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2,336,300 |
Laboratory testing for the antibodies that cause heparin-induced thrombocytopenia: how much class do we need?
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Heparin-induced thrombocytopenia (HIT) is usually caused by platelet-activating antibodies of immunoglobulin G class that recognize platelet factor-4 (PF4) bound to heparin or certain other polyanions. Commercial enzyme immunoassays (EIAs) for PF4/polyanion-reactive antibodies detect two immunoglobulin classes (IgA and IgM) besides IgG. To investigate whether the additional detection of these antibody classes improves or worsens assay operating characteristics, we compared the sensitivity and specificity of EIAs that detect these 3 immunoglobulin classes individually with that of a commercial EIA (Genetic Testing Institute, GTI), as well as a platelet-activation assay, the serotonin-release assay (SRA). We compared the operating characteristics of these 5 assays by evaluating 448 patients, in 14 of whom clinical HIT developed, who received either unfractionated or low molecular weight heparin in prospective studies that included systematic platelet-count monitoring and serologic evaluation for anti-PF4/polyanion antibodies. We found that the SRA and IgG and commercial EIAs had similar high sensitivity for HIT; however, diagnostic specificity (for unfractionated and low molecular weight heparin, respectively) varied considerably, as follows: SRA (95.1%, 97.2%) > IgG EIA (89.0%, 93.7%) > GTI EIA (74.2%, 87.6%). Additional detection of IgA and IgM antibodies by the GTI EIA worsened test specificity by detecting numerous nonpathogenic antibodies. Moreover, the frequency and magnitude of IgA and IgM antibody formation in non-HIT immune responses did not differ from that exhibited by patients in whom clinical HIT developed. We conclude that an EIA that detects anti-PF4/polyanion antibodies of only the IgG class has greater diagnostic usefulness in revealing clinical HIT than does an assay that also detects IgA and IgM class antibodies.
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2,336,301 |
Rapid, accurate genotyping of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 based on the use of denaturing HPLC.
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The genotypes of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) are related to alcohol dependence and some human disorders. Rapid, accurate genotyping methodologies for specific polymorphisms of these two genes are needed for molecular screening and testing of alcohol-related problems in populations. A polymerase chain reaction (PCR) composed of two separate amplicons was designed to generate sequences containing the polymorphic site of interest in the ADH1B and ALDH2 genes. The PCR amplicons for each sample were subjected to denaturing high-performance liquid chromatography (DHPLC), analysis performed under partially denaturing conditions as determined by profiling the mixture of a unique homozygous control and a tested sample amplicon. A total of 150 genomic DNA samples were tested to validate this assay by blind analysis. Direct DNA sequencing was performed on samples randomly selected from each of the genotype groups detected by DHPLC profiling. The results indicate 100% concordance between the sequencing analysis and the DHPLC detection. The method we present provides a reliable and fast genotyping procedure for molecular screening of alcohol-related problems.
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2,336,302 |
Speeding up a genetic algorithm for EPR-based spin label characterization of biosystem complexity.
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Complexity of biological systems is one of the toughest problems for any experimental technique. Complex biochemical composition and a variety of biophysical interactions governing the evolution of a state of a biological system imply that the experimental response of the system would be superimposed of many different responses. To obtain a reliable characterization of such a system based on spin-label Electron Paramagnetic Resonance (EPR) spectroscopy, multiple Hybrid Evolutionary Optimization (HEO) combined with spectral simulation can be applied. Implemented as the GHOST algorithm this approach is capable of handling the huge solution space and provides an insight into the "quasicontinuous" distribution of parameters that describe the biophysical properties of an experimental system. However, the analysis procedure requires several hundreds of runs of the evolutionary optimization routine making this algorithm extremely computationally demanding. As only the best parameter sets from each run are assumed to contribute into the final solution, this algorithm appears far from being optimized. The goal of this study is to modify the optimization routine in a way that 20-40 runs would be enough to obtain qualitatively the same characterization. However, to keep the solution diversity throughout the HEO run, fitness sharing and newly developed shaking mechanisms are applied and tested on various test EPR spectra. In addition, other evolutionary optimization parameters such as population size and probability of genetic operators were also varied to tune the algorithm. According to the testing examples a speed-up factor of 5-7 was achieved.
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2,336,303 |
Australian attitudes to DNA sample banks and genetic screening.
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An exploration via an anonymous questionnaire of Australian public attitudes towards medical genetics and sample banking revealed the overwhelming majority views these developments with thoughtful confidence. Continued public education and awareness of these issues will allow the public to make informed decisions and enhance vigilance towards the sometimes misleading coverage in the press and media.
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2,336,304 |
Novel mutations in the cytochrome P450 2C19 gene: a pitfall of the PCR-RFLP method for identifying a common mutation.
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CYP2C19 is a clinically important enzyme involved in the metabolism of therapeutic drugs such as (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2-5% of Caucasian populations, but at higher frequencies (18-23%) in Asians. CYP2C19*2 and CYP2C19*3, which are single-nucleotide polymorphisms of CYP2C19, are the main cause of PM phenotyping in homozygotes or compound heterozygotes. We report two novel mutations in the CYP2C19 gene identified by direct sequencing and subcloning procedures. One of these mutations was considered to be CYP2C19*3 by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). This result suggests that mutations classed as CYP2C19*3 might include other mutations. Further studies are needed to clarify the relationship between these novel mutations and enzyme activity.
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2,336,305 |
Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with dna and recombinant adenoviral vaccine vectors expressing Gag.
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The prophylactic efficacy of DNA and replication-incompetent adenovirus serotype 5 (Ad5) vaccine vectors expressing simian immunodeficiency virus (SIV) Gag was examined in rhesus macaques using an SIVmac239 challenge. Cohorts of either Mamu-A*01(+) or Mamu-A*01(-) macaques were immunized with a DNA prime-Ad5 boost regimen; for comparison, a third cohort consisting of Mamu-A*01(+) monkeys was immunized using the Ad5 vector alone for both prime and boost. All animals, along with unvaccinated control cohorts of Mamu-A*01(+) and Mamu-A*01(-) macaques, were challenged intrarectally with SIVmac239. Viral loads were measured in both peripheral and lymphoid compartments. Only the DNA prime-Ad5-boosted Mamu-A*01(+) cohort exhibited a notable reduction in peak plasma viral load (sevenfold) as well as in early set-point viral burdens in both plasma and lymphoid tissues (10-fold) relative to those observed in the control monkeys sharing the same Mamu-A*01 allele. The degree of control in each animal correlated with the levels of Gag-specific immunity before virus challenge. However, virus control was short-lived, and indications of viral escape were evident as early as 6 months postinfection. The implications of these results in vaccine design and clinical testing are discussed.
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2,336,306 |
Testing "species pair" hypotheses: evolutionary processes in the lichen-forming species complex Porpidia flavocoerulescens and Porpidia melinodes.
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Pairs of taxa are commonly found in lichen-forming ascomycetes that differ primarily in their reproductive modes: one taxon reproduces sexually, the other vegetatively. The evolutionary processes underlying such "species pairs" are unknown. The species pair formed by Porpidia flavocoerulescens (sexual) and Porpidia melinodes (vegetative) was chosen to investigate four previously proposed hypotheses. These hypotheses posit that species pairs are either two monophyletic, independently evolving species with contrasting reproductive mode; a single outcrossing species polymorphic with regard to its reproductive modes; a sexual mother lineage frequently giving rise to asexual spin-offs; or a complex of cryptic species. The phylogenetic patterns observed within the species pair in the present study were analyzed using stringent hypothesis testing and visualizations of relationships and conflict based on tree and network reconstructions. DNA sequences at the three analyzed loci revealed the same four to five deeply divergent lineages. A detailed analysis of DNA-sequence variability revealed closely linked gene loci, but high levels of conflict within each of the gene fragments, as well as between observed genetic lineages. The observed patterns of phylogenetic relationships, linkage, and conflict are not congruent with any of the previously proposed species pair hypotheses. Rather, it is proposed that the observed results can be explained by conflicting reproductive and nutritional requirements imposed by an obligate symbiotic lifestyle. These interacting constraints produce recurring selective sweeps within predominantly vegetatively reproducing lineages and are the main forces that shape the evolution within the investigated species pair.
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2,336,307 |
Using the PRACTICE mnemonic to apply cultural competency to genetics in medical education and patient care.
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Medical education curricula increasingly are incorporating courses on cultural competency and skills development in working with ethnically diverse patient populations as well as courses on genetics and genomics. The authors support these efforts and believe the next step is integration of genetics into cultural competency programs and similarly, cultural competency into genetics curricula. In this paper, the authors describe the work of the Genetics in Primary Care Faculty Development Working Group on Cultural Competency, a federally-funded initiative to prepare generalist faculty to teach genetics as part of ambulatory education. Over a 12-month period, this team wrote a module on cultural competency and nine new clinical cases, and developed the PRACTICE mnemonic (prevalence, risk, attitude, communication, testing, investigation, consent, empowerment) to help health care professionals integrate cultural competency skills in genetics into primary care. More specifically, the PRACTICE mnemonic integrates information emerging from experts in health disparities and doctor-patient communication to build a comprehensive model for addressing the relevance of culture and ethnicity in the delivery of genetic services. Lastly, this paper illustrates a systematic method of covering key areas of cultural competency through discussion of a patient with a genetic disorder as well as presents an argument as to why cultural competency is highly relevant to the delivery of genetic services especially as part of generalists' clinical practice.
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2,336,308 |
Silver-Russell syndrome-like features in a patient carrying a novel NF1 mutation.
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Mutations in the NF1 gene (17q11.2) cause neurofibromatosis type 1 (NF1), a pleiotropic and progressive autosomal dominant disorder with marked variability of clinical expression. Clinical diagnosis is usually readily achieved in most adult and adolescent patients due to the presence of at least two of the classic signs of NF1. However, the absence of many of the disease-defining features in young children frequently renders definite diagnosis impossible in this age group. Particularly, clinical diagnosis is challenging in young patients whose phenotypical presentation does not lie within the common spectrum of "typical" NF1 features. Sensitive and reliable molecular genetic testing can be of great help in these cases. Here, we report clinical and molecular findings in a 2-year-old boy with features of NF1. Severe growth retardation together with other dysmorphic features was also suggestive for Silver-Russell syndrome (SRS) in this patient. Molecular genetic testing identified a novel NF1 mutation and, thus, enabled a confident NF1 diagnosis despite the unusual phenotypical presentation in this patient.
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2,336,309 |
HLA-A and HLA-B allele frequencies in a mestizo population from Guadalajara, Mexico, determined by sequence-based typing.
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HLA-A and HLA-B genes were typed by DNA sequencing in a mestizo population from Guadalajara, Jalisco, Mexico. Thirty-seven HLA-A and 51 HLA-B alleles were observed in 103 samples. The common typical Amerindian alleles (>5%) and haplotypes (>or=2.0%) found were A*02010101, *24020101, *310102, B*350101, and *4002, and A*310102-B*4002, A*240201-B*350101, and the typical European alleles were A*010101, *29010101, B*1402, B*180101, and A*020101-B*1402, A*020101-B*510101, and A*3002-B*180101. This reflects the blending of the two main parental populations of mestizos: Amerindian and Iberian. Mexicans were found to be relatively closer to the Portuguese than to Spaniards. This proximity may indicate a larger Portuguese influence in Mexicans than previously considered. Present data contribute to the understanding of the genetic structure in Mexico.
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2,336,310 |
Lipid carriers for gene therapy.
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A wide variety of lipid molecules used as gene carriers has been reported and compared over the last twenty years. This review highlights a few examples of mechanistic analysis applied to the study of lipid carriers. The modular nature of the lipid structure offers itself up to a controlled, systematic analysis. Key to exploring structural variants is the understanding of the role each component and module plays in the formation of the lipoplex structure itself and their roles in the transfection pathway. Firstly, the lipid carrier must be able to package, and release into the cell its nucleic acid cargo. Uptake of lipoplexes into cells involves endocytic processes that lead inevitably to endosomal/liposomal degradation of the nucleic acid contents, unless lipid structures and designs are optimised to facilitate their release into the cytoplasm. Testing of possible endosomal escape mechanisms has led to improved lipid designs. For example, it was predicted that mixing of cationic lipids with shorter alkyl tails (<C18) from liposomes with the endosomal bilayer during the transfection process within the endosome should promote membrane fluidity, enhancing plasmid release and transfection efficiency. This hypothesis has been borne out numerous times. "Smart" molecules that respond to cellular cues such as endosomal pH have now been developed that appear to offer exciting opportunities for the future role of lipoplexes in clinical applications of gene therapy. The variability of cultured cell and model biological systems remains a challenge in designing improved lipids of general utility.
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2,336,311 |
DNA analysis of ingested tomato and pepper seeds.<Pagination><StartPage>330</StartPage><EndPage>333</EndPage><MedlinePgn>330-3</MedlinePgn></Pagination><Abstract><AbstractText>Ingested food is one of the important types of forensic evidence obtained during a medicolegal autopsy. Many materials containing seeds pass through the human digestive system and are still recognizable; thus, they can be valuable for providing investigative leads. Currently, the identification of seeds relies on microscopic and morphologic examination. However this method sometimes can be problematic. For example, the microscopic appearance of the ingested tomato and pepper seeds is very similar; thus, it is not always easy to distinguish these seeds by comparing their physical characteristics. Tomato and pepper seeds were selected as a model system to assess the value of performing DNA analysis as an alternate and/or complimentary means of seed identification. Results of blind testing indicate that the deoxyribonucleic acid-amplified fragment length polymorphism (DNA-AFLP) results were able to discriminate between pepper and tomato seed samples after they passed through the digestive system.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Cheng-Lung</ForeName><Initials>CL</Initials><AffiliationInfo><Affiliation>Nuclear Science Department, National Tsing Hua University, Taiwan, ROC.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coyle</LastName><ForeName>Heather Miller</ForeName><Initials>HM</Initials></Author><Author ValidYN="Y"><LastName>Palmbach</LastName><ForeName>Timothy M</ForeName><Initials>TM</Initials></Author><Author ValidYN="Y"><LastName>Hsu</LastName><ForeName>Ian C</ForeName><Initials>IC</Initials></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Henry C</ForeName><Initials>HC</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>United States</Country><MedlineTA>Am J Forensic Med Pathol</MedlineTA><NlmUniqueID>8108948</NlmUniqueID><ISSNLinking>0195-7910</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018744">DNA, Plant</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D002212" MajorTopicYN="N">Capsicum</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018744" MajorTopicYN="N">DNA, Plant</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="Y">analysis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004063" MajorTopicYN="Y">Digestion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005240" MajorTopicYN="N">Feasibility Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005243" MajorTopicYN="N">Feces</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005554" MajorTopicYN="N">Forensic Medicine</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018551" MajorTopicYN="N">Solanum lycopersicum</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D021141" MajorTopicYN="N">Nucleic Acid Amplification Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011110" MajorTopicYN="N">Polymorphism, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012639" MajorTopicYN="N">Seeds</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013045" MajorTopicYN="N">Species Specificity</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>2</Month><Day>8</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16304465</ArticleId><ArticleId IdType="doi">10.1097/01.paf.0000188084.25905.3b</ArticleId><ArticleId IdType="pii">00000433-200512000-00007</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16304426</PMID><DateCompleted><Year>2009</Year><Month>11</Month><Day>03</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4383</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal>Practical and ethical issues with genetic screening.<Pagination><StartPage>498</StartPage><EndPage>502</EndPage><MedlinePgn>498-502</MedlinePgn></Pagination><Abstract><AbstractText>Clinical hematologists are faced with a growing list of new genetic-based tools for identifying a patient's risk of disease. While many of the disease-specific tests are readily available, validation studies are required. Furthermore, genetic-based tests are being pushed to their technical limits, such as testing a single cell prior to embryo selection and transfer for couples at risk of genetic disease. As a result, misdiagnosis or misinterpretation of the data may result. As new genetic testing opportunities proliferate, the hematologist needs to be aware of the medical and legal issues surrounding their use. Furthermore, the hematologist needs to consider the psychological, ethical and social implications of this new field of genomic-based medicine.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wagner</LastName><ForeName>John E</ForeName><Initials>JE</Initials><AffiliationInfo><Affiliation>University of Minnesota, Box 366 UMHC, 420 Delaware Street, SE, Minneapolis, MN 55455, USA. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Hematology Am Soc Hematol Educ Program</MedlineTA><NlmUniqueID>100890099</NlmUniqueID><ISSNLinking>1520-4383</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D024682">BRCA2 Protein</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D024682" MajorTopicYN="N">BRCA2 Protein</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002675" MajorTopicYN="N">Child, Preschool</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004992" MajorTopicYN="Y">Ethics, Medical</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005199" MajorTopicYN="N">Fanconi Anemia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="Y">ethics</QualifierName><QualifierName UI="Q000523" MajorTopicYN="N">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D023281" MajorTopicYN="N">Genomics</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName><QualifierName UI="Q000639" MajorTopicYN="N">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006402" MajorTopicYN="N">Hematologic Diseases</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000523" MajorTopicYN="N">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007223" MajorTopicYN="N">Infant</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008206" MajorTopicYN="N">Lymphatic Diseases</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000523" MajorTopicYN="N">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009369" MajorTopicYN="N">Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010375" MajorTopicYN="N">Pedigree</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D035781" MajorTopicYN="N">Siblings</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2009</Year><Month>11</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16304426</ArticleId><ArticleId IdType="doi">10.1182/asheducation-2005.1.498</ArticleId><ArticleId IdType="pii">2005/1/498</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16304419</PMID><DateCompleted><Year>2009</Year><Month>11</Month><Day>03</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4383</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal>Inherited risk factors for venous thrombosis.<Pagination><StartPage>452</StartPage><EndPage>457</EndPage><MedlinePgn>452-7</MedlinePgn></Pagination><Abstract><AbstractText>Venous thrombosis occurs as a consequence of genetic and environmental risk factors. Since the discovery of factor V Leiden, the most common genetic risk factor, there has been intense interest in clarifying the roles of genes and the environment with thrombosis risk. The translation of this risk information to clinical practice is a challenging one in the setting of a rapidly expanding knowledge base that includes application of genetic medicine. There are benefits, but also potential harms, of testing for inherited disorders associated with thrombosis. This paper reviews inherited risk factors for thrombosis and discuss clinical applications of testing.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Cushman</LastName><ForeName>Mary</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Vermont, 208 South Park Drive, Suite 2, Colchester, VT 05446, USA. [email protected]</Affiliation></AffiliationInfo></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>Hematology Am Soc Hematol Educ Program</MedlineTA><NlmUniqueID>100890099</NlmUniqueID><ISSNLinking>1520-4383</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005338">Fibrin Fibrinogen Degradation Products</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C095381">factor V Leiden</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C036309">fibrin fragment D</NameOfSubstance></Chemical><Chemical><RegistryNumber>9001-24-5</RegistryNumber><NameOfSubstance UI="D005165">Factor V</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D004777" MajorTopicYN="N">Environment</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005165" MajorTopicYN="N">Factor V</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005190" MajorTopicYN="N">Family</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005338" MajorTopicYN="N">Fibrin Fibrinogen Degradation Products</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015994" MajorTopicYN="N">Incidence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011446" MajorTopicYN="N">Prospective Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012008" MajorTopicYN="N">Recurrence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012306" MajorTopicYN="N">Risk</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019851" MajorTopicYN="N">Thrombophilia</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020246" MajorTopicYN="N">Venous Thrombosis</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>35</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2009</Year><Month>11</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16304419</ArticleId><ArticleId IdType="doi">10.1182/asheducation-2005.1.452</ArticleId><ArticleId IdType="pii">2005/1/452</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16304366</PMID><DateCompleted><Year>2009</Year><Month>11</Month><Day>03</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4383</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal>Aplastic anemia: management of pediatric patients.
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Ingested food is one of the important types of forensic evidence obtained during a medicolegal autopsy. Many materials containing seeds pass through the human digestive system and are still recognizable; thus, they can be valuable for providing investigative leads. Currently, the identification of seeds relies on microscopic and morphologic examination. However this method sometimes can be problematic. For example, the microscopic appearance of the ingested tomato and pepper seeds is very similar; thus, it is not always easy to distinguish these seeds by comparing their physical characteristics. Tomato and pepper seeds were selected as a model system to assess the value of performing DNA analysis as an alternate and/or complimentary means of seed identification. Results of blind testing indicate that the deoxyribonucleic acid-amplified fragment length polymorphism (DNA-AFLP) results were able to discriminate between pepper and tomato seed samples after they passed through the digestive system.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Cheng-Lung</ForeName><Initials>CL</Initials><AffiliationInfo><Affiliation>Nuclear Science Department, National Tsing Hua University, Taiwan, ROC.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coyle</LastName><ForeName>Heather Miller</ForeName><Initials>HM</Initials></Author><Author ValidYN="Y"><LastName>Palmbach</LastName><ForeName>Timothy M</ForeName><Initials>TM</Initials></Author><Author ValidYN="Y"><LastName>Hsu</LastName><ForeName>Ian C</ForeName><Initials>IC</Initials></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>Henry C</ForeName><Initials>HC</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>United States</Country><MedlineTA>Am J Forensic Med Pathol</MedlineTA><NlmUniqueID>8108948</NlmUniqueID><ISSNLinking>0195-7910</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018744">DNA, Plant</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D002212" MajorTopicYN="N">Capsicum</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018744" MajorTopicYN="N">DNA, Plant</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="Y">analysis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004063" MajorTopicYN="Y">Digestion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005240" MajorTopicYN="N">Feasibility Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005243" MajorTopicYN="N">Feces</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005554" MajorTopicYN="N">Forensic Medicine</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018551" MajorTopicYN="N">Solanum lycopersicum</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D021141" MajorTopicYN="N">Nucleic Acid Amplification Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011110" MajorTopicYN="N">Polymorphism, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012639" MajorTopicYN="N">Seeds</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013045" MajorTopicYN="N">Species Specificity</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>2</Month><Day>8</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16304465</ArticleId><ArticleId IdType="doi">10.1097/01.paf.0000188084.25905.3b</ArticleId><ArticleId IdType="pii">00000433-200512000-00007</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16304426</PMID><DateCompleted><Year>2009</Year><Month>11</Month><Day>03</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4383</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal><ArticleTitle>Practical and ethical issues with genetic screening.</ArticleTitle><Pagination><StartPage>498</StartPage><EndPage>502</EndPage><MedlinePgn>498-502</MedlinePgn></Pagination><Abstract>Clinical hematologists are faced with a growing list of new genetic-based tools for identifying a patient's risk of disease. While many of the disease-specific tests are readily available, validation studies are required. Furthermore, genetic-based tests are being pushed to their technical limits, such as testing a single cell prior to embryo selection and transfer for couples at risk of genetic disease. As a result, misdiagnosis or misinterpretation of the data may result. As new genetic testing opportunities proliferate, the hematologist needs to be aware of the medical and legal issues surrounding their use. Furthermore, the hematologist needs to consider the psychological, ethical and social implications of this new field of genomic-based medicine.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Wagner</LastName><ForeName>John E</ForeName><Initials>JE</Initials><AffiliationInfo><Affiliation>University of Minnesota, Box 366 UMHC, 420 Delaware Street, SE, Minneapolis, MN 55455, USA. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Hematology Am Soc Hematol Educ Program</MedlineTA><NlmUniqueID>100890099</NlmUniqueID><ISSNLinking>1520-4383</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D024682">BRCA2 Protein</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D024682" MajorTopicYN="N">BRCA2 Protein</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002675" MajorTopicYN="N">Child, Preschool</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004992" MajorTopicYN="Y">Ethics, Medical</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005199" MajorTopicYN="N">Fanconi Anemia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="Y">ethics</QualifierName><QualifierName UI="Q000523" MajorTopicYN="N">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D023281" MajorTopicYN="N">Genomics</DescriptorName><QualifierName UI="Q000941" MajorTopicYN="N">ethics</QualifierName><QualifierName UI="Q000639" MajorTopicYN="N">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006402" MajorTopicYN="N">Hematologic Diseases</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000523" MajorTopicYN="N">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007223" MajorTopicYN="N">Infant</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008206" MajorTopicYN="N">Lymphatic Diseases</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000523" MajorTopicYN="N">psychology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009369" MajorTopicYN="N">Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010375" MajorTopicYN="N">Pedigree</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D035781" MajorTopicYN="N">Siblings</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2009</Year><Month>11</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16304426</ArticleId><ArticleId IdType="doi">10.1182/asheducation-2005.1.498</ArticleId><ArticleId IdType="pii">2005/1/498</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16304419</PMID><DateCompleted><Year>2009</Year><Month>11</Month><Day>03</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4383</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal><ArticleTitle>Inherited risk factors for venous thrombosis.</ArticleTitle><Pagination><StartPage>452</StartPage><EndPage>457</EndPage><MedlinePgn>452-7</MedlinePgn></Pagination><Abstract>Venous thrombosis occurs as a consequence of genetic and environmental risk factors. Since the discovery of factor V Leiden, the most common genetic risk factor, there has been intense interest in clarifying the roles of genes and the environment with thrombosis risk. The translation of this risk information to clinical practice is a challenging one in the setting of a rapidly expanding knowledge base that includes application of genetic medicine. There are benefits, but also potential harms, of testing for inherited disorders associated with thrombosis. This paper reviews inherited risk factors for thrombosis and discuss clinical applications of testing.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Cushman</LastName><ForeName>Mary</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medicine, University of Vermont, 208 South Park Drive, Suite 2, Colchester, VT 05446, USA. [email protected]</Affiliation></AffiliationInfo></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>Hematology Am Soc Hematol Educ Program</MedlineTA><NlmUniqueID>100890099</NlmUniqueID><ISSNLinking>1520-4383</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005338">Fibrin Fibrinogen Degradation Products</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C095381">factor V Leiden</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C036309">fibrin fragment D</NameOfSubstance></Chemical><Chemical><RegistryNumber>9001-24-5</RegistryNumber><NameOfSubstance UI="D005165">Factor V</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D004777" MajorTopicYN="N">Environment</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005165" MajorTopicYN="N">Factor V</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005190" MajorTopicYN="N">Family</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005338" MajorTopicYN="N">Fibrin Fibrinogen Degradation Products</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015994" MajorTopicYN="N">Incidence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011446" MajorTopicYN="N">Prospective Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012008" MajorTopicYN="N">Recurrence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012306" MajorTopicYN="N">Risk</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019851" MajorTopicYN="N">Thrombophilia</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020246" MajorTopicYN="N">Venous Thrombosis</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>35</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2009</Year><Month>11</Month><Day>5</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>11</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16304419</ArticleId><ArticleId IdType="doi">10.1182/asheducation-2005.1.452</ArticleId><ArticleId IdType="pii">2005/1/452</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16304366</PMID><DateCompleted><Year>2009</Year><Month>11</Month><Day>03</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4383</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Hematology. American Society of Hematology. Education Program</Title><ISOAbbreviation>Hematology Am Soc Hematol Educ Program</ISOAbbreviation></Journal><ArticleTitle>Aplastic anemia: management of pediatric patients.</ArticleTitle><Pagination><StartPage>104</StartPage><EndPage>109</EndPage><MedlinePgn>104-9</MedlinePgn></Pagination><Abstract>Aplastic anemia is a term describing the common findings of pancytopenia and marrow hypoplasia arising from a variety of disease states, including acquired aplastic anemia and a variety of congenital marrow failure states. The management of children with these disorders has been confounded by difficulties of diagnosis. The availability of molecular testing has assisted in partial resolution of this problem but has raised new issues, such as the potential of genetic predisposition and the management of asymptomatic individuals with molecular markers. Longitudinal data from large cohort studies and disease registries are providing a rational basis for making more informed treatment decisions for children with these disorders. In particular, the ability to subset patients more accurately has improved triage of treatments. Approaches to hematopoietic stem cell transplantation (SCT), using both conventional and alternative donors, are changing rapidly, and the long-term sequelae of newer approaches are not entirely clear. Improved diagnosis and longer survival have fostered an understanding of the multidisciplinary approach necessary to manage both the underlying problems and the significant sequelae of treatment in both acquired and congenital disease.
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2,336,312 |
Detecting periodic patterns in unevenly spaced gene expression time series using Lomb-Scargle periodograms.
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Periodic patterns in time series resulting from biological experiments are of great interest. The commonly used Fast Fourier Transform (FFT) algorithm is applicable only when data are evenly spaced and when no values are missing, which is not always the case in high-throughput measurements. The choice of statistic to evaluate the significance of the periodic patterns for unevenly spaced gene expression time series has not been well substantiated.</AbstractText>The Lomb-Scargle periodogram approach is used to search time series of gene expression to quantify the periodic behavior of every gene represented on the DNA array. The Lomb-Scargle periodogram analysis provides a direct method to treat missing values and unevenly spaced time points. We propose the combination of a Lomb-Scargle test statistic for periodicity and a multiple hypothesis testing procedure with controlled false discovery rate to detect significant periodic gene expression patterns.</AbstractText>We analyzed the Plasmodium falciparum gene expression dataset. In the Quality Control Dataset of 5080 expression patterns, we found 4112 periodic probes. In addition, we identified 243 probes with periodic expression in the Complete Dataset, which could not be examined in the original study by the FFT analysis due to an excessive number of missing values. While most periodic genes had a period of 48 h, some had a period close to 24 h. Our approach should be applicable for detection and quantification of periodic patterns in any unevenly spaced gene expression time-series data.</AbstractText>
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2,336,313 |
New insights into juvenile parotitis.
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We inquired about the possibility of a familial trend in juvenile parotitis and evaluated the role of SPINK1 mutations in juvenile parotitis.</AbstractText>The clinical records of all children admitted to the Helsinki University Hospital during 1995 to May 2003 because of swelling in the parotid gland were reviewed. A questionnaire on possible recurrences and on familial cases was mailed. As disturbances in trypsin inhibition might be involved in the pathogenesis, we assessed the SPINK1 gene encoding for Kazal-type trypsin inhibitor in voluntary patients. The study group comprised 133 children (boys 82 girls 51) with juvenile parotitis. The median age at presentation of first symptoms was 6.0 y (range 1-19 y).</AbstractText>Recurrent symptoms in the parotid gland were common (57%), and 29% of the children (38/133) had suffered from four or more episodes. A young age at the first episode of symptoms increased the likelihood of recurrences (p<0.0001). Familial cases of parotid swelling were common (22%; response rate 67%). A total of 47 patients (35%) agreed to testing for SPINK1 status. Four children had a major mutation (N34S or P55S), corresponding to an 8.5% (4/47) prevalence, but this was not different from the controls (5%).</AbstractText>It is likely that inherited factors are involved in the manifestation of juvenile parotitis in a subset of patients. It is tempting to speculate that disturbed proteolytic balance may play a role in the development of symptoms.</AbstractText>
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2,336,314 |
Chromosomal phylogeny of Robertsonian races of the house mouse on the island of Madeira: testing between alternative mutational processes.
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The ancestral karyotype of the house mouse (Mus musculus) consists of 40 acrocentric chromosomes, but numerous races exist within the domesticus subspecies characterized by different metacentric chromosomes formed by the joining at the centromere of two acrocentrics. An exemplary case is present on the island of Madeira where six highly divergent chromosomal races have accumulated different combinations of 20 metacentrics in 500-1000 years. Chromosomal cladistic phylogenies were performed to test the relative performance of Robertsonian (Rb) fusions, Rb fissions and whole-arm reciprocal translocations (WARTs) in resolving relationships between the chromosomal races. The different trees yielded roughly similar topologies, but varied in the number of steps and branch support. The analyses using Rb fusions/fissions as characters resulted in poorly supported trees requiring six to eight homoplasious events. Allowance for WARTs considerably increased nodal support and yielded the most parsimonious trees since homoplasy was reduced to a single event. The WART-based trees required five to nine WARTs and 12 to 16 Rb fusions. These analyses provide support for the role of WARTs in generating the extensive chromosomal diversification observed in house mice. The repeated occurrence of Rb fusions and WARTs highlights the contribution of centromere-related rearrangements to accelerated rates of chromosomal change in the house mouse.
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2,336,315 |
Acute graft versus host disease after liver transplantation: patterns of lymphocyte chimerism.
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The diagnosis of acute graft versus host disease (aGVHD) following liver transplantation can be difficult, since many of the clinical signs can be caused by drug reactions or viral infections. To establish criteria for the persistence of donor T-cells versus engraftment, we measured donor T-cells by short tandem repeat (STR) assays in 49 liver transplant patients for 8 or more weeks post-transplant. Donor CD3+ T-cells were detected in 38 of 49 patients, on POD 2 with a mean level of 5%. The top of the 99% confidence interval for weeks 1, 2, 3, 4 and 8 were 11, 6, 3, 2 and 3%. Donor CD8+ T-cells were measured in eight patients. The level of CD8+ T-cells was much less than that for CD3+ T-cells, except in two cases of apparent aGVHD. One patient developed severe aGVHD with donor T-cells as high as 84%. The other had 10% donor T-cells for more than 16 weeks associated with fever and neutropenia. We tested the sensitivity of PCR-ssp typing of HLA DR/DQ for donor T-cells. At least one donor type was detected in all samples with 1% or more donor DNA. Thus, higher levels of donor T-cell chimerism, particularly with a high proportion of CD8+ T-cells, strongly supports a diagnosis of aGVHD.
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2,336,316 |
Association between screening family medical history in general medical care and lower burden of cancer worry among women with a close family history of breast cancer.
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Soliciting family medical history (FMH) is the initial step in the process of screening for heritable cancer risk in medical care. We investigate whether recent solicitation of FMH in general medical care is associated with cancer worry among a sample of women having a first-degree relative with a breast cancer diagnosis.</AbstractText>Surveys were mailed to women registered with the Cancer Genetics Network having a first-degree relative with a breast cancer diagnosis and a regular source of medical care. The independent measure consisted of two items for solicitation of FMH based on validated measures of clinical interactions with one's physician; the dependent measure was a novel measure of cancer worry based on validated patient-centered measure of distress; and the secondary measures were 6-point scales for perceived likelihood of developing breast cancer and perceived severity of breast cancer as a health outcome.</AbstractText>A total of 353 women responded and met eligibility criteria (76.4% minimum response rate). One fifth reported no cancer worry during the past 4 weeks. After adjustment for age, education, pedigree features, and clustering within families, recent FMH solicitation was associated with lower odds of cancer worry (odds ratio = 0.58; 95% confidence interval = 0.51-0.70). FMH solicitation was associated with lower perceptions of the severity of developing breast cancer but not with the perception of cancer likelihood.</AbstractText>Our data do not support the hypothesis that FMH solicitation in general medical practice causes cancer worry. In fact, we observed a protective association possibly explained by influences on perceptions of breast cancer severity. Prospective research among less select populations is necessary.</AbstractText>
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2,336,317 |
Technical validation of a multiplex platform to detect thirty mutations in eight genetic diseases prevalent in individuals of Ashkenazi Jewish descent.
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This study determines the analytic accuracy of a Luminex bead-based commercial analyte-specific reagent for the simultaneous analysis of 30 mutations prevalent in Ashkenazi Jews at eight genetic disease loci.</AbstractText>DNA from 20 samples with known abnormal genotypes were run a total of 109 times. DNA from 820 patients with unknown genotypes submitted for Ashkenazi Jewish testing panels were analyzed using our current laboratory techniques. The 820 samples were then stripped of identifiers, coded, and reanalyzed using the Tm Biosciences (Toronto, Canada) Ashkenazi Jewish panel analyte-specific reagent in a blinded fashion. For the controls, comparisons were made with their known genotypes. For the patient samples, the results of the Tm assay were compared with the results of our current assay. For 24 of the 30 mutations, we had genomic DNA controls or detected patients' samples heterozygous for these mutations.</AbstractText>There were no discrepant results in the control or patient samples. In the patient samples, 19,680 genotyping reactions were performed without error in both our laboratory-developed single-disease assays and the Tm multiplex assay. Including the controls, 22,296 genotypes were determined without error.</AbstractText>The Tm Biosciences Ashkenazi Jewish analyte-specific reagent is capable of performing accurate analyses of 24 different mutations in eight different genes in a single multiplex reaction and can be used with confidence in the clinical molecular genetics laboratory.</AbstractText>
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2,336,318 |
Tay Sachs disease carrier screening in schools: educational alternatives and cheekbrush sampling.
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Tay Sachs disease carrier screening programs have been offered successfully worldwide since 1970. The programs typically offer education, testing, and counseling to provide reproductive choices. One such program has been offered to Jewish school students in Melbourne since 1998. In a time of increasing public awareness of genetics, programs require continuous evaluation and updating.</AbstractText>Over 2 successive years, a longitudinal evaluation involved students attending Jewish schools in Melbourne. Both qualitative and quantitative techniques were used to analyze alternative methods for education and sampling procedures. Comparisons involved (1) a computer-based resource versus an oral educational presentation and (2) blood sampling for enzyme and genetic testing versus cheekbrush testing for genetic sampling alone.</AbstractText>The education session was effective in significantly increasing students' knowledge (10.5% +/- 1.2%, P < .0001) and decreasing their anxiety about being a carrier (-12.2% +/- 1.6%, P < .0001). For the students, no significant differences were found between the computer-based resource and oral presentation. There were significantly more students accepting a carrier test and anxiety was lower when a cheekbrush test was offered compared with when a blood test was offered.</AbstractText>Computer-based instruction is equally effective, in addition to offering advantages of self-paced learning and minimization of human resources as an oral presentation within a genetic carrier screening program. Cheekbrush sampling is preferred to blood sampling and should be implemented into current practices for offering genetic screening programs. These results present alternatives to practices for genetic screening reflecting the current developing technology.</AbstractText>
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2,336,319 |
Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: cooperative study of 19 Italian laboratories.
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We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carrier's phenotype.</AbstractText>Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses.</AbstractText>A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15.</AbstractText>The presented and published data still do not allow any definite conclusions to be drawn concerning karyotype-phenotype correlations. Only concerted efforts to characterize molecularly the sSMCs associated or not with a clinical phenotype can yield results suitable for addressing karyotype-phenotype correlations in support of genetic counseling.</AbstractText>
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2,336,320 |
Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory.
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This study determines which clinical features predict positive test results among samples submitted for DNA-based diagnostic nevoid basal cell carcinoma syndrome (NBCCS) testing, and further defines the mutational spectrum of the PTCH gene.</AbstractText>DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction products from exons 1 to 23 of the PTCH gene were directly sequenced. Pedigree phenotypic information was obtained by written questionnaire.</AbstractText>Among 106 presumably unrelated pedigrees, 44 independent mutations were found in 47 families. There were 11 nonsense mutations; 1 in-frame deletion; 17 deletions, 6 insertions, and 1 deletion-insertion that generated frameshifts; 5 splice-site mutations; 1 in-frame duplication; and 2 presumptive missense mutations. Twenty-seven of 46 pedigrees (58.7%) with two or more typical radiographic or pathologic features of NBCCS tested positive for PTCH mutations. Of these, 26 had jaw cysts in combination with other characteristics or neoplasms including basal cell carcinomas, palmar pits, skeletal abnormalities, ocular abnormalities, medulloblastomas, cardiac or ovarian fibromas, calcification of the falx cerebri, polydactyly, cleft lip and/or palate, and agenesis of the corpus callosum or other central nervous system malformations. None of the 13 pedigrees solely affected by multiple or early-onset basal cell carcinomas and none of the four pedigrees with jaw cysts alone had PTCH mutations.</AbstractText>Pedigrees with multiple features of NBCCS were most likely to test positive for PTCH mutations. Pedigrees with multiple or early-onset basal cell carcinomas without other features of the disease did not test positive for PTCH mutations.</AbstractText>
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2,336,321 |
Deficiency of knowledge of genetics and genetic tests among general practitioners, gynecologists, and pediatricians: a global problem.
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The objective of this study was to assess knowledge of genetics and awareness of genetic tests among Dutch general practitioners (GPs), gynecologists (GYNs), and pediatricians (PEDs), as well as factors influencing their knowledge and awareness.</AbstractText>An anonymous questionnaire inquiry was used, validated with a sample of 52 clinical geneticists (CGs). The study was carried out in primary care (general practice) and secondary care (general and university hospitals) in The Netherlands. A random sample of 200 GPs, 300 GYNs, and 265 PEDs received a questionnaire. In addition, all registered CGs (58) received a questionnaire for validation. In total, 122 GPs, 187 GYNs, 164 PEDs, and 52 CGs returned a completed questionnaire. The main outcome measures were differences in knowledge scores between physicians working in different disciplines and factors influencing these scores.</AbstractText>Knowledge scores of GPs (mean 64% correct answers, 61%-66% [95% confidence interval]), GYNs (mean 75% correct answers, 73%-76% [95% confidence interval]), and PEDs (mean 81% correct answers, 79%-82% [95% confidence interval]) were lower than those in the CG validation group (mean 95% correct answers, 94%-96% [95% confidence interval]). The 5th percentile of GPs, GYNs, and PEDs was at approximately 40%, 52% and 62% correct answers, respectively. There was a specific lack of knowledge about DNA testing. In addition to specialty, important factors positively associated with the knowledge scores of nongeneticists are more recent graduation, having taken an elective course in genetics, and providing genetic counseling in their own practice.</AbstractText>The overall knowledge levels of genetics in many nongeneticist health care providers show clear deficiencies. This is in line with reports from other countries, showing that these deficiencies are a global problem.</AbstractText>
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2,336,322 |
Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.
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Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.
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2,336,323 |
Transmission ratio distortion in the spinal muscular atrophy locus: data from 314 prenatal tests.
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Spinal muscular atrophy (SMA) is a recessive neurodegenerative disorder characterized by the loss of alpha-motor neurons in the spinal cord and subsequent death of motor neuron cells. SMA occurs with a frequency of 1 in 6,000 live births, with a carrier frequency of 1 in 40, and is a leading genetic cause of infant mortality. SMA is caused by loss or mutation of the telomeric survival motor neuron gene (SMN1), which is deleted in almost 94% of SMA patients</AbstractText>To analyze the transmission ratio at the SMA locus, examining the segregation of the SMN1-deleted alleles in 314 fetuses from carrier parents who requested prenatal testing for the disease.</AbstractText>Prenatal diagnosis of SMA in families at 25% risk of the disease has been performed on chorionic villous sampling specimens, through direct detection of the SMN1 gene mutation and linkage analysis using microsatellite markers from the 5q13 region. Analysis of the genotypic/allelic frequencies of the SMN1 gene was performed using the chi2 test, assuming a recessive mendelian inheritance.</AbstractText>Of 314 fetuses analyzed, 95 were homozygous for the wild-type allele (30.3%), 154 were carriers (49.0%), and the remaining 65 were homozygous for the mutated allele (20.7%). Statistical analysis demonstrated that proportion of fetuses predicted with SMA is lower than 25% expected for a recessive disorder, resulting in a transmission rate of the SMN1-deleted allele deviant from the 50% expected in a random the segregation of a mendelian tract (p = 0.016)</AbstractText>This is the first study to evaluate the genotypic frequencies at the spinal muscular atrophy (SMA) locus based on data derived from prenatal analysis, which are not subject to ascertainment bias. The analysis showed a transmission ratio distortion at the SMA locus in favor of the SMN1 wild-type alleles.</AbstractText>
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2,336,324 |
Testing of a whole genome PCR scanning approach to identify genomic variability in four different species of lactic acid bacteria.
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Genomes can be markedly heterogeneous in conspecific bacterial strains. Genome sequences can be used to analyze genome plasticity via a PCR(2) (plasticity of chromosome revealed by PCR) approach. Small-sized chromosomes can indeed be fully amplified by long-range PCR with a set of primers designed using a reference strain and then applied to several other strains. Analysis of the resulting patterns can reveal genome plasticity. GenoFrag, a software package for the design of primers optimized for PCR(2) [N. Ben Zakour, M. Gautier, R. Andonov, D. Lavenier, M.F. Cochet, P. Veber, A. Sorokin, Y. Le Loir, GenoFrag: Software to design primers optimized for whole genome scanning by long-range PCR amplification, Nucleic Acids Res. 32 (2004) 17-24] was developed for the analysis of bacterial genome plasticity by whole genome amplification in approximately 10-kb-long fragments. By applying GenoFrag, we provide herewith evidence that genome plasticity can be analyzed in lactic acid bacteria using a PCR(2) approach. The genome sequences of Lactococcus lactis IL1403, Lactobacillus plantarum WCFS1, Lactobacillus bulgaricus ATCC11842 and Bifidobacterium longum NCC2705 were used to design four sets of primers. Each set was evaluated in silico to check that it ensured optimum coverage of the bacterial chromosome. To validate the primers generated by GenoFrag, a subset of primers was successfully used in LR-PCR experiments on genomic DNA from four L. bulgaricus strains.
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2,336,325 |
Genetic differentiation among geographic populations of Gonatocerus ashmeadi, the predominant egg parasitoid of the glassy-winged sharpshooter, Homalodisca coagulata.
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The aim of genetically comparing different populations of the same species of natural enemies is to identify the strain that is most adapted to the environment where it will be released. In the present study, Inter-Simple Sequence Repeat-Polymerase Chain Reaction (ISSR-PCR) was utilized to estimate the population genetic structure of Gonatocerus ashmeadi (Girault) (Hymenoptera: Mymaridae), the predominant egg parasitoid of Homalodisca coagulata (Say) (Homoptera:Cicadellidae), the glassy-winged sharpshooter. Six populations from throughout the U.S. and a population from Argentina identified as near G. ashmeadi were analyzed. Four populations (California; San Antonio, Texas; Weslaco, Texas [WTX-2]; and Florida) were field collected and two (Louisiana and Weslaco, Texas [WTX-1]) were reared. Three ISSR-PCR reactions were pooled to generate 41 polymorphic markers among the six U.S. populations. Nei's expected heterozygosity values (h), including the reared population from Louisiana, were high (9.01-14.3%) for all populations, except for a reared population from WTX-1 (2.9%). The total genetic diversity value (Ht) for the field populations was high (23%). Interestingly, the Florida population that was collected from one egg mass (siblings) generated the greatest number of polymorphic markers (20) and was observed with the highest gene diversity value (14.3%). All populations, except WTX-2 generated population-specific markers. Comparison of genetic differentiation estimates, which evaluate the degree of genetic subdivision, demonstrated good agreement between G(ST) and theta values, 0.38 and 0.50, respectively for field populations, and 0.44 and 0.50, respectively for all populations. Genetic divergence (D) indicated that the WTX-1 population was the most differentiated. Average D results from the Argentina population support the taxonomic data that it is a different species. The present results estimate the population genetic structure of G. ashmeadi, demonstrating genetic divergence and restricted gene flow (Nm = 0.83) among populations. These results are of interest to the Pierce's disease/glassy-winged sharpshooter biological control program because the key to successful biological control may not be in another species, but instead in different geographic races or biotypes.
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2,336,326 |
Retroviral insertional mutagenesis: past, present and future.
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Retroviral insertion mutagenesis screens in mice are powerful tools for efficient identification of oncogenic mutations in an in vivo setting. Many oncogenes identified in these screens have also been shown to play a causal role in the development of human cancers. Sequencing and annotation of the mouse genome, along with recent improvements in insertion site cloning has greatly facilitated identification of oncogenic events in retrovirus-induced tumours. In this review, we discuss the features of retroviral insertion mutagenesis screens, covering the mechanisms by which retroviral insertions mutate cellular genes, the practical aspects of insertion site cloning, the identification and analysis of common insertion sites, and finally we address the potential for use of somatic insertional mutagens in the study of nonhaematopoietic and nonmammary tumour types.
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2,336,327 |
Estimating the "effective number of codons": the Wright way of determining codon homozygosity leads to superior estimates.
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In 1990, Frank Wright introduced a method for measuring synonymous codon usage bias in a gene by estimation of the "effective number of codons," N(c). Several attempts have been made recently to improve Wright's estimate of N(c), but the methods that work in cases where a gene encodes a protein not containing all amino acids with degenerate codons have not been tested against each other. In this article I derive five new estimators of N(c) and test them together with the two published estimators, using resampling under rigorous testing conditions. Estimation of codon homozygosity, F, turns out to be a key to the estimation of N(c). F can be estimated in two closely related ways, corresponding to sampling with or without replacement, the latter being what Wright used. The N(c) methods that are based on sampling without replacement showed much better accuracy at short gene lengths than those based on sampling with replacement, indicating that Wright's homozygosity method is superior. Surprisingly, the methods based on sampling with replacement displayed a superior correlation with mRNA levels in Escherichia coli.
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2,336,328 |
Nano-carriers for DNA delivery to the lung based upon a TAT-derived peptide covalently coupled to PEG-PEI.
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Gene therapy aimed at the respiratory epithelium holds therapeutic potential for diseases such as cystic fibrosis and lung cancer. Polyethylenimine (PEI) has been utilized for gene delivery to the airways. In this study, we describe a new modification of PEI, in which an oligopeptide related to the protein transduction domain of HIV-1 TAT was covalently coupled to 25 kDa PEI (PEI) through a heterobifunctional polyethylenglycol (PEG) spacer resulting in a TAT-PEG-PEI conjugate. Improved DNA reporter gene complexation and protection was observed for small (approximately 90 nm) polyplexes as well as significantly improved stability against polyanions, Alveofact, bronchial alveolar lining fluid and DNase. To determine polyplex toxicity in vitro, MTT assays were performed and, for in vivo testing, the mice bronchial alveolar lavage was investigated for total cell counts, quantity of neutrophils, total protein and TNF-alpha concentration. All parameters suggest significantly lower toxicity for TAT-PEG-PEI. Transfection efficiencies of both PEI and TAT-PEG-PEI polyplexes with DNA were studied under in vitro conditions (A549) and in mice after intratracheal instillation. While luciferase expression in A549 cells was much lower for TAT-PEG-PEI (0.2 ng/mg protein) than for PEI (2 ng/mg), significantly higher transfection efficiencies for TAT-PEG-PEI were detected in mice. Reporter gene expression was distributed through bronchial and alveolar tissue. Thus, TAT-PEG-PEI represents a new approach to non-viral gene carriers for lung therapy, comprising protection for plasmid DNA, low toxicity and significantly enhanced transfection efficiency under in vivo conditions.
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2,336,329 |
Genetic testing for colon cancer among African-Americans in North Carolina.
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To describe attitudes and correlates of intention to take a genetic test for colon cancer in a population-based sample of African-Americans.</AbstractText>African-Americans (n = 658), age 18-70, in North Carolina completed an 11-page questionnaire between June-October 2003 that assessed attitudes (familiarity, perceived benefits and risks, anxiety, and confidentiality) and intention to take a genetic test for colon cancer and various participant characteristics.</AbstractText>Respondents expressed favorable attitudes and high intention regarding genetic testing for colon cancer: 87% would definitely/probably take a genetic test, although only 42% had read/heard a lot or some about genetic testing. Most agreed that genetic test results should be available to healthcare providers (79%) but not to health insurers (62%) or employers (82%). About a third were concerned that genetic testing could lead to discrimination. Correlates of intention differed by sex. Perceived benefits were significantly positively associated with intention among all respondents. However, being married (OR = 2.1, 95% CI: 1.2, 3.7), doctor as the main source of health information (OR = 2.4, 95% CI: 1.4, 3.9), and colon cancer family history (OR = 4.3, 95% CI: 1.6, 11.6) were significant only for women; some college education (OR = 4.1, 95% CI: 1.7, 9.7), importance of sharing test results with relatives (OR = 5.5, 95% CI: 1.6, 18.7), and colon cancer screening history (OR = 3.4, 95% CI: 1.6, 7.5) were only significant for men.</AbstractText>Respondents expressed high interest in genetic testing for colon cancer risk, although confidentiality of test results is a concern. Guidelines and policies for genetic testing specific to African-Americans should be established and future research should examine the prevalence of genetic testing.</AbstractText>
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2,336,330 |
Multiplex real-time PCR for detection of deletions and duplications in dystrophin gene.
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Genetic testing of Duchenne and Becker muscular dystrophies (DMD/BMD) is a difficult task due to the occurrence of deletions or duplications within dystrophin (DMD) gene that requires dose sensitive tests. We developed three multiplex quantitative real-time PCR assays for dystrophin exon 5, 45, and 51 within two major hotspots of deletion/duplication. Each exon was co-amplified with a reference X-linked gene and the copy number of the target fragment was calculated by comparative threshold cycle method (delta deltaC(t)). We compared the performance of this method with previously described end-point PCR fluorescent analysis (EPFA) by studying 24 subjects carrying DMD deletions or duplications. We showed that Q-PCR is an accurate and sensitive technique for the identification of deletions and duplications in DMD/BMD. Q-PCR is a valuable tool for independent confirmation of EPFA screening, particularly when deletions/duplications of single exons occur or for rapid identification of known mutations in at risk carriers.
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2,336,331 |
The bcl-2/IgH rearrangement in a population of 204 healthy individuals: occurrence, age and gender distribution, breakpoints, and detection method validity.
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This study assessed prevalence, frequency, age and gender distribution and breakpoint locations, and detection method validity for the bcl-2/IgH rearrangement in 204 healthy individuals. For this purpose, both classic two-step, nested, semi-quantitative PCR as well as a newly established sequence-specific, hybridization probe-based real-time quantitative PCR (RQ-PCR) were employed and tested for their sensitivity and specificity for detecting t(14;18) positive cells in healthy blood donors. Interestingly, almost a quarter (24%; 39/204) of all healthy individuals carried the translocation, confirming data of one large prior report [Summers KE, Goff LK, Wilson AG, Gupta RK, Lister TA, Fitzgibbon J. Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma. J Clin Oncol 2001;19(2):420-4]. Regarding presence as well as frequency of the translocation, no correlation to age (mean frequency 2.0:10(4), with a median of <l:10(4), for <40 years, and mean frequency 1.9:10(4), with a median of <l:10(4) for individuals>or=40 years) nor gender was detected. Comparing the two PCR approaches, a 95.1% concordance (194/204) regarding t(14;18) detection was determined for nested and RQ-PCR, with nested PCR being slightly more sensitive (reproducible detection limit l:10(5) cells versus 1:10(4); maximum detection limit l:10(6) versus 1:10(5)). Sequence analysis confirmed individual breakpoints for all samples analyzed (29/29), indicating detection validity for both PCR approaches and ruling out contamination. The breakpoint location distribution pattern appeared to be comparable to the pattern seen with follicular lymphoma (FL) patient collectives. In conclusion, clonal bcl-2/IgH rearrangements are indeed a very frequent observation in healthy individuals, and appear to be independent of age and gender in regard to presence and frequency. This represents a conflicting finding in context of potential biological significance, and presents a potential disruptive factor for minimal residual disease (MRD) monitoring in FL patients. Prospective future trials will have to clarify the biological significance of this important observation.
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2,336,332 |
Interleukin (IL)-2 and IL-12 responses to Chlamydia trachomatis infection in adolescents.
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Chlamydia trachomatis infects epithelial cells at the mucosal surface. While in vitro and animal studies have shown changes in mucosal T(H)1-associated cytokines in the presence of C. trachomatis infection and with its progression to the upper genital tract or clearance, in vivo cytokine responses to chlamydial infection in humans are not well understood. Using a quantitative enzyme-linked immunosorbent assay (ELISA), we examined the endocervical production of two T(H)1-associated cytokines, i.e. interleukin (IL)-2 and IL-12, in relation to C. trachomatis infection in adolescents. At a randomly selected visit for 396 females, median endocervical IL-2 levels were significantly lower (190 versus 283 pg/ml, P = 0.02) and median IL-12 levels significantly higher (307 versus 132 pg/ml, P < 0.001) in subjects testing positive versus negative for C. trachomatis. These divergent T(H)1-associated cytokine responses were: (1) confirmed in paired analyses of 96 individuals before and after infection within 6-month intervals, (2) reversible in 97 patients who cleared infection during consecutive visits, (3) not attributable to sociodemographic factors or other genital infections and (4) independent of common genetic variants at the IL2 and IL12B loci associated previously with differential gene expression. From these findings we infer that increased IL-12 and decreased IL-2, observed commonly during mucosal inflammation, are important features of mucosal immune defence against C. trachomatis infection.
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2,336,333 |
Translating RNA interference into therapies for human disease.
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RNA interference (RNAi) represents one of the most promising new frontiers in drug discovery. Breakthroughs in understanding RNA's extensive natural role in essential cellular processes have opened up the potential for a whole new class of drugs based on RNAi. Harnessing the natural process of RNAi, short, double-stranded RNA molecules are able to inhibit expression of genes in a sequence-specific manner. By targeting disease-causing genes, RNAi drugs have the potential to be more selective than traditional drugs, and thus more effective as well as less toxic. Over the past few years, important strides have been made in translating the promise of RNAi into therapies for human disease. In contrast to the extensive lead optimization steps typically required in small-molecule and protein drug discovery, RNAi drug candidates can be identified using bioinformatics to select sequences complementary to the target mRNA. The process of selecting an RNAi-based drug candidate may simply involve the synthesis and testing of a relatively small number of short double strands (duplexes) of RNA, incorporating chemical modifications that confer stability and direct these RNA duplexes to the appropriate tissues and cells, and/or formulating these RNA duplexes with appropriate delivery agents to achieve the same goals. As advances in RNAi therapeutics continue, the decades to come should bring a potent new class of drugs based on RNAi.
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2,336,334 |
Pharmacogenomics and drug development.
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It is generally anticipated that pharmacogenomic information will have a large impact on drug development and will facilitate individualized drug treatment. However, there has been relatively little quantitative modeling to assess how pharmacogenomic information could be best utilized in clinical practice. Using a quantitative model, this review demonstrates that efficacy is increased and toxicity is reduced when a genetically-guided dose adjustment strategy is utilized in a clinical trial. However, there is limited information available regarding the genetic variables affecting the disposition or mechanism of action of most commonly used medications. These genetic factors must be identified to enable pharmacogenomic testing to be routinely used in the clinic. A recently described murine haplotype-based computational genetic analysis method provides one strategy for identifying genetic factors regulating the pharmacokinetics and pharmacodynamics of commonly used medications.
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2,336,335 |
Hemophilia: a practical approach to genetic testing.
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Hemophilia and von Willebrand disease together account for the large majority of congenital bleeding disorders. Contemporary management, including development of safer clotting factor concentrates and increased emphasis on long-term follow-up in comprehensive hemophilia centers, has improved both quality of life and longevity for patients with congenital bleeding disorders. In addition to facilitating development of recombinant clotting factor concentrates, isolation and characterization of the respective genes have led to increasing availability of a repertoire of genetic tests that, although expensive, are critical for appropriate genetic counseling of affected patients and their family members. This article provides a practical approach to using genetic testing for hemophilia A and B.
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2,336,336 |
Multipoint linkage disequilibrium mapping using case-control designs.
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Case-control study has been and continues to be one of the most popular designs in epidemiology. More recently, this design has been adopted to test for candidate genes when searching for disease genetic etiology. In this report, we present a multipoint linkage disequilibrium (LD) mapping approach with the focus on estimating the location of the target trait locus. It builds upon a representation, which shows that the difference between a case and a control in probabilities of carrying the target allele of a marker is proportional to that of the trait locus and that the proportionality factor is simply a measure of LD between the trait locus and the marker. Our method has the desired properties that (1) there is no need to specify phases of genotypic data with multiple markers, (2) it provides an estimate of location of the disease locus along with sampling uncertainty to help investigators to narrow chromosomal regions, and (3) a single test statistic is provided to test for LD in the framed region rather than testing the hypothesis one marker at a time. Our simulation work suggests that the proposed method performs well in terms of bias and coverage probability. Extension of the proposed method to account for confounding and genetic heterogeneity is discussed. We apply the proposed method to a published case-control data set for cystic fibrosis.
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2,336,337 |
Application of bovine microsatellite markers for genetic diversity analysis of Swiss yak (Poephagus grunniens).
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In order to assess the applicability of bovine microsatellite markers for population genetic studies in Swiss yak, 131 bovine microsatellite markers were tested on a panel of 10 animals. Efficient amplification was observed for 124 markers (94.6%) with a total of 476 alleles, of which 117 markers (94.3%) were polymorphic. The number of alleles per locus among the polymorphic markers ranged from two to nine. Seven loci (ILSTS005, BMS424B, BMS1825, BMS672, BM1314, ETH123 and BM6017) failed to amplify yak genomic DNA. Two cattle Y-chromosome specific microsatellite markers (INRA126 and BM861) amplified genomic DNA from both male and female yaks. However, two additional markers on cattle Y-chromosome (INRA124 and INRA189) amplified DNA from only males. Of the polymorphic markers, 24 microsatellites proposed by CaDBase for within- and cross-species comparisons and two additional highly polymorphic markers (MHCII and TGLA73) were used to investigate the genetic variability and the population structure of a Swiss yak herd that included 51 additional animals. The polymorphic information content ranged from 0.355 to 0.752, while observed heterozygosity (HO) ranged from 0.348 to 0.823. Furthermore, a set of 13 markers, organized into three multiplex polymerase chain reactions, was evaluated for routine parentage testing. This set provided an exclusion probability in a family of four yaks (both parents and two offspring) of 0.995. These microsatellites serve as useful tools for genetic characterization of the yak, which continues to be an important domestic livestock species.
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2,336,338 |
Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia.
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Lungs are the central organ affected and targeted by Mycobacterium tuberculosis and immune processes in the lung are of critical importance in the pathogenesis of tuberculosis. A major lung defense against invading pathogens is provided by surfactant protein A, a multi-chain protein encoded by the SFTPA1 and SFTPA2 genes. Here, we investigated polymorphisms in the SFTPA1 and SFTPA2 genes for association with tuberculosis in 181 Ethiopian families comprising 226 tuberculosis cases. Four polymorphisms, SFTPA1 307A, SFTPA1 776T, SFTPA2 355C, and SFTPA2 751C, were associated with tuberculosis (P=0.00008; P=0.019, P=0.029 and P=0.042, respectively). Additional subgroup analysis in male, female and more severely affected patients provided evidence for SFTPA1/2-covariate interaction. Finally, out of five intragenic haplotypes identified in the SFTPA1 gene and nine identified in the SFTPA2 gene, 1A(3) was most significantly associated with tuberculosis susceptibility (P=0.026). These findings suggest that SFTPA1 and SFTPA2 modify the risk of tuberculosis susceptibility and that this risk is influenced by additional covariates.
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2,336,339 |
An unexpected Cowden syndrome case found among members of a large familial adenomatous polyposis kindred.
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Genetic testing is now considered the standard of care in the management of familial adenomatous polyposis (FAP). Non-carriers of mutations are excluded from endoscopic surveillance. During the systematic screening of the relatives of an affected member with FAP, one non-carrier of APC mutations was unexpectedly found with the typical Cowden syndrome phenotype. One large Algerian family with FAP was screened for an APC germline mutation. Moreover, we also performed a mutation search in the Cowden syndrome member for PTEN, BMPR1A or MADH4 (SMAD4) germline mutations. We identified a mutation in the APC gene that results in a truncated protein (Y935X) in the FAP proband, and subsequently in 12 FAP-affected members. Among the 12 APC mutation-negative members of this family, we found one member with the Cowden disease phenotype. However, the mutation analysis in the PTEN gene and the two other genes involved in juvenile polyposis, namely BMPR1A and MADH4 (SMAD4), in the Cowden syndrome patient failed to show any pathogenic mutation. Genetic testing is a powerful tool that can provide a definitive diagnosis for FAP. However, not all polyposes in the FAP family are adenomatous polyposes.
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2,336,340 |
Predisposing HLA-DQ2 and HLA-DQ8 haplotypes of coeliac disease and associated enteropathy in microscopic colitis.
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To assess the presence of both genetic and serological markers of coeliac disease in patients with microscopic colitis, and whether there was associated enteropathy.</AbstractText>HLA-DQ2, HLA-DQ8, serum immunoglobulin A-antiendomysial and immunoglobulin A-anti-tissue transglutaminase antibodies were investigated in 59 patients with microscopic colitis. Seventy healthy subjects acted as the control group. Endoscopic biopsies from the distal duodenum were obtained in DQ2-positive or DQ8-positive patients. Patients with histological changes compatible with gluten-sensitive enteropathy were started on a gluten-free diet.</AbstractText>Seventeen of 70 (24.3%) healthy controls were DQ2-positive. Twelve of 25 (48%) patients with lymphocytic colitis (P = 0.027 versus controls), and 11 of 34 (32.3%) with collagenous colitis (P = 0.38 versus controls) were DQ2-positive. There were no differences in the frequency of DQ8-positivity. The coeliac serology was positive in one patient. Duodenal biopsies were performed in 23 DQ2-positive and/or DQ8-positive patients. None had villous atrophy (Marsh III lesion) (0%; 95% confidence interval, 0-6.1). A Marsh type I lesion was found in four patients. Three of these patients were put on a gluten-free diet with disappearance of diarrhoea.</AbstractText>The results suggest that there is an association of lymphocytic colitis with HLA-DQ2 genes, which might be relevant in the pathogenesis of this disease. The association of microscopic colitis with Marsh type III coeliac disease seems to be rare, making it unnecessary to routinely screen for coeliac disease in microscopic colitis patients.</AbstractText>
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2,336,341 |
Rapid disease progression correlates with instability of mutant SOD1 in familial ALS.
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Studies on the clinical course of familial ALS suggest that the duration of illness is relatively consistent for each mutation but variable among the different mutations. The authors analyzed the relative amount of mutant compared with normal SOD1 protein in the erythrocytes from 29 patients with ALS with 22 different mutations. Turnover of mutant SOD1 correlated with a shorter disease survival time.
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2,336,342 |
DNA sequence analysis of the genetic environment of various blaCTX-M genes.
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Over a 3 year period (2000-2003) 21 Escherichia coli, 5 Klebsiella pneumoniae, 1 Serratia marcescens and 1 Proteus mirabilis producing CTX-M-type beta-lactamase were collected from five different hospitals in Paris, France. This study was conducted to analyse the genetic environment of these 28 bla(CTX-M) genes.</AbstractText>Antimicrobial susceptibility testing was performed by the disc diffusion method and MICs of various beta-lactams were determined by an agar dilution method. PCR was used to detect and sequence alleles encoding CTX-M, TEM, SHV and CMY enzymes. The genetic environment was analysed by amplification and direct sequencing using various set of PCR primers or cloning in pBK-CMV.</AbstractText>Sequence analysis revealed that these isolates contained seven different bla(CTX-M) genes: bla(CTX-M-1) (4 strains), bla(CTX-M-2) (2 strains), bla(CTX-M-3) (4 strains), bla(CTX-M-9) (1 strain), bla(CTX-M-14) (5 strains), bla(CTX-M-15) (11 strains), bla(CTX-M-24) (1 strain). TEM-1 was associated with CTX-M-type enzymes in 15 isolates. Two strains produced both CTX-M-15 and SHV-2 or CTX-M-14 and CMY-2. In 25 strains the insertion sequence ISEcp1 was located upstream of the 5' end of the bla(CTX-M) gene. Among these strains, in five isolates, ISEcp1 was disrupted by insertion sequences such as IS26 (in three of them) or IS1 or IS10. Insertion sequence IS903 was found downstream of bla(CTX-M-14) or bla(CTX-M-24). Examination of the other three bla(CTX-M) genes (two bla(CTX-M-2) and one bla(CTX-M-9)) by cloning, sequencing and PCR analysis revealed the presence of complex Class 1 integrons, In35, an integron similar to In60 and a novel integron.</AbstractText>This work further confirmed the predominant role of ISEcp1 in the mobilization of bla(CTX-M) genes of the CTX-M-1 cluster and the presence of In35, of an integron similar to In60 and a novel complex Class 1 integron.</AbstractText>
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2,336,343 |
Medium-chain acyl-CoA dehydrogenase deficiency: genotype-biochemical phenotype correlations.
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The fatty acid oxidation disorder most commonly identified by tandem mass spectrometry newborn screening is the potentially fatal medium-chain acyl-CoA dehydrogenase deficiency (MCAD). In clinically presenting cases, 80% are homozygous for the common mutation, c.985A > G and 18% heterozygous. We screened 592,785 babies and identified 34 with MCAD, 17 homozygous for c.985A > G, 14 with one copy, and 3 with no copy. We sequenced the exons of 19 patients, the 17 carrying one or no copy of c.985A > G, and two with marginal findings, and examined correlations between groups of mutations and biochemical markers. We found two known or putative pathogenic mutations in 18 of the 19 patients. Two mutations appeared more than once: c.199T > C, not recorded in clinically presenting cases (n = 4), and c.583G > A (n = 2). Patients homozygous for c.985A > G had the highest levels of neonatal octanoylcarnitine, plasma octanoylcarnitine when asymptomatic, and urinary acylglycines. Compound heterozygotes of c.985A > G and other mutations had intermediate levels, and those without c.985A > G, or heterozygous for that and c.199T > C had the lowest levels of these analytes. There was overlap in all values. The c.985A > G and c.583G > A mutations appear to have functional effects towards the severe end of the spectrum, and the c.199T > C mutation a smaller effect, as has been previously postulated. If these results are confirmed and extended, this could influence the advice given to parents of babies with MCAD detected by newborn screening, and make management more specific. In the meantime, all MCAD patients identified by newborn screening have, by definition, a functional defect and require careful clinical management.
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2,336,344 |
Testing of primers for the study of cyanobacterial molecular diversity by DGGE.
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Denaturing Gradient Gel electrophoresis (DGGE) is a PCR-based technique which is widely used in the study of microbial communities. Here, the use of the three specific 16S rRNA cyanobacterial specific primers CYA359F, CYA781R(a) and CYA781R(b) on the assessment of the molecular diversity of cyanobacterial communities is examined. Assignments of the reverse primers CYA781R(a) and CYA781R(b) with cyanobacterial strain sequences showed that the former preferentially targets filamentous cyanobacteria whereas the latter targets unicellular cyanobacteria. The influence of the GC clamp position on the forward or on reverse primer and the use of the two reverse primers separately or in equimolar mixture were investigated. Three environmental samples were subjected to amplification with 6 combinations of primers. The 6 banding patterns as well as the sequences of the bands extracted were analysed and compared. In addition, to assess the effect of the position of the GC clamp, the melting profiles of the sequences of Aphanizomenon flos-aquae PMC9707 and Synechococcus sp. MH305 were determined, with the GC clamp in the 3' or 5' position. Results showed that the use of two separate amplifications allowed a more complete study of the molecular diversity of the cyanobacterial community investigated. Furthermore, similar richness and identical phylogenetic assignments of extracted bands were obtained irrespective of the positioning of the GC clamp.
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2,336,345 |
On being at higher risk: a qualitative study of prenatal screening for chromosomal anomalies.
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This paper explores the meaning of higher risk status to women undergoing prenatal maternal screening for chromosomal anomalies. Quotations from lightly structured interviews and transcripts of pre-screening consultations in suburban London are used to illustrate pregnant women's diverse responses to the offer of screening, and to entering, living with and exiting from higher risk status. Some women reject screening in order to avoid the psychosocial and medical risks associated with higher risk status, or because they rule out pregnancy termination. They may question the risk selection implicitly built into the provision of preventative systems for some health problems but not others. Women who screen at higher risk may challenge this designation by questioning the system-specific probability used to separate them from the lower risk population. However, some experience distress even when they appreciate the precautionary basis on which their higher risk designation is based. They may find disengagement from higher risk status difficult after a diagnostic test has ruled out chromosomal anomalies. The findings highlight the complexity of communicating risk information to pregnant women and other screened populations, and emphasise the need to support those living with higher risk status and the benefits of keeping the time lived with this status as short as possible.
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2,336,346 |
Dietary flavonoids: effects on xenobiotic and carcinogen metabolism.
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Flavonoids are present in fruits, vegetables and beverages derived from plants (tea, red wine), and in many dietary supplements or herbal remedies including Ginkgo Biloba, Soy Isoflavones, and Milk Thistle. Flavonoids have been described as health-promoting, disease-preventing dietary supplements, and have activity as cancer preventive agents. Additionally, they are extremely safe and associated with low toxicity, making them excellent candidates for chemopreventive agents. The cancer protective effects of flavonoids have been attributed to a wide variety of mechanisms, including modulating enzyme activities resulting in the decreased carcinogenicity of xenobiotics. This review focuses on the flavonoid effects on cytochrome P450 (CYP) enzymes involved in the activation of procarcinogens and phase II enzymes, largely responsible for the detoxification of carcinogens. A number of naturally occurring flavonoids have been shown to modulate the CYP450 system, including the induction of specific CYP isozymes, and the activation or inhibition of these enzymes. Some flavonoids alter CYPs through binding to the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, acting as either AhR agonists or antagonists. Inhibition of CYP enzymes, including CYP 1A1, 1A2, 2E1 and 3A4 by competitive or mechanism-based mechanisms also occurs. Flavones (chrysin, baicalein, and galangin), flavanones (naringenin) and isoflavones (genistein, biochanin A) inhibit the activity of aromatase (CYP19), thus decreasing estrogen biosynthesis and producing antiestrogenic effects, important in breast and prostate cancers. Activation of phase II detoxifying enzymes, such as UDP-glucuronyl transferase, glutathione S-transferase, and quinone reductase by flavonoids results in the detoxification of carcinogens and represents one mechanism of their anticarcinogenic effects. A number of flavonoids including fisetin, galangin, quercetin, kaempferol, and genistein represent potent non-competitive inhibitors of sulfotransferase 1A1 (or P-PST); this may represent an important mechanism for the chemoprevention of sulfation-induced carcinogenesis. Importantly, the effects of flavonoids on enzymes are generally dependent on the concentrations of flavonoids present, and the different flavonoids ingested. Due to the low oral bioavailability of many flavonoids, the concentrations achieved in vivo following dietary administration tend to be low, and may not reflect the concentrations tested under in vitro conditions; however, this may not be true following the ingestion of herbal preparations when much higher plasma concentrations may be obtained. Effects will also vary with the tissue distribution of enzymes, and with the species used in testing since differences between species in enzyme activities also can be substantial. Additionally, in humans, marked interindividual variability in drug-metabolizing enzymes occurs as a result of genetic and environmental factors. This variability in xenobiotic metabolizing enzymes and the effect of flavonoid ingestion on enzyme expression and activity can contribute to the varying susceptibility different individuals have to diseases such as cancer. As well, flavonoids may also interact with chemotherapeutic drugs used in cancer treatment through the induction or inhibition of their metabolism.
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2,336,347 |
Muscle biopsy without centrally located nuclei in a male child with mild X-linked myotubular myopathy.
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In children with a myopathy, muscle biopsy, together with the clinical presentation, can guide further investigations. The presence of centrally located nuclei suggests a myotubular myopathy, and gene testing may confirm this diagnosis. We describe a male child with a mild form of X-linked myotubular myopathy for which repeated muscle biopsy did not show the characteristic pattern of centrally located nuclei. Myotubular myopathy was not contemplated, therefore, until a maternally related relative was shown to have the disorder. Genetic testing showed that the index case carried the same mutation in his MTM1 gene as this relative.
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2,336,348 |
Classification of microarray data with factor mixture models.
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The classification of few tissue samples on a very large number of genes represents a non-standard problem in statistics but a usual one in microarray expression data analysis. In fact, the dimension of the feature space (the number of genes) is typically much greater than the number of tissues. We consider high-density oligonucleotide microarray data, where the expression level is associated to an 'absolute call', which represents a qualitative indication of whether or not a transcript is detected within a sample. The 'absolute call' is generally not taken in consideration in analyses.</AbstractText>In contrast to frequently used cluster analysis methods to analyze gene expression data, we consider a problem of classification of tissues and of the variables selection. We adopted methodologies formulated by Ghahramani and Hinton and Rocci and Vichi for simultaneous dimensional reduction of genes and classification of tissues; trying to identify genes (denominated 'markers') that are able to distinguish between two known different classes of tissue samples. In this respect, we propose a generalization of the approach proposed by McLachlan et al. by advising to estimate the distribution of log LR statistic for testing one versus two component hypothesis in the mixture model for each gene considered individually, using a parametric bootstrap approach. We compare conditional (on 'absolute call') and unconditional analyses performed on dataset described in Golub et al. We show that the proposed techniques improve the results of classification of tissue samples with respect to known results on the same benchmark dataset.</AbstractText>The software of Ghahramani and Hinton is written in Matlab and available in 'Mixture of Factor Analyzers' on http://www.gatsby.ucl.ac.uk/~zoubin/software.html while the software of Rocci and Vichi is available upon request from the authors.</AbstractText>
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2,336,349 |
Fluorescence in situ hybridization for detecting transitional cell carcinoma: implications for clinical practice.
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To determine the diagnostic sensitivity of genetic studies using fluorescence in situ hybridization (FISH) for detecting both new and recurrent cases of transitional cell carcinoma (TCC) in a routine clinical practice setting, as bladder cancer has a significant risk of recurrence and progression to invasive disease and thus sensitive surveillance testing is very important.</AbstractText>FISH was performed using the UroVysion kit (Vysis Inc., Downers Grove, IL, USA) Consecutive patients were assessed using FISH, both to evaluate those with a history of TCC or with suspicious symptoms, and the FISH results were compared with concurrent biopsy and cytological assessments.</AbstractText>In all, 521 consecutive FISH tests from 300 patients were evaluated; 47% had a history of bladder cancer and 53% had suspicious symptoms. Of the 521 FISH tests, 24% were positive; concurrent cytology was available for 84% of the FISH tests, with a concordance rate of 78% (6% were positive for both and 72% were negative by both tests). For the discordant cases, FISH was positive and cytology negative in 21% of cases, and cytology was positive with a negative FISH for 1%. In all, 99 FISH tests had concurrent biopsy data. Of the 44 cases histologically positive for TCC, 32 were FISH-positive, resulting in an overall sensitivity (95% confidence interval) of 73 (60-88)%. FISH detected 95% of cases with high-grade carcinoma, while only seven of these 17 were positive by concurrent cytological assessment. FISH detected 56% and cytology detected 32% of low-grade lesions. FISH detected all nine new cases with positive histology. Overall, the specificity of FISH was 65 (53-78)%. Of 112 patients with previous TCC, 28 had a recurrence; 22 of these had positive FISH results.</AbstractText>FISH analysis has a high sensitivity for detecting new cases of TCC, as well as recurrences. From the present data FISH is considerably more sensitive and only slightly less specific than cytology in diagnosing TCC. Therefore, we recommend FISH as a useful initial diagnostic tool in patients suspected of both new and recurrent TCC.</AbstractText>
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2,336,350 |
The frequency of mucolipidosis type IV in the Ashkenazi Jewish population and the identification of 3 novel MCOLN1 mutations.
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Mucolipidosis type IV (MLIV) is a neurodegenerative lysosomal storage disorder that occurs in an increased frequency in the Ashkenazi Jewish (AJ) population. The frequency of the disease in this population has been established by the testing of 66,749 AJ subjects in the Dor Yeshorim program, a unique premarital population-screening program designed for the Orthodox Jewish community. A carrier rate of 0.0104 (95% C.I 0.0097-0.011) was found. The distribution of the 2 AJ founder mutations, namely, c.416-2A>G and c.1_788del, was determined to be 78.15% and 21.85%, respectively. Three novel mutations were identified in non-Jewish MLIV patients, a missense mutation c.1207C>T, p.Arg403Cys; a 2bp deletion, c.302_303delTC; and a nonsense, c.235C>T, Gln79X.
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2,336,351 |
Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss.
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Mutations in the transmembrane channel-like gene 1 (TMC1) cause prelingual autosomal recessive (DFNB7/11) and postlingual progressive autosomal dominant (DFNA36) nonsyndromic hearing loss. To determine the genetic causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) in the northeast and east of Turkey, 65 unrelated families without mutations in the protein coding region of the GJB2 (GJB2-negative) were analyzed. A genomewide scan for homozygosity and linkage analysis in one of these families revealed a 13.2 cM critical region between D9S273 and D9S153 at chromosome 9p13.2-q21.31 with a maximum two-point lod score of 4.00 at theta=0.0 for marker D9S175. TMC1 is in this critical region. Homozygosity screening with intragenic markers for TMC1 in the remaining 64 families suggested involvement of this gene in three additional families. Subsequent sequencing of TMC1 in these four families revealed four novel homozygous mutations, c.776A>G [p.Tyr259Cys], c.821C>T [p.Pro274Leu], c.1334G>A [p.Arg445His], and c.1083_1087delCAGAT [p.Arg362ProfrX6]. Our results indicate that TMC1 mutations account for at least 6% (4/65) of ARNSHL in GJB2-negative Turkish families from the northeast and east of Turkey.
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2,336,352 |
High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome.
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Germline mutations in the STK11 gene have been identified in 10-70% of patients with Peutz-Jeghers syndrome (PJS), an autosomal-dominant hamartomatous polyposis syndrome. A second locus was assumed in a large proportion of PJS patients. To date, STK11 alterations comprise mainly point mutations; only a small number of large deletions have been reported. We performed a mutation analysis for the STK11 gene in 71 patients. Of these, 56 met the clinical criteria for PJS and 12 were presumed to have PJS because of mucocutaneous pigmentation only or bowel problems due to isolated PJS polyps. No clinical information was available for the remaining three patients. By direct sequencing of the coding region of the STK11 gene, we identified point mutations in 37 of 71 patients (52%). We examined the remaining 34 patients by means of the multiplex ligation-dependent probe amplification (MLPA) method, and detected deletions in 17 patients. In four patients the deletion extended over all 10 exons, and in eight patients only the promoter region and exon 1 were deleted. The remaining deletions encompassed exons 2-10 (in two patients), exons 2-3, exons 4-5, or exon 8. When only patients who met the clinical criteria for PJS are considered, the overall mutation detection rate increases to 94% (64% point mutations and 30% large deletions). No mutation was identified in any of the 12 presumed cases. In conclusion, we found that approximately one-third of the patients who met the clinical PJS criteria exhibited large genomic deletions that were readily detectable by MLPA. Screening for point mutations and large deletions by direct sequencing or MLPA, respectively, increased the mutation detection rate in the STK11 gene up to 94%. There may be still other mutations in the STK11 gene that are not detectable by the methods applied here. Therefore, it is questionable whether a second PJS locus exists at all.
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2,336,353 |
A panel of 20 highly variable microsatellite polymorphisms in rhesus macaques (Macaca mulatta) selected for pedigree or population genetic analysis.
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This paper reports 20 new microsatellite loci that are highly polymorphic in rhesus macaques (Macaca mulatta). We screened known human microsatellite loci to identify markers that are polymorphic in rhesus macaques, and then selected specific loci that show substantial levels of heterozygosity and robust, reliable amplification. The 20 loci reported here were chosen to include one highly informative microsatellite from each rhesus monkey autosomal chromosome. Fourteen of the 20 polymorphisms are tetranucleotide repeats, and all can be analyzed using standard PCR and electrophoresis procedures. These new rhesus markers have an average of 15.5 alleles per locus and average heterozygosity of 0.83. This panel of DNA polymorphisms will be useful for a variety of different genetic analyses, including pedigree testing, paternity analysis, and population genetic studies. Many of these loci are also likely to be informative in other closely related Old World monkey species.
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2,336,354 |
Multiplexed microsatellites for rapid identification and characterization of individuals and populations of Cercopithecidae.
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Cross-amplification of 15 human microsatellites was performed successfully in cynomolgus (Macaca fascicularis) and rhesus (M. mulatta) macaques and 11 other Cercopithecidae species of biomedical and conservation relevance. To allow for quick, efficient, and high-throughput genotyping to assess intra- and interspecific genetic variation, we performed three multiplex sets, each comprised of five markers from different parts of the genome (i.e., autosomes, the MHC region, and the X-chromosome). These multiplex sets are likely to reveal allelic divergence between taxa, which could be used for their discrimination. Population studies on three regional populations of M. fascicularis and one of M. mulatta revealed that most of the loci, with the exception of one monomorphic locus, displayed polymorphisms (the expected heterozygosities were 0.48-0.91 for M. fascicularis, and 0.61-0.93 for M. mulatta), which makes them useful for population genetics. For the multiplex set M1, including the nonlinked autosomal markers, low probabilities of identity were observed: P(ID) values ranged from 8 x 10(-7) to 3 x 10(-5). This multiplex set is reliable for forensic applications, such as individual identification, parentage testing, and kinship analysis, in wild and captive populations.
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2,336,355 |
Macrophage migration inhibitory factor promotes intestinal tumorigenesis.
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<AbstractText Label="BACKGROUND & AIMS" NlmCategory="OBJECTIVE">The cytokine macrophage migration inhibitory factor (MIF) is expressed throughout the human gastrointestinal tract. Recently, protumorigenic activity of MIF has been described in several cancer models. Therefore, we investigated the expression and function of MIF during the early stages of intestinal tumorigenesis.</AbstractText>MIF messenger RNA, protein, and tautomerase activity were measured in normal intestinal mucosa and adenomas from patients with sporadic colorectal adenomas and in the adenomatous polyposis coli (Apc)Min/+ mouse model of intestinal tumorigenesis. MIF function was investigated by using VACO-235 human colorectal adenoma cells in vitro and by testing the effect of genetic deletion of Mif on ApcMin/+ mouse intestinal tumorigenesis.</AbstractText>MIF expression and tautomerase activity were increased in human and ApcMin/+ mouse intestinal adenomas compared with adjacent normal mucosa. Up-regulation of MIF occurred mainly in epithelial cells (associated with an increasing grade of dysplasia), but also in stromal plasma cells. Exogenous MIF inhibited apoptosis and promoted anchorage-independent growth of VACO-235 cells (maximal at 100 ng/mL). Homozygous deletion of Mif was associated with a reduction in the number and size of ApcMin/+ mouse adenomas (P = .025 for the difference in large [>7-mm] tumors) and decreased angiogenesis (43% decrease in mean tumor microvessel density), but there was no alteration in epithelial cell apoptosis or proliferation.</AbstractText>MIF expression is increased in sporadic human colorectal adenomas, and exogenous MIF drives tumorigenic behavior of epithelial cells in vitro. Mif also promotes intestinal tumorigenesis (predominantly via angiogenesis) in the ApcMin/+ mouse. Therefore, MIF is a potential colorectal cancer chemoprevention target.</AbstractText>
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2,336,356 |
MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer.
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<AbstractText Label="BACKGROUND & AIMS" NlmCategory="OBJECTIVE">Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by heterozygous germline sequence mutations of DNA mismatch repair genes, most frequently MLH1 or MSH2. A novel molecular mechanism for HNPCC has recently been suggested by the finding of individuals with soma-wide monoallelic hypermethylation of the MLH1 gene promoter. In this study, we determined the frequency and role of germline epimutations of MLH1 in HNPCC.</AbstractText>A cohort of 160 probands from HNPCC families who did not harbor germline sequence mutations in the mismatch repair genes were screened for methylation of the MLH1 and EPM2AIP1 promoters by combined bisulfite and restriction analyses. Allelic expression and family transmission of MLH1 were determined using polymorphisms in intron 4 and the 3' untranslated region.</AbstractText>One of 160 individuals had monoallelic MLH1 hypermethylation in peripheral blood, hair follicles, and buccal mucosa, indicative of a soma-wide alteration. Monoallelic transcription of the paternal MLH1 allele was shown using a heterozygous expressed polymorphism within the 3' untranslated region. The hypermethylated allele was maternally transmitted, however, the mother and siblings who inherited the same maternal homologue were unmethylated at MLH1, suggesting the epimutation arose as a de novo event.</AbstractText>Germline MLH1 epimutations are functionally equivalent to an inactivating mutation and produce a clinical phenotype that resembles HNPCC. Inheritance of epimutations is weak, so family history is not a useful guide for screening. Germline epimutations should be suspected in younger individuals without a family history who present with a microsatellite unstable tumor showing loss of MLH1 expression.</AbstractText>
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2,336,357 |
Bioethics, sport and the genetically enhanced athlete.
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This paper begins by acknowledging the interest taken by various international organisations in genetic enhancement and sport, including the US President's Council on Bioethics (July, 2002) and the World Anti-Doping Agency (March, 2002). It is noticed how sporting organisations have been particularly concerned to emphasize the 'threat' of genetics to sport, whereas other institutions have recognised the broader bioethical issues arising from this prospect, which do not readily reject the use of genetic technology in sport. Sports are identified as necessarily 'human' and 'moral' practices, the exploration of which can reveal greater insight into the intuitive fears about genetic modification. It is argued that anti-doping testing measures and sanctions unacceptably persecute the athlete. While there are substantial reasons to be concerned about the use of genetic modification in sport, the desire for policy ought not diminish the need for ethical research; nor ought such research embody the similar guise of traditional 'anti' doping strategies. Rather, the approach to genetics in sport must be informed more by broader social policies in bioethics and recognition of the greater goods arising from genetic technology.
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2,336,358 |
Ethical perspectives on life sciences research after mapping the human genome.
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The essay discusses ethical perspectives of life sciences research that can help us navigate a path across the genetic landscape that opens before us with the map of the human genome that was announced recently. We can rightly anticipate many drug discoveries and genetic therapies to cure, prevent, or alleviate devastating conditions. But we must also pause with appropriate apprehension about the possible dangers and difficulties we may encounter.
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2,336,359 |
Molloy v. Meier.
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Court Decision: 660 North Western Reporter, 2d Series 444; 2003 May 6 (date of decision). The Minnesota Court of Appeals, held that physicians consulted by a mother regarding the genetic condition of her child must advise her pursuant to the appropriate standard.. Kimberly Molloy consulted with defendant physicians about her biological daughter's developmental and behavioral problems. Meier, the defendant physician, suspected the child had Fragile X Syndrome and ordered genetic testing, but did not followup after Fragile X test results were not in the report she received. Molloy consulted with other physicians about her daughter and they too failed to diagnose or test the child. Molloy subsequently gave birth to another child, with her second husband, and this child also had Fragile X Syndrome. The court also held that, even if Molloy did not consult with the physician directly, a physician must notify a minor child's biological parent of a genetic abnormality. Molloy's suit was considered a wrongful conception suit, not a wrongful birth claim, because the alleged damage occurred at the conception of the second affected child and the plaintiff did not claim she would have aborted the child had a proper diagnosis been made.
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2,336,360 |
BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.
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It is believed that BRCA1 and BRCA2 germline mutations account for the majority of hereditary ovarian carcinomas; however, to the authors' knowledge, there are scant data on the prevalence and spectrum of mutations, genotype/phenotype correlations, tumor histology, and family history characteristics. To address this gap, the authors conducted a population-based study of 232 incident epithelial ovarian carcinomas in the Tampa Bay area.</AbstractText>Genetic testing for the BRCA1 and BRCA2 genes was performed through full sequencing and BRCA1 rearrangement testing.</AbstractText>Of 209 women with invasive ovarian carcinoma, 32 women (15.3%) had mutations in BRCA1 or BRCA2, including 20 BRCA1 mutations and 12 BRCA2 mutations. Of the BRCA2 mutations, 58% were outside the "ovarian cancer cluster region" (OCCR). Variants of uncertain significance were detected in 8.2% of women with invasive ovarian carcinoma. No mutations were identified in women with borderline or invasive mucinous tumors. Among the BRCA mutation-positive women, 63% had serous tumors. A family history of breast and/or ovarian carcinoma was reported in 65%, 75%, and 43.5% of relatives of BRCA1 carriers, BRCA2 carriers, and non-BRCA1/BRCA2 carriers, respectively.</AbstractText>The data from this study suggested that 1) previous studies may have underestimated the frequency of BRCA1 and BRCA2 mutations in ovarian carcinomas, especially outside the OCCR; 2) it may be reasonable to offer genetic counseling to any woman with an invasive, nonmucinous epithelial ovarian tumor; and 3) among patients with invasive ovarian carcinoma, family history is not sufficiently accurate to predict mutation status.</AbstractText>Copyright 2005 American Cancer Society.</CopyrightInformation>
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2,336,361 |
Bioengineering lactic acid bacteria to secrete the HIV-1 virucide cyanovirin.
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An urgent need exists to prevent the sexual transmission of HIV-1. With prevalence rates exceeding 35% in parts of sub-Saharan Africa, increasing attention has been placed on developing and testing microbicidal agents capable of preventing virus transmission at mucosal sites. HIV-1 microbicides must meet several requirements before their widespread use. The drugs must be able to neutralize a diversity of HIV-1 strains, not induce mucosal inflammation, be associated with minimal side effects, and be effective for a prolonged period after a single application. Recent work has demonstrated the utility of recombinant lactic acid bacteria (LAB) as agents of mucosal drug delivery. Here, we describe the bioengineering of strains of LAB to secrete the prototypic virucidal compound cyanovirin (CV-N) and demonstrate the anti-HIV-1 activity of secreted CV-N. Our results suggest that recombinant LAB may serve as effective microbicidal compounds and deserve in vivo testing in simian immunodeficiency virus models of mucosal virus transmission.
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2,336,362 |
Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax.
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While testing the functions of deletion mutants in the Hox protein Ultrabithorax (Ubx), we found that the embryonic repression function of Ubx on Distal-less transcription in limb primordia is highly concentration dependent. The steep sigmoidal relationship between in vivo Ubx concentration and Distal-less repression is dependent on the Ubx YPWM motif. This suggests that Ubx cooperatively assembles a multi-protein repression complex on Distal-less regulatory DNA with the YPWM motif as a key protein-protein interface in this complex. Our deletion mutants also provide evidence for a transcriptional activation domain in the N-terminal 19 amino acids of Ubx. This proposed activation domain contains a variant of the SSYF motif that is found at the N termini of many Hox proteins, and is conserved in the activation domain of another Hox protein, Sex combs reduced. These results suggest that the N-terminal region containing the SSYF motif has been conserved in many Hox proteins for its role in transcriptional activation.
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2,336,363 |
Testing for adaptive evolution of the female reproductive protein ZPC in mammals, birds and fishes reveals problems with the M7-M8 likelihood ratio test.
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Adaptive evolution appears to be a common feature of reproductive proteins across a very wide range of organisms. A promising way of addressing the evolutionary forces responsible for this general phenomenon is to test for adaptive evolution in the same gene but among groups of species, which differ in their reproductive biology. One can then test evolutionary hypotheses by asking whether the variation in adaptive evolution is consistent with the variation in reproductive biology. We have attempted to apply this approach to the study of a female reproductive protein, zona pellucida C (ZPC), which has been previously shown by the use of likelihood ratio tests (LRTs) to be under positive selection in mammals.</AbstractText>We tested for evidence of adaptive evolution of ZPC in 15 mammalian species, in 11 avian species and in six fish species using three different LRTs (M1a-M2a, M7-M8, and M8a-M8). The only significant findings of adaptive evolution came from the M7-M8 test in mammals and fishes. Since LRTs of adaptive evolution may yield false positives in some situations, we examined the properties of the LRTs by several different simulation methods. When we simulated data to test the robustness of the LRTs, we found that the pattern of evolution in ZPC generates an excess of false positives for the M7-M8 LRT but not for the M1a-M2a or M8a-M8 LRTs. This bias is strong enough to have generated the significant M7-M8 results for mammals and fishes.</AbstractText>We conclude that there is no strong evidence for adaptive evolution of ZPC in any of the vertebrate groups we studied, and that the M7-M8 LRT can be biased towards false inference of adaptive evolution by certain patterns of non-adaptive evolution.</AbstractText>
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2,336,364 |
An optimized DHPLC protocol for molecular testing of the EXT1 and EXT2 genes in hereditary multiple osteochondromas.
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Hereditary multiple osteochondromas (MO) is an autosomal dominant bone disorder characterized by the presence of bony outgrowths (osteochondromas or exostoses) on the long bones. MO is caused by mutations in the EXT1 or EXT2 genes, which encode glycosyltransferases implicated in heparan sulfate biosynthesis. Standard mutation analysis performed by sequencing analysis of all coding exons of the EXT1 and EXT2 genes reveals a mutation in approximately 80% of the MO patients. We have now optimized and validated a denaturing high-performance liquid chromatography (DHPLC)-based protocol for screening of all EXT1- and EXT2-coding exons in a set of 49 MO patients with an EXT1 or EXT2 mutation. Under the optimized DHPLC conditions, all mutations were detected. These include 20 previously described mutations and 29 new mutations - 20 new EXT1 and nine new EXT2 mutations. The protocol described here, therefore, provides a sensitive and cost-sparing alternative for direct sequencing analysis of the MO-causing genes.
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2,336,365 |
Assessment of the genetic causes of recessive childhood non-syndromic deafness in the UK - implications for genetic testing.
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Approximately one in 2000 children is born with a genetic hearing impairment, mostly inherited as a non-syndromic, autosomal recessive trait, for which more than 30 different genes have been identified. Previous studies have shown that one of these genes, connexin 26 (GJB2), accounts for 30-60% of such deafness, but the relative contribution of the many other genes is not known, especially in the outbred UK population. This lack of knowledge hampers the development of diagnostic genetic services for deafness. In an effort to determine the molecular aetiology of deafness in the population, 142 sib pairs with early-onset, non-syndromic hearing impairment were recruited. Those in whom deafness could not be attributed to GJB2 mutations were investigated further for other mapped genes. The genetic basis of 55 cases (38.7%) was established, 33.1% being due to mutations in the GJB2 gene and 3.5% due to mutations in SLC26A4. None of the remaining 26 loci investigated made a significant contribution to deafness in a Caucasian population. We suggest that screening the GJB2 and SLC26A4 genes should form the basis of any genetic testing programme for childhood deafness and highlight a number of important issues for consideration and future work.
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2,336,366 |
Loss of heterozygosity testing using real-time PCR analysis of single nucleotide polymorphisms.
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Colon cancer is a genetic disease, caused by mutations in different oncogenes and tumor-suppressor genes. The aim of this study is to evaluate the usefulness of real-time PCR SNP analysis as a new technique in the loss of heterozygosity (LOH) analysis at the E-cadherin gene locus in sporadic colon cancer.</AbstractText>One-hundred cases of human sporadic colon cancer and corresponding normal tissue samples were analyzed using two flanking polymorphic markers commonly used in the LOH analysis at the E-cadherin gene locus by conventional VNTR-LOH analysis. Two intragenic E-cadherin SNP markers were analyzed using real-time PCR SNP analysis.</AbstractText>LOH (17.6%) was detected using flanking markers, however, no LOH was detected when the intragenic E-cadherin SNP markers were introduced into our study. Since these markers are intragenic they more accurately represent the status of the E-cadherin gene than the previously used flanking markers.</AbstractText>In conclusion, real-time PCR SNP analysis was found to be more accurate, faster, simpler, and a more high-throughput method than the conventional VNTR-LOH analysis.</AbstractText>
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2,336,367 |
Advances in X-linked mental retardation.
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Mutations in genes on the X chromosome rival chromosome aberrations as a cause of mental retardation. Progress in the clinical and molecular delineation of X-linked mental retardation has outpaced progress in understanding autosomal mental retardation. This is a result in large part of the identification of large families in which mental retardation has segregated in an X-linked pattern and the greater ease with which molecular technologies can be applied to hemizygosity in males.</AbstractText>About one-third of the estimated 165 genes associated with syndromal mutations of genes on the X chromosome and one-fourth of the estimated 100 genes associated with nonsyndromal mutations of genes on the X chromosome have been identified. In a number of instances, the same gene is responsible for syndromal and nonsyndromal mutations of genes on the X chromosome. The molecular delineation of mutations of genes on the X chromosome has allowed certain conditions to be lumped together on the basis of allelism and has caused others that appear clinical similar to remain separate.</AbstractText>The clinical and molecular advances have allowed X-linked mental retardation to be more clearly delineated, have provided the means of confirmatory laboratory testing, and have ushered in an era of carrier testing, prenatal diagnosis, and prevention strategies.</AbstractText>
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2,336,368 |
The use of genetic testing in the evaluation of hearing impairment in a child.
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To review the role of genetic testing in the evaluation of hearing impairment in children.</AbstractText>The introduction of genetic testing has greatly enhanced the evaluation of deafness and hearing impairment in children. It can save time and money as well as providing patients, their families, and their physicians with important information; however, this testing is different from the medical testing that pediatricians typically order.</AbstractText>For patients and families to realize the benefits of genetic testing it must be done early in the evaluation process and must be accompanied by appropriate pretest and posttest counseling.</AbstractText>
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2,336,369 |
Clinical course of hearing and language development in GJB2 and non-GJB2 deafness following habilitation with hearing aids.
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Mutations in the GJB2 gene (connexin 26) are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss. Genetic testing of GJB2 may offer opportunities to predict the features of hearing loss and prognostication of speech-language development in children with hearing loss. The present study assessed the clinical features of hearing and some aspects of language development in congenital deafness due either to GJB2 mutations or to other factors in Japanese patients who had been habilitated with hearing aids. Thirty-five unrelated subjects with nonsyndromic, congenital, bilateral sensorineural hearing loss were enrolled in the study. Among them, 16 had biallelic GJB2 mutations related to hearing loss and 17 lacked such mutations. As has been reported in populations of European ancestry, the present Japanese subjects with GJB2 mutations had a relatively high incidence of the flat pattern audiogram and nonprogressive pure tone thresholds compared with subjects without GJB2 mutations. Subjects with GJB2 mutations and those without GJB2 mutations both showed a similar tendency in speech perception, some aspects of language development, and communication methods. In both groups, development of reading ability tended to be normal, but vocabulary development tended to be delayed. The present results establish the basis for future studies to aid in the evaluation and follow-up of patients with congenital hearing loss associated with GJB2 mutations who are habilitated with hearing aids.
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2,336,370 |
[Identification of response element gene sequence for non-steroid hormone transcription factors for the activation and up-regulation of L-plastin expression in prostate cancer].
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To search and identify the non-steroid receptor binding cis-acting elements in the L-plastin promoter in prostate cancer, and the correlative regulation pathway and transcription factors.</AbstractText>On the basis of construction of the L-plastin promoter luciferase vectors which were removed the steroid hormone receptor AR and ER binding elements, the promoter on the vector was nest-deleted by Exonuclease III and the relative luciferase plasmids were constructed. Transfected these twelve plasmids into prostate cancer cell line LNCaP under dihydrotestosterone-stimulated situation or not and test the intensity of luciferase, then we got the regulation message of every 200 bp part of the promoter in prostate cancer. After the analysis of relative programme, we got the possible regu- lation pathway of non-steroid hormone transcription factors. After removing the possible transcription factors binding site sequence by site-specific mutagenesis, the changes luciferase of activities proved our reasoning.</AbstractText>We succeed in segmental deletion of the L-plastin promoter, and constructing the relative plasmids containing part L-plastin promoter on luciferase vector pGL3-basic. After testing the luciferase activities of constructed plasmids, we found the sequence from 206 to 1 of L-plastin promoter had significant luciferase activity. The software TRANSFECT showed that there were binding elements for transcription factors AP-4 at seq-198 to 192 and SP-1 at seq-54 to 41 on the short part promoter (206 to 1). The recombinant plasmids deleted the AP-4 and SP-1 binding elements had lower luciferase activity than the wild-type.</AbstractText>There are some other non-steroid hormone pathway to regulate the expression of L-plastin except the steroid hormone pathway in prostate cancer. The main binding sites of the non-steroid hormone regulator lies in the sequence from 206 to 1. Transcription factors AP4 and SP-1 may up-regulated the expression of L-plastin by binding these sites.</AbstractText>
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2,336,371 |
A simple in vivo approach to investigate invasive trophoblast cells.
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Intrauterine trophoblast cell invasion is an essential part of hemochorial placentation. Aberrant trophoblast cell invasion has been associated with pathologies including preeclampsia and fetal growth restriction. In this study, we describe an in vivo method to assess trophoblast cell invasion using a transgenic rat model, constitutively expressing heat stable human placental alkaline phosphatase (Rosa 26 promoter driven human placental alkaline phosphatase, R26-hAP). Wild-type female Fischer 344 inbred rats were mated with hemizygous R26-hAP transgenic male Fischer 344 rats and sacrificed during the second half of pregnancy. Heat stable alkaline phosphatase (AP) activity associated with the invasive transgenic trophoblast cells was monitored in the wild-type uterine mesometrial compartment and used as an index of trophoblast cell invasion. The expression pattern of cytokeratins by invasive trophoblast cells mimicked the uterine mesometrial distribution of AP activity. Trophoblast cell invasion exhibited a gestation-dependent profile with peak invasion between days 18-20 of pregnancy. In summary, we have devised a simple in vivo method for assessing intrauterine trophoblast cell invasion. This technique should facilitate the discovery of endogenous regulatory mechanisms controlling trophoblast cell invasion and should represent an effective method of testing the impact of various environmental stressors on an essential part of hemochorial placentation.
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2,336,372 |
Triazine-based tyrosinase inhibitors identified by chemical genetic screening.
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As most of the available depigmenting agents exhibit only modest activity and some exhibit toxicities that lead to adverse side effects after long-term usage, there remains a need for novel depigmenting agents. Chemical genetic screening was performed on cultured melanocytes to identify novel depigmenting compounds. By screening a tagged-triazine library, we identified four compounds, TGH11, TGD10, TGD39 and TGJ29, as potent pigmentation inhibitors with IC50 values in the range of 10 microM. These newly identified depigmenting compounds were found to function as reversible inhibitors of tyrosinase, the key enzyme involved in melanin synthesis. Tyrosinase was further confirmed as the cellular target of these compounds by affinity chromatography. Kinetic data suggest that all four compounds act as competitive inhibitors of tyrosinase, most likely competing with L-3,4-dihydroxyphenylalanine (L-DOPA) for binding to the DOPA-binding site of the enzyme. No effect on levels of tyrosinase protein, processing or trafficking was observed upon treatment of melanocytes with these compounds. Cytotoxicity was not observed with these compounds at concentrations up to 20 muM. Our data suggest that TGH11, TGD10, TGD39 and TGJ29 are novel potent tyrosinase inhibitors with potential beneficial effects in the treatment of cutaneous hyperpigmentation.
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2,336,373 |
Pregnancy outcomes in women with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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Despite earlier detection, treatment, and surgical advances, fertility prognosis in women with classical 21-hydroxylase deficiency (21-OHD) is still low, especially in the salt-wasting (SW) form.</AbstractText>We analysed the course and outcome of four pregnancies in two simple virilizing (SV) and one SW patient.</AbstractText>The evaluation of carrier status indicated that all three fathers had two normal CYP21 genes. During the pregnancy, the dose of prednisolone was increased in one of the SV patients and the SW patient. In the SW patient who developed pre-eclampsia, the dose of fludrocortisone was also increased. Three patients gave birth to a total of four healthy girls who were heterozygotes for 21-OHD with normal genitalia (one by vaginal delivery and three by Caesarean section). Family studies revealed that the mother of the SW patient has nonclassical 21-OHD.</AbstractText>Improving a low birth rate in females with SW 21-OHD remains a problem and new approaches are required. If the mother has 21-OHD (even nonclassical 21-OHD), pre-conception counselling and paternal genotyping are advisable and prenatal dexamethasone therapy should be considered.</AbstractText>
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2,336,374 |
A statistical framework for haplotype block inference.
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The existence of haplotype blocks transmitted from parents to offspring has been suggested recently. This has created an interest in the inference of the block structure and length. The motivation is that haplotype blocks that are characterized well will make it relatively easier to quickly map all the genes carrying human diseases. To study the inference of haplotype block systematically, we propose a statistical framework. In this framework, the optimal haplotype block partitioning is formulated as the problem of statistical model selection; missing data can be handled in a standard statistical way; population strata can be implemented; block structure inference/hypothesis testing can be performed; prior knowledge, if present, can be incorporated to perform a Bayesian inference. The algorithm is linear in the number of loci, instead of NP-hard for many such algorithms. We illustrate the applications of our method to both simulated and real data sets.
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2,336,375 |
No incidence of DUMPS carriers in Polish dairy cattle.
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DUMPS (Deficiency of Uridine Monophosphate Synthase) is a hereditary recessive disorder in Holstein cattle causing early embryo mortality during its implantation in the uterus. The only way to avoid the economic losses is early detection of DUMPS carriers. Because American Holstein semen has been intensively imported to Poland since 1970, there was a risk that DUMPS could have spread in Polish dairy cattle. In our study, 2209 dairy cattle of the Polish Holstein breed have been screened by the DNA test. The dominant group was young bulls entering the testing program (1171) and proven bulls (781). They represented all sires entering Polish breeding programs between 1999 and 2003. Also, 257 sire dams were included in the screening program. No DUMPS carrier has been found. Our results then indicate that the population of dairy cattle reared in Poland is free from DUMPS. Because of the economical significance of the DUMPS mutation and its recessive mode of inheritance, attention has to be paid to any case of a bull having in his origin any known DUMPS carrier. Such a bull should be tested and if positive eliminated from the active population. Also, young bulls (testing bulls) should be screened for DUMPS if in their progeny a high incidence of embryo mortality is observed and their genealogy cannot exclude their relatedness to any DUMPS carriers.
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2,336,376 |
Rye SCAR markers for male fertility restoration in the P cytoplasm are also applicable to marker-assisted selection in the C cytoplasm.
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The study aimed at testing the usefulness of recently developed SCAR markers on rye (Secale cereale L.) chromosome 4R in hybrid breeding based on the C source of male sterility-inducing cytoplasm. Of 10 markers studied, 4 revealed polymorphisms between 2 inbred lines (544cms-C and Ot0-20) crossed to develop F2 and BC1 mapping populations. Analyses performed on 94 F2 and 93 BC1 plants allowed to extend a formerly constructed genetic map of chromosome arm 4RL. Three SCAR markers (SCP14M55, SCP15M55 and SCP16M58) were mapped in the vicinity of gene Rfc1, which restores male fertility in the C cytoplasm. The 3 tested SCAR markers proved to be effective in marker-assisted selection (MAS) for male fertility/sterility.
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2,336,377 |
Microarray-based pncA genotyping of pyrazinamide-resistant strains of Mycobacterium tuberculosis.
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Drug-resistant Mycobacterium tuberculosis poses a significant threat to the treatment of tuberculosis (TB). The current susceptibility testing for the first-line TB drug pyrazinamide (PZA) is not only time-consuming but also difficult, due to the requirement for acid pH for drug activity. Predominantly, resistance to PZA in M. tuberculosis is caused by mutations in the pncA gene, and the detection of pncA mutations can be an indicator of PZA resistance. In this study, the use of a previously developed microarray method for the rapid detection of PZA-resistant M. tuberculosis based on identifying mutations in the pncA gene was evaluated. Microarray analysis was performed in a blind manner on 33 clinical isolates of M. tuberculosis for which the sequence of the pncA gene had not previously been determined. The results showed that all mutations in PZA-resistant strains identified by DNA sequencing could be unambiguously detected by the microarray method. It is concluded that the microarray method is a valuable tool for the rapid screening and genetic identification of potential PZA-resistant M. tuberculosis strains.
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2,336,378 |
Tumour gene expression from C12 spermine amphiphile gene delivery systems.
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Gene therapy requires safe and efficient gene delivery systems. Towards this aim both the gene formulation and tumour transfection ability of C12 spermine amphiphiles were tested. Five amphiphiles were synthesised and characterised: 1-[N,N-bis(3-aminopropyl)-1,4-butane diamine] dodecane (12G0--a C12 spermine amphiphile), a poly(ethylene glycol) (PEG, MW = 2 kDa) derivative of 12G0, 1,12-[N,N-bis(3-aminopropyl)-1,4-butane diamine] dodecane (12G1--a C12 spermine bolaamphiphile) and N-methyl quaternary ammonium derivatives of both 12G0 (12QG0) and 12G1 (12QG1). All amphiphiles except 12G0, which precipitates, yield nanoparticles in aqueous media with and without DNA. Thus when 12G0 is substituted with either quaternary ammonium or PEG groups it forms nanoparticles both with and without DNA. The minimum nitrogen, phosphate ratio required to completely condense DNA (NP) was inversely proportional to the particles' zeta potential (zeta), NP = 1626/zeta(0.98). Biological testing showed that both PEG and quaternary ammonium groups diminished the membrane lytic ability of these C12 amphiphiles. On intratumoural injection, while PEG groups hamper gene transfer, the quaternary ammonium amphiphile (12QG0) produces tumour confined gene expression that is 80% of that produced by linear poly(ethylenimine) (LPEI, MW = 22 kDa); while the intratumoural injection of LPEI produced significant gene expression in the liver and lung, making 12QG0 suitable for the administration of cytotoxic tumouricidal genes.
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2,336,379 |
The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis.
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The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04-3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22-4.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.
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2,336,380 |
Microsatellite polymorphism in Japanese mongrel dogs.
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The genetic variability of 182 unrelated mongrel dogs living in various areas of Japan (from Hokkaido to Okinawa) was studied by collecting their blood. Ten microsatellite loci were chosen from different autosomal chromosomes. After combining a few rare adjoining alleles to allelic classes, it was confirmed that the Hardy-Weinberg equilibrium was attained in each locus. The polymorphic information contents (PICs) of the loci, Ren37A11, Ren48E01, AHTk253, ZuBeCa30, Ren277K09, Ren42N13, AHT130, PEZ03, PEZ12, and AHT121, were 0.58, 0.63, 0.67, 0.67, 0.68, 0.71, 0.79, 0.80, 0.80, and 0.80, and the power of discriminations (PDs) were 0.80, 0.85, 0.87, 0.88, 0.88, 0.89, 0.94, 0.94, 0.94, and 0.94, respectively. The combined mean exclusion chance (MEC) was 0.9995, indicating that these microsatellite loci are useful for kinship testing of Japanese dogs.
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2,336,381 |
Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies.
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Absence of the corpus callosum is often associated with cognitive deficits, autism, and epilepsy. Using a genomic microarray, the authors analyzed DNA from 25 patients with radiographically confirmed callosal anomalies and identified three patients with de novo copy number changes in chromosome regions 2q37, 6qter, and 8p. Chromosomal deletions and duplications may be a relatively common cause of cerebral malformations.
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2,336,382 |
A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome.
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To inform clinicians about a reproductive risk associated with spontaneous premature ovarian failure and the fragile X mental retardation 1 gene (FMR1).</AbstractText>Case report.</AbstractText>National Institutes of Health Clinical Center.</AbstractText><AbstractText Label="PATIENT(S)" NlmCategory="METHODS">A 35-year-old woman with confirmed spontaneous premature ovarian failure.</AbstractText><AbstractText Label="INTERVENTION(S)" NlmCategory="METHODS">FMR1 genetic testing.</AbstractText><AbstractText Label="MAIN OUTCOME MEASURE(S)" NlmCategory="METHODS">Number of CGG trinucleotide repeats in the 5' untranslated region of FMR1.</AbstractText><AbstractText Label="RESULT(S)" NlmCategory="RESULTS">Despite having ovarian failure the woman subsequently conceived and delivered a son with fragile X syndrome (>200 CGG repeats). She was then found to carry an FMR1 premutation (85 CGG repeats).</AbstractText><AbstractText Label="CONCLUSION(S)" NlmCategory="CONCLUSIONS">This is a real-life manifestation of a theoretical risk; a woman conceived subsequent to the diagnosis of spontaneous premature ovarian failure and has a child who manifests mental retardation due to fragile X syndrome. Women with spontaneous premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Should an FMR1 premutation be uncovered, this will allow patients to make informed reproductive decisions and help clinicians to properly diagnose family members who may have menstrual irregularity, developmental delay, or neurologic symptoms.</AbstractText>
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2,336,383 |
Genetic polymorphisms and multifactorial diseases: facts and fallacies revealed by the glucocorticoid receptor gene.
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In recent years enormous progress in determining the sequence of the human genome has led to a rapid development of research into polymorphisms in genes involved in complex diseases. It is clear, however, that there are important limitations in many of these association studies. Problems with reliable and reproducible phenotyping, the number of individuals studied, racial heterogeneity, population stratification (founder effect), functionality and multiple testing often mean that studies are not reproducible. In this review we describe a number of the limitations related to this type of research; from both our own experience with studies on polymorphisms in the glucocorticoid receptor gene, and shortcomings and solutions from the literature.
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2,336,384 |
[Cancer genetic predisposition: current events and perspectives 2005].
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Studies performed during these last twenty years have had a major impact on the understanding of carcinogenesis. They have opened a new field : cancer genetic predisposition. At the present time, most of the cancer predispositions linked to the alteration of one gene, associated with a high risk of cancer and with a specific phenotype have been identified. About 40 genes have been identified and have led to genetic testing. The indication of genetic testing, the management of at risk patients need the establishment of guidelines. The next challenge is the identification of cancer predisposing genes associated with low risk or modifying the effect of treatment.
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2,336,385 |
[Predictive testing: presymptomatic diagnosis in neurogenetic disorders].
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Presymptomatic testing is available since 15 years for Huntington disease and it is now possible for a number of other neurogenetic disorders, mostly neurodegenerative disorders. The possibility of determining the genetic status of an at-risk person for the disorder which run in his family raises questions because of the absence of preventive and curative treatments in most instances. In addition, being carrier does not tell you when the disease will start and how it will evolve, impairing the possibilities of planning the future. A pluridisciplinary approach to predictive testing with care before, during and after the test taking into account the medical, social and psychological aspects of the disease is good practice. At the present time, only a minority of at-risk individuals request presymptomatic testing and almost 50 % do not pursue until the results. The consequences of the test may be harmful, more frequently after an unfavorable than after a favorable result. Although the motivations and the outcome in terms of request for prenatal testing after a carrier result are different in Huntington's disease and spinocerebellar ataxias, our experience underlines the benefit of pluridisciplinary care and of time for decision taking. For other disorders like familial Alzheimer's disease, or familial Creutzfeldt-Jakob disease, the experience in presymptomatic testing is still limited but the situation seems similar to Huntington's disease because of the presence of dementia. It will be interesting to study the motivations and the outcome of the tests in disorders like autosomal dominant spastic paraplegias which usually do not reduce the life expectancy. Nevertheless, the overall situation might change greatly when efficient treatments will become available in these disorders.
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2,336,386 |
PGD patients' and providers' attitudes to the use and regulation of preimplantation genetic diagnosis.
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Preimplantation genetic diagnosis (PGD) providers and patients have a vested interest in policy related to the use and regulation of PGD. To understand their experiences and attitudes, 32 in-depth interviews were conducted. Participants included 13 people at risk of transmitting a single-gene alteration to their children (10/13 had actually used PGD to try to have an unaffected child) and 19 PGD service providers (four nurses, five genetic counsellors, two reproductive endocrinologists, two geneticists, two physician-geneticists, two embryologists, and two laboratory directors). Virtually all participants supported the use of PGD to avoid severe, life-threatening genetic illness or to select embryos that are a tissue match for a sick sibling, but their attitudes varied significantly over the appropriateness of using PGD to avoid adult-onset genetic disease, to select for sex, or to select for other non-medical characteristics. There was disagreement within the PGD provider community about whether or not PGD is experimental. Participants were more concerned about overzealous government regulation of PGD creating barriers to access than potential abuses of the technology, and expected the PGD provider community to take the lead in ensuring that PGD is used for ethically appropriate purposes.
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2,336,387 |
Spatial genetic structure of two HIV-I-resistant polymorphisms (CCR2-64 I and SDF1-3'A) alleles in population of Shandong Province, China.
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To explore the spatial genetic structure of two HIV-I-resistant polymorphisms (CCR2-64 I and SDF1-3'A) alleles in the population of Shandong Province, China.</AbstractText>Using the techniques of spatial stratified sampling and spatial statistics, the spatial genetic structure of the locus (CCR2-64 I and SDF1-3'A), which was shown to be important co-receptor for HIV infection, was quantified from the populations of 36 sampled counties of Shandong Province, and a total of 3147 and 3172 samples were taken for testing CCR2-64I and SDF1-3'A respectively from individuals without known history of HIV-I infection and AIDS symptoms.</AbstractText>There were significantly spatial genetic structures of the two alleles at different spatial distance classes on the scale of populations, but on the scale of individuals, no spatial structure was found in either the whole area of Shandong Province or the area of each sampled county. Although the change of frequencies of the two alleles with geographic locations in Shandong Province both showed gradual increase trends, their changing directions were inverse. The frequency of CCR2-64I allele gradually increased from the southwest to the northeast, while the frequency of SDF1-3'A allele gradually increased from the northeast to the southwest. However the RH to AIDS of combined types of their different genotypes did not represent obvious geographic diversity on the whole area of the Province.</AbstractText>The frequency of allele usually has some spatial genetic structures or spatial autocorrelation with different spatial distance classes, but the genotypes of individuals have random distribution in the same geographic area. Evaluating spatial distribution of the genetic susceptibility of HIV (AIDS) to CCR2-64I and SDF1-3'A alleles, should focus on the frequencies of combined genotypes of CCR2 and SDF1 based on the two-locus genotypes of each individual rather than the frequencies of CCR2-64I and SDF1-3'A alleles.</AbstractText>
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2,336,388 |
[Cystic fibrosis (CF) of adults--current problem of laryngologists. The role of genetic research].
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The goal of this work is to evaluate DNA in the direction of gene mutation in the patients with nasal polyps and/or recurring inflammation of the sinuses, and who tested negative for allergic basis of those ailments.</AbstractText>50 patients aged 20-45 have been included in the research by the University Hospital and the Laryngological Outpatient Clinic SPSK in Białystok. The patients had symptoms of nasal polyps and recurring inflammation of the sinuses. The analysis of DNA samples of the blood according to the PCR method using the ABI Prism 3100 device and testing for finding mutations of cystic fibrosis--The Cystic Fibrosis Assay.</AbstractText>We discovered 1 mutation of delta F508 in a 40-year-old patient, with recurring inflammation of nasal sinuses (described in the case of this patient).</AbstractText>The DNA research method can be used for discovering atypical forms of CF in patients with recurring symptoms of the inflammation of the sinuses and nasal polyps, and who tested negative for allergic basis of those ailments. A wide routine screening in the direction of the mutation of CF may lead to an explanation the reason of the nasal polyps and inflammation of the sinuses.</AbstractText>
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2,336,389 |
Behçet's disease and hereditary periodic fever syndromes: casual association or causal relationship?
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Mutations in the MEFV and the type 1 TNF receptor (TNFRSF 1A) genes have recently been linked to familial Mediterranean fever (FMF) and TNF receptor-associated periodic syndrome (TRAPS), respectively. A higher prevalence of Behçet's disease (BD) among FMF patients has been described compared to the general population. The aim of this study was to evaluate whether FMF TRAPS and BD could be genetically related.</AbstractText>We screened a cohort of 50 BD patients and 100 healthy subjects for the common MEFV and TNFRSF 1A mutations. An initial screening of exons 10 and 2 of the MEFV gene and exon 4 of the TNFRSF 1A was performed in all chromosomes.</AbstractText>The heterozygous MEFV mutation (K695R) was found in one (2%) BD patient. Analysis for FMF mutations in the control group revealed that 5 (5%) individuals bore MEFV gene mutations (3 were heterozygous for the E148Q and 2 were heterozygous for the A744S). At codon 202, there were no differences in allele frequencies between BD and control population: 73%R 27%Q in the BD patients vs 75%R 25%Q in controls. Concerning mutations in the TNFRSF 1A gene, the R92Q mutation was present in heterozygous state in one (2%) BD patient and in 4 (4%) controls without differences between allele frequencies: 99%R 1%Q in BD patients vs 98%R 2%Q in controls, respectively. There was no association between the clinical manifestations of BD patients and the presence of a particular polymorphism or a mutation.</AbstractText>Neither FMF nor TRAPS are genetically associated with BD in our cohort of Spanish patients.</AbstractText>
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2,336,390 |
Analytical verification of a PCR assay for identification of Bordetella avium.
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Bordetella avium is the etiologic agent of turkey coryza or bordetellosis, a respiratory disease responsible for substantial economic losses to the turkey industry. At present, identification of this bacterium relies on isolation and biochemical testing. Although a PCR for the detection of B. avium was proposed a number of years ago, lack of analytical verification precludes its use as a diagnostic tool. Furthermore, a number of details pertaining to the reaction conditions used are missing or unclear. In the present study we have identified an optimal set of PCR conditions for use with the previously described primer pair and determined the limit of detection under these conditions to be approximately 20 pg. Assay sensitivity is 100%, based on an analysis of 72 B. avium isolates from diverse geographic locations and covering a time span of at least 25 years. Evaluation of a separate group of 87 bacterial isolates from poultry, comprising both gram-positive and gram-negative commensals and pathogens representing 11 genera, demonstrated an assay specificity of 98.8%. Reproducibility is 100% using either purified genomic DNA or boiled cell lysates less than 3 days old. Sequence analysis of the B. avium PCR amplicons identified only three occasional sequence polymorphisms. These data indicate the B. avium PCR assay can provide clinically significant results.
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2,336,391 |
Mutagenic and cytotoxic effect of planifolin: a naphthopyranone dimer isolated from Paepalanthus planifolius.
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A naphthopyranone dimer, named planifolin, was isolated from a methylene chloride extract of the capitula of Paepalanthus planifolius Koern. The molecule (C(31)H(26)O(10)) appeared to be made up of two monomeric portions, semi-vioxanthin and paepalantine (an isocoumarin), linked by an ether bond, and it may possess several kinds of biological activity that can be related to its polyphenolic structure. Short-term tests that detect genetic damage can afford the information needed to evaluate carcinogenic risks of chemicals to humans. The Ames test, recommended for testing the mutagenicity of chemical compounds with potential pharmacological application, was used in the present study. The mutagenic activity was evaluated in Salmonella typhimurium strains TA100, TA98, TA102 and TA97a and the cytotoxic effect in McCoy cells. The in vitro cytotoxicity of planifolin to McCoy cells, tested in microculture with neutral red, showed a significant cytotoxic index (CI(50)) of 12.83 microg/mL. Planifolin showed mutagenic activity for TA100, TA98 and TA97a. The results indicate that this new naphthopyranone dimer causes mutations by substitution and by addition and deletion of bases in the sequence of DNA. Moreover, its mutagenic potential was increased by metabolic activation.
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2,336,392 |
HLA genes in Madeira Island (Portugal) inferred from sequence-based typing: footprints from different origins.
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Human leukocyte antigen (HLA)-A, HLA-B, and HLA-DRB1 polymorphisms were examined in Madeira Island populations. The data was obtained at high-resolution level, using sequence-based typing (SBT). The most frequent alleles at each loci were: A*020101 (24.6%), B*5101 (9.7%), B*440201 (9.2%), and DRB1*070101 (15.7%). The predominant three-loci haplotypes in Madeira were A*020101-B*510101-DRB1*130101 (2.7%) and A*010101-B*0801-DRB1*030101 (2.4%), previously found in north and central Portugal. The present study corroborates historical sources and other genetic studies that say Madeira were populated not only by Europeans, mostly Portuguese, but also sub-Saharan Africans due to slave trade. Comparison with other populations shows that Madeira experienced a stronger African influence due to slave trade than Portugal mainland and even the Azores archipelago. Despite this African genetic input, haplotype and allele frequencies were predominantly from European origin, mostly common to mainland Portugal.
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2,336,393 |
Detection of known haemophilia B mutations and carrier testing by microarray.
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The molecular basis of haemophilia B is heterogeneous and many mutations of the Factor IX (FIX) gene have been characterised. Using the allele-specific arrayed primer extension (AS-APEX) technology, we have designed a FIX array to simultaneously analyse 69 mutations found in British, Thai and Chinese patients. This technology overcomes the problem of multiple reverse dot-blot analysis and has a 100% accuracy in the detection of both affected subjects and carriers in families with known mutations. In seven unknown mutations from Thailand, the array could detect the specific mutation in five and in the remainders the normal primer at specific spots failed to extend due to a mutation a few nucleotides upstream, thus allowing their identification. Hence this FIX array can detect 53% of the 2891 mutation entries in the FIX database. Each of the microarray slide can be used for three different test samples and would be useful for carrier testing for common mutations and prenatal diagnosis. It is simpler and more cost effective than genome sequencing and would be particularly useful in laboratories with limited technical capabilities.
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2,336,394 |
Ethical issues and policy analysis for genetic testing: Huntington's disease as a paradigm for diseases with a late onset.
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This paper discusses the main ethical issues that arise when testing for genetic diseases with a late adult onset, such as Huntington's disease, take place. It is imperative to study genetic testing for HD and similar diseases because of the potential to influence future medical advances and the growing number of individuals who are considered pre-symptomatic. The main ethical issues are consent and privacy, prenatal testing and its implications, in addition to insurance discrimination. These issues are viewed from the perspective of genetic counselors, patients, the families of patients, and insurance companies. Policies put forth by the United States National Society of Genetic Counselors ("NSGC"), the Task Force on Genetic Testing, and the President's Council for Bioethics are also analyzed. Finally, new recommendations are proposed in order to ameliorate the ethical dilemmas encountered in genetic testing. These recommendations are largely based on existing policies and therefore involve amending current policies rather than revamping them.
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2,336,395 |
Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain.
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To investigate the prevalence and penetrance of hMSH6 mutations in Spanish HNPCC families that was negative for mutation in hMLH1 or hMSH2.</AbstractText>We used PCR-based DGGE assay and direct sequencing to screen for hMSH6 gene in 91 HNPCC families.</AbstractText>we have identified 10 families with germ-line mutations in the DNA sequence. These mutations included two intronic variation, three missense mutation, one nonsense mutation, and four silent mutations. Among the 10 germ-line mutations identified in the Spanish cohort, 8 were novel, perhaps, suggesting different mutational spectra in the Spanish population. Detailed pedigrees were constructed for the three families with a possible pathogenic hMSH6 mutation. The two silent mutations H388H and L758L, detected in a person affected of colorectal cancer at age 29, produce loss of the wild-type allele in the tumor sample. Immunohistochemical analysis showed that expression of MSH6 protein was lost only in the tumors from the carriers of V878A and Q263X mutations.</AbstractText>Altogether, our results indicate that disease-causing germ-line mutations of hMSH6 are very less frequent in Spanish HNPCC families.</AbstractText>
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2,336,396 |
Global transcriptional profiling of Shewanella oneidensis MR-1 during Cr(VI) and U(VI) reduction.
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Whole-genome DNA microarrays were used to examine the gene expression profile of Shewanella oneidensis MR-1 during U(VI) and Cr(VI) reduction. The same control, cells pregrown with nitrate and incubated with no electron acceptor, was used for the two time points considered and for both metals. U(VI)-reducing conditions resulted in the upregulation (> or = 3-fold) of 121 genes, while 83 genes were upregulated under Cr(VI)-reducing conditions. A large fraction of the genes upregulated [34% for U(VI) and 29% for Cr(VI)] encode hypothetical proteins of unknown function. Genes encoding proteins known to reduce alternative electron acceptors [fumarate, dimethyl sulfoxide, Mn(IV), or soluble Fe(III)] were upregulated under both U(VI)- and Cr(VI)-reducing conditions. The involvement of these upregulated genes in the reduction of U(VI) and Cr(VI) was tested using mutants lacking one or several of the gene products. Mutant testing confirmed the involvement of several genes in the reduction of both metals: mtrA, mtrB, mtrC, and menC, all of which are involved in Fe(III) citrate reduction by MR-1. Genes encoding efflux pumps were upregulated under Cr(VI)- but not under U(VI)-reducing conditions. Genes encoding proteins associated with general (e.g., groL and dnaJ) and membrane (e.g., pspBC) stress were also upregulated, particularly under U(VI)-reducing conditions, pointing to membrane damage by the solid-phase reduced U(IV) and Cr(III) and/or the direct effect of the oxidized forms of the metals. This study sheds light on the multifaceted response of MR-1 to U(VI) and Cr(VI) under anaerobic conditions and suggests that the same electron transport pathway can be used for more than one electron acceptor.
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2,336,397 |
Ethical considerations in presymptomatic testing for variant CJD.
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Variant Creutzfeldt-Jakob disease (vCJD) is a fatal, transmissible, neurodegenerative disorder for which there is currently no effective treatment. vCJD arose from the zoonotic spread of bovine spongiform encephalopathy. There is now compelling evidence for human to human transmission through blood transfusions from presymptomatic carriers and experts are warning that the real epidemic may be yet to come. Imperatives exist for the development of reliable, non-invasive presymptomatic diagnostic tests. Research into such tests is well advanced. In this article the ethical implications of the availability of these tests are elaborated and comparisons drawn with predictive genetic testing for Huntington's disease and screening for HIV. Paramount to considerations is the issue of whom to test, weighing up respect for personal autonomy against obligations to benefit and protect society. A paradigm is proposed similar to that used for HIV screening but with unique features: compulsory testing of all blood/organ donors and individuals undergoing surgery or invasive procedures who have a significant risk of disease transmission.
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2,336,398 |
Parental consent for newborn screening in southern Taiwan.
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With the advent of genetic technologies, many genetic/metabolic disorders can be detected asymptomatically but might be untreatable, and the benefits and risks of screening for them are not fully known. The purpose of this study is to explore current practice with regard to the parental consent process in newborn screening (NBS).</AbstractText>Staff in 23 obstetric clinics/hospitals that conduct NBS in one city of southern Taiwan were interviewed. Using content analysis, 15 interview transcripts, eight completed questionnaires, and other relevant documents from the 23 clinics/hospitals were analysed to reveal the framework of the parental consent process in NBS in southern Taiwan.</AbstractText>Three categories-informed consent, informed dissent, and no informed/consent-were developed to analyse the parental consent process in NBS.</AbstractText>The parental consent procedures in NBS and the quality of the information provided before obtaining consent vary widely. Because the traditional NBS was incorporated into routine paediatric practices in most clinics/hospitals, the most frequently encountered consent model is "informed dissent" (60.9%) and "no informed/consent" (30.4%); while an "informed consent" model (45.5%) is the frequent model for screening rare metabolic/genetic disorders.</AbstractText>Specific guidelines to regulate the parental consent process for NBS are essential. Further studies should investigate parental responses to NBS, taking these as the basis on which to establish an informed consent model in Taiwan.</AbstractText>
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2,336,399 |
Rapid identification of female haemophilia A carriers with deletions in the factor VIII gene by quantitative real-time PCR analysis.
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Large deletions of the factorVIII gene account for approximately 5% of severe haemophilia A patients. Although deletions are readily detectable in males, the identification of heterozygosity in possible carriers of these families still constitutes a challenge. In order to identify a deleted allele over the background of the normal allele in these carriers, we developed a rapid real-time quantitative PCR approach by means of LightCycler technology and SYBR green I for monitoring product formation. The method was applied to families with independent deletions (one in exon 14 and the other in exons 23-24) of the Factor VIII gene, thereby allowing a reliable determination of carrier or non-carrier status. The method is extremely versatile and can be adapted to other deletions within the factorVIII gene as well as to other diseases whose molecular pathology consists of deletions or duplications.
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