpha-2b weekly and ribavirin. She complained of seeing parasites and the larvae of fleas in her stools. This could not be confirmed by any technical examination. All the complaints disappeared after stopping pegylated interferon alpha-2b and reappeared after restarting it. She had a complete sustained viral response.

[ "An", "extremely", "rare", "case", "of", "delusional", "parasitosis", "in", "a", "chronic", "hepatitis", "C", "patient", "during", "pegylated", "interferon", "alpha-2b", "and", "ribavirin", "treatment", ".", "During", "treatment", "of", "chronic", "hepatitis", "C", "patients", "with", "interferon", "and", "ribavirin", ",", "a", "lot", "of", "side", "effects", "are", "described", ".", "Twenty-three", "percent", "to", "44", "%", "of", "patients", "develop", "depression", ".", "A", "minority", "of", "patients", "evolve", "to", "psychosis", ".", "To", "the", "best", "of", "our", "knowledge", ",", "no", "cases", "of", "psychogenic", "parasitosis", "occurring", "during", "interferon", "therapy", "have", "been", "described", "in", "the", "literature", ".", "We", "present", "a", "49-year-old", "woman", "who", "developed", "a", "delusional", "parasitosis", "during", "treatment", "with", "pegylated", "interferon", "alpha-2b", "weekly", "and", "ribavirin", ".", "She", "complained", "of", "seeing", "parasites", "and", "the", "larvae", "of", "fleas", "in", "her", "stools", ".", "This", "could", "not", "be", "confirmed", "by", "any", "technical", "examination", ".", "All", "the", "complaints", "disappeared", "after", "stopping", "pegylated", "interferon", "alpha-2b", "and", "reappeared", "after", "restarting", "it", ".", "She", "had", "a", "complete", "sustained", "viral", "response", "." ]

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19353688

Pure monosomy and pure trisomy of 13q21.2-31.1 consequent to a familial insertional translocation: exclusion of PCDH9 as the responsible gene for autosomal dominant auditory neuropathy (AUNA1). Insertional translocations (IT) are rare structural rearrangements. Offspring of IT balanced carriers are at high risk to have either pure partial trisomy or monosomy for the inserted segment as manifested by "pure" phenotypes. We describe an IT between chromosomes 3 and 13 segregating in a three-generation pedigree. Short tandem repeat (STR) segregation analysis and array-comparative genomic hybridization were used to define the IT as a 25.1 Mb segment spanning 13q21.2-q31.1. The phenotype of pure monosomy included deafness, duodenal stenosis, developmental and growth delay, vertebral anomalies, and facial dysmorphisms; the trisomy was manifested by only minor dysmorphisms. As the AUNA1 deafness locus on 13q14-21 overlaps the IT in the PCDH9 (protocadherin-9) gene region, PCDH9 was investigated as a candidate gene for deafness in both families. Genotyping of STRs and single nucleotide polymorphisms defined the AUNA1 breakpoint as 35 kb 5' to PCDH9, with a 2.4 Mb area of overlap with the IT. DNA sequencing of coding regions in the AUNA1 family and in the retained homologue chromosome in the monosomic patient revealed no mutations. We conclude that AUNA1 deafness does not share a common etiology with deafness associated with monosomy 13q21.2-q31.3; deafness may result from monosomy of PCHD9 or another gene in the IT, as has been demonstrated in contiguous gene deletion syndromes. Precise characterization of the breakpoints of the translocated region is useful to identify which genes may be contributing to the phenotype, either through haploinsufficiency or extra dosage effects, in order to define genotype-phenotype correlations.

[ "Pure", "monosomy", "and", "pure", "trisomy", "of", "13q21.2-31.1", "consequent", "to", "a", "familial", "insertional", "translocation", ":", "exclusion", "of", "PCDH9", "as", "the", "responsible", "gene", "for", "autosomal", "dominant", "auditory", "neuropathy", "(", "AUNA1", ")", ".", "Insertional", "translocations", "(", "IT", ")", "are", "rare", "structural", "rearrangements", ".", "Offspring", "of", "IT", "balanced", "carriers", "are", "at", "high", "risk", "to", "have", "either", "pure", "partial", "trisomy", "or", "monosomy", "for", "the", "inserted", "segment", "as", "manifested", "by", "``", "pure", "''", "phenotypes", ".", "We", "describe", "an", "IT", "between", "chromosomes", "3", "and", "13", "segregating", "in", "a", "three-generation", "pedigree", ".", "Short", "tandem", "repeat", "(", "STR", ")", "segregation", "analysis", "and", "array-comparative", "genomic", "hybridization", "were", "used", "to", "define", "the", "IT", "as", "a", "25.1", "Mb", "segment", "spanning", "13q21.2-q31.1", ".", "The", "phenotype", "of", "pure", "monosomy", "included", "deafness", ",", "duodenal", "stenosis", ",", "developmental", "and", "growth", "delay", ",", "vertebral", "anomalies", ",", "and", "facial", "dysmorphisms", ";", "the", "trisomy", "was", "manifested", "by", "only", "minor", "dysmorphisms", ".", "As", "the", "AUNA1", "deafness", "locus", "on", "13q14-21", "overlaps", "the", "IT", "in", "the", "PCDH9", "(", "protocadherin-9", ")", "gene", "region", ",", "PCDH9", "was", "investigated", "as", "a", "candidate", "gene", "for", "deafness", "in", "both", "families", ".", "Genotyping", "of", "STRs", "and", "single", "nucleotide", "polymorphisms", "defined", "the", "AUNA1", "breakpoint", "as", "35", "kb", "5", "'", "to", "PCDH9", ",", "with", "a", "2.4", "Mb", "area", "of", "overlap", "with", "the", "IT", ".", "DNA", "sequencing", "of", "coding", "regions", "in", "the", "AUNA1", "family", "and", "in", "the", "retained", "homologue", "chromosome", "in", "the", "monosomic", "patient", "revealed", "no", "mutations", ".", "We", "conclude", "that", "AUNA1", "deafness", "does", "not", "share", "a", "common", "etiology", "with", "deafness", "associated", "with", "monosomy", "13q21.2-q31.3", ";", "deafness", "may", "result", "from", "monosomy", "of", "PCHD9", "or", "another", "gene", "in", "the", "IT", ",", "as", "has", "been", "demonstrated", "in", "contiguous", "gene", "deletion", "syndromes", ".", "Precise", "characterization", "of", "the", "breakpoints", "of", "the", "translocated", "region", "is", "useful", "to", "identify", "which", "genes", "may", "be", "contributing", "to", "the", "phenotype", ",", "either", "through", "haploinsufficiency", "or", "extra", "dosage", "effects", ",", "in", "order", "to", "define", "genotype-phenotype", "correlations", "." ]

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21126715

A Taiwanese boy with congenital generalized lipodystrophy caused by homozygous Ile262fs mutation in the BSCL2 gene. Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disease that is characterized by a near-complete absence of adipose tissue from birth or early infancy. Mutations in the BSCL2 gene are known to result in CGL2, a more severe phenotype than CGL1, with earlier onset, more extensive fat loss and biochemical changes, more severe intellectual impairment, and more severe cardiomyopathy. We report a 3-month-old Taiwanese boy with initial presentation of a lack of subcutaneous fat, prominent musculature, generalized eruptive xanthomas, and extreme hypertriglyceridemia. Absence of mechanical adipose tissue in the orbits and scalp was revealed by head magnetic resonance imaging. Hepatomegaly was noticed, and histological examination of a liver biopsy specimen suggested severe hepatic steatosis and periportal necrosis. However, echocardiography indicated no sign of cardiomyopathy and he showed no distinct intellectual impairment that interfered with daily life. About 1 year later, abdominal computed tomography revealed enlargement of kidneys. He had a homozygous insertion of a nucleotide, 783insG (Ile262fs mutation), in exon 7 of the BSCL2 gene. We reviewed the genotype of CGL cases from Japan, India, China and Taiwan, and found that BSCL2 is a major causative gene for CGL in Asian.

[ "A", "Taiwanese", "boy", "with", "congenital", "generalized", "lipodystrophy", "caused", "by", "homozygous", "Ile262fs", "mutation", "in", "the", "BSCL2", "gene", ".", "Congenital", "generalized", "lipodystrophy", "(", "CGL", ")", "is", "a", "rare", "autosomal", "recessive", "disease", "that", "is", "characterized", "by", "a", "near-complete", "absence", "of", "adipose", "tissue", "from", "birth", "or", "early", "infancy", ".", "Mutations", "in", "the", "BSCL2", "gene", "are", "known", "to", "result", "in", "CGL2", ",", "a", "more", "severe", "phenotype", "than", "CGL1", ",", "with", "earlier", "onset", ",", "more", "extensive", "fat", "loss", "and", "biochemical", "changes", ",", "more", "severe", "intellectual", "impairment", ",", "and", "more", "severe", "cardiomyopathy", ".", "We", "report", "a", "3-month-old", "Taiwanese", "boy", "with", "initial", "presentation", "of", "a", "lack", "of", "subcutaneous", "fat", ",", "prominent", "musculature", ",", "generalized", "eruptive", "xanthomas", ",", "and", "extreme", "hypertriglyceridemia", ".", "Absence", "of", "mechanical", "adipose", "tissue", "in", "the", "orbits", "and", "scalp", "was", "revealed", "by", "head", "magnetic", "resonance", "imaging", ".", "Hepatomegaly", "was", "noticed", ",", "and", "histological", "examination", "of", "a", "liver", "biopsy", "specimen", "suggested", "severe", "hepatic", "steatosis", "and", "periportal", "necrosis", ".", "However", ",", "echocardiography", "indicated", "no", "sign", "of", "cardiomyopathy", "and", "he", "showed", "no", "distinct", "intellectual", "impairment", "that", "interfered", "with", "daily", "life", ".", "About", "1", "year", "later", ",", "abdominal", "computed", "tomography", "revealed", "enlargement", "of", "kidneys", ".", "He", "had", "a", "homozygous", "insertion", "of", "a", "nucleotide", ",", "783insG", "(", "Ile262fs", "mutation", ")", ",", "in", "exon", "7", "of", "the", "BSCL2", "gene", ".", "We", "reviewed", "the", "genotype", "of", "CGL", "cases", "from", "Japan", ",", "India", ",", "China", "and", "Taiwan", ",", "and", "found", "that", "BSCL2", "is", "a", "major", "causative", "gene", "for", "CGL", "in", "Asian", "." ]

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16252083

Polymorphisms of the DNA mismatch repair gene HMSH2 in breast cancer occurence and progression. The response of the cell to DNA damage and its ability to maintain genomic stability by DNA repair are crucial in preventing cancer initiation and progression. Therefore, polymorphism of DNA repair genes may affect the process of carcinogenesis. The importance of genetic variability of the components of mismatch repair (MMR) genes is well documented in colorectal cancer, but little is known about its role in breast cancer. hMSH2 is one of the crucial proteins of MMR. We performed a case-control study to test the association between two polymorphisms in the hMSH2 gene: an A --> G transition at 127 position producing an Asn --> Ser substitution at codon 127 (the Asn127Ser polymorphism) and a G --> A transition at 1032 position resulting in a Gly --> Asp change at codon 322 (the Gly322Asp polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 age-matched women (controls) by restriction fragment length polymorphism and allele-specific PCR. We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom-Richardson grading. A strong association between breast cancer occurrence and the Gly/Gly phenotype of the Gly322Asp polymorphism (odds ratio 8.39; 95% confidence interval 1.44-48.8) was found. Therefore, MMR may play a role in the breast carcinogenesis and the Gly322Asp polymorphism of the hMSH2 gene may be considered as a potential marker in breast cancer.

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18507837

Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort. INTRODUCTION: Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division. METHODS: We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis. RESULTS: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding. CONCLUSION: It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.

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26615423

Upregulation of centrosomal protein 55 is associated with unfavorable prognosis and tumor invasion in epithelial ovarian carcinoma. Centrosomal protein 55 (CEP55) is a cell cycle regulator implicated in development of certain cancers. However, characteristics of CEP55 expression and its clinical/prognostic significance are unclear in human epithelial ovarian carcinoma (EOC). Therefore, we investigated the expression and clinicopathological significance of CEP55 in patients with EOC and its role in regulating invasion and metastasis of ovarian cell lines. CEP55 mRNA and protein expression levels were detected by quantitative real-time PCR (qRT-PCR), Western blotting, and immunohistochemistry (IHC). Potential associations of CEP55 expression scores with clinical parameters and patient survival were evaluated. CEP55 function was investigated further using RNA interference, wound healing assay, transwell assay, immunofluorescence analysis, qRT-PCR, and Western blotting. CEP55 was significantly upregulated in ovarian cancer cell lines and lesions compared with normal cells and adjacent noncancerous ovarian tissues. In the 213 EOC samples, CEP55 protein levels were positively correlated with clinical stage (P < 0.001), lymph node metastasis (P < 0.001), intraperitoneal metastasis (P < 0.001), tumor recurrence (P < 0.001), differentiation grade (P < 0.001), residual tumor size (P < 0.001), ascites see tumor cells (P = 0.020), and serum CA153 level (P < 0.001). Moreover, patients with aberrant CEP55 protein expression showed tendencies to receive neoadjuvant chemotherapy (P < 0.001) and cytoreductive surgery (P = 0.020). By contrast, no significant correlation was detected between the protein levels and patient age, histological type, or serum CA125, CA199, CA724, NSE, CEA, and b-HCG levels. Patients with high CEP55 protein expression had shorter overall survival and disease-free survival compared with those with low CEP55 expression. Multivariate analysis implicated CEP55 as an independent prognostic indicator for EOC patients. Additionally, downregulation of CEP55 in ovarian cancer cells remarkably inhibited cellular motility and invasion. Aberrant CEP55 expression may predict unfavorable clinical outcomes in EOC patients and play an important role in regulating invasion in ovarian cancer cells. Thus, CEP55 may serve as a prognostic marker and therapeutic target for EOC.

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15000256

Single-strand conformation polymorphism analysis of the FMR1 gene in autistic and mentally retarded children in Japan. Fragile X syndrome is one of the most common causes of mental retardation in males, and patients with fragile X syndrome occasionally develop autism. It is usually caused by an expansion of the trinucleotide repeat in the 5'-untranslated region of the FMR1 gene, but in a small number of patients deletions and point mutations have been identified. We screened all 17 exons of the FMR1 gene for mutations in 90 autistic or mentally retarded children using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. No mutations were found in 76 male patients. However, one female patient was heterozygous for a normal allele and a mutant allele with an A to C substitution at nucleotide 879 in exon 9. This mutation was not found in 50 controls. Reverse transcription-PCR revealed that a large proportion of the mutant transcripts were spliced aberrantly, causing premature termination of the protein synthesis. Although uncommon, point mutations in the FMR1 gene may be a cause of autism and mental retardation in Japanese patients.

[ "Single-strand", "conformation", "polymorphism", "analysis", "of", "the", "FMR1", "gene", "in", "autistic", "and", "mentally", "retarded", "children", "in", "Japan", ".", "Fragile", "X", "syndrome", "is", "one", "of", "the", "most", "common", "causes", "of", "mental", "retardation", "in", "males", ",", "and", "patients", "with", "fragile", "X", "syndrome", "occasionally", "develop", "autism", ".", "It", "is", "usually", "caused", "by", "an", "expansion", "of", "the", "trinucleotide", "repeat", "in", "the", "5'-untranslated", "region", "of", "the", "FMR1", "gene", ",", "but", "in", "a", "small", "number", "of", "patients", "deletions", "and", "point", "mutations", "have", "been", "identified", ".", "We", "screened", "all", "17", "exons", "of", "the", "FMR1", "gene", "for", "mutations", "in", "90", "autistic", "or", "mentally", "retarded", "children", "using", "polymerase", "chain", "reaction", "(", "PCR", ")", "-single", "strand", "conformation", "polymorphism", "(", "SSCP", ")", "analysis", ".", "No", "mutations", "were", "found", "in", "76", "male", "patients", ".", "However", ",", "one", "female", "patient", "was", "heterozygous", "for", "a", "normal", "allele", "and", "a", "mutant", "allele", "with", "an", "A", "to", "C", "substitution", "at", "nucleotide", "879", "in", "exon", "9", ".", "This", "mutation", "was", "not", "found", "in", "50", "controls", ".", "Reverse", "transcription-PCR", "revealed", "that", "a", "large", "proportion", "of", "the", "mutant", "transcripts", "were", "spliced", "aberrantly", ",", "causing", "premature", "termination", "of", "the", "protein", "synthesis", ".", "Although", "uncommon", ",", "point", "mutations", "in", "the", "FMR1", "gene", "may", "be", "a", "cause", "of", "autism", "and", "mental", "retardation", "in", "Japanese", "patients", "." ]

[ "0", "0", "0", "0", "0", "0", "1", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "4", "0", "2", "2", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "2", "2", "0", "0", "4", "0" ]

19957053

Phenylephrine but not ephedrine reduces frontal lobe oxygenation following anesthesia-induced hypotension. BACKGROUND: Vasopressor agents are used to correct anesthesia-induced hypotension. We describe the effect of phenylephrine and ephedrine on frontal lobe oxygenation (S(c)O(2)) following anesthesia-induced hypotension. METHODS: Following induction of anesthesia by fentanyl (0.15 mg kg(-1)) and propofol (2.0 mg kg(-1)), 13 patients received phenylephrine (0.1 mg iv) and 12 patients received ephedrine (10 mg iv) to restore mean arterial pressure (MAP). Heart rate (HR), MAP, stroke volume (SV), cardiac output (CO), and frontal lobe oxygenation (S(c)O(2)) were registered. RESULTS: Induction of anesthesia was followed by a decrease in MAP, HR, SV, and CO concomitant with an elevation in S(c)O(2). After administration of phenylephrine, MAP increased (51 +/- 12 to 81 +/- 13 mmHg; P < 0.001; mean +/- SD). However, a 14% (from 70 +/- 8% to 60 +/- 7%) reduction in S(c)O(2) (P < 0.05) followed with no change in CO (3.7 +/- 1.1 to 3.4 +/- 0.9 l min(-1)). The administration of ephedrine led to a similar increase in MAP (53 +/- 9 to 79 +/- 8 mmHg; P < 0.001), restored CO (3.2 +/- 1.2 to 5.0 +/- 1.3 l min(-1)), and preserved S(c)O(2). CONCLUSIONS: The utilization of phenylephrine to correct hypotension induced by anesthesia has a negative impact on S(c)O(2) while ephedrine maintains frontal lobe oxygenation potentially related to an increase in CO.

[ "Phenylephrine", "but", "not", "ephedrine", "reduces", "frontal", "lobe", "oxygenation", "following", "anesthesia-induced", "hypotension", ".", "BACKGROUND", ":", "Vasopressor", "agents", "are", "used", "to", "correct", "anesthesia-induced", "hypotension", ".", "We", "describe", "the", "effect", "of", "phenylephrine", "and", "ephedrine", "on", "frontal", "lobe", "oxygenation", "(", "S", "(", "c", ")", "O", "(", "2", ")", ")", "following", "anesthesia-induced", "hypotension", ".", "METHODS", ":", "Following", "induction", "of", "anesthesia", "by", "fentanyl", "(", "0.15", "mg", "kg", "(", "-1", ")", ")", "and", "propofol", "(", "2.0", "mg", "kg", "(", "-1", ")", ")", ",", "13", "patients", "received", "phenylephrine", "(", "0.1", "mg", "iv", ")", "and", "12", "patients", "received", "ephedrine", "(", "10", "mg", "iv", ")", "to", "restore", "mean", "arterial", "pressure", "(", "MAP", ")", ".", "Heart", "rate", "(", "HR", ")", ",", "MAP", ",", "stroke", "volume", "(", "SV", ")", ",", "cardiac", "output", "(", "CO", ")", ",", "and", "frontal", "lobe", "oxygenation", "(", "S", "(", "c", ")", "O", "(", "2", ")", ")", "were", "registered", ".", "RESULTS", ":", "Induction", "of", "anesthesia", "was", "followed", "by", "a", "decrease", "in", "MAP", ",", "HR", ",", "SV", ",", "and", "CO", "concomitant", "with", "an", "elevation", "in", "S", "(", "c", ")", "O", "(", "2", ")", ".", "After", "administration", "of", "phenylephrine", ",", "MAP", "increased", "(", "51", "+/-", "12", "to", "81", "+/-", "13", "mmHg", ";", "P", "<", "0.001", ";", "mean", "+/-", "SD", ")", ".", "However", ",", "a", "14", "%", "(", "from", "70", "+/-", "8", "%", "to", "60", "+/-", "7", "%", ")", "reduction", "in", "S", "(", "c", ")", "O", "(", "2", ")", "(", "P", "<", "0.05", ")", "followed", "with", "no", "change", "in", "CO", "(", "3.7", "+/-", "1.1", "to", "3.4", "+/-", "0.9", "l", "min", "(", "-1", ")", ")", ".", "The", "administration", "of", "ephedrine", "led", "to", "a", "similar", "increase", "in", "MAP", "(", "53", "+/-", "9", "to", "79", "+/-", "8", "mmHg", ";", "P", "<", "0.001", ")", ",", "restored", "CO", "(", "3.2", "+/-", "1.2", "to", "5.0", "+/-", "1.3", "l", "min", "(", "-1", ")", ")", ",", "and", "preserved", "S", "(", "c", ")", "O", "(", "2", ")", ".", "CONCLUSIONS", ":", "The", "utilization", "of", "phenylephrine", "to", "correct", "hypotension", "induced", "by", "anesthesia", "has", "a", "negative", "impact", "on", "S", "(", "c", ")", "O", "(", "2", ")", "while", "ephedrine", "maintains", "frontal", "lobe", "oxygenation", "potentially", "related", "to", "an", "increase", "in", "CO", "." ]

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18441470

Complete atrioventricular block secondary to lithium therapy. Sinus node dysfunction has been reported most frequently among the adverse cardiovascular effects of lithium. In the present case, complete atrioventricular (AV) block with syncopal attacks developed secondary to lithium therapy, necessitating permanent pacemaker implantation. Serum lithium levels remained under or within the therapeutic range during the syncopal attacks. Lithium should be used with extreme caution, especially in patients with mild disturbance of AV conduction.

[ "Complete", "atrioventricular", "block", "secondary", "to", "lithium", "therapy", ".", "Sinus", "node", "dysfunction", "has", "been", "reported", "most", "frequently", "among", "the", "adverse", "cardiovascular", "effects", "of", "lithium", ".", "In", "the", "present", "case", ",", "complete", "atrioventricular", "(", "AV", ")", "block", "with", "syncopal", "attacks", "developed", "secondary", "to", "lithium", "therapy", ",", "necessitating", "permanent", "pacemaker", "implantation", ".", "Serum", "lithium", "levels", "remained", "under", "or", "within", "the", "therapeutic", "range", "during", "the", "syncopal", "attacks", ".", "Lithium", "should", "be", "used", "with", "extreme", "caution", ",", "especially", "in", "patients", "with", "mild", "disturbance", "of", "AV", "conduction", "." ]

[ "2", "2", "2", "0", "0", "3", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "2", "0", "2", "2", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0" ]

18399341

Clinical comparison of cardiorespiratory effects during unilateral and conventional spinal anaesthesia. BACKGROUND: Spinal anaesthesia is widely employed in clinical practice but has the main drawback of post-spinal block hypotension. Efforts must therefore continue to be made to obviate this setback OBJECTIVE: To evaluate the cardiovascular and respiratory changes during unilateral and conventional spinal anaesthesia. METHODS: With ethical approval, we studied 74 American Society of Anesthesiologists (ASA), physical status class 1 and 2 patients scheduled for elective unilateral lower limb surgery. Patients were randomly allocated into one of two groups: lateral and conventional spinal anaesthesia groups. In the lateral position with operative side down, patients recived 10 mg (2mls) of 0.5% hyperbaric bupivacaine through a 25-gauge spinal needle. Patients in the unilateral group were maintained in the lateral position for 15 minutes following spinal injection while those in the conventional group were turned supine immediately after injection. Blood pressure, heart rate, respiratory rate and oxygen saturation were monitored over 1 hour. RESULTS: Three patients (8.1%) in the unilateral group and 5 (13.5%) in the conventional group developed hypotension, P= 0.71. Four (10.8%) patients in the conventional group and 1 (2.7%) in the unilateral group, P= 0.17 required epinephrine infusion to treat hypotension. Patients in the conventional group had statistically significant greater fall in the systolic blood pressures at 15, 30 and 45 minutes when compared to the baseline (P= 0.003, 0.001 and 0.004). The mean respiratory rate and oxygen saturations in the two groups were similar. CONCLUSION: Compared to conventional spinal anaesthesia, unilateral spinal anaesthesia was associated with fewer cardiovascular perturbations. Also, the type of spinal block instituted affected neither the respiratory rate nor the arterial oxygen saturation.

[ "Clinical", "comparison", "of", "cardiorespiratory", "effects", "during", "unilateral", "and", "conventional", "spinal", "anaesthesia", ".", "BACKGROUND", ":", "Spinal", "anaesthesia", "is", "widely", "employed", "in", "clinical", "practice", "but", "has", "the", "main", "drawback", "of", "post-spinal", "block", "hypotension", ".", "Efforts", "must", "therefore", "continue", "to", "be", "made", "to", "obviate", "this", "setback", "OBJECTIVE", ":", "To", "evaluate", "the", "cardiovascular", "and", "respiratory", "changes", "during", "unilateral", "and", "conventional", "spinal", "anaesthesia", ".", "METHODS", ":", "With", "ethical", "approval", ",", "we", "studied", "74", "American", "Society", "of", "Anesthesiologists", "(", "ASA", ")", ",", "physical", "status", "class", "1", "and", "2", "patients", "scheduled", "for", "elective", "unilateral", "lower", "limb", "surgery", ".", "Patients", "were", "randomly", "allocated", "into", "one", "of", "two", "groups", ":", "lateral", "and", "conventional", "spinal", "anaesthesia", "groups", ".", "In", "the", "lateral", "position", "with", "operative", "side", "down", ",", "patients", "recived", "10", "mg", "(", "2mls", ")", "of", "0.5", "%", "hyperbaric", "bupivacaine", "through", "a", "25-gauge", "spinal", "needle", ".", "Patients", "in", "the", "unilateral", "group", "were", "maintained", "in", "the", "lateral", "position", "for", "15", "minutes", "following", "spinal", "injection", "while", "those", "in", "the", "conventional", "group", "were", "turned", "supine", "immediately", "after", "injection", ".", "Blood", "pressure", ",", "heart", "rate", ",", "respiratory", "rate", "and", "oxygen", "saturation", "were", "monitored", "over", "1", "hour", ".", "RESULTS", ":", "Three", "patients", "(", "8.1", "%", ")", "in", "the", "unilateral", "group", "and", "5", "(", "13.5", "%", ")", "in", "the", "conventional", "group", "developed", "hypotension", ",", "P=", "0.71", ".", "Four", "(", "10.8", "%", ")", "patients", "in", "the", "conventional", "group", "and", "1", "(", "2.7", "%", ")", "in", "the", "unilateral", "group", ",", "P=", "0.17", "required", "epinephrine", "infusion", "to", "treat", "hypotension", ".", "Patients", "in", "the", "conventional", "group", "had", "statistically", "significant", "greater", "fall", "in", "the", "systolic", "blood", "pressures", "at", "15", ",", "30", "and", "45", "minutes", "when", "compared", "to", "the", "baseline", "(", "P=", "0.003", ",", "0.001", "and", "0.004", ")", ".", "The", "mean", "respiratory", "rate", "and", "oxygen", "saturations", "in", "the", "two", "groups", "were", "similar", ".", "CONCLUSION", ":", "Compared", "to", "conventional", "spinal", "anaesthesia", ",", "unilateral", "spinal", "anaesthesia", "was", "associated", "with", "fewer", "cardiovascular", "perturbations", ".", "Also", ",", "the", "type", "of", "spinal", "block", "instituted", "affected", "neither", "the", "respiratory", "rate", "nor", "the", "arterial", "oxygen", "saturation", "." ]

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24717468

A comparison of severe hemodynamic disturbances between dexmedetomidine and propofol for sedation in neurocritical care patients. OBJECTIVE: Dexmedetomidine and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and propofol. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with dexmedetomidine or propofol. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 dexmedetomidine and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or bradycardia in either the unmatched or matched cohorts. CONCLUSIONS: Severe hypotension and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or propofol. Providers should similarly consider the likelihood of hypotension or bradycardia before starting either sedative.

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biored_tokenized

Dataset Card for "biored_tokenized"