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2,336,500 |
Design and psychometric evaluation of the Psychological Adaptation to Genetic Information Scale.
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To develop and psychometrically evaluate the Psychological Adaptation to Genetic Information Scale (PAGIS).</AbstractText>A cross-sectional, Web-based survey of participants (n=323) recruited via Internet electronic mailing lists or Websites for people affected by genetic diseases.</AbstractText>Item analysis, confirmatory principal components analysis, and internal consistency reliability using Cronbach's alpha were used to construct the 26-item PAGIS.</AbstractText>Five factors (nonintrusiveness, support, self-worth, certainty, and self-efficacy) explained 57.7% of the variance in psychological adaptation to genetic information. The internal consistency reliability of the total PAGIS was .90, and the subscale reliabilities ranged from .77 to .87.</AbstractText>Psychological adaptation to genetic information is a multidimensional phenomenon comprised of nonintrusiveness, support, self-worth, certainty, and self-efficacy. The PAGIS has initial reliability and validity for use in future research.</AbstractText>
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2,336,501 |
Preparation of peptide-targeted phagemid particles using a protein III-modified helper phage.<Pagination><StartPage>493</StartPage><EndPage>497</EndPage><MedlinePgn>493-7</MedlinePgn></Pagination><Abstract><AbstractText>Ligand or peptide-targeted phagemid particles are being pursued as vehicles for receptor-mediated gene delivery. Here we describe a helper phage in which the protein III (pIII) protein is modified by the addition of a ligand peptide sequence at the amino terminus. Phagemid particles can be prepared with the help of this modified helper phage and should display the ligand peptide in most of the pIII proteins on the phagemid surface. Using such a method, it is not necessary for the phagemid to encode the pIII protein, which leaves a larger space for cloning genes of interest. In addition, the technique should allow for the rapid testing of peptide ligands selected from phage display libraries using phagemids encoding various reporter genes (e.g., green fluorescent protein, luciferase, beta-galactosidase) and therapeutic genes.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Zonghai</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Fudan University, Shanghai, Shanghai, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Jie</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>Ruijiao</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Xu</LastName><ForeName>Yuhong</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Gu</LastName><ForeName>Jianren</ForeName><Initials>J</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Biotechniques</MedlineTA><NlmUniqueID>8306785</NlmUniqueID><ISSNLinking>0736-6205</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004277">DNA, Single-Stranded</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008024">Ligands</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019151">Peptide Library</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010455">Peptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>147336-22-9</RegistryNumber><NameOfSubstance UI="D049452">Green Fluorescent Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>9007-49-2</RegistryNumber><NameOfSubstance UI="D004247">DNA</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.13.12.-</RegistryNumber><NameOfSubstance UI="D008156">Luciferases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.2.1.23</RegistryNumber><NameOfSubstance UI="D001616">beta-Galactosidase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017104" MajorTopicYN="N">Bacteriophage M13</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001435" MajorTopicYN="N">Bacteriophages</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001709" MajorTopicYN="N">Biotechnology</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015153" MajorTopicYN="N">Blotting, Western</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019556" MajorTopicYN="N">COS Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002478" MajorTopicYN="N">Cells, Cultured</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003001" MajorTopicYN="N">Cloning, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004247" MajorTopicYN="N">DNA</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004277" MajorTopicYN="N">DNA, Single-Stranded</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018014" MajorTopicYN="Y">Gene Transfer Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017930" MajorTopicYN="N">Genes, Reporter</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005822" MajorTopicYN="N">Genetic Vectors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049452" MajorTopicYN="N">Green Fluorescent Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008024" MajorTopicYN="N">Ligands</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008156" MajorTopicYN="N">Luciferases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019151" MajorTopicYN="N">Peptide Library</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010455" MajorTopicYN="N">Peptides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017434" MajorTopicYN="N">Protein Structure, Tertiary</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001616" MajorTopicYN="N">beta-Galactosidase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>21</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>12</Month><Day>13</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>21</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16235561</ArticleId><ArticleId IdType="doi">10.2144/000112007</ArticleId><ArticleId IdType="pii">000112007</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16235319</PMID><DateCompleted><Year>2006</Year><Month>02</Month><Day>24</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>21</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>4</Issue><PubDate><Year>2005</Year><Month>Oct</Month><Day>19</Day></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal>Inhaled bronchodilators for cystic fibrosis.
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Ligand or peptide-targeted phagemid particles are being pursued as vehicles for receptor-mediated gene delivery. Here we describe a helper phage in which the protein III (pIII) protein is modified by the addition of a ligand peptide sequence at the amino terminus. Phagemid particles can be prepared with the help of this modified helper phage and should display the ligand peptide in most of the pIII proteins on the phagemid surface. Using such a method, it is not necessary for the phagemid to encode the pIII protein, which leaves a larger space for cloning genes of interest. In addition, the technique should allow for the rapid testing of peptide ligands selected from phage display libraries using phagemids encoding various reporter genes (e.g., green fluorescent protein, luciferase, beta-galactosidase) and therapeutic genes.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Zonghai</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Fudan University, Shanghai, Shanghai, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Jie</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>Ruijiao</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Xu</LastName><ForeName>Yuhong</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Gu</LastName><ForeName>Jianren</ForeName><Initials>J</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Biotechniques</MedlineTA><NlmUniqueID>8306785</NlmUniqueID><ISSNLinking>0736-6205</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004277">DNA, Single-Stranded</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008024">Ligands</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019151">Peptide Library</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010455">Peptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>147336-22-9</RegistryNumber><NameOfSubstance UI="D049452">Green Fluorescent Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>9007-49-2</RegistryNumber><NameOfSubstance UI="D004247">DNA</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.13.12.-</RegistryNumber><NameOfSubstance UI="D008156">Luciferases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.2.1.23</RegistryNumber><NameOfSubstance UI="D001616">beta-Galactosidase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017104" MajorTopicYN="N">Bacteriophage M13</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001435" MajorTopicYN="N">Bacteriophages</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001709" MajorTopicYN="N">Biotechnology</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015153" MajorTopicYN="N">Blotting, Western</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019556" MajorTopicYN="N">COS Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002478" MajorTopicYN="N">Cells, Cultured</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003001" MajorTopicYN="N">Cloning, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004247" MajorTopicYN="N">DNA</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004277" MajorTopicYN="N">DNA, Single-Stranded</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018014" MajorTopicYN="Y">Gene Transfer Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017930" MajorTopicYN="N">Genes, Reporter</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005822" MajorTopicYN="N">Genetic Vectors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049452" MajorTopicYN="N">Green Fluorescent Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008024" MajorTopicYN="N">Ligands</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008156" MajorTopicYN="N">Luciferases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019151" MajorTopicYN="N">Peptide Library</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010455" MajorTopicYN="N">Peptides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017434" MajorTopicYN="N">Protein Structure, Tertiary</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001616" MajorTopicYN="N">beta-Galactosidase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>21</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>12</Month><Day>13</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>21</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16235561</ArticleId><ArticleId IdType="doi">10.2144/000112007</ArticleId><ArticleId IdType="pii">000112007</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16235319</PMID><DateCompleted><Year>2006</Year><Month>02</Month><Day>24</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>21</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>4</Issue><PubDate><Year>2005</Year><Month>Oct</Month><Day>19</Day></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal><ArticleTitle>Inhaled bronchodilators for cystic fibrosis.</ArticleTitle><Pagination><StartPage>CD003428</StartPage><MedlinePgn>CD003428</MedlinePgn></Pagination><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Recurrent wheeze and breathlessness are common in people with cystic fibrosis, and bronchodilators are commonly prescribed. Despite their wide-scale and often long-term use, there is limited objective evidence about their efficacy in cystic fibrosis.<AbstractText Label="OBJECTIVES" NlmCategory="OBJECTIVE">To evaluate the effectiveness of inhaled bronchodilators in children and adults with cystic fibrosis.<AbstractText Label="SEARCH STRATEGY" NlmCategory="METHODS">We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic databases searches, and handsearches of relevant journals and abstract books of conference proceedings. Latest search of the Group's Trials Register: August 2005<AbstractText Label="SELECTION CRITERIA" NlmCategory="METHODS">Randomised or quasi-randomised trials comparing inhaled bronchodilators to placebo or another inhaled bronchodilator in people with CF, diagnosed clinically and by sweat or genetic testing and at all stages and severity of lung disease.<AbstractText Label="DATA COLLECTION AND ANALYSIS" NlmCategory="METHODS">The authors independently extracted data and assessed trial quality. If data were missing, the primary author was contacted where possible. The data were subgrouped into classes of bronchodilator and for each class into short-term effects (less than one week) and long-term effects (greater or equal to one week).<AbstractText Label="MAIN RESULTS" NlmCategory="RESULTS">The search identified 43 references. Fourteen trials, with a total of 257 participants, were suitable for inclusion. The trials were all cross-over in design; in this case a meta-analysis was not possible. There were varied conclusions from the different trials, reflecting their heterogeneity. Compared to placebo, short-acting beta-2 agonists increased forced expiratory volume at one second (FEV(1)) in the short term in three out of five trials, and in the long-term increased peak expiratory flow rate in individuals who had been shown to have bronchial hyperreactivity or bronchodilator responsiveness or both. Compared to placebo, long-acting beta-2 agonists increased FEV(1) and forced expiratory flow between 25% and 75% of expiratory flow (FEF 25-75%) in the short term in participants known to have bronchodilator responsiveness, but produced inconsistent results in long-term trials. Short acting-anticholinergics had no consistent effect on lung function tests in either the short or the long term. We found no published trials of fenoterol, formoterol or tiotropium and the use of these agents in cystic fibrosis cannot be supported.<AbstractText Label="AUTHORS' CONCLUSIONS" NlmCategory="CONCLUSIONS">It was not possible to determine fully the effectiveness of inhaled bronchodilators in cystic fibrosis as a meta-analysis was not possible. However, both short and long-acting beta-2 agonists can be beneficial both in the short and long term in individuals with demonstrable bronchodilator responsiveness or bronchial hyperrresponsiveness.
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2,336,502 |
Genomic rearrangement at 10q24 in non-syndromic split-hand/split-foot malformation.
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Split-hand/split-foot malformation (SHFM) is a congenital limb malformation characterized by a median cleft of hand and/or foot due to the absence of central rays. Five loci for syndromic and non-syndromic SHFM, termed SHFM1-5, have been mapped to date. Recently, a 0.5 Mb tandem genomic duplication was found at chromosome 10q24 in SHFM3 families. To refine the minimum duplicated region and to further characterize the SHFM3 locus, we screened 28 non-syndromic SHFM families for tandem genomic duplication of 10q24 by Southern blot and sequence analysis of the dactylin gene. Of 28 families, only two showed genomic rearrangements. Representative patients from the two families exhibit typical SHFM, with symmetrically affected hands and feet. One patient is a familial case with a 511,661 bp tandem duplication, whereas the second is a sporadic case arising from a de novo, 447,338 bp duplication of maternal origin. The smaller duplication in the second patient contained the LBX1, BTRC, POLL, and DPCD genes and a disrupted extra copy of the dactylin gene, and was nearly identical to the smallest known duplicated region of SHFM3. Our results indicate that genomic rearrangement of SHFM3 is rare among non-syndromic SHFM patients and emphasize the importance of screening for genomic rearrangements even in sporadic cases of SHFM.
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2,336,503 |
Screening of ARX in mental retardation families: Consequences for the strategy of molecular diagnosis.
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Mutations in the human ARX gene have been shown to cause nonsyndromic X-linked mental retardation (MRX) as well as syndromic forms such as X-linked lissencephaly with abnormal genitalia (XLAG), Partington syndrome and X-linked infantile spasm. The most common causative mutation, a duplication of 24 bp, was found in families with a variety of phenotypes, but not in the more severe XLAG phenotypes. The aim of the study was to access the frequency of ARX mutations in families with established or putative X-linked mental retardation (XLMR) collected by the European XLMR Consortium. We screened the entire coding region of ARX for mutations in 197 novel XLMR families by denaturing high-performance liquid chromatography, and we identified eight mutations (six c.428_451dup24, one insertion and one novel missense mutation p.P38S). To better define the prevalence of ARX mutations, we included previously reported results of 157 XLMR families. Together, these data showed the relatively high rate (9.5%) of ARX mutations in X-linked MR families and an expectedly low rate in families with affected brother pairs (2.2%). This study confirms that the frequency of ARX mutations is high in XLMR, and the analysis of ARX in MRX should not be limited to duplication.
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2,336,504 |
Isolation, characterization and mapping of simple sequence repeat markers in zoysiagrass (Zoysia spp.).
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The genus Zoysia consists of 16 species that are naturally distributed on sea coasts and grasslands around the Pacific. Of these, Zoysia japonica, Zoysia matrella, and Zoysia tenuifolia are grown extensively as turfgrasses, and Z. japonica is also used as forage grass in Japan and other countries in East Asia. To develop simple sequence repeat (SSR) markers for zoysiagrass (Zoysia spp.), we used four SSR-enriched genomic libraries to isolate 1,163 unique SSR clones. All four libraries contained a high percentage of perfect clones, ranging from 67.1 to 96.0%, and compound clones occurred with higher frequencies in libraries A (28.6%) and D (11.6%). From these clones, we developed 1,044 SSR markers when we tested all 1,163 SSR primer pairs. Using all 1,044 SSR markers, we tested one screening panel consisting of eight Zoysia clones for testing PCR amplifications, from which five unrelated clones, among the eight, were used for polymorphism assessment, and found that the polymorphic information content ranged from 0 (monomorphic loci) to 0.88. Of the 1,044 SSR markers, 170 were segregated in our mapping population and we mapped 161 on existing amplified fragment length polymorphism-based linkage groups, using this mapping population. These SSR markers will provide an ideal marker system to assist with gene targeting, quantitative trait locus mapping, variety or species identification, and marker-assisted selection in Zoysia species.
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2,336,505 |
Genetic variation in bone growth patterns defines adult mouse bone fragility.
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Femoral morphology and composition were determined for three inbred mouse strains between ages E18.5 and 1 year. Genotype-specific variation in postnatal, pubertal, and postpubertal growth patterns and mineral accrual explained differences in adult bone trait combinations and thus bone fragility.</AbstractText>Fracture risk is strongly regulated by genetic factors. However, this regulation is generally considered complex and polygenic. Therefore, the development of effective genetic-based diagnostic and treatment tools hinges on understanding how multiple genes and multiple cell types interact to create mechanically functional structures. The goal of this study was to connect variability in whole bone mechanical function, including measures of fragility, to variability in the biological processes underlying skeletal development. We accomplished this by testing for variation in bone morphology and composition among three inbred mouse strains from E18.5 to 1 year of age.</AbstractText>Mid-diaphyseal cross-sectional areas, diameters, moments of inertia, and ash content were determined for three strains of mice with widely differing adult whole bone femoral mechanical properties (A/J, C57BL/6J, and C3H/HeJ) at E18.5 and postnatal days 1, 7, 14, 28, 56, 112, 182, and 365 (n = 5-15 mice/strain/age).</AbstractText>Significant differences in the magnitude and rate of change in morphological and compositional bone traits were observed among the three strains at each phase of growth, including prenatal, postnatal, pubertal, and adult ages. These genotype-specific variations in growth patterns mathematically determined how variation in adult bone trait combinations and mechanical properties arose. Furthermore, six bone traits were identified that characterize phenotypic variability in femoral growth. These include (1) bone size and shape at postnatal day 1, (2) periosteal and (3) endosteal expansion during early growth, (4) periosteal expansion and (5) endosteal contraction in later growth, and (6) ash content. These results show that genetic variability in adult bone traits arises from variation in biological processes at each phase of growth.</AbstractText>Inbred mice achieve different combinations of adult bone traits through genotype-specific regulation of bone surface activity, growth patterns, and whole bone mineral accrual throughout femoral development. This study provides a systematic approach, which can be applied to the human skeleton, to uncover genetic control mechanisms influencing bone fragility.</AbstractText>
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2,336,506 |
Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry.
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Ten years after BRCA1 and BRCA2 were first identified as major breast cancer susceptibility genes, the spectrum of mutations and modifiers of risk among many ethnic minorities remain undefined.</AbstractText>To characterize the clinical predictors, spectrum, and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse high-risk clinic population and to evaluate the performance of the BRCAPRO statistical model in predicting the likelihood of a mutation.</AbstractText><AbstractText Label="DESIGN, SETTING, AND PARTICIPANTS" NlmCategory="METHODS">Comparative analysis of families (white, Ashkenazi Jewish, African American, Hispanic, Asian) with 2 or more cases of breast and/or ovarian cancer among first- and second-degree relatives. Families were identified at US sites between February 1992 and May 2003; in each family, the individual with the highest probability of being a mutation carrier was tested.</AbstractText>Frequency of BRCA1 and BRCA2 mutations and area under the receiver operating characteristic curve for the BRCAPRO model.</AbstractText>The mutation spectrum was vastly different between families of African and European ancestry. Compared with non-Hispanic, non-Jewish whites, African Americans had a lower rate of deleterious BRCA1 and BRCA2 mutations but a higher rate of sequence variations (27.9% vs 46.2% and 44.2% vs 11.5%; P<.001 for overall comparison). Deleterious mutations in BRCA1 and BRCA2 were highest for Ashkenazi Jewish families (69.0%). Early age at diagnosis of breast cancer and number of first- and second-degree relatives with breast and ovarian cancer were significantly associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation. In discriminating between mutation carriers, BRCAPRO performed as well in African American families as it did in white and Jewish families, with an area under the curve of 0.77 (95% confidence interval, 0.61-0.88) for African American families and 0.70 (95% confidence interval, 0.60-0.79) for white and Jewish families combined.</AbstractText>These data support the use of BRCAPRO and genetic testing for BRCA1 and BRCA2 mutations in the management of high-risk African American families. Irrespective of ancestry, early age at diagnosis and a family history of breast and ovarian cancer are the most powerful predictors of mutation status and should be used to guide clinical decision making.</AbstractText>
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2,336,507 |
Approach to genetic analysis in the diagnosis of hereditary autoinflammatory syndromes.
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Hereditary autoinflammatory syndromes are characterized by recurrent episodes of fever and inflammation. Seven subtypes have been described, caused by mutations in four different genes. Apart from a common phenotype of lifelong recurrent inflammatory attacks, all subtypes have distinct features and specific therapeutic options, which emphasizes the need for a specific diagnosis in each case. Our aim was to examine whether genetic screening would allow classification of previously unclassified patients, and whether individual patients suffering from an autoinflammatory syndrome carry additional mutations in one of the other autoinflammatory genes.</AbstractText>We included 60 patients with an unclassified autoinflammatory syndrome, 87 patients diagnosed with either hyper-IgD syndrome, familial Mediterranean fever (FMF) or tumour necrosis factor (TNF)-receptor-associated periodic syndrome and 50 healthy controls. Deoxyribonucleic acid samples were screened for the most prevalent mutations in the MEFV, TNFRSF1A, MVK and CIAS1 genes.</AbstractText>We found only one possible diagnosis of FMF in the 60 previously unclassified patients. Two low-penetrance mutations were found in equal numbers in the groups of patients and controls.</AbstractText>Screening of highly prevalent mutations in known genes involved in these disorders does not yield additional relevant information. Differential diagnosis of hereditary autoinflammatory syndromes can be made by thorough clinical examination followed by targeted genetic analysis of the one or two most likely syndromes. High-prevalence low-penetrant mutations from autoinflammatory genes do not occur more frequently in patients with hereditary autoinflammatory syndromes compared with the general population.</AbstractText>
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2,336,508 |
Hemochromatosis: genetic testing and clinical practice.
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The availability of a facile treatment for hemochromatosis renders early diagnosis of iron overload syndromes mandatory, and in many instances genetic testing allows identification of individuals at risk of developing clinical disease before pathologic iron storage occurs. Numerous proteins implicated in iron homeostasis have recently come to light, and defects in the cognate genes are associated with iron storage. Although most adult patients with hereditary iron overload are homozygous for the C282Y mutation of the HFE gene, an increasing number with hereditary iron storage have an HFE genotype not characteristic of the disease. Heterozygosity for mutations in the gene encoding ferroportin 1 (FPN1) is probably the second most common genetic cause of hereditary iron storage in adults; here the primarily affected cell is the macrophage. Rare defects, including mutations in the transferrin receptor 2 (TFR2) gene, have also been identified in pedigrees affected with "non-HFE hemochromatosis." Homozygous mutations in the newly identified genes encoding hemojuvelin (HFE2) and hepcidin (HAMP) cause juvenile hemochromatosis. At the same time, heterozygosity for mutations in these genes can modify the clinical expression of iron storage in patients predisposed to iron storage in adult life. Hemochromatosis might thus be considered as a polygenic disease with strong environmental influences on its clinical expression. As our mechanistic understanding of iron pathophysiology improves, our desire to integrate clinical decision making with the results of laboratory tests and molecular analysis of human genes poses increasing challenges.
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2,336,509 |
Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease.
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<AbstractText Label="BACKGROUND & AIMS" NlmCategory="OBJECTIVE">A 5-fold increase of hepatic copper concentration is considered as the best available test for diagnosis of hepatic Wilson's disease (WD). However, the sensitivity and specificity of this test have never been fully investigated.</AbstractText>Copper content was measured by flame atomic absorption spectroscopy in 114 liver biopsies obtained at diagnosis of WD, in 219 patients with noncholestatic liver diseases (including 144 with chronic hepatitis C and 44 with nonalcoholic fatty liver disease), and in 26 without evidence of liver disease.</AbstractText>Liver copper content was >250 microg/g in 95 WD patients (83.3%), between 50 and 250 microg/g in 15, and below 50 microg/g in 4. It did not correlate with age (r(2) = .003), the grade of fibrosis, or the presence of stainable copper. Liver copper content was >250 or between 50 and 250 microg/g in 3 (1.4%) and 20 (9.1%) of 219 patients with noncholestatic liver diseases, respectively. By lowering the cutoff from 250 to 75 microg/g, the sensitivity of liver copper content to diagnose WD increased from 83.3% (95% confidence interval, 75.2%-89.6%) to 96.5% (91.3%-99.1%), but the specificity decreased from 98.6% (96.0%-99.7%) to 95.4% (91.8%-97.8%).</AbstractText>There is no gold standard for the diagnosis of WD. Liver copper content is a useful parameter, but a value below 250 microg/g does not exclude WD. Diagnosis requires the combination of a variety of clinical and biochemical tests.</AbstractText>
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2,336,510 |
Wilson's Disease.
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Wilson's disease (WD) is an autosomal recessive inherited disorder leading to impaired intrahepatic trafficking and biliary excretion of copper, resulting in the accumulation of copper in various organs including the liver, cornea, and brain. The WD gene (OMIM 277900) codes for a copper transporting P-type ATPase (ATP7B). Although the finding of the gene resulted in a major breakthrough for understanding the pathophysiology of WD, the role of genetic testing in the clinical management of WD patients is not yet established. There is no gold standard for diagnosis of WD. Diagnosis requires a combination of clinical and biochemical tests. None of these parameters alone allows a certain diagnosis of WD. To facilitate diagnosis, a scoring system was developed at the 8th International Meeting on Wilson Disease in Leipzig, Germany in 2001. For clinical purposes, the use of mutation analysis is limited by the occurrence of many mutations (more than 200) causing WD. In contrast to direct DNA sequencing, direct mutation detection by using allele-specific probes is rapid and clinically very helpful, if a mutation occurs with a reasonable frequency in the population (ie, H1069Q in European WD patients or R778L in WD patients from the Far East). To date, mutation analysis is the only reliable tool for screening the family of an index case with known causative mutation. Alternatively, haplotype analysis can be used to address diagnostic dilemmas in differentiating heterozygote gene carriers and affected asymptomatic siblings.
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2,336,511 |
Assessing controversial direct-to-consumer advertising for hereditary breast cancer testing: reactions from women and their physicians in a managed care organization.
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To describe the impact on patients and physicians at a managed care organization (MCO) of a direct-to-consumer advertising (DTC-ad) campaign concerning testing for the BRCA1 and BRCA2 genes.</AbstractText>Observational study.</AbstractText>In 2003, we mailed a 30-item questionnaire to 750 randomly chosen female members of Kaiser Permanente Colorado (KPCO) aged 25 to 54 years, and 100 female KPCO members with a history of breast cancer genetic referral. We mailed a 7-item questionnaire to 180 randomly chosen KPCO primary care providers.</AbstractText>Of 394 patient respondents, 245 (62%) reported exposure to the DTC-ad of whom 63% reported that the DTC-ad caused no anxiety at all. A high level of perceived breast cancer risk and being of Hispanic ethnicity each were independently associated with reported anxiety due to the DTC-ad (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.35, 7.73, and adjusted OR = 4.19, 95% CI = 1.48, 11.83, respectively). Greater knowledge was seen among respondents exposed to the DTC-ad than among those reporting no exposure (P = .015). Of the physician respondents, 84% reported that the DTC-ad caused no strain on the doctor-patient relationship, and nearly 80% reported no effect on daily clinical practice. Genetic referrals soared more than 200% compared with the prior year, when there was no advertising.</AbstractText>The DTC-ad had a marked impact on genetic services, but little apparent negative impact on patients or primary care providers at an MCO.</AbstractText>
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2,336,512 |
Rapid determination of trisomy 21 from amniotic fluid cells using single-nucleotide polymorphic loci.
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Rapid detection of trisomy 21 is an important goal for prenatal genetic centers. Fluorescent-PCR and DNA fragment analysis was developed a decade ago and thousands of samples were analyzed in routine practice using this method. Quantitative real-time PCR with melting curve analysis using SNP markers for trisomy 21 detection was described recently. We studied the reliability of this method on a cohort of samples of Hungarian patients.</AbstractText>DNA was isolated with silica adsorption method from amniotic fluid cells. We investigated 67 trisomy 21 and 62 diploid samples in the study. Quantitative real-time PCR was performed using hybridization probes combined with melting curve analysis. Peak areas under the derivative curves were determined and analyzed.</AbstractText>The SNP marker WIAF 899 was informative in 41.86% of cases and WIAF 2643 in 48.83%. The melting curve area ratios were significantly different between trisomic and normal cases for WIAF 899 (trisomic 0.5246 +/- 0.2498 vs 0.8347 +/- 0.5234; p < 0.001), while in the case of WIAF 2643, they were not different.</AbstractText>Combined and selected SNP markers could be valuable tools for rapid trisomy 21 detection in prenatal genetic screening.</AbstractText>Copyright 2005 John Wiley & Sons, Ltd</CopyrightInformation>
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2,336,513 |
Predicting the result of additional second-trimester markers from a woman's first-trimester marker profile: a new concept in Down syndrome screening.
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To describe a method for deciding whether an individual's first-trimester Down syndrome screening test result justifies further testing in the second trimester.</AbstractText>Statistical modelling was used to estimate the distribution of second-trimester marker profiles for a given first-trimester profile and hence the probability of a final positive result, using a 1 in 250 term cut-off. A multi-variate log Gaussian model was used with published parameters. Markers were maternal serum pregnancy-associated plasma protein-A and free beta-human chorionic gonadotrophin (hCG) at 10 weeks, nuchal translucency at 11 weeks, and second-trimester maternal serum alpha-fetoprotein, total hCG, unconjugated estriol and inhibin-A. To illustrate the method, the model was applied to a published series of 24 Down syndrome and 367 unaffected pregnancies.</AbstractText>Modelling predicts that for 63% Down syndrome and 0.4% unaffected pregnancies having first-trimester tests, there is a 50% or more probability of a final positive result. A step-wise sequential screening policy based on immediate prenatal diagnosis for those with high probability and second-trimester testing for the remainder would have a 90% detection rate and 1.7% false-positive rate. Modelling also predicts 8.0% Down syndrome and 89% unaffected pregnancies with probabilities below 3%. A contingent screening policy restricting second-trimester testing to those with 3-49% probabilities would have an 88% detection rate and 1.4% false-positive rate.</AbstractText>Predicting the probability of a positive final result from the first-trimester marker profile has potential utility, either as a decision aide for individual women or as a formal part of screening policy in selecting a subset of women for second-trimester testing.</AbstractText>Copyright 2005 John Wiley & Sons, Ltd</CopyrightInformation>
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2,336,514 |
Rapid detection of chromosomal aneuploidies in uncultured amniocytes by multiplex ligation-dependent probe amplification (MLPA).
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To test whether multiplex ligation-dependent probe amplification (MLPA) can be used for the detection of aneuploidy of chromosomes 13, 18, 21, X, and Y in uncultured amniocytes.</AbstractText>We performed a prospective study based on 527 amniotic fluid samples. Chromosome copy numbers were determined by analysing the relative amount of PCR product of chromosome-specific MLPA probes. Results were available within 48 h and were compared with those of karyotyping.</AbstractText>There were 517 conclusive MLPA tests. In 514 tests, results were concordant with those of karyotyping. There were two cases of 69,XXX triploidy that could not be detected by MLPA and there was one false-positive result. Here, MLPA indicated a 47,XXY fetus, whereas the karyotype was 46,XY. We correctly identified all 23 cases of autosomal trisomy and the single case of monosomy X in samples collected from 16 up to 36 weeks of gestation. In 10 cases (2%), the result was inconclusive owing to an insufficient amount of DNA.</AbstractText>Sensitivity, specificity, and failure rate of MLPA were comparable to those of FISH and QF-PCR. Aneuploidy screening in uncultured amniocytes by MLPA is feasible in a clinical diagnostic setting, yielding an informative and rapid result in 98% of cases.</AbstractText>Copyright 2005 John Wiley & Sons, Ltd.</CopyrightInformation>
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2,336,515 |
Detection of a novel dystrophin gene mutation through carrier analysis performed during prenatal diagnosis in a case with intragenic recombination.
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To report a multi-technical approach to Duchenne muscular dystrophy (DMD) mutation testing through carrier analysis, in the prenatal diagnosis of a male foetus without a known mutation segregating in the family and with inconclusive results of linkage analysis.</AbstractText>Haplotype analysis with the DMD region markers for assigning the carrier status of the mother and for prenatal diagnosis of foetal DNA; semiquantitative multiplex analysis of maternal and foetal DNA for the promoter and for 34 exons of the DMD gene; sequencing analysis of the maternal and foetal DNA for confirmation of the results.</AbstractText>Because of an intragenic recombination of the DMD gene in foetal DNA, haplotype analysis gave inconclusive results. Semiquantitative PCR analysis displayed a pattern compatible with a heterozygous exon 60 mutation in the mother's DNA, while foetal DNA showed a normal migration pattern. Sequencing analysis confirmed the presence of a novel 7 base-pair deletion in exon 60 of the DMD gene in the mother and excluded the deletion in the foetus.</AbstractText>Semiquantitative PCR results allowed the DMD mutation detection in the mother and the exclusion in the foetus, showing its crucial importance in prenatal diagnosis in those cases where linkage analysis is not conclusive.</AbstractText>Copyright 2005 John Wiley & Sons, Ltd.</CopyrightInformation>
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2,336,516 |
Reduction in diagnostic and therapeutic interventions by non-invasive determination of fetal sex in early pregnancy.
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This study reviews our clinical experience of non-invasive techniques for early sex determination. It assesses the effectiveness of these techniques at reducing invasive prenatal testing for X-linked genetic disease or for ambiguous development of the external genitalia.</AbstractText>A prospective cohort study of 30 pregnancies was referred to a tertiary unit for prenatal diagnosis. Fetal gender was determined using two non-invasive techniques: analysis of free fetal DNA (ffDNA) in maternal plasma and ultrasound visualisation. The results were compared to fetal gender determined by invasive testing or at birth.</AbstractText>Fetal gender was accurately determined by analysis of ffDNA at a mean of 10 + 1 (7 + 6 to 14 + 1) weeks' gestation in all cases. Ultrasound assessment was accurate in 20 of the 23 cases where this was attempted at 12 + 0 (10 + 4 to 14 + 1) weeks' gestation, but could not be determined in the remaining 3 cases. Thirteen of 28 (46%) women chose not to have invasive testing on the basis of these findings.</AbstractText>Both the techniques appear to offer an accurate means of assessing fetal gender, giving parents the option of avoiding invasive testing in the 50% of cases where the fetus would not be affected. The molecular technique is performed at an earlier gestation, but female fetal status is predicted by a negative test result. Ultrasound cannot be applied until 11 weeks' gestation but diagnostic signs are sought in both sexes. Combining these approaches offers a highly sensitive method of non-invasive determination of gender in high-risk pregnancies. Health professionals, clinical geneticists and genetics associates, in particular, who refer women at high risk should be aware of these non-invasive options for prenatal sex determination.</AbstractText>Copyright 2005 John Wiley & Sons, Ltd</CopyrightInformation>
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2,336,517 |
Seroconversion following nonoccupational postexposure prophylaxis against HIV.
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The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP.</AbstractText>HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation.</AbstractText>Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus.</AbstractText>As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.</AbstractText>
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2,336,518 |
COL6A1, the candidate gene for ossification of the posterior longitudinal ligament, is associated with diffuse idiopathic skeletal hyperostosis in Japanese.
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Genetic screening of collagen 6A1 gene (COL6A1) in patients with diffuse idiopathic skeletal hyperostosis (DISH) recruited in Japan and the Czech Republic.</AbstractText>To investigate allelic associations between DISH and nucleotide variants of COL6A1.</AbstractText>DISH is a skeletal hyperostotic disease characterized by ligamentous ossification of the anterolateral side of the spine. Ossification of the posterior longitudinal ligament (OPLL) is a related disorder with DISH, and COL6A1 was identified as a susceptibility gene to OPLL. COL6A1 was examined for susceptibility in DISH patients from Japan and the Czech Republic.</AbstractText>Seven single nucleotide polymorphisms of COL6A1 were genotyped by direct sequencing. The allele frequencies were compared between 97 Japanese DISH patients and 298 Japanese controls, and between 96 Czech DISH patients and 96 Czech controls by chi2 test.</AbstractText>The intron 32 (-29) single nucleotide polymorphisms of COL6A1 was significantly associated with the Japanese DISH patients (chi2 = 9.33; P = 0.0022), but not with the Czech DISH patients.</AbstractText>Because COL6A1 could be a susceptibility to the occurrence of DISH and OPLL in the Japanese population, we consider that COL6A1 could be responsible for the hyperostotic state, leading to ectopic bone formation in the spinal ligament.</AbstractText>
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2,336,519 |
Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes.
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Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q21.</AbstractText>We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M-D), essential myoclonus (E-M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested.</AbstractText>Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M-D and five E-M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non-carriers. None of the patients had severe psychiatric disorders.</AbstractText>This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).</AbstractText>
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2,336,520 |
Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status.
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Mutations in the BRCA1 (MIM 113705) gene are found in many families with multiple cases of breast and ovarian cancer, and women with a BRCA1 mutation are at significantly higher risk of developing breast and ovarian cancer than are the general public.</AbstractText>We obtained blood samples and pedigree information from 3568 unselected cases of early-onset breast cancer and 609 unselected patients with ovarian cancer from hospitals throughout Poland. Genetic testing was performed for three founder BRCA1 mutations. We also calculated the risk of breast and ovarian cancer to age 75 in the first degree relatives of carriers using Kaplan-Meier methods.</AbstractText>The three founder BRCA1 mutations were identified in 273 samples (187 with 5382insC, 22 with 4153delA, and 64 with C61G). A mutation was present in 4.3% of patients with breast cancer and 12.3% of patients with ovarian cancer. The overall risk of breast cancer to age 75 in relatives was 33% and the risk of ovarian cancer was 15%. The risk for breast cancer was 42% higher among first degree relatives of carriers of the C61G missense mutation compared to other mutations (HR = 1.42; p = 0.10) and the risk for ovarian cancer was lower than average (OR = 0.26; p = 0.03). Relatives of women diagnosed with breast cancer had a higher risk of breast cancer than relatives of women diagnosed with ovarian cancer (OR = 1.7; p = 0.03).</AbstractText>The risk of breast cancer in female relatives of women with a BRCA1 mutation depends on whether the proband was diagnosed with breast or ovarian cancer.</AbstractText>
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2,336,521 |
A large-scale screen for artificial selection in maize identifies candidate agronomic loci for domestication and crop improvement.
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Maize (Zea mays subsp mays) was domesticated from teosinte (Z. mays subsp parviglumis) through a single domestication event in southern Mexico between 6000 and 9000 years ago. This domestication event resulted in the original maize landrace varieties, which were spread throughout the Americas by Native Americans and adapted to a wide range of environmental conditions. Starting with landraces, 20th century plant breeders selected inbred lines of maize for use in hybrid maize production. Both domestication and crop improvement involved selection of specific alleles at genes controlling key morphological and agronomic traits, resulting in reduced genetic diversity relative to unselected genes. Here, we sequenced 1095 maize genes from a sample of 14 inbred lines and chose 35 genes with zero sequence diversity as potential targets of selection. These 35 genes were then sequenced in a sample of diverse maize landraces and teosintes and tested for selection. Using two statistical tests, we identified eight candidate genes. Extended gene sequencing of these eight candidate loci confirmed that six were selected throughout the gene, and the remaining two exhibited evidence of selection in the 3' portion of each gene. The selected genes have functions consistent with agronomic selection for nutritional quality, maturity, and productivity. Our large-scale screen for artificial selection allows identification of genes of potential agronomic importance even when gene function and the phenotype of interest are unknown.
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2,336,522 |
Thresholds as a unifying theme in regulatory toxicology.
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The scientific basis for the US Food and Drug Administration (FDA) threshold of regulation is discussed in relation to its toxicological testing recommendations for food contact substances and the existing methods it employs for exposure estimation. A case is made that the FDA's threshold of regulation is a natural extension of its toxicity testing regime. The genetic toxicity tests recommended in the exposure-based toxicological testing framework for food contact substances are examined regarding their ability to predict positively carcinogens of varying potency. In addition, the computational toxicology program MULTICASE v. 3.1 is also examined for its ability to predict positively carcinogens of varying potency. It is concluded that MULTICASE can provide equivalent results to genetic toxicity tests at the lowest dietary concentrations.
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2,336,523 |
Genetic counseling issues in urea cycle disorders.
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The goal of counseling families that have a urea cycle disorder (UCD) is to facilitate the process of scientific understanding, emotional acceptance, and decision-making in a nondirective way. A proper understanding of the genes involved, inheritance patterns, available testing, and complicating factors is critical to serving the families' needs. This article summarizes the needed information, in particular describing the complexities of prenatal testing and counseling issues for each UCD. Included case histories illustrate the genetic counseling process and the decision-making scenarios for two families.
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2,336,524 |
Testing the modularity of the N-terminal amphipathic helix conserved in picornavirus 2C proteins and hepatitis C NS5A protein.
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The N-terminal region of the picornaviral 2C protein is predicted to fold into an amphipathic alpha-helix that is responsible for the protein's association with membranes in the viral RNA replication complex. We have identified a similar sequence in the N-terminal region of NS5A of hepaciviruses that was recently shown to form an amphipathic alpha-helix. The conservation of the N-terminal region in two apparently unrelated proteins of two different RNA virus families suggested that this helix might represent an independent module. To test this hypothesis, we constructed chimeric poliovirus (PV) genomes in which the sequence encoding the N-terminal 2C amphipathic helix was replaced by orthologous sequences from other picornaviral genomes or a similar sequence from NS5A of HCV. Effects of the mutations were assessed by measuring the accumulation of viable virus and viral RNA in HeLa cells after transfection, examining membrane morphology in cells expressing chimeric proteins and by in vitro analysis of RNA translation, protein processing and negative strand RNA synthesis in HeLa cell extracts. The chimeras manifested a wide range of growth and RNA synthesis phenotypes. The results are compatible with our hypothesis, although they demonstrate that helix exchangeability may be restricted due to requirements for interactions with other viral components involved in virus replication.
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2,336,525 |
Functional characterization of a novel Cx26 (T55N) mutation associated to non-syndromic hearing loss.
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Mutations of the GJB2 gene, encoding connexin 26, are the most common cause of hereditary congenital hearing loss in many countries and account for up to 50% of cases of autosomal-recessive non-syndromic deafness. By contrast, only a few GJB2 mutations have been reported to cause an autosomal-dominant form of non-syndromic deafness. Here, we report a family from Southern Italy affected by non-syndromic autosomal dominant post-lingual hearing loss, due to a novel missense mutation in the GJB2 gene, a threonine to asparagine amino acid substitution at codon 55 (T55N). Functional studies indicated that the mutation T55N produces a protein that, although expressed to levels similar to those of the wt counterpart, is deeply impaired in its intracellular trafficking and fails to reach the plasma membrane. The mutation T55N is located at the apex of the first extracellular loop of the protein, a region suggested to play a role in protein targeting and a site for other two mutations, G59A and D66H, causing dominant forms of deafness.
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2,336,526 |
Results of cochlear implantation in two children with mutations in the OTOF gene.
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The purpose of the study is to present the results of cochlear implantation in case of deafness involving mutations in the OTOF gene. This form of deafness is characterized by the presence of transient evoked otoacoustic emissions (TEOAE). In cases of profound deafness with preserved TEOAE, two main etiologies should be considered: either an auditory neuropathy (a retrocochlear lesion) or an endocochlear lesion. It is essential to differentiate these two entities with regards to therapy and screening.</AbstractText>We report two children who presented with profound prelingual deafness, confirmed by the absence of detectable responses to auditory evoked potentials (AEP), associated with the presence of bilateral TEOAE. Genetic testing revealed mutations in OTOF, confirming DFNB9 deafness. Both patients have been successfully implanted (with a follow-up of 18 and 36 months, respectively).</AbstractText>Clinical (oral production, closed and open-set words and sentences list, meaningful auditory integration scale), audiometric evaluation (TEOAE, AEP) before and after implantation, and neural response telemetry (NRT).</AbstractText>Both patients present a good quality of clinical responses and electrophysiological tests after implantation, indicating satisfactory functioning of the auditory nerve. This confirms the endocochlear origin of DFNB9 and suggests that these mutations in OTOF lead to functional alteration of inner hair cells.</AbstractText>In the absence of a context of neurological syndrome, the combination of absent AEP and positive TEOAE should lead to a genetic screening for mutations in OTOF, in order to undertake the appropriate management.</AbstractText>
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2,336,527 |
Phylogenetics by likelihood: evolutionary modeling as a tool for understanding the genome.
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Molecular evolutionary studies provide a means of investigating how cells function and how organisms adapt to their environment. The products of evolutionary studies provide medically important insights to the source of major diseases, such as HIV, and hold the key to understand the developing immunity of pathogenic bacteria to antibiotics. They have also helped mankind understand its place in nature, casting light on the selective forces and environmental conditions that resulted in modern humans. The use of likelihood as a framework for statistical modeling in phylogenetics has played a fundamental role in studying molecular evolution, enabling rigorous and robust conclusions to be drawn from sequence data. The first half of this article is a general introduction to the likelihood method for inferring phylogenies, the properties of the models used, and how it can be used for statistical testing. The latter half of the article focuses on the emerging new generation of phylogenetic models that describe heterogeneity in the evolutionary process along sequences, including the recoding of protein coding sequence data to amino acids and codons, and various approaches for describing dependencies between sites in a sequence. We conclude with a detailed case study examining how modern modeling approaches have been successfully employed to identify adaptive evolution in proteins.
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2,336,528 |
Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy.
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Most girls with Rett syndrome develop normally prior to the appearance of the typical symptoms. A presymptomatic phase is also observed in many inborn errors of metabolism that are included in newborn screening programs. Diagnostic testing for mutations or large genomic rearrangements involving methyl-CpG binding protein 2 gene (MECP2) is highly sensitive and identifies mutations in up to 95% of female individuals with classic Rett syndrome. This has prompted some to ask whether MECP2 testing should be included in newborn and prenatal screening programs. We review current and evolving practices in these programs, emphasizing their relevance to Rett syndrome. The availability of a reliable test and the characteristic early latent phase, which creates a window of opportunity for early treatment, favor universal newborn screening for Rett syndrome. However, the high cost and the lack of an effective presymptomatic treatment make universal newborn screening for Rett syndrome impractical at present. In contrast, prenatal diagnosis should be offered to the parents of an affected child if the responsible mutation has been identified in the index case.
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2,336,529 |
Molecular diagnosis of Rett syndrome.
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In 1999, mutations in the MECP2 gene were identified as the primary cause of Rett syndrome. MECP2 mutations can be found in 70% to 80% of all clinically defined Rett syndrome cases; in classic Rett syndrome, this frequency is even higher. In most cases, missense and nonsense mutations affecting functionally important domains can be found. Additionally, a hot spot for small deletions has been defined, and several gross rearrangements have also been described. Among female individuals with Rett syndrome, the spectrum of clinical phenotypes is broad, but most fulfill the diagnostic criteria. In contrast, male individuals with mutations in the MECP2 gene are rare, and only a minority have clinical symptoms resembling Rett syndrome.
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2,336,530 |
The human secretin gene in children with autistic spectrum disorder: screening for polymorphisms and mutations.
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We screened 29 children with autism for mutation in the human secretin gene using single-strand conformation polymorphism. No mutation was detected in exon 2, 3, or 4. Polymerase chain reaction and DNA sequence of 5' variable number of tandem repeats showed two polymorphisms with deletion or duplication of a repeat unit that failed to show any gene expression with transient transfection assay. We did not find evidence of a relationship between human secretin gene mutation and autism.
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2,336,531 |
A Single multiplexed allele-specific polymerase chain reaction for simultaneous detection of alpha1-antitrypsin S and Z mutations.
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Alpha1-antitrypsin (AAT) deficiency is an inherited disorder that can cause lung disease in adults and liver disease in adults and children. The S and Z mutations are the two most common mutations found in the AAT-deficient patients. We have developed a simple multiplexed allele-specific-PCR to detect both the S and Z mutations and the corresponding wild-type alleles. Polymerase chain reaction (PCR) product could be resolved on an agarose gel or using any fluorescent gel detection system. We obtained accurate genotyping results for the four alleles; the S, Z, and their corresponding wild-type alleles for all investigated samples simultaneously. The approach described in this paper is rapid, cost effective, and reliable and can also be adaptable into any laboratory setting because of its simplicity.
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2,336,532 |
Hereditary nonpolyposis colorectal cancer family members' perceptions about the duty to inform and health professionals' role in disseminating genetic information.
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This study's aim was to ascertain hereditary nonpolyposis colorectal cancer (HNPCC) families' views on the duty to inform with particular focus on the role of health professionals in disseminating familial genetic information. Eighty members of 16 families with a clinical or molecular diagnosis of HNPCC completed qualitative interviews regarding views on family members' right to know and who should disseminate familial genetic information. Most indicated that everyone in the family should know about the presence of a mutation in the family, with family members themselves being the preferable informant, supported by health professionals who were seen as helpful in overcoming barriers. All but one respondent indicated that if a parent did not test and presumably did not inform his/her child about the family mutation, the child should be informed by other family members or by a health professional. Many were attuned to confidentiality concerns, but judged them to be outweighed by the importance of family members knowing about the mutation and undertaking proper surveillance. Respondents were more private about the disclosure of individual results to other family members, clearly distinguishing personal results from familial genetic information. These families with a hereditary colon cancer syndrome favor open sharing of genetic information within the family, and desire the supportive involvement of health care professionals in disseminating genetic information.
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2,336,533 |
Cystic fibrosis newborn screening: a pilot study to maximize carrier screening.
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Newborn screening for cystic fibrosis (CF) is expanding because early diagnosis has been shown to result in improved nutrition and growth. Most newborns identified by a mutation panel have a single detected mutation and require sweat testing to exclude an additional undetected mutation. The resulting identification of CF carrier newborns, although not the primary purpose of screening, has three potential benefits, (1) the detection of trait-trait couples, (2) presymptomatic testing of these couples' previously born children who may have undetected CF, and (3) a carrier parent alerting his/her extended family members to the chance of also being a CF carrier. Reaping each benefit requires genetic counseling of parents and their accepting carrier testing. The purpose of this study was to utilize the sweat testing visit to educate parents about the value of carrier testing for themselves and their blood relatives. We compared special care (genetic counseling after explaining the sweat test result and offering of parental DNA testing, all on the sweat test visit) versus standard care (sweat test result reported by phone to the parents the next day by the newborn's physician, ideally with the recommendation to arrange genetic counseling and parental carrier testing). In the first year of New York State CF screening, 64 newborns with one detected mutation were reported in the nine-county region that includes Rochester. Of these, parents of 39 agreed to participate in the study and to be randomized to special or standard care. Sixty-one parents completed both the initial and 1-year follow-up questionnaires (30 couples and one mother). Of the 61 parents, 23 had carrier testing after the birth of the baby. The frequency of such parental testing was significantly higher in the special care group (17/34 or 50%) than in the standard care group (6/27 or 22%) (p < 0.05). This is the first evidence from a randomized trial that genetic counseling and offering carrier testing to parents on the sweat test visit increases identification of carrier parents. Such identification detects trait-trait parents and facilitates carrier testing among relatives.
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2,336,534 |
Genotype-based screening for hereditary hemochromatosis: II. Attitudes toward genetic testing and psychosocial impact--a report from a German pilot study.
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In collaboration with the German Sickness Fund (Kaufmännische Krankenkasse-KKH), we conducted a pilot study on DNA-based population screening of hereditary hemochromatosis (HH) in Germany. The health insurance organization KKH briefly informed their members about the possibility to participate voluntarily in this pilot project. A total of 5882 KKH members contacted us and received detailed information on the aim of the project and clinical and genetic aspects of HH. Of these individuals, 3961 requested HFE genotyping. After genotype results had been communicated to the participants' general practitioner, we sent a self-administered questionnaire to all homozygous (n = 67) and heterozygous (n = 485) as well as 448 wild-type study participants (sigma = 1000) to assess the psychosocial impact of HFE genotyping. In addition, questionnaires were sent to 8000 randomly selected members of the KKH to investigate their attitude toward genetic testing. Six hundred thirty-one (63.1%) of the test participants and 2141 (26.8%) of the randomly chosen KKH members responded. A total of 59.1% of the members would generally accept predictive genetic testing and 3.7% objected to such tests in principle. Individuals with higher educational status accepted predictive testing significantly more often than individuals with less education. Of the tested individuals, 69.9% thought that participation in the pilot study was probably beneficial for them and 1% (5 heterozygotes and 1 wild-type) thought that it was probably harmful. Of the participants, 94.6% judged their decision to have participated in the pilot study as right and 0.3% (2 heterozygotes) as probably wrong. Only very few of the tested individuals underwent pretest (1 case) or posttest (11 cases) genetic counseling. We conclude that genotype- based screening for HH is generally accepted and was perceived as beneficial. Negative psychosocial consequences are rare and could presumably have been prevented by delivering appropriate pretest and posttest information.
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2,336,535 |
Initial screening transferrin saturation values, serum ferritin concentrations, and HFE genotypes in whites and blacks in the Hemochromatosis and Iron Overload Screening Study.
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We compared initial screening data of 44,082 white and 27,124 black Hemochromatosis and Iron Overload Screening (HEIRS) Study participants. Each underwent serum transferrin saturation (TfSat) and ferritin (SF) measurements without regard to fasting, and HFE C282Y and H63D genotyping. Elevated measurements were defined as: TfSat more than 50% (men), more than 45% (women); and SF more than 300 ng/ml (men), more than 200 ng/ml (women). Mean TfSat and percentages of participants with elevated TfSat were significantly greater in whites than in blacks. Mean SF and percentages of participants with elevated SF were significantly greater in blacks than in whites. TfSat and SF varied by gender and age in whites and blacks. Prevalences of genotypes that included either C282Y or H63D were significantly greater in whites than in blacks. The prevalence of elevated TfSat and SF plus genotypes C282Y/C282Y, C282Y/H63D, or H63D/H63D was 0.006 in whites and 0.0003 in blacks. Among whites with HFE C282Y homozygosity, 76.8% of men and 46.9% of women had elevated TfSat and SF values. Three black participants had HFE C282Y homozygosity; one had elevated TfSat and SF values. Possible explanations for differences in TfSat and SF in whites and blacks and pertinence to the detection of hemochromatosis, iron overload, and other disorders with similar phenotypes are discussed.
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2,336,536 |
Large deletion at the TSC1 locus in a family with tuberous sclerosis complex.
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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. Here we describe a deletion encompassing the TSC1 gene and two neighboring transcripts on chromosome 9q34 in six affected individuals from a family with TSC. To our knowledge, this is the first report of such a large deletion at the TSC1 locus and indicates that screening for similar mutations at the TSC1 locus is warranted in individuals with TSC.
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2,336,537 |
Comparison of amplification refractory mutation system and polymerase chain reaction-restriction fragment length polymorphism techniques used for the investigation of MEFV gene exon 10 point mutations in familial Mediterranean fever patients living in Cukurova region (Turkey).
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Familial Mediterranean fever (FMF) is an autosomal recessive inherited disease characterized by recurrent fever, serositis and arthritis. The disease is highly prevalent in Mediterranean basin populations. Recently, the gene responsible for FMF (MEFV) was cloned and at least 40 MEFV gene mutations have been identified. The most frequently observed mutations in the MEFV gene are M694V, M694I, M680I, and V726A. These occur within exon 10 of the gene, and account for 85% of the known MEFV alleles. In this study, the reliability and economical aspects of amplification refractory mutation system (ARMS) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques were compared for analyzing the frequencies of the major point mutations of 90 unrelated patients with FMF from the Cukurova region in Turkey. Both techniques yielded similar results: The ratio of independent alleles of 90 patients carrying one of the tested mutations was 81.1%; patients consisted of 12 different genotypes. In 64 of 90 patients (71.1%) mutations were observed in both alleles. Thirty-six patients (40%) were homozygous for the same mutation, 28 (31.1%) were heterozygous for different mutations. Eighteen patients (20%) were heterozygous for one allele with one of the four mutations but the other allele was unknown. In 8 patients (8.8%) no mutation could be detected. The most frequently observed mutation was M694V (51.66%), followed by M680I (17.22%), V726A (10.55%), and M694I (1.66%). In conclusion ARMS and PCR-RFLP techniques were equally reliable to detect the mutations in Turkish FMF patients. However, the ARMS technique was found to be more rapid and economical than the PCR-RFLP techniques.
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2,336,538 |
Arrayed primer extension: a robust and reliable genotyping platform for the diagnosis of single gene disorders: beta-thalassemia and thiopurine methyltransferase deficiency.
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Mutation screenings, which were conventionally carried out individually because of different assay conditions, are usually time consuming and not cost effective. Using microarray technology, simultaneous molecular diagnosis of multiple mutations on a single platform is possible. To evaluate this idea, we developed a DNA chip platform to simultaneously detect 23 mutations of the beta-globin gene and 9 mutations of thiopurine methyltransferase (TPMT) gene based on the principle of arrayed primer extension (APEX). A blinded test consisting of 200 DNA samples with known genotypes was performed to validate this strategy. High genotyping accuracy of 97.3% and 100% for beta-globin and TPMT genes, respectively, were achieved. Further analysis on the fluorescent intensity demonstrated clear separation between the real signal and the background noise, which enabled us to set two cutoff values (V(lower) = 4.0 and V(upper) = 12.0) to determine the genotype quantitatively. Our results showed that APEX is a highly reliable genotyping strategy to detect mutations that cause beta-thalassemia or TPMT enzyme deficiency.
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2,336,539 |
Constitutional and somatic RB1 mutation spectrum in nonfamilial unilateral and bilateral retinoblastoma in India.
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An epidemiologic survey has indicated a comparatively high prevalence of retinoblastoma (Rb) in Asian countries. Recently, the development of preventive strategies in nonfamilial Rb has become a major goal. The present studies were designed for identification and characterization of constitutional and somatic RB1 gene mutations by conventional cytogenetics, fluorescent in situ hybridization (FISH) and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-DNA sequencing. Of 34 patients 32 were nonfamilial and 2 were familial Rb. Maternal inheritance of del (13q14) was common. FISH was sensitive in detecting monoallelic RB1 deletion/deletion mosaicism as a first genetic hit in 20% of cases. Somatic and germline RB1 point mutations affected exons 3, 17, 20, and 21 and these were identified as novel mutations. Involvement of exon 20 as a predisposing mutation in sporadic unilateral retinoblastoma (URB) probably suggests the susceptibility of exon 20 to unknown etiologic factors in our population. A de novo RB1 deletion along with transmitted RB1 point mutation from an asymptomatic parent was identified as a unique predisposing RB1 mutation chimerism in a URB case that later evolved to bilateral retinoblastoma (BRB). The predisposing mutations such as del (13q), RB1 mono-allelic deletion and RB1 point mutation in sporadic Rb were de novo as well as transmitted mutations from asymptomatic/symptomatic parents. The RB1 mutation incidence was comparatively higher (25%) in nonfamilial Rb with emphasis on high prevalence in sporadic URB (18% versus 0%-9% in the literature series). The present studies demonstrated the efficacy of a multitechnique approach to detect various types of constitutional RB1 mutations such as RB1 deletion, deletion mosaicism, point mutation, mutation chimerism in patients of symptomatic/asymptomatic parents.
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2,336,540 |
Identification of novel cystinuria mutations and polymorphisms in SLC3A1 and SLC7A9 genes: absence of SLC7A10 gene mutations in cystinuric patients.
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Cystinuria represents 3% of nephrolithiasis in humans with an overall prevalence of 1 in 7,000 neonates. Two genes have been reported to account for the genetic basis of cystinuria, the SLC3A1 and the SLC7A9. Recently, the possible involvement of the SLC7A10 gene in the genetic basis of the disorder was also reported. In the present study, we found a total of 15 mutations in 20 Greek cystinuric patients. Eight mutations are novel, 4 in the SLC3A1: F266S, T351I, R456C, and N516D, and 4 in the SLC7A9: 479-1G>C, Y232C, D233E, and 1399+1G>T. Furthermore, 2 polymorphisms were identified in the SLC3A1 gene and 16 polymorphic variants were also found in the SLC7A9 gene of which the 235+18C>A, 604+10G>A, and 604+24T>C are novel. Finally, no mutation was found in the SLC7A10 gene in all patients. Only, the novel 634+8C>G and the previously reported 913-11C+T polymorphisms were identified in the SLC7A10 gene. In conclusion, a spectrum of SLC3A1 and SLC7A9 mutations are responsible for the genetic basis of cystinuria in Greek patients.
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2,336,541 |
Identification and characterization of variant alleles at CODIS STR loci.
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Short tandem repeat (STR) profiles from 32,671 individuals generated by the ABI Profiler Plus and Cofiler systems were screened for variant alleles not represented within manufacturer-provided allelic ladders. A total of 85 distinct variants were identified at 12 of the 13 CODIS loci, most of which involve a truncated tetranucleotide repeat unit. Twelve novel alleles, identified at D3S1358, FGA, D18S51, D5S818, D7S820 and TPOX, were confirmed by nucleotide sequence analysis and include both insertions and deletions involving the repeat units themselves as well as DNA flanking the repeat regions. Population genetic data were collected for all variants and frequencies range from 0.0003 (many single observations) to 0.0042 (D7S820 '10.3' in North American Hispanics). In total, the variant alleles identified in this study are carried by 1.6% of the estimated 1 million individuals tested annually in the U.S. for the purposes of parentage resolution. A paternity case involving a recombination event of paternal origin is presented and demonstrates how variant alleles can significantly strengthen the genetic evidence in troublesome cases. In such instances, increased costs and turnaround time associated with additional testing may be eliminated.
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2,336,542 |
The effects of skeletal preparation techniques on DNA from human and non-human bone.
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The forensic pathologist increasingly relies on the forensic anthropologist to be the consulting expert in human identification. Likewise, if identification is not possible from visual inspection of skeletal remains, the forensic biologist may be called upon to conduct DNA analysis. The possibility of downstream DNA testing needs to be considered when skeletal preparation techniques are employed to deflesh human remains, as they have the potential to strongly impact genetic analyses and subsequent identification. In this study, three cleaning techniques, boiling bone in water, in bleach, and in powdered detergent/sodium carbonate, were tested for their effect on nuclear and mtDNA recovery from a variety of human and non-human bones. A statistically significant reduction in DNA yields occurred in non-human bones cleaned with bleach, and DNA degradation was apparent electrophoretically. The human bones also showed much lower yields from bleach cleaning, while the detergent/carbonate method allowed the largest segments of DNA to be amplified, indicating it may have a less degradative effect on bone DNA than either of the other cleaning processes.
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2,336,543 |
Allometry for sexual size dimorphism: testing two hypotheses for Rensch's rule in the water strider Aquarius remigis.
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Within any given clade, male size and female size typically covary, but male size often varies more than female size. This generates a pattern of allometry for sexual size dimorphism (SSD) known as Rensch's rule. I use allometry for SSD among populations of the water strider Aquarius remigis (Hemiptera, Gerridae) to test the hypothesis that Rensch's rule evolves in response to sexual selection on male secondary sexual traits and an alternative hypothesis that it is caused by greater phenotypic plasticity of body size in males. Comparisons of three populations reared under two temperature regimes are combined with an analysis of allometry for genital and somatic components of body size among 25 field populations. Contrary to the sexual-selection hypothesis, genital length, the target of sexual selection, shows the lowest allometric slope of all the assayed traits. Instead, the results support a novel interpretation of the differential-plasticity hypothesis: that the traits most closely associated with reproductive fitness (abdomen length in females and genital length in males) are "adaptively canalized." While this hypothesis is unlikely to explain Rensch's rule among species or higher clades, it may explain widespread patterns of intraspecific variation in SSD recently documented for many insect species.
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2,336,544 |
Developing unified theories in ecology as exemplified with diversity gradients.
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A scientific field matures as its theoretical underpinnings consolidate around unified theories: conceptual structures consisting of a few general propositions that encompass a wide domain of phenomena and from which can be derived an array of models. We demonstrate this process with a synthetic theory of ecological gradients and species richness. Our unified theory rests on four propositions. First, variation in some environmental factor effects variation in the number of individuals creating a gradient. Second, in a uniform environment of fixed area, more individuals lead to more species. Third, the variance of an environmental factor increases with its mean for sites of equal area. Fourth, all nonmonotonic relationships (i.e., hump shaped or U shaped) require a trade-off in organismal performance or in population characteristics with respect to the environmental gradient. We identify 17 models that link environmental gradients with diversity, show their relationship to our framework, and describe issues surrounding their empirical testing. We illustrate how a general theory can be used to build new models such as that for the U-shaped productivity-diversity relationship. Finally, we discuss how our theory could be unified further with other theories of diversity and indicate other areas of ecology that are ripe for unification. By providing an example of the process of theory unification, we hope to encourage such efforts throughout ecology.
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2,336,545 |
Update on cancer vaccines.
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Vaccination against cancer has had a variable history, with claims of success often fading into disappointment. The reasons for this include poor vaccine design, inadequate understanding of the nature of the immune response, and a lack of objective measures to evaluate performance. The impact of genetic technology has changed everything. We now have multiple strategies to identify candidate tumor antigens, and we understand more about activation and regulation of immunity against cancer. There are novel vaccine strategies to activate specific attack on tumor cells. We also have modern assays using surrogate markers of performance to correlate with clinical effects. It is timely to select significant relevant papers to illustrate the growing potential for patients with cancer.</AbstractText>Recent findings include tumor antigen discovery and vaccine formulation, relevant knowledge concerning mechanisms of induction of effective immunity from preclinical models, and translation into clinical trials with objective evaluation of performance.</AbstractText>The ability of the immune response to dispose of cancer cells is clear. Passive transfer of antibody or immune cells is already clinically successful. We are now in a position to harness new gene-based information to design vaccines capable of inducing effective and long-lasting immunity. Safe vaccines could be used either in patients or in transplant donors. Pilot clinical trials are the means of testing performance, with continuing vaccine design modification to target specific antigens in different cancers.</AbstractText>
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2,336,546 |
Relationship between the extent of chromosomal losses and the pattern of CpG methylation in gastric carcinomas.
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The extent of unilateral chromosomal losses and the presence of microsatellite instability (MSI) have been classified into high-risk (high- and baseline-level loss) and low-risk (low-level loss and MSI) stem-line genotypes in gastric carcinomas. A unilateral genome-dosage reduction might stimulate compensation mechanism, which maintains the genomic dosage via CpG hypomethylation. A total of 120 tumor sites from 40 gastric carcinomas were examined by chromosomal loss analysis using 40 microsatellite markers on 8 chromosomes and methylation analysis in the 13 CpG (island/non-island) regions near the 10 genes using the bisulfite-modified DNAs. The high-level-loss tumor (four or more losses) showed a tendency toward unmethylation in the Maspin, CAGE, MAGE-A2 and RABGEF1 genes, and the other microsatellite-genotype (three or fewer losses and MSI) toward methylation in the p16, hMLH1, RASSF1A, and Cyclin D2 genes (p<0.05). The non-island CpGs of the p16 and hMLH1 genes were hypomethylated in the high-level-loss and hypermethylated in the non-high-level-loss sites (p<0.05). Consequently, hypomethylation changes were related to a high-level loss, whereas the hypermethylation changes were accompanied by a baseline-level loss, a low-level loss, or a MSI. This indicates that hypomethylation compensates the chromosomal losses in the process of tumor progression.
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2,336,547 |
Science and law. When should judges admit or compel genetic tests?
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During the past two decades, the use of DNA tests has revolutionized court proceedings in criminal and paternity cases. On the horizon is a new challenge for judges--whether to admit or compel genetic tests to confirm or predict genetic diseases and conditions in many more judicial contexts, e.g., decisions regarding culpability, sentencing, liability, causation, and damages. This Policy Forum reports on an empirical study of how judges would analyze these issues. The authors discuss the challenges these types of cases will bring to the court-room and suggest a series of questions that judges should consider in evaluating the need for genetic information in legal cases.
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2,336,548 |
Genetic variation in the choline acetyltransferase (CHAT) gene may be associated with the risk of Alzheimer's disease.
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Several independent linkage studies have mapped a broad susceptibility region for Alzheimer's disease (AD) on the long arm of chromosome 10. There are several biological candidate genes in this region, including choline acetyltransferase (CHAT). A number of studies have examined the role of CHAT genetic variants with AD risk and age-at-onset (AAO), but the results are equivocal. We examined the association of three Single Nucleotide Polymorphisms (SNPs) in the CHAT gene in 1001 white sporadic late-onset AD (LOAD) cases and 708 white controls. We also examined the role of these three SNP with quantitative traits of AD including AAO, disease duration, and Mini-Mental State Examination (MMSE) score. We observed both allelic and genotypic associations of the intron 9 SNP with AD risk in the total sample (p = 0.029 for genotype and p = 0.028 for allele frequency differences) as well as among non-APOE*4 carriers (p = 0.007 for genotype and p = 0.006 for allele frequency differences). Three-site haplotype analysis confirmed that haplotypes determined by the intron 9 SNP were associated with either risk (p = 0.0009) or protective (p = 0.0082) effects among non-APOE*4 carriers. The three CHAT SNPs also showed a modest association with MMSE score. Our data suggest that genetic variation in the CHAT gene may be associated with AD risk and quantitative traits related to AD.
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2,336,549 |
Minimum prevalence of spinocerebellar ataxia 17 in the north east of England.
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To determine the minimum prevalence of spinocerebellar ataxia type 17 (SCA17) in the north east of England.</AbstractText>A defined region containing 2,516,500 individuals with 192 families with undiagnosed ataxia, 90 patients with a Huntington's disease-like phenotype and 292 controls. The number of (CAG/CAA)(n) repeats in the SCA17/TBP gene was determined by fluorescent PCR and sequenced in affected individuals.</AbstractText>The mean repeat size for 584 control alleles was 34 (S.D.=3.58), ranging from 25 to 40. Two index cases had larger alleles with repeat lengths greater than the control range. Affected family members presented in adult life with ataxia followed by extrapyramidal features and cognitive impairment. In one family 44 repeats were associated with a younger age of onset than has been previously described.</AbstractText>The minimum prevalence of SCA17 in the north east of England was 0.16/100,000 (upper 95% confidence interval 0.31/100,000).</AbstractText>
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2,336,550 |
Genetics: uphold the rights of all clients to informed decision-making and voluntary action.<Pagination><StartPage>48</StartPage><EndPage>51</EndPage><MedlinePgn>48-51</MedlinePgn></Pagination><Abstract><AbstractText>This article discusses the rights of patients in relation to types of genetic tests and the broader implications for families. Use and misuse of genetic information is considered, including scenarios and points to consider. The use of a non-directive approach in genetic counselling is emphasised and multifactorial disorders, prenatal diagnosis and learning disabilities are discussed.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Haydon</LastName><ForeName>Jo</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Clinical Genetics Unit, Birmingham.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nurs Stand</MedlineTA><NlmUniqueID>9012906</NlmUniqueID><ISSNLinking>0029-6570</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D005817" MajorTopicYN="N">Genetic Counseling</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="Y">Genetic Testing</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006806" MajorTopicYN="N">Human Rights</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007258" MajorTopicYN="N">Informed Consent</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>11</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16223195</ArticleId><ArticleId IdType="doi">10.7748/ns2005.09.20.3.48.c3965</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16223057</PMID><DateCompleted><Year>2006</Year><Month>01</Month><Day>17</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0363-468X</ISSN><JournalIssue CitedMedium="Print"><Issue>15</Issue><PubDate><Year>2005</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Journal of studies on alcohol. Supplement</Title><ISOAbbreviation>J Stud Alcohol Suppl</ISOAbbreviation></Journal>COMBINE genetics study: the pharmacogenetics of alcoholism treatment response: genes and mechanisms.
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This article discusses the rights of patients in relation to types of genetic tests and the broader implications for families. Use and misuse of genetic information is considered, including scenarios and points to consider. The use of a non-directive approach in genetic counselling is emphasised and multifactorial disorders, prenatal diagnosis and learning disabilities are discussed.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Haydon</LastName><ForeName>Jo</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Clinical Genetics Unit, Birmingham.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nurs Stand</MedlineTA><NlmUniqueID>9012906</NlmUniqueID><ISSNLinking>0029-6570</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D005817" MajorTopicYN="N">Genetic Counseling</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="Y">Genetic Testing</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006806" MajorTopicYN="N">Human Rights</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007258" MajorTopicYN="N">Informed Consent</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>11</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16223195</ArticleId><ArticleId IdType="doi">10.7748/ns2005.09.20.3.48.c3965</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16223057</PMID><DateCompleted><Year>2006</Year><Month>01</Month><Day>17</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0363-468X</ISSN><JournalIssue CitedMedium="Print"><Issue>15</Issue><PubDate><Year>2005</Year><Month>Jul</Month></PubDate></JournalIssue><Title>Journal of studies on alcohol. Supplement</Title><ISOAbbreviation>J Stud Alcohol Suppl</ISOAbbreviation></Journal><ArticleTitle>COMBINE genetics study: the pharmacogenetics of alcoholism treatment response: genes and mechanisms.</ArticleTitle><Pagination><StartPage>56</StartPage><EndPage>33</EndPage><MedlinePgn>56-64; discussion 33</MedlinePgn></Pagination><Abstract><AbstractText Label="OBJECTIVE" NlmCategory="OBJECTIVE">Partial efficacy of treatment and differences in adverse events across individuals are a challenge and an opportunity in the treatment of alcoholism. Individuation of therapy and understanding origins of differential treatment response may require identification of inherited functional variants of genes. The neurobiology of reward, executive cognitive function, anxiety and dysphoria have been identified as critical domains that may have a genetic basis that could predict treatment response.<AbstractText Label="METHOD" NlmCategory="METHODS">The COMBINE Study presents a unique opportunity to evaluate specific genetic loci (markers) that affect neurobiology central to addiction and extended withdrawal. The study also addresses variation in drug metabolism and action. Candidate genetic markers are selected for study based on functionality and abundance.<AbstractText Label="RESULTS" NlmCategory="RESULTS">COMT Vall58Met is a common (minor allele frequency 0.42), functional, catecholamine-metabolizing enzyme polymorphism with threefold relevance. Vall58Met alters executive cognitive function, stress and anxiety responses and brain endogenous opioid function. OPRM1 Asn40Asp is a common (minor allele frequency 0.10), functional polymorphism of the mu-opioid receptor, which may serve as a gatekeeper molecule in naltrexone's actions and was recently reported to affect naltrexone response. HTTLPR (minor allele frequency 0.40) alters serotonin transporter function to affect anxiety, dysphoria and obsessional behavior, which are assessed in COMBINE and may be related to relapse and addictive behavior.<AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">All genetic testing is consented through a separate human research protocol, and the testing is conducted nonclinically, confidentially and apart from the clinical record to protect human research participants who have volunteered for this aspect of COMBINE.
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2,336,551 |
The impact of receiving genetic test results on general and cancer-specific psychologic distress among members of an African-American kindred with a BRCA1 mutation.
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Numerous studies have examined short-term and long-term psychologic responses to genetic testing for breast/ovarian carcinoma susceptibility in clinic samples and among families who participated in genetic linkage studies. However, to the authors' knowledge, the vast majority of studies focused on non-Latino whites and women. In this prospective study, the authors investigated the psychologic impact of receiving carrier-specific BRCA1 test results as part of a genetic education/counseling intervention in female and male members of an African-American kindred with a BRCA1 mutation.</AbstractText>Eighty-five of 101 participating kindred members (84%) underwent genetic counseling/education and testing according to an established protocol. Participants completed in-person or telephone-administered, computer-assisted interviews. At baseline and after the receipt of test results (1 mo, 4 mos, and 12 mos), general psychologic distress (i.e., anxiety and depression) and cancer-specific distress were measured. Statistical analyses were performed using linear mixed-model approaches for longitudinal data.</AbstractText>The hypothesis that mutation carriers, particularly women who had no personal history of breast carcinoma, were expected to report greater distress than noncarriers was not supported. After controlling for socioeconomic status and personal history of breast/ovarian carcinoma, noncarriers reported significant declines in the distress measures (depressive symptoms, anxiety and cancer-related worries), whereas distress was not altered markedly in carriers after genetic risk notification.</AbstractText>The current findings suggested that individuals receiving BRCA1 test results who learn that they are not carriers of a deleterious mutation may experience psychologic benefits. Furthermore, those who learned that they were mutation carriers did not appear to have adverse, clinically meaningful psychologic outcomes.</AbstractText>
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2,336,552 |
Sensorineural hearing loss in children and adults with Williams syndrome.
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Williams syndrome (WS) is a genetic neurodevelopmental disorder, most often accompanied by mild-to-moderate mental retardation. Individuals with WS show unique communication strengths and impairments that are challenging to treat in community, educational, and vocational settings. Many issues regarding characteristics of auditory sensitivity in WS remain to be resolved. Our purpose was to obtain behavioral (screening and pure-tone audiometry) and objective (distortion product otoacoustic emission-DPOAE) measures of auditory system function from a group of 27 individuals with WS, 6-48 years of age. These measures were gathered both at an international professional conference (n = 19) and in a clinic setting (n = 8). In the behavioral screening conditions, 16/19 (84%) of the individuals failed the hearing screening; and in the behavioral diagnostic hearing condition, 6/8 (75%) demonstrated sensorineural hearing loss (SNHL) and 1/8 demonstrated a hearing loss of undetermined type. In the objective DPOAE testing, 19/25 (76%) had DPOAE absolute amplitudes below the 5th percentile for ears with normal hearing [Gorga et al. (1997); Ear Hear 18(6):440-455]. We report SNHL in 14/18 (78%) of school-age children with WS. Post hoc analyses revealed a significant effect for age, suggesting a pattern of progressive hearing loss. An effect size analysis indicated a clinically meaningful difference in the hearing sensitivity between school-aged children and adults in the high frequencies (4,000 and 8,000 Hz). Similar hearing loss phenotype was observed in patients with familial nonsyndromic supravalvular aortic stenosis (SVAS), suggesting that molecular defects in the elastin gene in the pathogenesis of SNHL in WS. This study highlights the importance of early and regular hearing testing for WS patients and suggests that elastin may have a previously unappreciated function in maintaining hearing sensitivity.
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2,336,553 |
Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf.
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Genetic and auditory studies of 731 children with severe-to-profound hearing loss in US schools for the deaf and 46 additional children receiving clinical services for hearing loss ranging from moderate to profound demonstrated that mutations in the connexin 26 (GJB2) and connexin 30 (GJB6) genes explain at least 12% of those with nonsyndromic sensorineural deafness. Otoacoustic emissions (OAEs) testing to detect functional outer hair cells indicated that 76 of the children had emissions and therefore may have (as yet unconfirmed) auditory neuropathy/dys-synchrony (AN/AD). Five of these children with OAEs were GJB2 homozygotes or compound heterozygotes with the genotypes 35delG/35delG, W77X/W77X, 35delG/360delGAG, 35delG/V95M, and V84M/M34T. In particular, unilateral AN/AD was confirmed in a child with moderate hearing loss and the 35delG/V95M genotype. Detecting OAEs in individuals with GJB2 mutations suggests that lack of functional gap junctions as a result of GJB2 mutations does not necessarily destroy all outer hair cell function.
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2,336,554 |
Mapping quantitative trait loci affecting variation in Drosophila triacylglycerol storage.
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Recent genetic studies indicate that Drosophila melanogaster could be a powerful model to identify genes involved in mammalian adipocyte differentiation and fat storage. The objective of our study was to identify quantitative trait loci (QTLs) that contribute to variation in triacylglycerol (TAG) storage in two D. melanogaster laboratory strains.</AbstractText>We used two genetic mapping procedures to identify loci with main and epistatic effects on TAG storage. First, using 68 recombinant inbred lines derived from the unrelated Oregon R and Russian 2b strains, we mapped the location of QTLs affecting TAG storage using both composite interval mapping and Bayesian epistatic methods. Second, we used the quantitative deficiency mapping procedure to identify candidate genes affecting this trait within one of the QTLs identified on the second chromosome. For both mapping experiments, flies were cultured in standard conditions. TAG content of 4- to 5-day-old flies, adjusted for live body mass and total proteins, was used as the phenotypic measure.</AbstractText>Multiple QTLs associated with variation in TAG storage were identified by the genome-wide recombination mapping method, and some of them were sex-specific. The QTLs had main effects, but a male-specific epistatic interaction between two QTLs was also found. Finally, two closely linked QTLs were detected by deficiency mapping at 57E1-57E3 and 57E4-57F1 on chromosome 2, the first of which causes female-specific variation in TAG between the Oregon R and 2b strains.</AbstractText>Our results suggest that variation in TAG storage in D. melanogaster is controlled by different genetic mechanisms and different sets of QTLs in male and female flies.</AbstractText>
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2,336,555 |
Shotgun haplotyping: a novel method for surveying allelic sequence variation.
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Haplotypic sequences contain significantly more information than genotypes of genetic markers and are critical for studying disease association and genome evolution. Current methods for obtaining haplotypic sequences require the physical separation of alleles before sequencing, are time consuming and are not scaleable for large surveys of genetic variation. We have developed a novel method for acquiring haplotypic sequences from long PCR products using simple, high-throughput techniques. This method applies modified shotgun sequencing protocols to sequence both alleles concurrently, with read-pair information allowing the two alleles to be separated during sequence assembly. Although the haplotypic sequences can be assembled manually from the resultant data using pre-existing sequence assembly software, we have devised a novel heuristic algorithm to automate assembly and remove human error. We validated the approach on two long PCR products amplified from the human genome and confirmed the accuracy of our sequences against full-length clones of the same alleles. This method presents a simple high-throughput means to obtain full haplotypic sequences potentially up to 20 kb in length and is suitable for surveying genetic variation even in poorly-characterized genomes as it requires no prior information on sequence variation.
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2,336,556 |
Application of phylogenetic networks in evolutionary studies.
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The evolutionary history of a set of taxa is usually represented by a phylogenetic tree, and this model has greatly facilitated the discussion and testing of hypotheses. However, it is well known that more complex evolutionary scenarios are poorly described by such models. Further, even when evolution proceeds in a tree-like manner, analysis of the data may not be best served by using methods that enforce a tree structure but rather by a richer visualization of the data to evaluate its properties, at least as an essential first step. Thus, phylogenetic networks should be employed when reticulate events such as hybridization, horizontal gene transfer, recombination, or gene duplication and loss are believed to be involved, and, even in the absence of such events, phylogenetic networks have a useful role to play. This article reviews the terminology used for phylogenetic networks and covers both split networks and reticulate networks, how they are defined, and how they can be interpreted. Additionally, the article outlines the beginnings of a comprehensive statistical framework for applying split network methods. We show how split networks can represent confidence sets of trees and introduce a conservative statistical test for whether the conflicting signal in a network is treelike. Finally, this article describes a new program, SplitsTree4, an interactive and comprehensive tool for inferring different types of phylogenetic networks from sequences, distances, and trees.
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2,336,557 |
How to establish a high-risk cancer genetics clinic: limitations and successes.<Pagination><StartPage>469</StartPage><EndPage>474</EndPage><MedlinePgn>469-74</MedlinePgn></Pagination><Abstract><AbstractText>The development of technology to locate and isolate cancer susceptibility genes has brought together the fields of oncology, cancer control, genetics, and genetic counseling to create a new specialty of cancer risk counseling with the goal to communicate more accurate information about personal cancer risk profiles based on personal and family histories. As cancer risk assessment and counseling services become standard of care in medical practice, their availability is increasingly moving from comprehensive cancer centers and academic institutions to community settings. High-risk cancer genetics clinics in the community face several challenges, including staffing, time commitment, costs, and unique quality control issues. The societal benefits include a more educated public armed with the information needed to make health decisions appropriate for the individual level of risk.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Daly</LastName><ForeName>Mary B</ForeName><Initials>MB</Initials><AffiliationInfo><Affiliation>Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stearman</LastName><ForeName>Beth</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Masny</LastName><ForeName>Agnes</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Sein</LastName><ForeName>Elaine</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Mazzoni</LastName><ForeName>Susan</ForeName><Initials>S</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Curr Oncol Rep</MedlineTA><NlmUniqueID>100888967</NlmUniqueID><ISSNLinking>1523-3790</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005817" MajorTopicYN="N">Genetic Counseling</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020022" MajorTopicYN="N">Genetic Predisposition to Disease</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="Y">Genetic Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009369" MajorTopicYN="N">Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010375" MajorTopicYN="N">Pedigree</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>32</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>12</Month><Day>16</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16221384</ArticleId><ArticleId IdType="doi">10.1007/s11912-005-0012-2</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>J Med Genet. 2005 Oct;42(10):749-55</Citation><ArticleIdList><ArticleId IdType="pubmed">15784723</ArticleId></ArticleIdList></Reference><Reference><Citation>Ann Intern Med. 2003 Apr 1;138(7):571-5</Citation><ArticleIdList><ArticleId 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IdType="pubmed">15612172</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Med Genet A. 2003 Jul 1;120A(1):63-71</Citation><ArticleIdList><ArticleId IdType="pubmed">12794694</ArticleId></ArticleIdList></Reference><Reference><Citation>Health Technol Assess. 2005 Feb;9(3):iii-iv, 1-126</Citation><ArticleIdList><ArticleId IdType="pubmed">15694064</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Hum Genet. 1995 Mar;56(3):760-8</Citation><ArticleIdList><ArticleId IdType="pubmed">7887432</ArticleId></ArticleIdList></Reference><Reference><Citation>Am J Med Genet A. 2003 Apr 15;118A(2):146-55</Citation><ArticleIdList><ArticleId IdType="pubmed">12655495</ArticleId></ArticleIdList></Reference><Reference><Citation>Patient Educ Couns. 2003 Nov;51(3):217-27</Citation><ArticleIdList><ArticleId IdType="pubmed">14630378</ArticleId></ArticleIdList></Reference><Reference><Citation>AWHONN Lifelines. 2004 Oct-Nov;8(5):434-40</Citation><ArticleIdList><ArticleId IdType="pubmed">15560622</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16220891</PMID><DateCompleted><Year>2005</Year><Month>12</Month><Day>15</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0038-0814</ISSN><JournalIssue CitedMedium="Print"><Issue>698</Issue><PubDate><Year>2005</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Soins; la revue de reference infirmiere</Title><ISOAbbreviation>Soins</ISOAbbreviation></Journal>[Genetic counseling].
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The development of technology to locate and isolate cancer susceptibility genes has brought together the fields of oncology, cancer control, genetics, and genetic counseling to create a new specialty of cancer risk counseling with the goal to communicate more accurate information about personal cancer risk profiles based on personal and family histories. As cancer risk assessment and counseling services become standard of care in medical practice, their availability is increasingly moving from comprehensive cancer centers and academic institutions to community settings. High-risk cancer genetics clinics in the community face several challenges, including staffing, time commitment, costs, and unique quality control issues. The societal benefits include a more educated public armed with the information needed to make health decisions appropriate for the individual level of risk.
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2,336,558 |
Students investigating the antiproliferative effects of synthesized drugs on mouse mammary tumor cells.
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The potential for personalized cancer management has long intrigued experienced researchers as well as the naïve student intern. Personalized cancer treatments based on a tumor's genetic profile are now feasible and can reveal both the cells' susceptibility and resistance to chemotherapeutic agents. In a weeklong laboratory investigation that mirrors current cancer research, undergraduate and advanced high school students determine the efficacy of common pharmacological agents through in vitro testing. Using mouse mammary tumor cell cultures treated with "unknown" drugs historically recommended for breast cancer treatment, students are introduced to common molecular biology techniques from in vitro cell culture to fluorescence microscopy. Student understanding is assessed through laboratory reports and the successful identification of the unknown drug. The sequence of doing the experiment, applying logic, and constructing a hypothesis gives the students time to discover the rationale behind the cellular drug resistance assay. The breast cancer experiment has been field tested during the past 5 yr with more than 200 precollege/undergraduate interns through the Gains in the Education of Mathematics and Science program hosted by the Walter Reed Army Institute of Research.
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2,336,559 |
Predictive power of maternal serum and amniotic fluid CRP and PAPP-A concentrations at the time of genetic amniocentesis for the preterm delivery.
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To investigate whether maternal serum and amniotic fluid CRP and PAPP-A concentrations at the time of genetic amniocentesis are markers of preterm delivery.</AbstractText>One hundred and forty-one pregnant women were included in this prospective study. Amniotic fluid and maternal serum CRP and PAPP-A concentrations were determined by using commercially available kits. Receiver-operating characteristic (ROC) analysis was performed to determine the efficacy of maternal serum and amniotic fluid CRP and PAPP-A levels in predicting women with preterm delivery.</AbstractText>The prevalence of spontaneous preterm delivery before 37 weeks of gestation was 9.9%. ROC analysis revealed that amniotic fluid CRP level was the only parameter, which had a significant power in the prediction of preterm delivery. The optimum cut-off level was 0.65 mg/L. The sensitivity and specificity were 92.9% and 78.7%, respectively.</AbstractText>The amniotic fluid CRP level has a high sensitivity and specificity in the prediction of preterm delivery and this may be helpful in predicting preterm delivery during genetic amniocentesis.</AbstractText>
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2,336,560 |
Methods for the isolation and identification of Listeria spp. and Listeria monocytogenes: a review.
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Listeria monocytogenes is an important food-borne pathogen and is widely tested for in food, environmental and clinical samples. Identification traditionally involved culture methods based on selective enrichment and plating followed by the characterization of Listeria spp. based on colony morphology, sugar fermentation and haemolytic properties. These methods are the gold standard; but they are lengthy and may not be suitable for testing of foods with short shelf lives. As a result more rapid tests were developed based on antibodies (ELISA) or molecular techniques (PCR or DNA hybridization). While these tests possess equal sensitivity, they are rapid and allow testing to be completed within 48 h. More recently, molecular methods were developed that target RNA rather than DNA, such as RT-PCR, real time PCR or nucleic acid based sequence amplification (NASBA). These tests not only provide a measure of cell viability but they can also be used for quantitative analysis. In addition, a variety of tests are available for sub-species characterization, which are particularly useful in epidemiological investigations. Early typing methods differentiated isolates based on phenotypic markers, such as multilocus enzyme electrophoresis, phage typing and serotyping. These phenotypic typing methods are being replaced by molecular tests, which reflect genetic relationships between isolates and are more accurate. These new methods are currently mainly used in research but their considerable potential for routine testing in the future cannot be overlooked.
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2,336,561 |
Breast cancer and ovarian cancer genetics.
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Breast and ovarian cancers are the second and fifth leading causes of cancer death, respectively, among women in the United States. Individuals with breast cancer have a 20--30% chance of having at least one relative with the disease. However, only 5--10% of the cases are a direct result of germline mutations in highly penetrable genes, such as BRCA1 and BRCA2 (BRCA1/2) as well as genes TP53 and PTEN. Since 1996, genetic testing for these mutations has been clinically available. A strategy for the management of women at increased familial risk of breast and ovarian cancers is described, which includes genetic assessment, chemoprevention, radiologic screening, and clinical and self-examination. Genetic testing should occur within a cancer genetic clinic after genetic counseling. A blood sample allows determination of the presence of the BRCA1 and BRCA2 genes, the TP53 gene, the PTEN gene, and the ATM gene. Tumor examination has identified a growth factor receptor gene, human epidermal growth factor receptor (HER-2). With regard to diet and lifestyle, women at increased risk of breast cancer could be advised to reduce dietary fat, avoid obesity, decrease alcohol consumption, and take regular exercise. Although chemoprotection is a valuable consideration, it is important to emphasize that the use of Tamoxifen in BRCA1 and BRCA2 mutation carriers is not established, nor is the optimum duration of benefit. An overview of the main outcomes of the current published studies confirms a 38% decrease in breast cancer incidence with Tamoxifen but recommends its use be restricted to women at high risk of breast cancer and low risk for potential side effects. The role of bilateral risk-reducing mastectomy or prophylactic mastectomy has been controversial for several reasons, including the psychosocial significance of the breast in Western cultures, the wide acceptance of breast conservation in surgery for early breast cancer, and the previous lack of data on its efficacy. The surgical procedure should aim to remove substantially all at-risk breast tissue. However, there is a balance between reduction of cancer risk and cosmetic outcome. Bilateral prophylactic oophorectomy can significantly decrease ovarian cancer risk in women who carry BCRA1 mutations. Oophorectomy lowers the risk of breast cancer, even in women who have previously used hormone replacement therapy. There are no published randomized controlled trials examining the effectiveness of mammographic screening in women under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer. under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer.
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2,336,562 |
Efficient in vivo xenogeneic retroviral vector-mediated gene transduction into human hepatocytes.
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We developed a method for efficient retroviral vector-mediated gene transfer into human hepatocytes, using a human hepatocyte-bearing mouse model. Normal human hepatocytes were transplanted into the livers of immunodeficient and liver-damaged mice. Donor hepatocytes multiplied and replaced the host hepatocytes, which yielded human hepatocyte-bearing mice (human hepatocyte-chimeric mice). As control cells, rat hepatocytes were similarly transplanted. The replacement level reached 86% at 8 weeks and 100% at 5 weeks posttransplantation of human and rat hepatocytes, respectively. Human and rat hepatocytes in the host liver showed a high bromodeoxyuridine-labeling index during the first 2 weeks posttransplantation. Human- and rat-chimeric mice were injected 7 and 10 days posttransplantation, respectively, with retroviral vectors carrying the beta-galactosidase gene and were thereafter injected daily for 20 and 10 days, respectively. The level of beta-galactosidase-positive hepatocytes in the human- and rat-chimeric mice reached 7.1 +/- 1.8% at 8 weeks and 5.3 +/- 0.9% at 5 weeks after transplantation, respectively. The human hepatocyte-chimeric mouse will be useful for testing the ability of vectors to transduce human cells.
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2,336,563 |
Manifestations of cystic fibrosis diagnosed in adulthood.
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This review highlights the phenotypic features that lead to the diagnosis of cystic fibrosis in adults, and the prognosis of these patients.</AbstractText>With the widespread availability of genetic testing and a greater appreciation of the clinical spectrum of the disease, the diagnosis of cystic fibrosis is being made with increasing frequency in adults. Clinical features that lead to the diagnosis include respiratory symptoms and chronic airway infection with typical cystic fibrosis pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, as well as nontuberculous mycobacteria. Often these patients have previously received diagnoses of asthma, chronic bronchitis, or emphysema. Pancreatic insufficiency is much less common in the adult receiving the diagnosis, but pancreatitis occurs with greater frequency. Occasionally, individuals receive diagnoses of apparent single-organ manifestations such as idiopathic pancreatitis or congenital bilateral absence of the vas deferens, but with negligible involvement of the respiratory tract. On rare occasions, patients receiving the diagnosis as adults can present with classic features of the disease. Although lung disease is generally less severe in cystic fibrosis patients receiving the diagnosis as adults than in adult patients who received the diagnosis as infants, the extent of bronchiectasis can nonetheless be severe. The clinical course of patients receiving a diagnosis of cystic fibrosis in adulthood is largely unknown, but frequently they have milder disease and a more favorable prognosis.</AbstractText>Clinicians must be aware of the potential for adults with chronic respiratory tract infections, unexplained bronchiectasis, congenital bilateral absence of the vas deferens, or pancreatitis to have cystic fibrosis despite the age at presentation.</AbstractText>
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2,336,564 |
A new congenital form of X-linked autophagic vacuolar myopathy.
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In a new family with X-linked congenital autophagic vacuolar myopathy (AVM), seven affected boys presented with congenital hypotonia, dyspnea, and dysphagia with delayed motor milestones. Muscle pathology revealed autophagic vacuoles with sarcolemmal features, multilayered basal lamina with marked sarcolemmal deposition of C5-9 membrane attack complex and calcium, histologically indistinguishable from childhood-onset X-linked myopathy with excessive autophagy (XMEA). Haplotype analysis suggests that this new AVM and XMEA may be allelic despite different clinical presentations.
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2,336,565 |
Analysis of mutation of the plasma cholinesterase gene in a man who had died following a traffic accident.
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We analyzed mutation of the butyrylcholinesterase (BCHE) gene in a 69-year-old man on whom a forensic autopsy had been performed after he had died following a traffic accident. Extremely low plasma cholinesterase activity had been pointed out by the emergency doctor at the hospital prior to his death and based on this, organophosphorus poisoning had been suspected. However, no pesticides, which could have reduced the plasma cholinesterase activity, were detected by toxicological analysis using GC/MS. Subsequently, one base insertion was found in exon 2. The frame shift mutation had occurred because a homozygous extra T had been inserted between nucleotides 1343 and 1344, resulting in the appearance of a stop codon in codon 454 (AGA454TAA, Arg454stop). This heterozygous frame shift mutation at this point was identified in the man's son. It is likely that there may be many such latent patients with abnormal plasma cholinesterase activity, and accordingly we should always bear this fact in mind and should carry out molecular genetic testing for an accurate diagnosis of this deficiency.
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2,336,566 |
Identification of gene markers based on well validated and subcategorized stressed animals for potential clinical applications in PTSD.
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Post-traumatic stress disorder (PTSD) is a complex mental disorder that can develop in response to traumatic experiences. The molecular mechanisms underlying the pathology of PTSD are poorly understood, and this lack of knowledge hampers our ability to find superior therapeutic approaches to the treatment of this disorder. There are two main reasons for our lack of study in this area: here is no sufficiently validated animal model and lack of large-scale studies for the search of underlying molecular mechanisms. Thus, to promote research on PTSD (especially its molecular mechanisms) and to set molecular basis for searching novel medications of this disorder, large-scale, genome-wide interrogation of a significant amount of genes based upon a well validated animal model is demanded. We hypothesize that a significant number of genes are involved in PTSD. It is only with a large number of these genes identified in specific samples of PTSD-related population, and then it is possible for a sufficient understanding of the pathology at the molecular level of a PTSD, as well as for enhancing the PTSD's therapeutic and preventative strategies. Two prerequisites are needed for testing this hypothesis: (1) relative pure samples from a well validated animal model; and (2) genome-wide screening of PTSD molecular targets. For the animal model, we suggest to use the predator-exposure paradigm, in which rats are exposed to a predator, this model has previously been evaluated behaviorally well emulated the clinical symptoms of PTSD. For a better stringency, three criteria can be used to further validate this animal model: analogous (similarity of behavior), predictive (predictability of drug response) and biological mechanism (e.g., electrophysiological and pathological change in amygdala). For large-scale molecular target screening, the new microarray technology, which can profile expression of tens of thousands genes simultaneously, is the method of choice. The validity and practicability of this hypothesis and the strategy for its testing have been supported by our preliminary laboratory data.
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2,336,567 |
In-depth analysis of spatial cognition in Williams syndrome: A critical assessment of the role of the LIMK1 gene.
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The LIM kinase1 protein (LIMK1) is thought to be involved in neuronal development and brain function. However, its role in spatial cognition in individuals with Williams syndrome (WS) is currently ambiguous, with conflicting reports on the cognitive phenotypes of individuals who do not have classic WS but harbour partial deletions including LIMK1. Two families with partial WS deletions have been described with deficits in visuospatial cognition (Frangiskakis, J. M., Ewart, A. K., Morris, C. A., Mervis, C. B., Bertrand, & J., Robinson, et al. (1996). LIM-kinase 1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell, 86, 59-69), in contrast to others with similar partial deletions who did not display spatial impairments (Tassabehji, M., Metcalfe, K., Karmiloff-Smith, A., Carette, M. J., Grant, J., & Dennis, N., et al. (1999). Williams syndrome: Use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. American Journal of Human Genetics, 64, 118-125). To determine the role of LIMK1 in the highly penetrant visuospatial deficits associated with classic WS, it is essential to investigate the discrepancies between the two studies. Previous research used a standardised task to measure spatial cognition, which may not pick up subtle impairments. We therefore undertook more extensive testing of the spatial cognition of two adults with partial genetic deletions in the WS critical region (LIMK1 and ELN only), who had not displayed spatial impairments in the previous study, and compared them to two high-functioning adults with WS matched on verbal ability. All participants completed a broad battery of 16 perceptual and constructive spatial tests, and the clear-cut spatial difficulties observed in the WS group were not found in the partial deletion group. These findings rule out the claim that the deletion of one copy of LIMK1 is alone sufficient to result in spatial impairment, but leave open the possibility that LIMK1 contributes to the WS cognitive deficits if deleted in combination with other genes within the WS deletion. We conclude that a deeper assessment of WS at the genetic level is required before the contribution of specific genes to phenotypic outcomes can be fully understood.
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2,336,568 |
Host microsatellite alleles in malaria predisposition?
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Malaria is a serious, sometimes fatal, disease caused by Plasmodium infection of human red blood cells. The host-parasite co-evolutionary processes are well understood by the association of coding variations such as G6PD, Duffy blood group receptor, HLA, and beta-globin gene variants with malaria resistance. The profound genetic diversity in host is attributed to polymorphic microsatellites loci. The microsatellite alleles in bacterial species are known to have aided their survival in fatal environmental conditions. The fascinating question is whether microsatellites are genomic cushion in the human genome to combat disease stress and has cause-effect relationships with infections.</AbstractText>It is hypothesized that repeat units or alleles of microsatellites TH01 and D5S818, located in close proximity to beta-globin gene and immune regulatory region in human play a role in malaria predisposition. Association of alleles at aforesaid microsatellites with malaria infection was analysed. To overrule the false association in unrecognized population stratification, structure analysis and AMOVA were performed among the sampled groups.</AbstractText>Associations of microsatellite alleles with malaria infection were verified using recombination rate, Chi-square, and powerful likelihood tests. Further investigation of population genetic structure, and AMOVA was done to rule out the confounding effects of population stratification in interpretation of association studies.</AbstractText>Lower recombination rate (theta) between microsatellites and genes implicated in host fitness; positive association between alleles-13 (D5S818), 9 (TH01) and strong susceptibility to Plasmodium falciparum; and alleles-12 (D5S818) and 6 (TH01) rendering resistance to human host were evident. The interesting fact emerging from the study was that while predisposition to malaria was a prehistoric attribute, among TH01 alleles; evolution of resistant allele-6 was a recent phenomenon, which could conceivably be driven by infection related selective forces. The host's microsatellite allelic associations with malaria infection were valid in the light of low genetic variance between sampled groups and no population stratification.</AbstractText>
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2,336,569 |
[Genetic polymorphism of Y-chromosome short tandem repeat in Elunchun ethnic group of China].
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To reveal the allelic frequencies and haplotype frequencies of ten Y-chromosome short tandem repeats(STR) loci (DYS392, DYS438, DYS439, DYS456, DYS459, DYS460,DYS461, DYS462, DYS389I and DYS389II systems) in an Elunchun population sample.</AbstractText>PCR and polyacrylamidegel electrophoresis(PAGE) followed by silver staining were performed to analyze the blood samples from 102 unrelated Elunchun male individuals.</AbstractText>The allele diversity values for each locus ranged from 0.418(DYS461) to 0.727(DYS389 I). Gene diversities were higher than 0.5 except DYS462(0.479) and DYS461 (GATAA7.2)(0.418). Furthermore, 101 haplotypes from 10 Y-chromosome STRs loci were found in the sample and a high haplotype diversity 0.99 was determined.</AbstractText>The above findings suggest that the ten Y-chromosome STR loci are valuable Y-specific markers for establishing Y-STR database, understanding human origin, paternity testing and personal identification.</AbstractText>
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2,336,570 |
Single nucleotide polymorphisms detection based on DNA microarray technology: HLA as a model.
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The significance of DNA variations among individuals, including single nucleotide polymorphisms (SNPs) and/or genome nucleotide mutations as well as to their detection by using new technology, will improve and facilitate the knowledge of each gene sequence. Microarray may provide information about thousands of gene simultaneously, leading to a more rapid and accurate genotyping. In this view, we developed a new methodology as an example for the detection of SNPs based on DNA microarray, using a panel of HLA alleles representative of loci A, B, DRB1. A panel of 180 oligonucleotide probes was selected to identify polymorphic positions located in exons 2 and 3 of HLA-A and B, and in exon 2 of HLA-DRB1 locus. Each oligonucleotide sequence was designed with a nucleotide mismatch located in the same position as the center of the hybridization sequence. Hybridization experiments were carried out with genomic probes constructed with an asymmetric PCR strategy. The amplified DNAs were obtained from bone marrow cells of donors previously typed for transplant. The results obtained were showing that the method was reliable thus providing a feasible technique both for HLA typing and for the investigation of other regions of genetic and clinical interest including polymorphisms correlated with different autoimmune diseases.
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2,336,571 |
Forensic potential of the STR DXYS156 in Mexican populations: inference of X-linked allele null.
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The pentanucleotide STR (TAAAA)n DXYS156 offers advantages for genetic identity testing. In addition to establish the gender, DXYS156 expands the DNA profile and is able to indicate the possible geographic origin of the individual. We analyzed DXYS156 in 757 individuals of both sexes from Mexican populations. We studied the cosmopolitan Mestizo population and six Mexican ethnic groups: Tarahumaras, Purépechas, Nahuas, Mayas, Huicholes and Mezcala Indians. The six shorter (4-10) and the three larger alleles (11-13) were specific for the X and Y-chromosomes, respectively. A random distribution of alleles into genotypes was observed in males and females from each population. We estimated the power of exclusion for paternity testing according to the son's gender, and the power of discrimination in forensic casework. In addition, we detected a relatively high frequency of an X-linked allele null, principally in Mexican-Mestizos (3.6%), which must be considered when DXYS156 be applied for identification purposes.
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2,336,572 |
Asthma and COPD in cystic fibrosis intron-8 5T carriers. A population-based study.
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Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD).</AbstractText>We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV1 decline and risk of asthma or COPD.</AbstractText>5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV1 decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV1 decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV1 of 19 ml compared with 21 ml in 7T homozygous controls (t-test: P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (chi2: P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank: P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI: 1.5-78) and 6.3 (0.84-47) in 7T homozygotes with vs. without an F508del allele.</AbstractText>Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele.</AbstractText>
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2,336,573 |
Nine mutations including three novel mutations among Russian patients with acute intermittent porphyria.
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Acute intermittent porphyria (AIP) is a metabolic disease due to a partial deficiency of hydroxymethylbilane synthase (HMBS) in heme biosynthesis. Direct sequencing of genomic DNA samples of 11 unrelated Russian AIP patients, 32 of their relatives and 50 healthy controls from northwestern Russia including Saint Petersburg revealed nine mutations in the HMBS gene. Three novel mutations, c.825+5G>C, c.825+3_825+6del, and c.770T>C, resulted in varying amounts of abnormal transcripts, r.822_825del and [r.770U>C, r.652_771del, r.613_771del]. Six mutations, c.77G>A (p.R26H), c.517C>T (p.R173W), c.583C>T (p.R195C), c.673C>T (p.R225X), c.739T>C (p.C247R), and c.748G>C (p.E250A), have previously been identified in AIP patients from Western and other Eastern European populations. All mutations expressed in COS-1 cells demonstrated low residual activities (0.1-1%). The majority of the mutations were family-specific and also confirmed allelic heterogeneity among Russian AIP patients. The diversity of mutations may reflect the old international history of Saint Petersburg and immigration of people from other parts of Europe.
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2,336,574 |
Transition of the pregnancy rate of bisected bovine embryos after co-transfer with trophoblastic vesicles prepared from in vivo-cultured in vitro-fertilized embryos.
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Bisected bovine embryos were co-transferred with trophoblastic vesicles (TVs). These TVs were prepared by dissection of conceptuses that were collected by uterine flushing after culture for seven days in the uterus following transfer of embryos derived by in vitro fertilization (IVF). Pregnancy diagnoses were performed twice, between Day 26 and Day 43 and between Day 38 and Day 73 post-estrus by ultrasonography. The pregnancy rate was significantly increased at first pregnancy diagnosis when demi-embryos were transferred with TVs (66.7%, 16/24) compared with the control group (34.5%, 10/29) (P < 0.05). Three losses occurred in the co-transfer group between the first and second pregnancy diagnosis. The final pregnancy rates according to delivered offspring were 41.7% (10/24) and 27.6% (8/29), respectively. There were no statistically significant differences between the pregnant and non-pregnant groups with regard to the average diameter of the TVs measured before transfer at three points during the gestation period. The birth weight and gestation lengths of the offspring were almost the same for the co-transfer and control groups. In the co-transfer group, the genetic identities of calves from the separated embryos were not affected by the TVs, as confirmed by parental blood type testing. Delivered offspring in co-transferred groups showed normal morphology. In conclusion, the present study indicates that co-transfer of TVs prepared from conceptuses cultured in vivo following transfer of IVF embryos enhances the fertility of demi-embryos during the early stages of pregnancy, as has similarly been shown in previous research for those prepared from in vivo embryos.
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2,336,575 |
Genetic testing and its implications: human genetics researchers grapple with ethical issues.
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To better understand ethical issues involved in the field of human genetics and promote debate within the scientific community, the author surveyed scientists who engage in human genetics research about the pros, cons, and ethical implications of genetic testing. This study contributes systematic data on attitudes of scientific experts. The survey finds respondents are highly supportive of voluntary testing and the right to know one's genetic heritage. The majority consider in utero testing and consequent pregnancy termination acceptable for cases involving likelihood of serious disease but disapprove for genetic reasons they consider arbitrary, leaving a gray area of distinguishing between treatment of disorders and enhancement still to be resolved. While safeguarding patient confidentiality versus protecting at-risk third parties (kin, reproductive partners) presents a dilemma, preserving privacy from misuse by institutional third parties (employers, insurers) garners strong consensus for legislation against discrimination. Finally, a call is made for greater genetic literacy.
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2,336,576 |
An overview of the role of genotyping in the diagnosis of the primary hyperoxalurias.
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The aim of this paper is to give an overview of our current state of knowledge with respect to genotyping for the primary hyperoxalurias and the role of molecular genetics alongside the more traditional biochemical and enzymatic tests for the diagnosis and prognosis of these disorders. The published literature was reviewed to establish the frequency of different mutations and thus the value of testing for a limited number of these mutations in patients with clinical suspicion of primary hyperoxaluria (PH). This approach was compared with whole gene sequencing of the AGXT and GRHPR genes. A limited genetic screen can provide a first line test for PH1 and PH2 in symptomatic patients and can provide a full diagnosis in approximately a third of cases. Molecular genetic analysis is essential for carrier testing and prenatal diagnosis. The value of molecular genetics in prognosis requires a wider evidence base.
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2,336,577 |
Genetic algorithm for analysis of mutations in Parkinson's disease.
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Mitochondrial genetics has unique features that impede analysis of the biological significance of mitochondrial mutations. Simple searches for differences in total mutational load between normal and pathological samples have been frequently unrewarding, raising the possibility that more complex patterns of mutations may be responsible for some conditions. We explore this possibility in the context of Parkinson's disease (PD).</AbstractText>We report the development of a modified genetic algorithm suited for detection of biologically meaningful patterns of mitochondrial mutations. The algorithm is applied to a database of mutations derived from biological samples, and verified by the use of shuffled data, and repeated leave-one-out testing.</AbstractText>It is possible to derive, from a very small sample, multiple accurate classifier functions that correlate with biological features. The methodology is validated statistically through experiments with fabricated data.</AbstractText>This algorithm might be generally applicable to conditions where interactions among multiple mitochondrial DNA mutations are important. The patterns embodied in the classifier functions obtained should be the subject of further experimental study.</AbstractText>
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2,336,578 |
Genetic variability at the LXR gene (NR1H2) may contribute to the risk of Alzheimer's disease.
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We have initiated a systematic analysis of the role of cholesterol metabolizing genes as risk factors for Alzheimer's disease pathogenesis. As part of this analysis, we have assessed the NR1H2 gene on chromosome 19 and report here a modest association with the locus in sibpairs with late onset disease.
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2,336,579 |
Genetic diagnosis of PLP gene duplications/deletions in patients with Pelizaeus-Merzbacher disease.
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Genetic diagnosis of PLP gene duplications/deletions in patients with Pelizaeus-Merzbacher disease.PMD is an X-linked recessive disorder due to a proteolipid protein (PLP) deficiency. Duplications of PLP gene were shown to be the principle cause of the disorder, accounting for an estimated 50-70% of cases. To define a simple and reliable method for genetic diagnosis of PMD, a group of 42 patients with clinical manifestation of PMD was analyzed by means of real-time quantitative PCR. Parallel fluorescence in situ hybridization (FISH) analysis was performed on the same group of patients. Real-time PCR found seventeen samples had increased gene dosage, whereas FISH detected sixteen duplicated samples. Both methods identified a sample with PLP gene deletion. Our results indicate that real-time PCR is a sensitive and reliable method for the detection of gene duplications/deletions. We further discussed the advantages and limitations of each method in clinical diagnosis of PMD.
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2,336,580 |
Discrepancies in upper and lower limb patterning in split hand foot malformation.
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Discrepancies in upper and lower limb patterning in split hand foot malformation. Split hand foot malformation (SHFM) is genetically heterogeneous with five loci mapped to date. Highly variable in presentation, it can occur as an isolated finding or with other anomalies. The genetic heterogeneity and clinical variability make genetic counselling of SHFM families challenging. By establishing genotype/phenotype correlations, one can provide insight into responsible developmental genes and help to direct mapping efforts and target genetic testing, ultimately providing more accurate information for family members. Preaxial involvement of the upper extremities was a significant discriminating limb-specific variable in our analysis of genetically mapped SHFM cases. This finding, which was originally identified through descriptive epidemiology, was subsequently confirmed by discriminant function analysis (p < 0.0001) to be a significant locus discriminator. Preaxial involvement of the upper extremities was most commonly seen at the SHFM3 locus mapped to chromosome 10q24 (OMIM 600095) and consisted of proximally placed thumbs and/or triphalangeal thumbs (TPT), preaxial polydactyly and/or absence of the first ray. These patients' feet, however, tended to show a classical central longitudinal deficiency without a significant preaxial component. This article discusses this discrepant clefting pattern between the upper and lower extremities and proposes potential mechanisms.
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2,336,581 |
Subtelomeric chromosome aberrations: still a lot to learn.
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Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.
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2,336,582 |
Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip.
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Human cytochrome P450 (CYP)3A is a major P450 enzyme found in the liver and gastrointestinal tract. It plays an important role in the metabolism of a wide variety of drugs, some endogenous steroids and harmful environmental contaminants. It has been shown that CYP3A alleles encoding enzymes with little or no activity are largely created by single nucleotide polymorphisms (SNPs) in the sequences of these genes. The most prevalent of these SNPs are often of low allelic frequency, and many are specific to certain ethnic groups. Therefore, an accurate determination of their frequency in any given ethnic population requires investigations involving large sample sizes. A genotyping chip with enzyme-colorimetric detection was developed and used for simultaneous analysis of 22 known CYP3A SNPs in 451 Han Chinese subjects. Following multiplex polymerase chain reaction and allele-specific primer extension labeling, an enzymatic colorimetry detection system was employed to visualize genotype patterns on a nylon membrane. With this robust system, accurate discrimination ratios were obtained, and approximately 9,922 genotypes were determined. We found that the major CYP3A SNPs in the Chinese subjects were CYP3A4*4 (allele frequency 2.4%), CYP3A4*5 (0.7%), CYP3A4*18A (2.7%) and CYP3A5*3C (70.2%). Most of the major CYP3A4 SNPs found in other ethnicities were not found in this study. Using these SNPs, 11 haplotypes were identified. Comparison between present and previous studies shows that CYP3A4*4 and CYP3A4*5 alleles were Chinese-specific. The genotyping chip developed in this study is an efficient, economic and accurate system for screening multiple SNPs in a large population. Application of such technology is expected to be less labor intensive and easier to adapt to specific searches when compared with other methodologies.
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2,336,583 |
beta2-Adrenergic receptor polymorphisms and asthma in the North Indian population.
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The beta(2)-adrenergic receptor (ADRB2) polymorphisms are known to be functionally relevant and disease modifying in subjects with asthma. However, the association of these polymorphisms with asthma remains to be established. Our objective is to investigate the association of the ADRB2 polymorphisms and haplotypes with asthma in North Indian subjects.</AbstractText>A subset of 101 unrelated cases and 55 unrelated unaffected individuals were used for a case-control disease-association test.</AbstractText>Ten variable single nucleotide polymorphism (SNP) sites within a span of 2.193 kb were identified in the ADRB2 gene by the sequencing and genotyping of 351 bronchial asthma patients and healthy individuals. The distributions of genotype and allele frequencies for individual SNPs in the ADRB2 gene and ADRB2 haplotype frequencies were estimated in unrelated asthmatics and healthy individuals. No significant association was observed between ADRB2 genotypes and alleles with disease status after Bonferroni correction for multiple testing (reference p value = 0.0083). However, haplotype GGCTTTGCAA was found to be significantly associated with asthma (p = 0.021) in the studied population.</AbstractText>Our results suggest that there is likely to be a functional significance of the ADRB2 gene with asthma.</AbstractText>
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2,336,584 |
Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing.
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The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.
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2,336,585 |
The person-affecting restriction, comparativism, and the moral status of potential people.<Pagination><StartPage>185</StartPage><EndPage>195</EndPage><MedlinePgn>185-95</MedlinePgn></Pagination><Abstract><AbstractText>Traditional ethical theories have paradoxical implications in regards to questions concerning procreation and our moral duties to future people. It has been suggested that the crux of the problem resides in an all too 'impersonal' axiology and that the problems of population axiology can be solved by adopting a 'Person Affecting Restriction' which in its slogan form states that an outcome can only be better than another if it is better for people. This move has been especially popular in the context of medical ethics where many of the problems of population axiology are actualized. Examples are embryo or egg selection, pre-implantation genetic testing, assisted reproduction programmes, abortion, just to mention a few. I discuss a number of different interpretations of the Restriction and in particular one interpretation which I call Comparativism. According to this view, we should draw a distinction between uniquely and non-uniquely realizable people. The former people only exist in one out of two possible outcomes, whereas the latter exist in both of the compared outcomes. The idea is that we should give more weight to the well-being of non-uniquely realizable people or take it into account in a different way as compared to the well-being of uniquely realizable people. I argue that the different versions of the Person Affecting Restriction and Comparativism either have counterintuitive implications of their own or are compatible with traditional theories such as Utilitarianism.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Arrhenius</LastName><ForeName>Gustaf</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Philosophy, Stockholm University, Sweden. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Belgium</Country><MedlineTA>Ethical Perspect</MedlineTA><NlmUniqueID>101227772</NlmUniqueID><ISSNLinking>1370-0049</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D026688" MajorTopicYN="N">Bioethical Issues</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D028663" MajorTopicYN="Y">Ethical Theory</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D028723" MajorTopicYN="N">Personhood</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010684" MajorTopicYN="Y">Philosophy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012098" MajorTopicYN="N">Reproduction</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="Y">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D026712" MajorTopicYN="N">Value of Life</DescriptorName></MeshHeading></MeshHeadingList><OtherID Source="KIE">121932</OtherID><KeywordList Owner="KIE"><Keyword MajorTopicYN="N">Genetics and Reproduction</Keyword><Keyword MajorTopicYN="N">Philosophical Approach</Keyword></KeywordList><GeneralNote Owner="KIE">22 refs.</GeneralNote><GeneralNote Owner="KIE">KIE Bib: reproduction</GeneralNote></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>10</Month><Day>27</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16206457</ArticleId><ArticleId IdType="doi">10.2143/ep.10.3.503884</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">16206439</PMID><DateCompleted><Year>2005</Year><Month>10</Month><Day>26</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0962-9564</ISSN><JournalIssue CitedMedium="Print"><Issue>191</Issue><PubDate><Year>2003</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Bulletin of medical ethics</Title><ISOAbbreviation>Bull Med Ethics</ISOAbbreviation></Journal>Scandinavian recommendations: sperm donation.
|
Traditional ethical theories have paradoxical implications in regards to questions concerning procreation and our moral duties to future people. It has been suggested that the crux of the problem resides in an all too 'impersonal' axiology and that the problems of population axiology can be solved by adopting a 'Person Affecting Restriction' which in its slogan form states that an outcome can only be better than another if it is better for people. This move has been especially popular in the context of medical ethics where many of the problems of population axiology are actualized. Examples are embryo or egg selection, pre-implantation genetic testing, assisted reproduction programmes, abortion, just to mention a few. I discuss a number of different interpretations of the Restriction and in particular one interpretation which I call Comparativism. According to this view, we should draw a distinction between uniquely and non-uniquely realizable people. The former people only exist in one out of two possible outcomes, whereas the latter exist in both of the compared outcomes. The idea is that we should give more weight to the well-being of non-uniquely realizable people or take it into account in a different way as compared to the well-being of uniquely realizable people. I argue that the different versions of the Person Affecting Restriction and Comparativism either have counterintuitive implications of their own or are compatible with traditional theories such as Utilitarianism.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Arrhenius</LastName><ForeName>Gustaf</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Department of Philosophy, Stockholm University, Sweden. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Belgium</Country><MedlineTA>Ethical Perspect</MedlineTA><NlmUniqueID>101227772</NlmUniqueID><ISSNLinking>1370-0049</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D026688" MajorTopicYN="N">Bioethical Issues</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D028663" MajorTopicYN="Y">Ethical Theory</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D028723" MajorTopicYN="N">Personhood</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010684" MajorTopicYN="Y">Philosophy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012098" MajorTopicYN="N">Reproduction</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="Y">ethics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D026712" MajorTopicYN="N">Value of Life</DescriptorName></MeshHeading></MeshHeadingList><OtherID Source="KIE">121932</OtherID><KeywordList Owner="KIE"><Keyword MajorTopicYN="N">Genetics and Reproduction</Keyword><Keyword MajorTopicYN="N">Philosophical Approach</Keyword></KeywordList><GeneralNote Owner="KIE">22 refs.</GeneralNote><GeneralNote Owner="KIE">KIE Bib: reproduction</GeneralNote></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>10</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>10</Month><Day>27</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>10</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16206457</ArticleId><ArticleId IdType="doi">10.2143/ep.10.3.503884</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">16206439</PMID><DateCompleted><Year>2005</Year><Month>10</Month><Day>26</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0962-9564</ISSN><JournalIssue CitedMedium="Print"><Issue>191</Issue><PubDate><Year>2003</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Bulletin of medical ethics</Title><ISOAbbreviation>Bull Med Ethics</ISOAbbreviation></Journal><ArticleTitle>Scandinavian recommendations: sperm donation.</ArticleTitle><Pagination><StartPage>8</StartPage><EndPage>9</EndPage><MedlinePgn>8-9</MedlinePgn></Pagination><Abstract>The Danish Council of Ethics is continuing its tradition of publishing in English both its annual report and the report of one substantial investigation each year. With its report for 2002 is the second part of its report on ethical problems concerning assisted reproduction, which examines anonymity and selection in sperm donation. There follow the Council's summary of its recommendations, with an introductory note.
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2,336,586 |
[The significance of screening tests for aneuploidies in populations at low and high maternal-age-related risk].
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The aim of this study was to evaluate the validity of the triple test and the screen test in maternal populations at low and high maternal-age-related risk for fetal aneuploidy.</AbstractText>As a whole, 9,680 pregnant women at low risk and 627 at high risk underwent the triple test; 2,780 pregnant women at low risk and 408 at high risk underwent the screen or combined test; sensitivity, specificity, false positives and detection rate were compared between populations using Student's t-test.</AbstractText>The triple test showed a detection rate of 75% in the low and 83.3% in the high risk population with a difference (P<0.003) for detection of trisomies 21 and 18 between the 2 populations; the screen test had a detection rates of 100% and 90% in the 2 populations, respectively, with a difference (P<0.005) between the 2 tests.</AbstractText>Both tests are reliable for screening aneuploidies in the low risk population, the screen test having better performance; in the high risk population, the number of invasive procedures can be reduced by 78% with the triple test and by 84% with the screen test.</AbstractText>
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2,336,587 |
Clinicopathological features of and risk factors for multiple primary melanomas.
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The incidence of multiple primary melanomas ranges from 1.3% to 8.0% in large retrospective reviews; however, the impact of certain risk factors is not understood.</AbstractText>To determine the incidence of multiple primary melanomas (MPM) from a prospective, single-institution, multidisciplinary database, and to describe the clinical and pathological characteristics and risk factors specific to these patients.</AbstractText>Review of a prospectively maintained database at Memorial Sloan-Kettering Cancer Center in New York, NY.</AbstractText>A total of 4484 patients diagnosed with a first primary melanoma between January 1, 1996, and December 31, 2002.</AbstractText>Incidence of and risk factors for MPM.</AbstractText>Three hundred eighty-five patients (8.6%) had 2 or more primary melanomas, with an average of 2.3 melanomas per MPM patient. Seventy-eight percent had 2 primary melanomas. For 74% of patients, the initial melanoma was the thickest tumor. Fifty-nine percent presented with their second primary tumor within 1 year. Twenty-one percent of MPM patients had a positive family history of melanoma compared with only 12% of patients with a single primary melanoma (SPM) (P<.001). Thirty-eight percent of MPM patients had dysplastic nevi compared with 18% of SPM patients (P<.001). The estimated cumulative 5-year risk of a second primary tumor for the entire cohort was 11.4%, with almost half of that risk occurring within the first year. For patients with a positive family history or dysplastic nevi, the estimated 5-year risk of MPM was significantly higher at 19.1% and 23.7%, respectively. The most striking increase in incidence for the MPM population was seen for development of a third primary melanoma from the time of second primary melanoma, which was 15.6% at 1 year and 30.9% at 5 years.</AbstractText>The incidence of MPM is increased in patients with a positive family history and/or dysplastic nevi. These patients should undergo intensive dermatologic screening and should consider genetic testing.</AbstractText>
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2,336,588 |
Posttraumatic stress associated with cancer history and BRCA1/2 genetic testing.
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A subset of women who are at elevated cancer risk due to family history exhibit evidence of cancer-specific distress. These stress responses may represent symptoms of posttraumatic stress disorder (PTSD). The present study assessed rates of PTSD related to personal or family cancer history and BRCA1/2 testing.</AbstractText>Participants were 84 women enrolled in a larger project focused on genetic testing decisions. Semistructured diagnostic interviews were used to identify instances of threshold and subthreshold PTSD.</AbstractText>Results indicated that 16.7% of the women reported current threshold or subthreshold PTSD related to personal or family cancer history. An additional 26.2% reported past-only cancer-related threshold or subthreshold PTSD. Of the 65 women who received BRCA1/2 results and completed the test-related PTSD module, only 7.7% reported threshold or subthreshold PTSD related to the genetic testing process. However, when rates were examined based on carrier status, 25.0% of BRCA1/2 carriers reported test-related threshold or subthreshold PTSD compared with only 10.0% of variants and 2.3% of noncarriers.</AbstractText>Results from this study suggest that both personal and family cancer diagnoses can be significant stressors for a subset of high-risk women. Rates of threshold and subthreshold PTSD related to genetic testing appear to be less common, although carriers may be at higher risk for significant posttraumatic symptoms.</AbstractText>
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2,336,589 |
Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians.
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Therapeutic phlebotomy for hereditary hemochromatosis is relatively safe and presumably efficacious when offered before cirrhosis develops, so screening primary care patients is of substantial interest.</AbstractText>To conduct a systematic review of the evidence on 1) the prevalence of the disease in primary care, 2) the risk for morbid or fatal complications for untreated patients, 3) the diagnostic usefulness of transferrin saturation and serum ferritin level in identifying early disease, 4) the efficacy of early treatment, and 5) whether the benefits of screening outweigh the risks.</AbstractText>MEDLINE search from 1966 through April 2004, complemented by reference review of identified original studies and review articles published in English.</AbstractText>PubMed Clinical Queries filters search of prognosis, diagnosis, etiology, or treatment were used depending on the question. Two authors reviewed all titles and abstracts.</AbstractText>Two investigators independently reviewed extracted data.</AbstractText>The prevalence of hereditary hemochromatosis was 1 in 169 patients to 1 in 556 patients (n = 3 studies). Uncontrolled, prospective studies of genetic homozygous patients did not consistently identify a link to overt hereditary hemochromatosis. A serum ferritin level less than 1000 microg/L was predictive of absence of cirrhosis. Six studies demonstrated reduced survival in patients with cirrhosis. Diagnostic studies varied with respect to case definition. No blinded, independent comparisons of screening tests with the gold standard (biopsy or results of quantitative phlebotomy) or randomized, controlled trials of phlebotomy were identified. Cost-effectiveness analysis was limited by lack of prospective data on the natural history of the disease.</AbstractText>Varied case definition and lack of prospective cohort studies or randomized trials.</AbstractText>The available evidence does not demonstrate that benefits outweigh the risks and costs of screening for hemochromatosis.</AbstractText>
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2,336,590 |
Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians.
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Hereditary hemochromatosis is a genetic disorder of iron metabolism. Diagnosis of hereditary hemochromatosis is usually based on a combination of various genetic or phenotypic criteria. Decisions regarding screening are difficult because of the variable penetrance of mutations of the HFE gene and the absence of any definitive trials addressing the benefits and risks of therapeutic phlebotomy in asymptomatic patients or those with only laboratory abnormalities. The purpose of this guideline is to increase physician awareness of hereditary hemochromatosis, particularly the variable penetrance of genetic mutations; aid in case finding; and explain the role of genetic testing. This guideline provides recommendations based on a review of evidence in the accompanying background paper by Schmitt and colleagues. The target audience for this guideline is internists and other primary care physicians. The target patient population is all persons who have a probability or susceptibility of developing hereditary hemochromatosis, including the relatives of individuals who already have the disease.
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2,336,591 |
Association Cluster Detector: a tool for heuristic detection of significance clusters in whole-genome scans.
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Whole genome scans analyze large sets of genetic markers, mainly single nucleotide polymorphisms, over the entire genome in order to find variants and regions associated with complex traits so these can be further investigated. Analyzing the results of such scans becomes difficult due to multiple testing problems and to the genomic distributions of recombination, linkage disequilibrium and true associations, which generate an extremely complex network of dependences between markers. Here we present Association Cluster Detector (ACD), a simple tool aiming to ease the analysis of the results of whole genome scans. ACD facilitates correction for multiple tests using several standard procedures and implements a sliding-window heuristic method that helps in detecting potentially interesting candidate regions by exploiting the property of non-random distribution of significantly associated markers.</AbstractText>The tool can be downloaded from http://www.upf.es/cexs/recerca/bioevo/softanddata.htm</AbstractText>
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2,336,592 |
Analyzing microarray data using quantitative association rules.
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We tackle the problem of finding regularities in microarray data. Various data mining tools, such as clustering, classification, Bayesian networks and association rules, have been applied so far to gain insight into gene-expression data. Association rule mining techniques used so far work on discretizations of the data and cannot account for cumulative effects. In this paper, we investigate the use of quantitative association rules that can operate directly on numeric data and represent cumulative effects of variables. Technically speaking, this type of quantitative association rules based on half-spaces can find non-axis-parallel regularities.</AbstractText>We performed a variety of experiments testing the utility of quantitative association rules for microarray data. First of all, the results should be statistically significant and robust against fluctuations in the data. Next, the approach should be scalable in the number of variables, which is important for such high-dimensional data. Finally, the rules should make sense biologically and be sufficiently different from rules found in regular association rule mining working with discretizations. In all of these dimensions, the proposed approach performed satisfactorily. Therefore, quantitative association rules based on half-spaces should be considered as a tool for the analysis of microarray gene-expression data.</AbstractText>The code is available from the authors on request.</AbstractText>
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2,336,593 |
Detection of the placental epigenetic signature of the maspin gene in maternal plasma.
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The discovery of fetal DNA in the plasma of pregnant women has opened up new approaches for noninvasive prenatal diagnosis and monitoring. Up to now, the lack of a fetal DNA marker that can be universally detected in maternal plasma has limited the clinical application of this technology. We hypothesized that epigenetic differences between the placenta and maternal blood cells could be used for developing such a marker. By using bisulfite DNA sequencing, the methylation status of the maspin gene promoter in placental tissues and paired maternal blood cells from pregnant women was analyzed. The maspin gene promoter was found to be hypomethylated in placental tissues and densely methylated in maternal blood cells. Genotyping of a single nucleotide polymorphism within the unmethylated maspin sequences in maternal plasma demonstrated that these sequences were derived from the fetus. By using real-time quantitative methylation-specific PCR, unmethylated maspin sequences were detected in maternal plasma in all three trimesters of pregnancy and were cleared within 24 h after delivery. The maternal plasma concentration of unmethylated maspin sequences was elevated by a median of 5.7 times in preeclamptic pregnancies compared with nonpreeclamptic pregnancies. Hypomethylated maspin DNA is the first universal marker for fetal DNA in maternal plasma, thus allowing the measurement of fetal DNA concentrations in pregnancy-associated disorders, irrespective of fetal gender and genetic polymorphisms. Differential DNA methylation between the placenta and maternal blood cells may be exploited to develop further markers for noninvasive prenatal assessment.
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2,336,594 |
Multiplexed variation scanning for 1,000 amplicons in hundreds of patients using mismatch repair detection (MRD) on tag arrays.
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Identification of the genetic basis of common disease may require comprehensive sequence analysis of coding regions and regulatory elements in patients and controls to find genetic effects caused by rare or heterogeneous mutations. In this study, we demonstrate how mismatch repair detection on tag arrays can be applied in a case-control study. Mismatch repair detection allows >1,000 amplicons to be screened for variations in a single laboratory reaction. Variation scanning in 939 amplicons, mostly in coding regions within a linkage peak, was done for 372 patients and 404 controls. In total, >180 Mb of DNA was scanned. Several variants more prevalent in patients than in controls were identified. This study demonstrates an approach to the discovery of susceptibility genes for common disease: large-scale direct sequence comparison between patients and controls. We believe this approach can be scaled up to allow sequence comparison in the whole-genome coding regions among large sets of cases and controls at a reasonable cost in the near future.
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2,336,595 |
Whole genome linkage scan of recurrent depressive disorder from the depression network study.
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Genome-wide linkage analysis was carried out in a sample of 497 sib pairs concordant for recurrent major depressive disorder (MDD). There was suggestive evidence for linkage on chromosome 1p36 where the LOD score for female-female pairs exceeded 3 (but reduced to 2.73 when corrected for multiple testing). The region includes a gene, MTHFR, that in previous studies has been associated with depressive symptoms. Two other regions, on chromosomes 12q23.3-q24.11 and 13q31.1-q31.3, showed evidence for linkage with a nominal P < 0.01. The 12q peak overlaps with a region previously implicated by linkage studies of unipolar and bipolar disorders and contains a gene, DAO, that has been associated with both bipolar disorder and schizophrenia. The 13q peak lies within a region previously linked strongly to panic disorder. A fourth modest peak with an LOD of greater than 1 on chromosome 15q lies within a region that showed genome-wide significant evidence of a recurrent depression locus in a previous sib-pair study. Both the 12q and the 15q findings remained significant at genome-wide level when the data from the present study and the previous reports were combined.
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2,336,596 |
Chronic beryllium disease and sensitization at a beryllium processing facility.
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We conducted a medical screening for beryllium disease of 577 former workers from a beryllium processing facility. The screening included a medical and work history questionnaire, a chest radiograph, and blood lymphocyte proliferation testing for beryllium. A task exposure and a job exposure matrix were constructed to examine the association between exposure to beryllium and the development of beryllium disease. More than 90% of the cohort completed the questionnaire, and 74% completed the blood and radiograph component of the screening. Forty-four (7.6%) individuals had definite or probable chronic beryllium disease (CBD), and another 40 (7.0%) were sensitized to beryllium. The prevalence of CBD and sensitization in our cohort was greater than the prevalence reported in studies of other beryllium-exposed cohorts. Various exposure measures evaluated included duration; first decade worked; last decade worked; cumulative, mean, and highest job; and highest task exposure to beryllium (to both soluble and nonsoluble forms). Soluble cumulative and mean exposure levels were lower in individuals with CBD. Sensitized individuals had shorter duration of exposure, began work later, last worked longer ago, and had lower cumulative and peak exposures and lower nonsoluble cumulative and mean exposures. A possible explanation for the exposure-response findings of our study may be an interaction between genetic predisposition and a decreased permanence of soluble beryllium in the body. Both CBD and sensitization occurred in former workers whose mean daily working lifetime average exposures were lower than the current allowable Occupational Safety and Health Administration workplace air level of 2 microg/m3 and the Department of Energy guideline of 0.2 microg/m3.
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2,336,597 |
Construction and in vitro characterization of a chimeric simian and human immunodeficiency virus with the RANTES gene.
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Chimeric simian-human immunodeficiency virus (SHIV) containing the env gene of HIV-1 infects macaque monkeys and provides basic information that is useful for the development of HIV-1 vaccines. Regulated-on-activation-normal-T-cell-expressed-and-secreted (RANTES), a CC-chemokine, enhances antigen-specific T helper type-1 responses against HIV-1. With the final goal of testing the adjuvant effects of RANTES in SHIV-macaque models, we constructed a SHIV having the RANTES gene (SHIV-RANTES) and characterized its properties in vitro. SHIV-RANTES replicated both in human and monkey T cell lines. Along with SHIV-RANTES replication, RANTES was detected in the supernatant of human and monkey cell cultures, at maximal levels of 98.5 and 4.1 ng/ml, respectively. A flow cytometric analysis showed that the expressed RANTES down-modulated CC-chemokine receptor 5 (CCR5) on PM1 cells, which was restored by adding anti-RANTES antibody. UV-irradiated culture supernatants from the SHIV-RANTES-infected cells suppressed replication of CCR5-tropic HIV-1 BaL in PM-1 cells. Differentiating real-time RT-PCR showed that pre-infection of SHIV-RANTES in C8166 cells expressing CCR5 suppressed the replication of HIV-1 BaL. Biological activity of the expressed RANTES and the inserted RANTES gene in SHIV-RANTES remained stable after 10 passages. These results suggest that SHIV-RANTES is worth testing in macaque models.
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2,336,598 |
Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing.
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To describe the development and follow-up confirmatory results of the routine cystic fibrosis (CF) newborn screening (NBS) program in Wisconsin.</AbstractText>CF NBS has been performed on a routine clinical basis in Wisconsin since July 1994. The 2-tiered immunoreactive trypsinogen (IRT)/DNA technique was used on dried blood on filter paper spots. From July 1994 to February 2002, mutation analysis was for the DeltaF508 allele. Beginning in March 2002, multimutation analysis of 25 CF mutations was performed. Infants with a positive result on NBS were seen in certified CF centers for sweat testing by means of quantitative pilocarpine iontophoresis, and families received genetic counseling.</AbstractText>From July 1994 to February 2002, there were 120 cases of CF detected by means of NBS (509,794 infants screened), with 53 DeltaF508 homozygotes and 67 compound heterozygotes. There were 8 clinically diagnosed cases of CF (no DeltaF508 allele). The CF incidence was 1:3983 (95%CI, 1:3373-1:4774). From March 2002 to June 2003, multimutation analysis identified 21 cases of classic CF (90,142 infants screened). Sweat tests were successfully performed in infants younger than 1 month.</AbstractText>Early diagnosis of CF through NBS was successfully performed, with an estimated sensitivity rate of 99% using the IRT/25 CFTR multimutation assay.</AbstractText>
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2,336,599 |
Understanding newborn screening system issues with emphasis on cystic fibrosis screening.
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Newborn screening (NBS) includes biochemical testing for certain medical conditions that can cause devastating consequences if left undetected and untreated. Mandated screening requires a complex support system to ensure its effectiveness. There are 51 separate NBS programs in the United States, all with different administrative structures and screening panels. Only 8 states mandate screening for cystic fibrosis (CF) and 2 of these are just beginning. Optional NBS for CF reaches significant numbers of newborns in 3 other states but the CF screens are only projected to reach about 20% of the newborn population in 2005. Forthcoming recommendations for NBS screening from the federal Advisory Committee on Heritable Diseases and Genetic Disorders in Newborns and Children (ACHDGDNC) will impact decisions about NBS panels and professional and consumer advocacy will play an important role in deciding the directions in which NBS programs move. For effective CF NBS, CF care centers will need to partner with NBS programs to ensure optimal health benefits, and programs will need to continually evaluate diagnostic and outcome data in order to refine their screening protocols.
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