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2,338,700 |
Advances in acute lymphoblastic leukemia.
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Current literature.</AbstractText>Acute lymphoblastic leukemia (ALL) is a stem cell disorder characterized by an overproduction of lymphoblasts in the bone marrow that eventually spill into circulation, producing lymphocytosis. As with the other acute leukemias, the most common symptoms experienced by patients include fatigue, bleeding, and recurrent infections resulting from the suppression of normal hematopoiesis in the bone marrow by the accumulating blasts. ALL primarily affects children and exhibits the best response to standard chemotherapy as compared to acute myeloblastic leukemias (AML). Further, remission rates are highest among ALL patients, many of whom are experiencing sustained remissions suggesting cure. In light of early treatment successes, researchers began to investigate modifications of standard treatment regimens to accommodate variability in weight, age, and response to therapy among children with ALL. Individualized treatment plans were implemented where some patients received a reduced intensity course of therapy to minimize drug toxicity while others received drug intensification to maximize response. More recently, research efforts have been directed at the elucidation of leukemogenic mechanisms implicated in ALL to identify specific protein mutants that can be used to design drugs tailored to interfere with the activity of these mutant protein targets. Identification of chimeric proteins produced from chromosomal translocations and gene expression profiles from microarray analyses are the primary techniques used to identify the potential therapeutic targets.</AbstractText>Several reliable prognostic indicators have been identified and are being used to improve therapeutic planning and outcome prediction in ALL patients. Individualized treatment regimens have been developed based on the specific characteristics of each patient to minimize treatment related adverse events and maximize response. Through the use of cytogenetic, molecular, and microarray testing, ALL classification schemes have improved and potential therapeutic targets have been identified. It is anticipated that the next major advance in the treatment of ALL will involve the use of designer therapies developed to specifically interfere with particular molecular abnormalities producing the leukemogenic aberration to the normal signal transduction pathways.</AbstractText>
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2,338,701 |
Should children and adolescents undergo genetic testing?
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Genetic testing comes in many shapes and sizes. The decision to undergo genetic testing must involve consideration of the medical, psychosocial, and reproductive benefits and risks of testing. The evaluation of risks and benefits varies significantly both between and within families. Pediatricians should keep up with the rapid advances in genetic medicine and the myriad of tests that are being developed and marketed. They also need to be familiar with the psychosocial risks and benefits that these new tests generate for individuals, families and communities. In some situations, genetic testing is merely another diagnostic tool; in other situations, genetic testing offers information about the risks for future diseases. Pediatricians need to be knowledgeable about tests that are indicated clinically and their potential psychosocial implications to best serve children, adolescents, and their families.
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2,338,702 |
Ethical dilemmas in the treatment of children with disabilities.
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Issues relating to the treatment of children with disabilities, such as withholding treatment, organ donation, research, genetic screening, and prenatal diagnosis, all present ethical dilemmas. These issues always need to be reviewed to determine which ethical considerations apply. Identifying relevant principles, one can conclude which take precedence and what is ethically permissible. As with so many other medical responsibilities, this can be consulted, learned, practiced and improved upon. Pediatricians caring for children with disabilities can study and enhance their capacity for ethical reflection, so as to participate fully in these important decision-making processes.
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2,338,703 |
[Arctic and southern freshwater pearl mussel Margaritifera margaritifera with long and short life span as a model system for testing longevity mechanisms].
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The freshwater pearl mussel (Margaritifera margartifera) is one of the longest lived animals, attaining ages in excess of 150 years in polar climates. Because of its long life, the species may be useful for studying genetic and physiological mechanisms contributing to longevity. An ongoing study is comparing 6 southern populations in Spain, with maximum recorded ages of 28-40 years, to 3 Arctic populations in northwest Russia, with maximum ages of 114-190 years. Within Arctic populations, 40% of mussels live more than 100 years in rivers that are pristine. Possible evolutionary significance of northern longevity is an adaptation to severe cold and unstable environments in high gradient rivers. During winter, mussels have a near-famine existence during the Polar Night, and experience some shell damage from ice formation and flows. In summer, periodic droughts result in exposure and desiccation. In response to adversity, pearl mussels have acquired effective mechanisms for shell reparation and tissue healing and regeneration. Northern populations have low metabolic rates, reducing energy expenditure for growth under normal as well as extreme conditions. However, this species is capable of increasing metabolic rate for tissue regeneration and self-healing. The physiological adaptations to sustain longevity may provide useful clues to impedence of the aging process.
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2,338,704 |
Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series.
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Although BRCA1 and BRCA2 were identified in 1994 and 1995, respectively, to the authors' knowledge the optimal management of women with BRCA-associated breast carcinoma remains incompletely defined. The current study evaluates the appropriateness of breast-conserving therapy (BCT) in women with BRCA mutations.</AbstractText>Between May 1992 and October 2003, 87 female participants in genetic testing protocols were identified who 1) were found to have deleterious germline BRCA mutations and 2) reported a history of invasive breast carcinoma that was treated with wide local excision and radiation therapy. Clinical records were reviewed and follow-up was updated.</AbstractText>The 87 subjects underwent BCT for 95 invasive breast tumors (8 women received BCT for metachronous bilateral tumors). In all 95 treated breasts, the 5-year and 10-year probabilities of metachronous ipsilateral breast carcinoma (MIBC) were 11.2% and 13.6%, respectively. Among the 87 subjects, the 5-year and 10-year probabilities of metachronous contralateral breast carcinoma (CBC) after treatment of the index tumor were 11.9% and 37.6%. No clinical factors were identified that were associated with either MIBC or CBC, including the use of tamoxifen or chemotherapy.</AbstractText>Women with BRCA-associated breast carcinoma who undergo BCT appear to have risks of MIBC that are similar to those reported for young women without known mutations. The indications for unilateral mastectomy in this group of women should be the same as those for women with nonhereditary carcinoma. However, significant risks of CBC and possibly late MIBC may prompt the serious consideration of bilateral mastectomy as a preventive measure.</AbstractText>
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2,338,705 |
New joint covariance- and marginal-based tests for association and linkage for quantitative traits for random and non-random sampling.
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We develop novel statistical tests for transmission disequilibrium testing (tests of linkage in the presence of association) for quantitative traits using parents and offspring. These joint tests utilize information in both the covariance (or more generally, dependency) between genotype and phenotype and the marginal distribution of genotype. Using computer simulation we test the validity (Type I error rate control) and power of the proposed methods, for additive, dominant, and recessive modes of inheritance, locus-specific heritability of the trait 0.05, 0.1, 0.2 with allele frequencies of P=0.2 and 0.4, and sample sizes of 500, 200, and 100 trios. Both random sampling and extreme sampling schemes were investigated. A multinomial logistic joint test provides the highest overall power irrespective of sample size, allele frequency, heritability, and modes of inheritance.
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2,338,706 |
[Molecular cytogenetic techniques and their application in clinical diagnosis].
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Cytogenetics analysis is at present the basic element of the diagnostic process of genetic disorders which are caused by chromosomal abnormalities. Since the chromosome banding technique has been introduced in the 1970s, it has been available as a diagnostic tool of a number of clinical syndromes. It enabled to prove the causal association between specific chromosomal abnormalities and clinical features observed in patients. However, since banding resolution is not always sufficient for the identification of chromosomal abnormalities, additional techniques for solving diagnostic dilemma of classical cytogenetics are needed. A new field of cytogenetics -- molecular cytogenetics, the product of a combination of cytogenetics and molecular biology, has increased the resolution and diagnostic utility of cytogenetic analysis. The basic method of molecular cytogenetics is fluorescence in situ hybridization (FISH). It enables a specific detection of unique sequences, chromosomal regions or entire chromosomes in metaphase, interphase cells or in tissue sections. In this article FISH technique and its modifications such as multicolor FISH (M-FISH, SKY, CCK), Primed In Situ Labelling (PRINS) and Comparative Genomic Hybridization (CGH) are presented. The range of applications and the use of these techniques for the identification of chromosomal abnormalities in relation to diagnostic possibilities of the classical methods of karyotyping is also discussed.
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2,338,707 |
Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36.
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To identify the chromosomal location of the gene causing snowflake vitreoretinal degeneration (SVD), an autosomal dominant retinal degeneration characterized by small yellow-white dots in the retina, fibrillar anomaly of the vitreous humor, and retinal detachment.</AbstractText>Clinical data were collected on 31 family members by history and examination. Thirteen family members underwent prospective examination. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point and multipoint linkage analysis was performed (FASTLINK version of the MLINK program and the VITESSE algorithm, both available at http://linkage.rockefeller.edu/soft/list.html). Direct DNA sequencing of amplified genomic DNA and mRNA was performed for candidate gene analysis.</AbstractText>The SVD locus was linked to markers in a region of chromosome 2q36 defined by D2S2158 and D2S2202, based on meiotic breakpoint mapping of affected individuals. A maximum two-point lod score of 5.5 was obtained with marker D2S172 at theta; = 0 within this region. Direct DNA sequencing of all 52 exons of the COL4A3 gene revealed no potentially pathogenic coding sequence variation or evidence for deletion.</AbstractText>The genetic locus for SVD lies in a 9 Mb region flanked by D2S2158 and D2S2202. Localization of SVD to a genomic region distinct from both Wagner disease and the Stickler syndromes indicates that SVD is a distinct genetic entity. The absence of coding sequence variation in the only collagen gene within the disease-region, suggests a novel pathogenesis for vitreoretinal degeneration. Snowflake vitreoretinal degeneration should be considered in the differential diagnosis of families with fibrillar anomaly of the vitreous.</AbstractText>
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2,338,708 |
Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation.
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Mutations in mitochondrial DNA (mtDNA), particularly those in the 12S rRNA gene, have been shown to be associated with sensorineural hearing loss. Here we report the clinical and sequence analysis of the entire mitochondrial genome in three Chinese subjects with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluation showed a variable phenotype of hearing impairment including the age of onset and audiometric configuration in these subjects. Sequence analysis of the complete mitochondrial genomes in three subjects showed the distinct sets of mtDNA polymorphism, in addition to the identical mitochondrial 12S rRNA T1095C mutation. This mutation was previously identified to be associated with hearing impairment in three families from different genetic backgrounds. The T1095C mutation was absent in 364 Chinese control. In fact, the occurrence of the T1095C mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. Among other nucleotide changes, the A2238G and T2885C mutations in the 16S rRNA, the I175V mutation in the CO2, the F16L mutation in the A6 and the V112M mutation in the ND6 exhibited a high evolutionary conservation. These data suggest that the T1095C mutation may be associated with aminoglycoside-induced and non-syndromic hearing impairments and A2238G and T2885C mutations in the 16S rRNA, the I175V mutation in the CO2, the F16L mutation in the A6 and the V112M mutation in the ND6 may contribute to the phenotypic expression of the T1095C mutation in these subjects.
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2,338,709 |
Molecular classification of scrapie strains in mice using gene expression profiling.
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Transmissible spongiform encephalopathy strains demonstrate specific prion characteristics, each with specific incubation times, and strain-specific patterns of deposition of the misfolded isoform of prion, PrPSc, in the brains of infected individuals. Different biochemical properties, including glycosylation profiles and the degree of proteinase resistance, have been shown to be strain-specific. However, no relationship between these properties and the phenotypic differences in the subsequent diseases has as yet been determined. Here we explore the utility of gene expression profiles to identify differences in the host response to different strains of prion agent. We identify 114 genes that exhibit significantly different levels of expression in mice infected with three strains of scrapie. These genes represent a pool of genes involved in a strain-specific response to prion disease. We have identified the most discriminatory genes from this list utilizing a wrapper-based feature selection algorithm with external cross-validation.
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2,338,710 |
High-throughput gene sequencing assay development for hereditary nonpolyposis colon cancer.
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Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colon cancer syndrome and is responsible for as many as 10% of all colorectal cancers. Hereditary nonpolyposis colorectal cancer is autosomally dominant with a prevalence of 1 in 200-2000 and exhibits incomplete penetrance. Affected individuals have an approximately 70% lifetime risk of colon cancer with a mean age of onset of 44 years and an approximately 40% lifetime risk of endometrial cancer. At least 5 mismatch repair genes (MLH1, MSH2, MSH6, PMS1, PMS2) have been implicated in HNPCC; however, no predominant mutations were found in these genes. Mutation detection by direct sequencing has proven to be the most sensitive method. We have developed high-throughput full-length sequencing assays of the MLH1, MSH2, and MSH6 genes. These 3 genes account for approximately 90% of all germline mutations found in HNPCC. In our assays, 19 exons of MLH1, 16 exons of MSH2, 10 exons of MSH6, and the adjacent splice sites were amplified using polymerase chain reaction and loaded onto a capillary sequencing machine. Results were analyzed using sequence analysis software and stored in a relational database. Our assay method was validated using 15 affected patients and normal controls. It is anticipated that our high-throughput assay technique will provide accurate diagnoses for patients at risk for HNPCC and thereby facilitate early curative intervention.
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2,338,711 |
Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.
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Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG (IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.
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2,338,712 |
[Clinical and genetic analysis of juvenile parkinsonism in Russia].
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Clinical and genetic analysis of juvenile parkinsonism was performed in 26 sibs from 20 families. Heterogeneity of the disorder was observed. Mutations in the parkin gene (locus PARK2, chromosome 6q25.2-27), with the prevalence of deletions over point mutations, have been identified in 41%. The comparative clinical analyses of patients examined confirmed the phenotypical polymorphism of "parkinopathy". We also showed the absence of asymmetric manifestation--an important and underestimated so far sign of the disease. The results of the study may be considered as a valuable clue to the clinical diagnosis of parkin-related juvenile parkinsonism in Russian population and implemented for mutation screening and medico-genetic counseling of affected families.
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2,338,713 |
[Recent advances in immunologic laboratory testing for rheumatic diseases].
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Immunologic laboratory tests serve critical roles in the care of patients with various rheumatic diseases. These tests can provide relevant information of rheumatic diseases based on their immunopathophysiological condition. Although immunologic laboratory tests are quite useful for the determination of diagnosis and the estimation of disease activity, organ involvement and prognosis, they are frequently misused and resulted in an inappropriate diagnosis and treatment. Appropriate use of immunologic laboratory tests and accurate clinical interpretation of the test results can prevent false diagnosis and unnecessary treatment. In order to improve clinical care of patients with rheumatic diseases, clinicians caring patients with rheumatic disease should recognize meanings, characteristics and limitations of each result of immunologic laboratory testing. This article reviewed recent advances in immunologic laboratory testing such as antinuclear antibody, anti-DNA antibody and anti-neutrophil cytoplasmic antibody, and introduced guidelines for these testing. These guidelines based on evidences of EBM may contribute to the appropriate use of immunologic laboratory tests for rheumatic diseases.
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2,338,714 |
[Germline mutation of BRCA1 gene in Polish families with strong aggregation of breast and/or ovarian cancer based on coding sequence analysis using the SSCP method].
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The aim of the study was to identify possible BRCA1 germline mutations in Polish families with strong aggregation of breast and/or ovarian cancer. Identification was based on analysis of the entire coding region using SSCP--"Phast System" technique. The study group consisted of 34 women with breast or/and ovarian cancer from families with aggregation of breast and/or ovarian cancer referred from the Oncology Center in Szczecin. Breast and ovarian cancer cases were revealed in 16 families, breast cancer in 17 and ovarian cancer in 1 family. Blood samples for genetic analyses were taken from at least one affected woman from each family. As a rule, samples were taken from the youngest woman. Genomic DNA was prepared from peripheral blood leukocytes with the nonenzymatic rapid method described by Lahiri and Nurnberger. The entire coding region of the BRCA1 gene was screened for the presence of germline mutations by use of Single Stranded Conformation Polymorphism (SSCP) followed by direct sequencing of variants. Primers used for PCR amplification of the BRCA1 gene have been described in the Breast Cancer Information Core (BIC) database. Samples were sequenced with the use of fluorescent dideoxy-chain terminators from the ABI Prism Kit (PE Biosystems) and model 373 automated sequencer (PE Biosystems). Four mutations were found in exon 5 (4/9) and three in exon 11 (3/9) of the BRCA1 gene. The two mutations in exon 20--5382insC (2/9) could not be identified using SSCP and required sequencing. Three BRCA1 abnormalities--C61G, 3819de15 and 5382insC, were the most frequent mutations detected in Polish families with strong aggregation of breast and/or ovarian cancers. These three abnormalities were most frequent in hereditary breast-ovarian cancer syndrome (6/9), followed by hereditary breast cancer-site specific syndrome (3/9). The present study and literature data suggest that the most effective strategy for DNA testing for cancer susceptibility genes is to identify the type and frequency of mutations in families with strong familial aggregation of cancers.
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2,338,715 |
Successful umbilical cord blood transplantation for Fanconi anemia using preimplantation genetic diagnosis for HLA-matched donor.
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Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, and a high incidence of myelodysplasia and acute myeloid leukemia. Stem cell transplantation is the only curative treatment. In the absence of matched- sibling donor, an alternative mismatched family or matched unrelated donor can be used, but the results are inferior to the matched-sibling transplant and carry a high risk of morbidity and mortality. Preimplantation genetic diagnosis (PGD) has been increasingly used in recent years for mutation analysis for many genetic disorders and results in the birth of healthy children, saving the need for the termination of pregnancy of an affected embryo. The use of PGD for combined analysis of mutation and HLA-matching was reported for the first time in 2001. This enables the birth of an unaffected child who can serve as a donor for an affected sibling in need for stem cell transplantation. We report successful cord blood transplantation for a Fanconi anemia patient from his HLA-matched sibling, born after PGD that included mutation analysis for Fanconi anemia and HLA typing. PGD can provide an unaffected donor for a sibling affected by genetic disease in the absence of a compatible related donor.
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2,338,716 |
Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma.
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Folate and methionine are important nutrients in the "one-carbon" metabolism that is closely associated with DNA synthesis and DNA methylation. Genetic variation in these pathways may change susceptibility to cancer development. We have previously reported associations between lymphoma risk and germline polymorphisms in genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase (MTR A2756G), finding the genotype other than the MTHFR 677CC/1298AA to confer a half-risk compared to the MTHFR 677CC/1298AA and a 3-fold higher risk with the MTR GG genotype than the AA/AG genotypes. To confirm the association and explore the histological difference, we extended the previous case series. A case-control study was conducted in Japan with a total of 372 lymphoma cases and 500 noncancer controls examined for genotypes. The relative risks were estimated by unconditional logistic regression analysis. In overall analyses, the age-sex adjusted odds ratio (OR) for the subjects harboring MTHFR 677T or 1298C alleles relative to 677CC/1298AA genotype was 0.58 (95% confidence interval: 0.41-0.83, P = 0.002). The MTR GG genotype showed an OR of 1.75 (0.87-3.52, P = 0.114). These findings were validated in separate analyses of the 273 new incident cases. Subgroup analyses according to histological subtype [diffuse large B-cell lymphoma (DLB), follicular lymphoma (FL), low-grade lymphoma of mucosa associated lymphoid tissue (MALT), and others] illustrated similar associations with certain exceptions for FL and MALT. Our data showed an association between the MTHFR polymorphisms and malignant lymphoma risk for all histological subtypes, although the extent of contribution of these polymorphisms may differ somewhat with histological subtype. Lack of association with MTR polymorphism was also confirmed.
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2,338,717 |
CARD15 gene mutations and risk for early surgery in pediatric-onset Crohn's disease.
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<AbstractText Label="BACKGROUND & AIMS" NlmCategory="OBJECTIVE">The risk for Crohn's disease (CD) is determined in part by genetic factors. Three recently described mutations in the CARD15(NOD2) gene have been associated with adult-onset CD. We investigated the effect of CARD15 mutations on disease manifestation, disease progression, and the risk for early surgery in childhood-onset CD.</AbstractText>Genotyping for 3 CARD15 mutations: R702W, G908R, and 3020insC, was performed in 186 children with CD from a prospective cohort. A transmission-disequilibrium test was used to test for association with CD. Genotype with disease location and behavior was tested with logistic regression analysis. The effect of mutations on surgical outcome was evaluated using a Cox proportional hazard analysis.</AbstractText>The mean age at CD diagnosis was 12.4 years. The frequency of allelic mutations observed was 6.6% for R702W, 6% for G908R, and 13.1% for 3020insC. Of Caucasian CD children, 42% had at least one CARD15 mutation. None of the non-Caucasian children with CD had any CARD15 mutation. A significant association was detected for 3020insC (P = .0045). Ileal location (odds ratio, 4.3; P = .003) and stricturing disease (odds ratio, 6.6; P = .0001) was more frequent and the risk for surgery was higher (hazard ratio, 5.8; P < .0001) and surgery occurred earlier (hazard ratio, 2.24) in those children with 3020insC mutation compared with those without 3020insC.</AbstractText>In children with pediatric-onset CD, early development of stricturing behavior leading to surgical resection is influenced by ileal location and 3020insC variant of the CARD15 mutation. Genetic testing may identify children with CD who are at risk for early surgery.</AbstractText>
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2,338,718 |
High-resolution mapping of the Rym4/Rym5 locus conferring resistance to the barley yellow mosaic virus complex (BaMMV, BaYMV, BaYMV-2) in barley (Hordeum vulgare ssp. vulgare L.).
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Soil-borne barley yellow mosaic virus disease--caused by a complex of at least three viruses, i.e. Barley mild mosaic virus (BaMMV), Barley yellow mosaic virus (BaYMV) and BaYMV-2--is one of the most important diseases of winter barley in Europe. The two genes rym4, effective against BaMMV and BaYMV, and rym5, additionally effective against BaYMV-2, comprise a complex locus on chromosome 3HL, which is of special importance to European barley breeding. To provide the genetic basis for positional cloning of the Rym4/Rym5 locus, two high-resolution maps were constructed based on co-dominant flanking markers (MWG838/Y57c10 - MWG010/Bmac29). Mapping at a resolution of about 0.05% rec., rym4 has been located 1.07% recombination distal of marker MWG838 and 1.21% recombination proximal to marker MWG010. Based on a population size of 3,884 F2 plants (0.013% recombination) the interval harbouring rym5 was delimited to 1.49+/-0.14% recombination. By testing segmental recombinant inbred lines (RILs) for reaction to the different viruses at a resolution of 0.05% rec. (rym4) and 0.019% rec. (rym5), no segregation concerning the reaction to the different viruses could be observed. AFLP-based marker saturation for rym4, using 932 PstI+2/MseI+3 primer combinations only resulted in three markers with the closest one linked at 0.9% recombination to the gene. Two of these markers detected epialleles arising from the differential cytosine methylation of PstI sites. Regarding rym5, profiling of 1,200 RAPD primers (about 18,000 loci) and 2,048 EcoRI+3/MseI+3 AFLP primer combinations (about 205,000 loci) resulted in one RAPD marker and seven AFLP markers tightly linked to the resistance gene. Flanking markers with the closest linkage to rym5 (0.05% and 0.88% recombination) were converted into STS markers. These markers provide a starting point for chromosomal walking and may be exploited in marker-assisted selection for virus resistance based on rym5.
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2,338,719 |
Molecular markers linked to papaya ring spot virus resistance and Fusarium race 2 resistance in melon.
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In melon, the Fom-1 gene confers monogenic resistance against the soil-borne fungus Fusarium oxysporum f. sp. melonis, races 0 and 2, while the closely linked Prv gene specifies resistance against the papaya ring spot virus. Markers linked to these resistance (R) genes were identified using two recombinant inbred line populations, derived from crosses between Cucumis melo Vedrantais and C. melo PI 161375, and between C. melo Vedrantais and C. melo PI 414723, respectively. Using bulked segregant analysis, as well as systematic scoring of the mapping populations, we developed two amplified fragment length polymorphism markers, two random amplified polymorphic DNA markers and five restriction fragment length polymorphism (RFLP) markers linked to this locus. Four of the RFLP sequences bear homology to nucleotide-binding site-leucine-rich repeat R genes, indicating the presence of a significant R-gene cluster in this locus. Our study provides the most closely linked markers published so far for these important traits. It also improves the resolution of the whole linkage group IX, which was difficult to order in our previous studies. Two of the markers were converted to cleaved amplified polymorphic sequence markers to facilitate their application in marker-assisted selection. Testing these two markers in several melon lines revealed different marker haplotypes in the melon germplasm and supported multiple, independent origin of the Fusarium races 0 and 2 resistance trait.
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2,338,720 |
Risk of cancer at sites other than the breast in Swedish families eligible for BRCA1 or BRCA2 mutation testing.
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Population-based data on the risk of cancer in families eligible for BRCA1/2 mutation testing may help to reach a consensus about the association of BRCA1/2 mutations with cancer at sites other than the breast and may reveal new, non-BRCA1/2 related components of the familial clustering of cancer in those families.</AbstractText>The families of the Swedish Family-Cancer Database with at least three generations (n = 944,723) were classified according to the criteria proposed by the German Consortium for Hereditary Breast and Ovarian Cancer. The cancer incidences in the classified families were compared with the incidences in the general population. The percentages of individuals with cancer in families eligible for BRCA1/2 mutation testing were compared with data in the literature to estimate the proportion of malignancies related to BRCA1/2 mutations.</AbstractText>Families with two breast cancers before the age of 50 years showed increased risk of early onset pancreatic, prostate and ovarian cancers; families with ovarian and breast cancers presented increased incidences for ovarian and ocular cancers; families with two breast cancers, at least one of them under the age of 50 years, showed increased risks of prostate and primary liver cancers. Stomach cancer before age 70 years was twice as frequent in families with breast and ovarian cancers as in the general population. BRCA1/2 mutations probably explain most of the aggregation of ovarian cancer in families with male breast cancer, and in families with at least two breast cancers diagnosed before age 50 years.</AbstractText>The association of BRCA1/2 mutations with ovarian, pancreatic, prostate and stomach cancers was confirmed at a population level. However, the clustering of early pancreatic cancer in families with two breast cancers under age 50 years, the aggregation of ovarian cancer in families with breast and ovarian cancers, and the increased incidence of early onset prostate cancer in families with male breast cancer seem to be due to other effects unrelated to BRCA1/2 mutations.</AbstractText>
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2,338,721 |
Clinical trial design for microarray predictive marker discovery and assessment.
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Transcriptional profiling technologies that simultaneously measure the expression of thousands of mRNA species represent a powerful new clinical research tool. Similar to previous laboratory analytical methods including immunohistochemistry, PCR and in situ hybridization, this new technology may also find its niche in routine diagnostics. Outcome predictors discovered by these methods may be quite different from previous single-gene markers. These novel tests will probably combine the information embedded in the expression of multiple genes with mathematical prediction algorithms to formulate classification rules and predict outcome. The performance of machine learning-algorithm-based diagnostic tests may improve as they are trained on larger and larger sets of samples, and several generations of tests with improving accuracy may be introduced sequentially. Several gene-expression profiling-technology platforms are mature enough for clinical testing. The most important next step that is needed for further progress is the development and validation of multigene predictors in prospectively designed clinical trials to determine the true accuracy and clinical value of this new technology. This manuscript reviews methodological and statistical issues relevant to clinical trial design to discover and validate multigene predictors of response to therapy.
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2,338,722 |
The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk.
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Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20-30% of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We investigated eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, the two adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. A case-control study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of either Ile655Val (OR = 1.05, 95% CI = 0.82-1.34, P = 0.728) or Ala1170Pro (OR = 0.94, 95% CI = 0.74-1.20, P = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could also not be detected. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95% CI = 1.08-6.08, P = 0.028). The rare Val654 variant is linked with the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654-Val655 allele provokes receptor dimerization and activation, thus stimulating kinase activity and cell transformation. We hypothesize that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict a worse prognosis.
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2,338,723 |
A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.
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The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.
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2,338,724 |
Severe hemophilia A due to a 1.3 kb factor VIII gene deletion including exon 24: homologous recombination between 41 bp within an Alu repeat sequence in introns 23 and 24.
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Partial or complete factor (F)VIII gene deletions are found in about 5% of families with severe hemophilia A. Relatively few deletions have been well characterized and, of these, recombination occurred between either common repeat elements or non-homologous sequences. In evaluating a family with severe hemophilia A, an exon 24 deletion was suspected when no fragment was obtained on attempted PCR amplifications. A combination of the 5' primer of exon 23 and the 3' primer of exon 25 fragments was used with prolonged extension times to amplify a normal 2.9 kb fragment that included exons 23 through 25; the patient's amplified product was 1.6 kb indicating a 1.3 kb deletion. A mixture of normal and patient DNA showed both sized fragments as did that from an obligate carrier. Carrier detection was applied to two women at risk; one was and one was not a carrier. Sequencing the proband's 1.6 kb fragment revealed that a 1328 bp deletion occurred between homologous sequences of 287 and 285 bp in introns 23 and 24, respectively; these share 85% identity. Blast nucleotide search revealed that these represent Alu elements. Comparison with an alignment of each of the two homologous sequences further localized recombination to a 41-bp segment. However, a simple recombination event would not account for the proband's sequence. The most likely explanation is that the homologous recombination was accompanied by incomplete mismatch repair.
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2,338,725 |
Information and effective number of meioses in linkage analysis.
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In this paper we introduce two information criteria in linkage analysis. The setup is a sample of families with unusually high occurrence of a certain inheritable disease. Given phenotypes from all families, the two criteria measure the amount of information inherent in the sample for 1) testing existence of a disease locus harbouring a disease gene somewhere along a chromosome or 2) estimating the position of the disease locus. Both criteria have natural interpretations in terms of effective number of meioses present in the sample. Thereby they generalize classical performance measures directly counting number of informative meioses. Our approach is conditional on observed phenotypes and we assume perfect marker data. We analyze two extreme cases of complete and weak penetrance models in particular detail. Some consequences of our work for sampling of pedigrees are discussed. For instance, a large sibship family with extreme phenotypes is very informative for linkage for weak penetrance models, more informative than a number of small families of the same total size.
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2,338,726 |
A model for estimating joint maternal-offspring effects on seed development in autogamous plants.
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We present a statistical model for testing and estimating the effects of maternal-offspring genome interaction on the embryo and endosperm traits during seed development in autogamous plants. Our model is constructed within the context of maximum likelihood implemented with the EM algorithm. Extensive simulations were performed to investigate the statistical properties of our approach. We have successfully identified a quantitative trait locus that exerts a significant maternal-offspring interaction effect on amino acid contents of the endosperm in maize, demonstrating the power of our approach. This approach will be broadly useful in mapping endosperm traits for many agriculturally important crop plants and also make it possible to study the genetic significance of double fertilization in the evolution of higher plants.
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2,338,727 |
Linkage analysis of ordinal traits for pedigree data.
|
Linkage analysis is used routinely to map genes for human diseases and conditions. However, the existing linkage-analysis methods require that the diseases or conditions either be dichotomized or measured by a quantitative trait, such as blood pressure for hypertension. In the latter case, normality is generally assumed for the trait. However, many diseases and conditions, such as cancer and mental and behavioral conditions, are rated on ordinal scales. The objective of this study was to establish a framework to conduct linkage analysis for ordinal traits. We propose a latent-variable, proportional-odds logistic model that relates inheritance patterns to the distribution of the ordinal trait. We use the likelihood-ratio test for testing evidence of linkage. By means of simulation studies, we find that the power of our proposed model is substantially higher than that of the binary-trait-based linkage analysis and that our test statistic is robust with regard to certain parameter misspecifications. By using our proposed method, we performed a genome scan of the hoarding phenotype in a data set with 53 nuclear families, which were collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). Standard linkage scans using hoarding as a dichotomous trait were also performed by using GENEHUNTER and ALLEGRO. Both GENEHUNTER and ALLEGRO failed to reveal any marker significantly linked to the binary hoarding phenotypes. However, our method identified three markers at 4q34-35 (P = 0.0009), 5q35.2-35.3 (P = 0.0001), and 17q25 (P = 0.0005) that manifest significant allele sharing.
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2,338,728 |
The optimal measure of linkage disequilibrium reduces error in association mapping of affection status.
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We have developed a simple yet powerful approach for disease gene association mapping by linkage disequilibrium (LD). This method is unique because it applies a model with evolutionary theory that incorporates a parameter for the location of the causal polymorphism. The method exploits LD maps, which assign a location in LD units (LDU) for each marker. This approach is based on single marker tests within a composite likelihood framework, which avoids the heavy Bonferroni correction through multiple testing. As a proof of principle, we tested an 890 kb region flanking the CYP2D6 gene associated with poor drug-metabolizing activity in order to refine the localization of a causal mutation. Previous LD mapping studies using single markers and haplotypes have identified a 390 kb significant region associated with the poor drug-metabolizing phenotype on chromosome 22. None of the 27 Single nucleotide polymorphisms was within the gene. Using a metric LDU map, the commonest functional polymorphism within the gene was located at 14.9 kb from its true location, surrounded within a 95% confidence interval of 172 kb. The kb map had a relative efficiency of 33% compared with the LDU map. Our findings indicate that the support interval and location error are smaller than any published results. Despite the low resolution and the strong LD in the region, our results provide evidence of the substantial utility of LDU maps for disease gene association mapping. These tests are robust to large numbers of markers and are applicable to haplotypes, diplotypes, whole-genome association or candidate region studies.
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2,338,729 |
Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women.
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Schizophrenia is a complex disorder with a polygenic inheritance. Catechol-O-methyltransferase (COMT) plays a significant role in the regulation of dopaminergic systems. A polymorphism at COMT Val108/158Met has been identified in association with schizophrenia. We examined the allele and genotype association of the COMT Val108/158Met polymorphism of 297 unrelated schizophrenic patients who strictly met DSM-IV criteria for schizophrenia, and 341 healthy controls. We found significant difference in allele and genotype frequencies between schizophrenic patients and controls (chi2=13.030; P=0.001). The allele frequency of the COMT-L was 45.79% in the total schizophrenic patients, and 41.50% in controls. The genotype frequency of the COM-LL was 21.2% in the total schizophrenic patients, and 11.4% in controls (OR=2.085; 95% CI=1.350-3.219; chi2=11.293; P=0.001). With a separate sex analysis, the frequency of the COMT-L allele was moderately distributed in male schizophrenia (chi2=6.177; df=2; P=0.046). The COMT-LL genotype had a 1.818-fold increased risk for schizophrenia (OR=1.818; 95% CI=1.010-3.273; chi2=4.048; P=0.044). The frequency of the COMT-L allele was even more significantly distributed in women schizophrenia (chi2=7.797; df=2; P=0.020). The COMT-LL genotype had remarkably more increased risk for schizophrenia (OR=2.456; 95% CI=1.287-4.687; chi2=7.710; P=0.005). In conclusion, our results provide strong evidence for a role of the COMT-L allele and LL genotype in the etiopathophysiology of schizophrenia with a sexual difference.
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2,338,730 |
Detection of colorectal cancer by a quantitative fluorescence determination of DNA amplification in stool.
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DNA amplification of exfoliated cells in stool represents an inexpensive and rapid test, but has only 50% to 60% sensitivity. A new quantitative method, called fluorescence long DNA, was developed and validated in our laboratory on stool obtained from 86 patients with primary colorectal cancer and from 62 healthy individuals. It consists of the amplification of stool DNA with fluorescence primers and the quantification of the amplification using a standard curve. Results are arbitrarily expressed in nanograms. The potential of the new method compared to the conventional approach was analyzed in a subgroup of 94 individuals (56 patients and 38 healthy volunteers). In the present series, DNA amplification analysis showed a specificity of 97% and a sensitivity of only 50%. Conversely, fluorescence DNA evaluation, using the best cutoff of 25 ng, showed a sensitivity of about 76% and a specificity of 93%. Similar sensitivity was observed regardless of Dukes stage, tumor location, and size, thus also permitting the detection of early-stage tumors. The present study seems to indicate that quantitative fluorescence DNA determination in stool successfully identifies colorectal cancer patients with a sensitivity comparable, if not superior, to that of multiple gene analysis but at a lower cost and in a shorter time.
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2,338,731 |
Testing geographical pathways of speciation in a recent island radiation.
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Determining the mode, or geographical context, of speciation is a critical first step to understanding the evolutionary mechanisms that cause new species to arise. In this study, we estimated phylogenetic relationships in the cerasina species group of the Hawaiian cricket genus Laupala (Orthoptera: Gryllidae) to test competing phylogeographical hypotheses and thus infer the mode of speciation. A previous phylogenetic result based on nuclear sequence data suggested that populations of L. cerasina on the Big Island of Hawaii are the result of two independent colonizations from Maui, implying parallel speciation and convergent song evolution, and contradicting systematic hypotheses based on behavioural and morphological data. We used amplified fragment length polymorphisms to investigate further the relationships among species and populations in the cerasina species group. Results of these analyses provide a robust estimate of phylogenetic relationships and support the phylogeographical history indicated by behavioural and morphological data.
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2,338,732 |
Ecological and life history characteristics predict population genetic divergence of two salmonids in the same landscape.
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Ecological and life history characteristics such as population size, dispersal pattern, and mating system mediate the influence of genetic drift and gene flow on population subdivision. Bull trout (Salvelinus confluentus) and mountain whitefish (Prosopium williamsoni) differ markedly in spawning location, population size and mating system. Based on these differences, we predicted that bull trout would have reduced genetic variation within and greater differentiation among populations compared with mountain whitefish. To test this hypothesis, we used microsatellite markers to determine patterns of genetic divergence for each species in the Clark Fork River, Montana, USA. As predicted, bull trout had a much greater proportion of genetic variation partitioned among populations than mountain whitefish. Among all sites, FST was seven times greater for bull trout (FST = 0.304 for bull trout, 0.042 for mountain whitefish. After removing genetically differentiated high mountain lake sites for each species FST, was 10 times greater for bull trout (FST = 0.176 for bull trout; FST = 0.018 for mountain whitefish). The same characteristics that affect dispersal patterns in these species also lead to predictions about the amount and scale of adaptive divergence among populations. We provide a theoretical framework that incorporates variation in ecological and life history factors, neutral divergence, and adaptive divergence to interpret how neutral and adaptive divergence might be correlates of ecological and life history factors.
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2,338,733 |
Spatial genetic structure in a metapopulation of the land snail Cepaea nemoralis (Gastropoda: Helicidae).
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Habitat fragmentation is a major force affecting demography and genetic structure of wild populations, especially in agricultural landscapes. The land snail Cepaea nemoralis (L.) was selected to investigate the impact of habitat fragmentation on the spatial genetic structure of an organism with limited dispersal ability. Genetic and morphological patterns were investigated at a local scale of a 500 m transect and a mesoscale of 4 x 4 km in a fragmented agricultural landscape while accounting for variation in the landscape using least-cost models. Analysis of microsatellite loci using expected heterozygosity (HE), pairwise genetic distance (FST/1-FST) and spatial autocorrelograms (Moran's I) as well as shell characteristics revealed spatial structuring at both scales and provided evidence for a metapopulation structure. Genetic diversity was related to morphological diversity regardless of landscape properties. This pointed to bottlenecks caused by founder effects after (re)colonization. Our study suggests that metapopulation structure depended on both landscape features and the shape of the dispersal function. A range of genetic spatial autocorrelation up to 80 m at the local scale and up to 800 m at the mesoscale indicated leptokurtic dispersal patterns. The metapopulation dynamics of C. nemoralis resulted in a patchwork of interconnected, spatially structured subpopulations. They were shaped by gene flow which was affected by landscape features, the dispersal function and an increasing role of genetic drift with distance.
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2,338,734 |
Absence of myocilin and optineurin mutations in a large Philippine family with juvenile onset primary open angle glaucoma.
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To analyze the role of the two primary open angle glaucoma (POAG) genes, myocilin (MYOC) and optineurin (OPTN), in a large Philippine family segregating autosomal dominant juvenile onset open angle glaucoma (JOAG).</AbstractText>The coding sequences of the MYOC and OPTN genes were screened in 27 family members by polymerase chain reaction and direct sequencing. The specific MYOC promoter polymorphism (MYOC.mtl) was identified by restriction endonuclease assay. All of the ABI MD-10 microsatellite markers on chromosomes 1, 2, 3, 7, 8, and 10, which harbor the six known POAG loci, were analyzed for linkage with POAG.</AbstractText>No mutation was identified in this large kindred. Instead, three polymorphisms (-80G->A, -1000G->C, R76K) in MYOC and four polymorphisms (T34T, M98K, R545Q, IVS7+24G->A) in OPTN were found. All markers flanking the six known POAG loci gave LOD scores not more than 1.1. Non-parametric linkage analysis for all these markers resulted in p values more than 0.05.</AbstractText>Both mutation testing and linkage analysis provide strong evidence against MYOC and OPTN being the causative gene in this large family. It indicates that unidentified genes will underlie the occurrence of glaucoma in this family.</AbstractText>
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2,338,735 |
Confirmation and genetic dissection of a major quantitative trait locus for alcohol preference drinking.
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In previous work, we created congenic strains that carry the DBA/2IBG (D2) region for alcohol preference on chromosome 2, on an otherwise C57BL/6IBG (B6) background. Here, we report construction and testing of interval-specific congenic recombinant strains (ISCRSs) for the purpose of narrowing the quantitative trait loci (QTL) interval.</AbstractText>ISCRSs were derived by identifying mice that carry recombination events in the D2 interval, during the backcrossing for congenics. Recombinant mice were backcrossed to B6, and progeny that carry the reduced chromosome 2 region were tested for its effect on the alcohol preference phenotype.</AbstractText>We developed multiple ISCR strains, which spanned the QTL interval. Three of these showed the D2 phenotype of reduced alcohol consumption. The overlap of two of these strains reduced the QTL interval from 66.8 to 3.5 Mb. A third positive ISCRS suggests the possibility of a second, linked QTL.</AbstractText>Use of ISCRSs can narrow a QTL region to a few Mb. This reduced interval size will facilitate identification of candidate genes, through bioinformatics, gene expression, and DNA sequencing strategies. Potential difficulties, including reduced power as a result of variable phenotypes or small effect size, are discussed.</AbstractText>
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2,338,736 |
Association of HLA-DM polymorphism with the production of antiphospholipid antibodies.
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To investigate whether variation in the HLA-DM gene is important in producing a group of pathogenic autoantibodies-antiphospholipid antibodies (aPL)-on the basis that HLA class II restricted antigen presentation is involved in the production of aPL.</AbstractText>HLA-DMA and DMB polymorphisms were genotyped by polymerase chain reaction combined with restriction enzyme digestion in 51 white patients with primary antiphospholipid syndrome (APS), 82 with systemic lupus erythematosus (SLE) (42 with APS and 40 without APS), and 109 healthy white controls. The association with the aPL profile was examined.</AbstractText>The distribution of DMA alleles in APS patients and in patients with APS associated with SLE was significantly different from that in controls by 4x2 chi(2) test with 3 degrees of freedom (p = 0.035 and 0.011, respectively), but it was not different between SLE patients without APS and controls. The allelic distribution of DMA was also different between patients with IgG class anticardiolipin antibody or those with lupus anticoagulant (LA) and controls (p = 0.012 and 0.007, respectively) and between patients with and without LA among SLE patients (p = 0.035). All these differences included the increase in DMA*0102 in the former groups.</AbstractText>The results suggest that HLA-DMA*0102 or its linked gene(s) form one of the genetic risks for the production of aPL.</AbstractText>
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2,338,737 |
HLA typing in focal myositis.
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It is still controversial if idiopathic focal myositis is a part of systemic polymyositis. We present here four patients, including identical twins, with focal myositis accompanied by the same HLA typings. Gradually developing unilateral calf muscle pain was an initial symptom in all patients. Neither muscular weakness nor creatine kinase (CK) elevation was observed, while minimal inflammatory findings such as erythrocyte sedimentation rate (ESR) increase appeared in serum. Magnetic resonance imaging (MRI) revealed localized abnormalities of calf muscles. Biopsy specimen was characterized by perimysial and endomysial inflammatory infiltration consisted of T cells and macrophages and rare necrotic fibers. Corticosteroid administrations ameliorated their symptoms and signs, though recurrence occurred along with decreasing doses. HLA typings common to all patients were A2, B62, Cw3, and DQ3, whereas HLA-D DNA typings were DQB1 *0303 for two patients, and DQB1*0302 for three patients. These findings suggest that at least some focal myositis may be a new disease unit, with a common genetic background but not a part of systemic polymyositis.
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2,338,738 |
The role of host organism, transcriptional switches and reporter mechanisms in the performance of Hg-induced biosensors.
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The purpose of this study was to comprehensively compare the response of nine biosensors capable of being induced by Hg. Induction by Hg was based upon the insertion of merR, merB, zntA and zntR promoter genes. LuxCDABE or lucFF reporter genes expressed luminescence, and host organisms were Escherichia coli, Vibrio anguillarum and Pseudomonas fluorescens. The role of transcriptional switches, reporter mechanism and host organism was to be investigated.</AbstractText>All biosensors were subjected to the same assay conditions. Sensors had their own individual growth characteristics and response to the doses of Hg tested. Maximum bioluminescence response was induced by concentrations of Hg between 2.5 nm and 5 microM. E. coli pRB28 was found to detect levels of Hg as low as 1.6 nm and yet was capable of operating in a concentration range of up to 12.5 microM.</AbstractText>The response of the sensors demonstrated their suitability for analysis under environmentally relevant concentrations. The sensitivity of the sensors, the optimum range and the expediency of the assay could not be related to a single sensor trait. It may be concluded that biosensor performance is dependent on more than one of the single factors studied.</AbstractText>The results show that comparative testing of sensors is an important step in evaluating the relevance and performance of biosensors prior to routine environmental application.</AbstractText>
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2,338,739 |
Role of 14-bp deletion in the HLA-G gene in the maintenance of pregnancy.
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Differential expression of human leukocyte antigens (HLAs) on trophoblast has been the focus of many studies, specially on extravillous cytotrophoblast cells, which migrates into the maternal uterine tissues. These invading cells do not express classical major histocompatibility complex class I (-A and -B) and class II molecules, along with low expression of HLA-C. HLA-G is the predominantly expressed antigen along with HLA-E. Hence, it is believed that expressed antigens may be involved in materno-fetal tolerance. In the present study, we have studied 14-bp deletion polymorphism in the exon-8 of the non-classical HLA-G antigen. There was no difference in the frequency of deletion/insertion polymorphism in fertile normal women and recurrent spontaneous abortion (RSA) women. However, the number of heterozygotes (-14b/+14b) were increased in RSA women. The probable mechanism for the increase of heterozygotes in recurrent fetal loss is discussed in light of soluble HLA-G.
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2,338,740 |
HLA-Cw*1214 allele arisen via recombination between HLA-Cw*070201 and HLA-Cw*120201.
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Allelic polymorphism of the major histocompatibility complex arises mostly from gene conversion. Intralocus gene conversion usually involves limited fragments of DNA, whereas recombination involving large fragments of DNA is considered to be a rare event. During routine sequencing-based typing of donors for the National Marrow Donor Program, a new HLA-C allele was identified in a Caucasian donor. The allele, HLA-Cw*1214, proved to be the product of recombination between HLA-Cw*070201 and HLA-Cw*120201. Exons 1, 2, the 3' end of exon 3 and exon 4 (with one mismatch) belong to HLA-Cw*120201, whereas part of exon 3 belongs to HLA-Cw*070201. Sequencing with primers based in exon 2 and exon 3 showed that intron 2 of the new allele also belonged completely to HLA-Cw*1202. The recombination event apparently occurred within exon 3 with the first point of recombination somewhere between codons 92 and 134 and the second one between codons 157 and 181.
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2,338,741 |
Immunogenetics of HLA null alleles: implications for blood stem cell transplantation.
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The transplantation of haematopoietic stem cells is a potentially curative therapy for a variety of haematological and non-haematological diseases. Matching of donor and recipient for human leucocyte antigens (HLA) is pivotal for the success of blood stem cell transplantation. HLA null alleles are characterized by the lack of a serologically detectable product. Because serological HLA diagnostics are increasingly replaced by DNA-based typing methods considering only small regions of the genes, null alleles may be misdiagnosed as normally expressed variants. The failure to identify an HLA null allele as a non-expressed variant in the stem cell transplantation setting may result in an HLA mismatch that is highly likely to stimulate allogeneic T cells and to trigger graft-vs-host disease. For some HLA null alleles, the translation into a truncated polypeptide chain seems possible, which thus might act as minor histocompatibility antigens. Because the prevalence of HLA null alleles may be around 0.3% or even higher, a screening strategy for HLA null alleles should, therefore, be implemented in the clinical laboratory. It may consist of the combination of serology and standard molecular typing techniques. As the standard molecular techniques are sometimes troublesome especially for characterizing the cytosine island at the 5' end of HLA class I exon 4 and need continuously be updated, an alternative approach may consist of sequencing all samples from genomic DNA for exons 2-3 or 4 (class I) or exon 2 (class II), including the adjacent intron splicing sites. This approach will detect 36/40 so far known non-expressed variants and has the potential to easily uncover novel variants, thus essentially minimizing the risk of overlooking these challenging variants.
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2,338,742 |
A pilot study on genotype announcement to induce smoking cessation by Japanese smokers.
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Genotype announcements related to susceptibility to hazardous effects of smoking may be effective to induce smoking cessation.</AbstractText>Subjects were municipal government employees, 63 young smokers employed in the previous year and 59 smokers with more than 45 pack-years, who were invited to educational sessions against smoking held in December 2003 and February 2004, respectively. In the session, those who wished genetic susceptibility tests (GSTM1, GSTT1, and NQO1 C609T) were enrolled in the study. The smoking habit was ascertained three times: at the session, one month later, just before the genotype announcement, and at the follow-up three months after the announcement.</AbstractText>Fifty eight (92.1%) and 49 (83.1%) smokers participated in the study, respectively. One out of 58 smokers was not a habitual smoker, so was not included in the analysis. The smoking cessation rates were 15.8% (9 participants) and 6.1% (3 participants) just before the genotype announcement, and 7.0% (4 participants) and 10.2% (5 participants) at the follow-up, respectively. All subjects were satisfied with the genotype testing except for two who rather regretted participating, but one of whom actually quit smoking.</AbstractText>The present pilot study without controls indicated that the effects of genotype announcements in this framework on smoking cessation were less than might have been expected. The temporary effect of the session on younger smokers may have been due to the participation per se. The potential effects of genotype announcements for heavy smokers should now be examined in studies with adequate controls.</AbstractText>
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2,338,743 |
Emergence of new strains of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit.
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Genetically distinct strains of methicillin-resistant Staphylococcus aureus (MRSA) of community rather than hospital origin have emerged in many areas of the United States. We determined if MRSA strains causing bacteremia in infants treated from birth in a neonatal intensive care unit (NICU) demonstrated the genetic traits of community-associated MRSA.</AbstractText>A retrospective cohort study was conducted among NICU infants with bacteremia due to MRSA during 2003 in a large tertiary care center NICU in Houston. MRSA isolates were characterized by antimicrobial susceptibility testing and staphylococcal cassette chromosome mec (SCCmec) typing by polymerase chain reaction. All MRSA cases were reviewed for clinical severity of infection and outcome.</AbstractText>During 2003, a total of 8 (47%) of 17 infants with bacteremia due to S. aureus had MRSA infection. Isolates from 6 (75%) of these 8 infants carried the SCCmec genes (class B mec and ccr2) that are characteristic of community MRSA; 4 isolates were type IVa. All 6 isolates were resistant to beta-lactam antibiotics and erythromycin; 1 was also resistant to clindamycin. One isolate was nontypeable, and another carried the SCCmec type II gene (typical of hospital-associated strains) and was susceptible only to vancomycin. Seven (88%) of 8 infants presented in septic shock. Despite initial treatment with vancomycin, 3 (38%) died, and 3 survivors had complications requiring prolonged antimicrobial therapy; these 6 infants had MRSA isolates with genetic characteristics of isolates of community origin.</AbstractText>Community-associated MRSA strains have emerged as a significant cause of sepsis in neonates hospitalized in NICU since birth and have caused disseminated infection with substantial morbidity and mortality.</AbstractText>
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2,338,744 |
Perceptions of genetic discrimination among at-risk relatives of colorectal cancer patients.
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To explore the concerns of at-risk relatives of colorectal cancer patients about genetic discrimination and their awareness of current legislative protections.</AbstractText>A questionnaire was sent to unaffected individuals with a family history of colorectal cancer who had enrolled in the Johns Hopkins Hereditary Colorectal Cancer Registry (N = 777).</AbstractText>Of the 470 respondents, approximately half rated their level of concern about genetic discrimination as high. The majority of respondents, 79%, learned about genetic discrimination from at least one media source (television, newspapers, magazines, and radio). If they were to pursue genetic testing, respondents with a higher level of concern about genetic discrimination would be significantly more likely to pay out of pocket, use an alias, or ask for test results to be excluded from their medical record. Awareness and understanding of legislation regarding genetic discrimination was found to be minimal.</AbstractText>Findings from this study demonstrate the negative effect of concerns about genetic discrimination on decisions about utilization of genetic services. Stronger legislative protections against genetic discrimination and increased public education through the scientific community and media sources are needed.</AbstractText>
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2,338,745 |
Family communication about positive BRCA1 and BRCA2 genetic test results.
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The identification of a BRCA1 or BRCA2 genetic mutation can provide important health information to individuals who receive this result, but it can also provide crucial cancer risk information to family members. Most of the research on communication of genetic test results has focused on first degree relatives. The purpose of this retrospective study was to examine the process of communicating a positive BRCA1 or BRCA2 genetic test result to male and female first, second, and third degree relatives.</AbstractText>Participants were 38 female mutation carriers who responded to a written survey assessing the number and relationship of relatives informed, methods used to inform relatives, topics discussed, and motivations and barriers for communication.</AbstractText>Overall, 59% (470/803) of first, second, and third degree relatives were informed. The proportion of informed parents, siblings, and offspring was nearly twice that of more distant relatives including nieces, nephews, aunts, uncles, grandchildren, and cousins (88% versus 45%; P = 0.02). The method of communication differed by the gender of the relative, as did some of the topics discussed. The most important reasons for discussing the genetic test results were (1) to inform the relatives of their risk, (2) to suggest that they be tested, and (3) to fulfill a perceived duty to inform. The major barrier to communication was little contact and/or emotionally distant relationships.</AbstractText>Female mutation carriers act on a perceived duty to inform close relatives of their positive test result; however, there is a need for genetic counseling strategies that address communication with more distant relatives.</AbstractText>
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2,338,746 |
Genetic tests and their evaluation: can we answer the key questions?
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The rapid pace of research in the field of genetics has already yielded many benefits. The development of new genetic tests is one such example. Before there can be widespread uptake of these tests they need to be evaluated to confirm the benefits of their use. The authors review some of the key features of the evaluation of diagnostic tests focusing on analytical and clinical validity. Test properties such as sensitivity, specificity, likelihood ratios, positive and negative predictive values, and how they relate to molecular genetic testing are discussed. Associated issues such as the concepts of disease definition, imperfect reference standards, and false positives are also explored. The authors suggest possible approaches to addressing some of the problems identified.
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2,338,747 |
Mycobacterium cosmeticum sp. nov., a novel rapidly growing species isolated from a cosmetic infection and from a nail salon.
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Four isolates of a rapidly growing Mycobacterium species had a mycolic acid pattern similar to that of Mycobacterium smegmatis, as determined by HPLC analyses. Three of the isolates were from footbath drains and a sink at a nail salon located in Atlanta, GA, USA; the fourth was obtained from a granulomatous subdermal lesion of a female patient in Venezuela who was undergoing mesotherapy. By random amplified polymorphic DNA electrophoresis and PFGE of large restriction fragments, the three isolates from the nail salon were shown to be the same strain but different from the strain from the patient in Venezuela. Polymorphisms in regions of the rpoB, hsp65 and 16S rRNA genes that were shown to be useful for species identification matched for the two strains but were different from those of other Mycobacterium species. The 16S rRNA gene sequence placed the strains in a taxonomic group along with Mycobacterium frederiksbergense, Mycobacterium hodleri, Mycobacterium diernhoferi and Mycobacterium neoaurum. The strains produced a pale-yellow pigment when grown in the dark at the optimal temperature of 35 degrees C. Biochemical testing showed that the strains were positive for iron uptake, nitrate reduction and utilization of d-mannitol, d-xylose, iso-myo-inositol, l-arabinose, citrate and d-trehalose. The strains were negative for d-sorbitol utilization and production of niacin and 3-day arylsulfatase, although arylsulfatase activity was observed after 14 days. The isolates grew on MacConkey agar without crystal violet but not on media containing 5 % (w/v) NaCl or at 45 degrees C. They were susceptible to ciprofloxacin, amikacin, tobramycin, cefoxitin, clarithromycin, doxycycline, sulfamethoxazole and imipenem. The name Mycobacterium cosmeticum sp. nov. is proposed for this novel species; two strains, LTA-388(T) (=ATCC BAA-878(T)=CIP 108170(T)) (the type strain) and 2003-11-06 (=ATCC BAA-879=CIP 108169) have been designated, respectively, for the strains of the patient in Venezuela and from the nail salon in Atlanta, GA, USA.
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2,338,748 |
Genetic selection for health traits using producer-recorded data. I. Incidence rates, heritability estimates, and sire breeding values.
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The objective of this study was to determine the feasibility of genetic selection for health traits in dairy cattle using data recorded in on-farm herd management software programs. Data regarding displaced abomasum (DA), ketosis (KET), mastitis (MAST), lameness (LAME), cystic ovaries (CYST), and metritis (MET) were collected between January 1, 2001 and December 31, 2003 in herds using Dairy Comp 305, DHI-Plus, or PCDART herd management software programs. All herds in this study were either participants in the Alta Genetics (Watertown, WI) Advantage progeny testing program or customers of the Dairy Records Management Systems (Raleigh, NC) processing center. Minimum lactation incidence rates were applied to ensure adequate reporting of these disorders within individual herds. After editing, DA, KET, MAST, LAME, CYST, and MET data from 75,252 (313), 52,898 (250), 105,029 (429), 50,611 (212), 65,080 (340), and 97,318 (418) cows (herds) remained for analysis. Average lactation incidence rates were 0.03, 0.10, 0.20, 0.10, 0.08, and 0.21 for DA, KET, MAST, LAME, CYST, and MET (including retained placenta), respectively. Data for each disorder were analyzed separately using a threshold sire model that included a fixed parity effect and random sire and herd-year-season of calving effects; both first lactation and all lactation analyses were carried out. Heritability estimates from first lactation (all lactation) analyses were 0.18 (0.15) for DA, 0.11 (0.06) for KET, 0.10 (0.09) for MAST, 0.07 (0.06) for LAME, 0.08 (0.05) for CYST, and 0.08 (0.07) for MET. Corresponding heritability estimates for the pooled incidence rate of all diseases between calving and 50 d postpartum were 0.12 and 0.10 for the first and all lactation analyses, respectively. Mean differences in PTA for probability of disease between the 10 best and 10 worst sires were 0.034 for DA, 0.069 for KET, 0.130 for MAST, 0.054 for LAME, 0.039 for CYST, and 0.120 for MET. Based on the results of this study, it appears that genetic selection against common health disorders using data from on-farm recording systems is possible.
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2,338,749 |
Testing nested phylogenetic and phylogeographic hypotheses in the Plethodon vandykei species group.
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Mesic forests in the North American Pacific Northwest occur in two disjunct areas: along the coastal and Cascade ranges of Oregon, Washington, and British Columbia as well as the Northern Rocky Mountains of Idaho, Montana, and British Columbia. Over 150 species or species complexes have disjunct populations in each area, and a priori hypotheses based on phytogeography and geology potentially explain the disjunction via either dispersal or vicariance. Here, we test these hypotheses in the disjunct salamander complex Plethodon vandykei and P. idahoensisby collecting genetic data (669 bp of Cyt b) from 262 individuals. Maximum likelihood analysis indicated reciprocal monophyly of these species, supporting the ancient vicariance hypothesis, whereas parametric bootstrap and Bayesian hypothesis testing allow rejection of the dispersal hypothesis. The coalescent estimate of the time since population divergence (estimated using MDIV) is 3.75 x 106 years, and the 95%credibility interval of this value overlaps with the geological estimate of vicariance, but not the hypothesized dispersal. These results are congruent with the pattern seen in other mesic forest amphibian lineages and suggest disjunction in amphibians may be a concerted response to a geological/climatological event. WithinP. idahoensis, we tested the corollary hypothesis of an inland Pleistocene refugium in the Clearwater drainage with nested clade analysis and coalescent estimates of population growth rate (g). Both analyses support post-Pleistocene expansion from the Clearwater refugium. We corroborated this result by calculating Tajima's Dand mismatch distribution within each drainage, showing strong evidence for recent population expansion within most drainages. This work demonstrates the utility of statistical phylogeography and contributes two novel analytical tools: tests of stationarity with respect to topology in the Bayesian estimation, and the use of coalescent simulations to test the significance of the population growth-rate parameter.
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2,338,750 |
Monocyte derived dendritic cell responses in common variable immunodeficiency.
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The phenotype and function of monocyte derived dendritic cells (MdDC) were investigated in 25 patients with common variable immunodeficiency (CVID) to test for abnormalities that might help explain the failure of antibody production. Using MHC class II DR and CD86 as markers of maturation, DCs from the majority of CVID patients were normal. However 5 patients, the majority of whom had affected family members who had previously been shown to have a susceptibility genetic locus in the MHC region, expressed abnormally low levels of DR on repeated testing, in some cases associated with a reduced capacity to support antigen stimulated T cell proliferation; nevertheless costimulatory molecules for production of IL-13, IL-10 and IFN-gamma from T cells were intact. In contrast to DCs from healthy donors, DCs from many CVID patients had high spontaneous production of IL-8 and lipopolysaccharide stimulation often caused a reduction in DR expression. Expression of other cytokines (IL-1a, IL-6 and IL-12), either before or after LPS stimulation, was normal. The data suggests there is a fundamental defect in the maturation of MdDCs in a subset of CVID patients that may compromise antigen presentation and subsequent antibody production.
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2,338,751 |
The individuality of mice.
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Mutant mice simulating human CNS disorders are used as models for therapeutic drug development. Drug evaluation requires a coherent correlation between behavioral phenotype and drug status. Variations in behavioral responses could mask such correlations, a problem highlighted by the three-site studies of Crabbe et al. (1999) and Wahlsten et al. (2003a). Factors contributing to variation are considered, focusing on differences between individual animals. Genetic differences due to minisatellite variation suggest that each mouse is genetically distinct. Effects during gestation, including maternal stress, influence later life behavior; while endocrine exchanges between fetus and parent, and between male and female fetuses dependent on intrauterine position, also contribute. Pre and perinatal nutrition and maternal attention also play a role. In adults, endocrine cyclicity in females is a recognized source of behavioral diversity. Notably, there is increasing recognition that groups of wild and laboratory mice have complex social structures, illustrated through consideration of Crowcroft (1966). Dominance status can markedly modify behavior in test paradigms addressing anxiety, locomotion and aggressiveness, to an extent comparable to mutation or drug status. Understanding how such effects amplify the behavioral spectrum displayed by otherwise identical animals will improve testing.
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2,338,752 |
Can an apple a day keep the doctor away?<Pagination><StartPage>3419</StartPage><EndPage>3429</EndPage><MedlinePgn>3419-29</MedlinePgn></Pagination><Abstract><AbstractText>The modern pharmaceutical industry based on synthetic chemistry severed the historical connection between plants, food and medicines. The growing costs of discovering new chemical entity-based drugs through high throughput screening methods may yet again reconnect plants and human health at a new level of technological sophistication. Multi-component botanical therapeutics that comprise functional foods, dietary supplements and botanical drugs hold several advantages over conventional drugs that may earn them a more prominent place in the medicine of the future. They can deliver mixtures of multi-functional molecules with potentiating and synergistic effects and pleiotropic targeting at a reasonable cost and with fewer regulatory constraints. They are well suited for long-term disease prevention in an era of genetic testing and increased life expectancy. They also provide additional vehicles for delivering health and wellness. Technologies that address the needs of discovery, development and manufacturing of multi-component botanical therapeutics are emerging. They include computational and bioinformatics approaches, cell based gene expression and high-content screening systems, and phytochemical elicitation and unique plant cultivation / extraction methods designed to optimize the production of bioactives, standardize overall extract composition and assure batch-to-batch product consistency. Nevertheless, multi-component botanical therapeutics carry risks associated with potential interactions with conventional drugs and adverse reactions, which are difficult to detect and diagnose. They face problems of acceptance by the medical community and pharmaceutical industry, safety and efficacy validation, poor standardization and quality control, and difficulties in identifying active ingredients and determining their complex mode(s) of action. Solving these problems will accelerate the merger of grocery stores with pharmacies and agriculture with chemical manufacturing and provide physicians and patients with broader and more individualized choices for disease prevention and treatment.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Raskin</LastName><ForeName>Ilya</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Biotech Center, Cook College, Rutgers University, 59 Dudley Rd., New Brunswick, New Jersey 08901-8520, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ripoll</LastName><ForeName>Christophe</ForeName><Initials>C</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>U01 TW006674</GrantID><Acronym>TW</Acronym><Agency>FIC NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United Arab Emirates</Country><MedlineTA>Curr Pharm Des</MedlineTA><NlmUniqueID>9602487</NlmUniqueID><ISSNLinking>1381-6128</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004353" MajorTopicYN="N">Drug Evaluation, Preclinical</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004347" MajorTopicYN="N">Drug Interactions</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005502" MajorTopicYN="N">Food</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008517" MajorTopicYN="N">Phytotherapy</DescriptorName><QualifierName UI="Q000639" MajorTopicYN="Y">trends</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010944" MajorTopicYN="N">Plants</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011322" MajorTopicYN="N">Primary Prevention</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015203" MajorTopicYN="N">Reproducibility of Results</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>89</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>11</Month><Day>17</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>12</Month><Day>21</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>11</Month><Day>17</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15544525</ArticleId><ArticleId IdType="doi">10.2174/1381612043383070</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15544153</PMID><DateCompleted><Year>2005</Year><Month>05</Month><Day>17</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1134-7198</ISSN><JournalIssue CitedMedium="Internet"><Issue>20</Issue><PubDate><Year>2004</Year><Season>Jan-Jun</Season></PubDate></JournalIssue><Title>Revista de derecho y genoma humano = Law and the human genome review</Title><ISOAbbreviation>Rev Derecho Genoma Hum</ISOAbbreviation></Journal>[25 recommendations on the ethical, judicial, and social impact of genetic tests. Brussels 2004].
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The modern pharmaceutical industry based on synthetic chemistry severed the historical connection between plants, food and medicines. The growing costs of discovering new chemical entity-based drugs through high throughput screening methods may yet again reconnect plants and human health at a new level of technological sophistication. Multi-component botanical therapeutics that comprise functional foods, dietary supplements and botanical drugs hold several advantages over conventional drugs that may earn them a more prominent place in the medicine of the future. They can deliver mixtures of multi-functional molecules with potentiating and synergistic effects and pleiotropic targeting at a reasonable cost and with fewer regulatory constraints. They are well suited for long-term disease prevention in an era of genetic testing and increased life expectancy. They also provide additional vehicles for delivering health and wellness. Technologies that address the needs of discovery, development and manufacturing of multi-component botanical therapeutics are emerging. They include computational and bioinformatics approaches, cell based gene expression and high-content screening systems, and phytochemical elicitation and unique plant cultivation / extraction methods designed to optimize the production of bioactives, standardize overall extract composition and assure batch-to-batch product consistency. Nevertheless, multi-component botanical therapeutics carry risks associated with potential interactions with conventional drugs and adverse reactions, which are difficult to detect and diagnose. They face problems of acceptance by the medical community and pharmaceutical industry, safety and efficacy validation, poor standardization and quality control, and difficulties in identifying active ingredients and determining their complex mode(s) of action. Solving these problems will accelerate the merger of grocery stores with pharmacies and agriculture with chemical manufacturing and provide physicians and patients with broader and more individualized choices for disease prevention and treatment.
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2,338,753 |
Two-Stage sampling designs for gene association studies.
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We consider two-stage case-control designs for testing associations between single nucleotide polymorphisms (SNPs) and disease, in which a subsample of subjects is used to select a panel of "tagging" SNPs that will be considered in the main study. We propose a pseudolikelihood [Pepe and Flemming, 1991: JASA 86:108-113] that combines the information from both the main study and the substudy to test the association with any polymorphism in the original set. SNP-tagging [Chapman et al., 2003: Hum Hered 56:18-31] and haplotype-tagging [Stram et al., 2003a; Hum Hered 55:27-36] approaches are compared. We show that the cost-efficiency of such a design for estimating the relative risk associated with the causal polymorphism can be considerably better than for a single-stage design, even if the causal polymorphism is not included in the tag-SNP set. We also consider the optimal selection of cases and controls in such designs and the relative efficiency for estimating the location of a causal variant in linkage disequilibrium mapping. Nevertheless, as the cost of high-volume genotyping plummets and haplotype tagging information from the International HapMap project [Gibbs et al., 2003; Nature 426:789-796] rapidly accumulates in public databases, such two-stage designs may soon become unnecessary.
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2,338,754 |
HygR and PurR plasmid vectors for episomal transfection of Trypanosoma cruzi.
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This work describes the development and functional testing of two episomes for stable transfection of Trypanosoma cruzi. pHygD contained the 5'- and 3'- flanking regions of the gene encoding the cathepsin B-like protease of T. cruzi as functional trans-splicing and polyadenylation signals for the hygR ORF. Evidence is presented to support extrachromosomal maintenance and organization as tandem repeats in transfected parasites. pPac was derived from pHygD by replacement of the entire hygR ORF with a purR coding region. The ability to modify pHygD and the availability of the complete DNA sequence make these plasmids useful tools for the genetic manipulation of T. cruzi.
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2,338,755 |
Community genetic services in Latin America and regional network of medical genetics. Recommendations of a World Health Organization consultation.
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The World Health Organization sponsored a Consultation on Community Genetic Services and a Regional Network of Medical Genetics in Latin America in Porto Alegre, Brazil, on June 19, 2003. The main recommendations of the meeting included: (a) the call for government funding of services, research and education in medical genetics; (b) the conduct of epidemiological research on the prevalence and types of birth defects, genetic disorders and genetic predispositions to common diseases; (c) the education of health professionals in genetics; (d) the education of genetic professionals in community health and public health genetics; (e) the fostering of interactions between clinical geneticists, public health personnel, primary health care workers and community organizations, and (f) a better planning of regionalized services to avoid duplication and inefficiency.
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2,338,756 |
Screening of SNPs at 18 positional candidate genes, located within the GD-1 locus on chromosome 14q23-q32, for susceptibility to Graves' disease: a TDT study.
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Graves' disease (GD) is a complex autoimmune thyroid disorder with a strong genetic component. Genome-wide screens resolved several susceptibility loci that contribute to the development of GD. One of the susceptibility loci (GD-1 locus) was mapped on chromosome 14q31. However, a susceptibility gene located within the GD-1 locus remains undefined. Here we screen eighteen single nucleotide polymorphisms (SNPs), each is situated at a corresponding positional candidate gene, located within the GD-1 susceptibility locus on chromosome 14q23-q32, for predisposition to GD using the transmission disequilibrium test in 126 simplex Russian families affected with GD. Among SNPs tested, a significant preferential transmission of the Ala allele (41 transmissions vs. 17 nontransmissions, corrected P=0.031) of the Thr92Ala SNP within the DIO2 gene, encoding type II iodothyronine deiodinase, from parents to affected children was found in a Russian family data set. The Thr92Ala SNP of the DIO2 gene and the D727E substitution of the thyrotropin receptor (TSHR) gene have been found to be in pair-wise linkage disequilibrium. The A92/E727 haplotype showed significant preferential transmission from parents to affected sibling (17 transmissions vs. 8 nontransmissions, P=0.039) in simplex families. This suggests that the Thr92Ala variant of the DIO2 gene is associated or may be in linkage disequilibrium with a functional DIO2 polymorphism which involves in the development of GD in a Russian population.
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2,338,757 |
The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum.
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Peroxisome biogenesis disorders in the Zellweger syndrome spectrum (PBD-ZSS) are caused by defects in at least 12 PEX genes required for normal organelle assembly. Clinical and biochemical features continue to be used reliably to assign patients to this general disease category. Identification of the precise genetic defect is important, however, to permit carrier testing and early prenatal diagnosis. Molecular analysis is likely to expand the clinical spectrum of PBD and may also provide data relevant to prognosis and future therapeutic intervention. However, the large number of genes involved has thus far impeded rapid mutation identification. In response, we developed the PEX Gene Screen, an algorithm for the systematic screening of exons in the six PEX genes most commonly defective in PBD-ZSS. We used PCR amplification of genomic DNA and sequencing to screen 91 unclassified PBD-ZSS patients for mutations in PEX1, PEX26, PEX6, PEX12, PEX10, and PEX2. A maximum of 14 reactions per patient identified pathological mutations in 79% and both mutant alleles in 54%. Twenty-five novel mutations were identified overall. The proportion of patients with different PEX gene defects correlated with frequencies previously identified by complementation analysis. This systematic, hierarchical approach to mutation identification is therefore a valuable tool to identify rapidly the molecular etiology of suspected PBD-ZSS disorders.
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2,338,758 |
The presence of vasal vessels in men with congenital bilateral absence of the vas deferens.
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We characterized spermatic cord microanatomy in men with congenital bilateral absence of the vas deferens (CBAVD) presenting for varicocelectomy. We discuss the implications of these findings for varicocele repair.</AbstractText>Between 1997 and 2003, 8 men with CBAVD underwent a total of 11 microsurgical subinguinal varicocelectomies at microsurgical epididymal sperm aspiration and cryopreservation. All 8 men had palpable grades II to III varicoceles and in 6 varicoceles were repaired due to painful symptomatology, while 2 had testicular hypotrophy with an abnormal hormonal profile. Three men had bilateral varicoceles repaired, while 5 underwent unilateral varicocelectomy. All patients provided a thorough history and underwent physical examination, hormonal evaluation, semen analysis, genetic testing and renal ultrasonography.</AbstractText>Intraoperative microsurgical dissection confirmed dilated internal and external spermatic veins, and absence of the vas deferens in all 11 spermatic cords. Characteristic tortuous vasal vessels of normal caliber were clearly identified in all 11 (100%) of these spermatic cords between the internal and external spermatic fasciae in the location where the vas deferens is usually found.</AbstractText>Despite the absence of the vas deferens normal sized, orthotopically located vasal vessels were present in 100% of the spermatic cords examined. Furthermore, the caliber of the vasal veins was sufficient to provide adequate venous return from the testis following ligation of the internal and external spermatic veins. In patients with CBAVD presenting for varicocele repair standard microsurgical varicocelectomy with ligation of all internal and external spermatic veins can be performed without the risk of testicular congestion secondary to inadequate venous drainage.</AbstractText>
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2,338,759 |
Minnesota Colorectal Cancer Initiative: successful development and implementation of a community-based colorectal cancer registry.
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The aim of the Minnesota Colorectal Cancer Initiative is to implement risk-specific interventions to decrease colorectal cancer morbidity and mortality by 1) assisting clinicians to identify and educate individuals and families at high and increased risk for colorectal cancer; 2) providing professional and community education; 3) maintaining a database to evaluate the effectiveness of preventive intervention strategies; and 4) facilitating colorectal cancer research.</AbstractText>Two physician groups and the University Cancer Center founded the Minnesota Colorectal Cancer Initiative as a not-for-profit organization. Health care organizations, pharmaceutical companies, a consulting firm, and other practice groups provide continuing financial and other support. A database registry, risk-assessment survey, and consent document were developed and then were approved by an institutional review board. A trial enrollment was conducted. Minnesota Colorectal Cancer Initiative services are available to the public. Participants are actively recruited through member organizations. Minnesota Colorectal Cancer Initiative assesses hereditary risk and will document family history in the medical record on request. A personally targeted reply letter reviews risk factors and recommends specific screening and surveillance strategies for participants and their family members, and when appropriate, provides information regarding genetic counseling and testing services. Minnesota Colorectal Cancer Initiative services are free to participants.</AbstractText>Since 1999, Minnesota Colorectal Cancer Initiative has sent individually tailored reply letters providing risk-specific information about colorectal cancer to 717 participants and more than 3200 of their first-degree and second-degree relatives. More than 200 families, previously unidentified as having histories suggestive of hereditary colorectal cancer (attenuated familial polyposis and hereditary nonpolyposis colorectal cancer), have been identified; genetic services were explained and recommended. A formal program evaluation confirmed that Minnesota Colorectal Cancer Initiative provides useful information and materials and promotes intrafamilial communication about colon cancer risk and recommendations.</AbstractText>Minnesota Colorectal Cancer Initiative is a model of effective collaboration between academic and community health care providers. A community-based registry is a unique way to identify and provide personal, risk-specific information to large numbers of people at increased or high risk for colorectal cancer.</AbstractText>
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2,338,760 |
Genetic services in Colombia.
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Medical genetic services, including clinical genetics, cytogenetics, biochemical and molecular genetics and paternity testing, are performed in Colombia in the more developed medical schools or university institutions, in nine major cities of the country. Accessibility to genetic services is limited by medical care reimbursement laws which do not cover clinical genetic services nor genetic tests. Paternity testing is performed free of charge by a governmental welfare institution, if a legal claim is made against an alleged father. Basic teaching of genetics in medical schools is mandatory, but is very uneven and limited to the better schools. Postgraduate medical genetic training is offered by four different programs of similar quality. Research is performed on some of the most prevalent genetic conditions and on population genetic issues.
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2,338,761 |
Genetic services in Chile.
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Demographic changes in Chile have positioned congenital malformations as a major cause of infant morbidity and mortality. At the same time, medical genetics has become increasingly important in relation to the diagnosis and management of individuals with birth defects and hereditary conditions as well as in the study of pathological pregnancies and reproductive problems. In addition, recent advances in genomic research are expanding the relevance of medical genetics to medicine as a whole. This article reviews the clinical genetic resources currently available in Chile; the teaching of genetics in undergraduate, graduate, and continued medical education; some relevant interventions that have taken place in our country, e.g. the expansion of the newborn screening program and the initiation of a folic acid fortification program, and recent efforts to enhance population access to clinical genetics services.
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2,338,762 |
Genetic services and research in the state of Minas Gerais, Brazil.
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The state of Minas Gerais in Brazil has a surface of 586,528 km(2), and 18 million inhabitants. Infant mortality rate is 20/1,000, and congenital anomalies are its second cause. There are 11 medical schools where basic genetics, but not clinical genetics, is taught. Genetic services in the state include: newborn screening for hypothyroidism, phenylketonuria, sickle cell disease and cystic fibrosis; clinical-genetic diagnostic evaluation and counseling; prenatal diagnosis, fetal medicine and paternity testing. Medical genetic services and research are underdeveloped because of limitations such as lack of health policies in genetics, small number of trained specialists, little knowledge about genetics among health professionals and low reimbursement rates.
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2,338,763 |
Novel insights into the aetiology and pathogenesis of hypopituitarism.
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Recent advances in our knowledge of pituitary development, acquired mainly from animal models, have enhanced our understanding of the aetiology of isolated growth hormone deficiency (IGHD) and combined pituitary hormone deficiency (CPHD), as well as several syndromic forms of growth hormone deficiency (GHD). A number of developmental genes known to be important for organ commitment and cell differentiation and proliferation (HESX1, LHX3, LHX4, PROP1 and PIT1) have been implicated in CPHD with or without other syndromic features. Phenotypes associated with these genetic mutations and their inheritance may be highly variable. Functional analyses of these mutations reveal valuable insights into the function of the proteins and hence into the effect of these mutations on phenotype. Novel insights have been gained into the mechanisms whereby these genes are associated with particular phenotypes as a result of murine transgenesis, e.g. type II autosomal dominant GHD. Mutations within known genes account for a small proportion of cases of IGHD and CPHD, suggesting the role of other as yet unidentified genetic and environmental factors. Hence, genetic testing will in the future have a greater role to play in understanding the mechanisms leading to particular hypopituitary phenotypes and also in predicting the evolution of these disorders. There is, however, no substitute for careful delineation of the phenotype prior to undertaking genetic studies.
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2,338,764 |
Iranian national thalassaemia screening programme.
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Iran's experience shows that genetic screening can be successful in lower resource countries and also provides some lessons for high resource nations
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2,338,765 |
Diagnosis of norwalk virus infection by indirect enzyme immunoassay detection of salivary antibodies to recombinant norwalk virus antigen.
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Simple diagnostic tests are needed for the detection of norovirus (NoV) outbreaks. Salivary antibody assays provide an attractive alternative to collecting and testing serum or stool samples. Antibodies to Norwalk virus (NV) in oral fluid samples were compared with NV antibodies in serum collected from 38 volunteers challenged with NV inoculum. Pre- and postchallenge (day 4, 8, 14, and 21) saliva and serum samples were examined by enzyme immunoassay (EIA) using recombinant NV antigen. Of 18 infected subjects (those who shed NV in stool or who demonstrated immunoglobulin G [IgG] seroconversion), 15 (83%) had > or =4-fold increases in NV-specific salivary IgA and 15 (83%) had > or =4-fold increases in NV-specific salivary IgG when prechallenge and postchallenge saliva samples were compared. When the results of the IgA and IgG assays were combined, all 18 infected subjects showed > or =4-fold increases in NV-specific salivary IgG or IgA postchallenge titers compared to their prechallenge titers. One of 19 uninfected subjects had a > or =4-fold increase in NV-specific salivary IgG. The sensitivity of the combined assay results was 100%, and the specificity was 95%. NV-specific salivary IgA titers peaked around 14 days postchallenge. NV-specific salivary IgG and serum IgG titers continued to rise through 21 days postchallenge. The application of this EIA to an elementary school outbreak indicated that 67% of the subjects with confirmed infections had >4-fold rises in anti-NoV IgA when an antigen in the same genetic cluster as the outbreak virus was used. This is the first documented mucosal antibody response to NoV in children. This EIA provides a useful approach for diagnosing NoV outbreaks.
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2,338,766 |
Detection of low level genomic alterations by comparative genomic hybridization based on cDNA micro-arrays.
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The accumulation of genomic alterations is an important process in tumor formation and progression. Comparative genomic hybridization performed on cDNA arrays (cDNA aCGH) is a common method to investigate the genomic alterations on a genome-wide scale. However, when detecting low-level DNA copy number changes this technology requires the use of noise reduction strategies due to a low signal to noise ratio.</AbstractText>Currently a running average smoothing filter is the most frequently used noise reduction strategy. We analyzed this strategy theoretically and experimentally and found that it is not sensitive to very low level genomic alterations. The presence of systematic errors in the data is one of the main reasons for this failure. We developed a novel algorithm which efficiently reduces systematic noise and allows for the detection of low-level genomic alterations. The algorithm is based on comparison of the biological relevant data to data from so-called self-self hybridizations, additional experiments which contain no biological information but contain systematic errors. We find that with our algorithm the effective resolution for +/-1 DNA copy number changes is about 2 Mb. For copy number changes larger than three the effective resolution is on the level of single genes.</AbstractText>
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2,338,767 |
ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'.
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Among the many educational materials produced by the European Society of Human Reproduction and Embryology (ESHRE) are guidelines. ESHRE guidelines may be developed for many reasons but their intent is always to promote best quality practices in reproductive medicine. In an era in which preimplantation genetic diagnosis (PGD) has become a reality, we must strive to maintain its efficacy and credibility by offering the safest and most effective treatment available. The dominant motivators for the development of current comprehensive guidelines for best PGD practice were (i) the absence of guidelines and/or regulation for PGD in many countries and (ii) the observation that no consensus exists on many of the clinical and technical aspects of PGD. As a consequence, the ESHRE PGD Consortium undertook to draw up guidelines aimed at giving information, support and guidance to potential, fledgling and established PGD centres. The success of a PGD treatment cycle is the result of great attention to detail. We have strived to provide a similar level of detail in this document and hope that it will assist staff in achieving the best clinical outcome for their patients.
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2,338,768 |
Factors influencing intention to obtain a genetic test for a hereditary disease in an affected group and in the general public.
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To ensure successful implementations of genetic screening in the future, the attitudes of the public are an important factor to consider. The primary aim of this study is to investigate the intention to take a genetic test for an unidentified hereditary disease. A further objective is to assess the predictive values of attitudes, subjective norms, and perceived personal control on the intention to take a genetic test. These aims are investigated in two groups differing in their experience and knowledge of genetic testing.</AbstractText>A questionnaire was developed according to the Theory of Planned Behavior (TPB) and mailed to a random sample of 1000 persons from the general public and to 330 persons in FAP families. The response rate was 60% and 74%, respectively.</AbstractText>The probability of taking a genetic test was high in both groups but significantly higher in the FAP group. The attitudes of the FAP group were significantly more positive when compared to the attitudes of the general public. For the persons in the FAP group, the most significant others in the decision to take a genetic test were their children, whereas spouses proved to be the most important significant others in the general public. The most important predictor of the intention to take a test in both groups was attitude, accounting for 64% of the variance.</AbstractText>The study indicated that most of the individuals in the FAP group and many in the general public intended to take a genetic test. Our findings suggest that living in an affected group and having some kind of experience of a hereditary disease may lead to an even more positive attitude to genetic testing. Using the TPB, attitudes were found to be the strongest predictor of intention to take a genetic test in both groups.</AbstractText>
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2,338,769 |
First study of CF mutations in the CFTR gene of Iranian patients: detection of DeltaF508, G542X, W1282X, A120T, R117H, and R347H mutations.
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Thirty-seven unrelated Iranian CF families were screened for the presence of seven common mutations (DeltaF508, G542X, W1282X, G551D, N1303K, 1717-1G-->A, and 621-1G-->T) using ARMS PCR and exons 4 and 7 of the CFTR gene by SSCP method. This study resulted in the identification of 26.8 per cent of all CF alleles: DeltaF508 (16.2 per cent), W1282X (4 per cent), G542X (2.7 per cent), R117H (1.3 per cent), R347H (1.3 per cent), and A120T (1.3 per cent) mutations were detected. To the best of our knowledge, it is the first report of an Asian subject carrying the A120T mutation. Our findings suggest heterogeneity in the Iranian population, stressing the need to draw attention to sequence analysis in order to find population-specific mutations.
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2,338,770 |
Identifying and testing for hereditary susceptibility to common cancers.
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Hereditary cancer syndromes account for an estimated 5% of breast, ovarian, and colon cancers. The rapid discovery of cancer-related genes in the last 15 years has propelled the field of cancer genetic risk assessment forward. With patients becoming increasingly aware of available genetic testing options, it is important that various health professionals become knowledgeable in identifying and advising patients at increased risk for a hereditary cancer syndrome. This article will outline the components of providing a hereditary cancer risk assessment with a focus on hereditary breast and ovarian cancer syndrome and hereditary colon cancer.
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2,338,771 |
Clinical trials in neurological disorders using AAV vectors: promises and challenges.
|
Currently, there are five phase I clinical trials of recombinant adeno-associated viral vectors for the treatment of neurological disorders that are approved or likely to be approved shortly. Two trials are testing different strategies to treat Parkinson's disease (PD), the third trial is aimed at treating Canavan's disease, a pediatric leukodystrophy, the fourth trial targets Alzheimer's disease (AD), and the fifth will attempt to target the lysosomal storage disorder, Batten's disease. All four clinical trials rely on the de novo expression of an enzyme or a trophic factor to correct neuropathology. Ironically, the theories used to choose enzymes for the two PD trials were widely divergent, whereas the enzymatic strategy used for one of the PD trials and the Canavan's trial have remarkable similarities. Other gene therapy treatment strategies for PD and other disorders, such as amyotrophic lateral sclerosis, are also on the horizon.
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2,338,772 |
A large-scale study of the random variability of a coding sequence: a study on the CFTR gene.
|
Coding single nucleotide substitutions (cSNSs) have been studied on hundreds of genes using small samples (n(g) approximately 100-150 genes). In the present investigation, a large random European population sample (average n(g) approximately 1500) was studied for a single gene, the CFTR (Cystic Fibrosis Transmembrane conductance Regulator). The nonsynonymous (NS) substitutions exhibited, in accordance with previous reports, a mean probability of being polymorphic (q > 0.005), much lower than that of the synonymous (S) substitutions, but they showed a similar rate of subpolymorphic (q < 0.005) variability. This indicates that, in autosomal genes that may have harmful recessive alleles (nonduplicated genes with important functions), genetic drift overwhelms selection in the subpolymorphic range of variability, making disadvantageous alleles behave as neutral. These results imply that the majority of the subpolymorphic nonsynonymous alleles of these genes are selectively negative or even pathogenic.
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2,338,773 |
Proteomics, genomics and the future of medical education.
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The completion of the human genome project in 2003 ushered in the era of genomics, the systematic study of our DNA sequence. Proteomics, the study of the full complement of proteins present in a cell, is a natural extension of genomics. Together, the information obtainable through genomics and proteomics has tremendous potential to change clinical practice. The application of such information to medical diagnosis and treatment will require significant changes in the training of physicians. All students and physicians in training will need to acquire enough knowledge of the underlying science, including medical genetics, epidemiology, bioinformatics and statistics, so they will intuitively understand the technology and recognize the strengths and limitations of genomic/proteomic tests. Because genomic or proteomic testing may yield extensive information about a person's genetic makeup and disease risks, consideration will need to be given throughout the medical curriculum to the ethical issues raised by the application of this new technology to the diagnosis and treatment of patients.
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2,338,774 |
Novel MYOC gene mutation, Phe369Leu, in Japanese patients with primary open-angle glaucoma detected by denaturing high-performance liquid chromatography.
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To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC).</AbstractText>Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58 degrees C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced.</AbstractText>Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG.</AbstractText>Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.</AbstractText>
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2,338,775 |
Testing the conservation of the translational machinery over evolution in diverse environments: assaying Thermus thermophilus ribosomes and initiation factors in a coupled transcription-translation system from Escherichia coli.
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Ribosomes from the extreme thermophile Thermus thermophilus are capable of translation in a coupled transcription-translation system derived from Escherichia coli. At 45 degrees C, T.thermophilus ribosomes translate at approximately 25-30% of the maximal rate of E.coli ribosomes, and synthesize full-length protein. T.thermophilus and E.coli subunits can be combined to effect translation, with the spectrum of proteins produced depending upon the source of the 30S subunit. In this system, T.thermophilus ribosomes function in concert with E.coli translational factors and tRNAs, with elongation and release factors being supplied from the E.coli extract, and purified initiation factors (IFs) being added exogenously. Cloned and purified T.thermophilus IF1, IF2 and IF3 supported the synthesis of the same products in vitro as the E.coli factors, although the relative levels of some polypeptides were factor dependent. We conclude that, at least between these two phylogenetically distant species, translational factor function and subunit-subunit interactions are conserved. This functional compatibility is remarkable given the extreme and highly divergent environments to which these species have adapted.
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2,338,776 |
Methodology and preliminary results from the neurocognitive outcomes of depression in the elderly study.
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A methodology is presented for following a cohort of older depressed patients to examine neurocognitive outcomes of depression. A total of 265 depressed individuals and 138 healthy, nondepressed controls age 60 and older who completed at least 1 year of follow-up data underwent periodic clinical evaluation by a geriatric psychiatrist. A subset of 141 patients and 137 controls had neuropsychological testing. A consensus panel of experts reviewed 63 depressed subjects with suspected cognitive impairment. Twenty-seven individuals in the depressed group were assigned diagnoses of dementia, including 11 with Alzheimer's disease, 8 with vascular dementia, and 8 with dementia of undetermined etiology. In addition, 25 individuals had other forms of cognitive impairment, and 11 were considered cognitively normal. Among elderly controls, 2 developed substantial cognitive impairment with clinical diagnoses of dementia. Among the depressed group, the incidence rates for dementia for this age are much higher than would be expected. These results are consistent with prior evidence linking depression and later dementia. Future studies are needed to examine neuroimaging and genetic, clinical, and social predictors of neurocognitive decline in depression.
|
2,338,777 |
BRCA1 and BRCA2 mutations in a study of African American breast cancer patients.
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The spectrum of mutations in BRCA1 and BRCA2 among African Americans has not been well characterized because most studies to date have been done in Caucasian families. According to Myriad Genetic Laboratories, Inc., only approximately 3% of individuals undergoing BRCA1/BRCA2 testing reported African American ancestry. Data from previous studies show that among African American women a greater proportion of breast cancer cases are diagnosed at age <45 years in comparison with Caucasians. Because breast cancer occurring at a young age is one of the hallmarks of high penetrance genes, the prevalence, spectrum, and effects of BRCA1/BRCA2 mutations may differ substantially between African Americans and Caucasians, and further investigation is warranted. We conducted a hospital-based study of African American breast cancer patients with early age at diagnosis (</=45 years) or family history of breast or ovarian cancer. We identified four deleterious mutations in BRCA1 or BRCA2 among the 10 families tested, of which two were novel BRCA2 mutations, one was the west African founder mutation (BRCA1 943ins10), and one was a recurrent mutation that may be a candidate for a second African American founder mutation (BRCA1 IVS13+1G>A). Our results support previous data in demonstrating that (a) the spectrum of mutations among African Americans is unique, (b) family history of breast cancer is an important predictor of hereditary cancer susceptibility among African Americans, and (c) empirical data may be useful in estimating mutation risk among African Americans.
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2,338,778 |
A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam.
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N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations ( approximately 35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs.
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2,338,779 |
[Recognising hereditary non-polyposis colorectal cancer without a clear family history].
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In 3 patients, 2 men aged 46 and 51 years and a woman aged 54 years, with colorectal cancer there was insufficient information on the basis of the family history to diagnose 'hereditary non-polyposis colorectal cancer' (HNPCC). Further investigation showed microsatellite instability in the tumour material, an indicator for a mutation in DNA-'mismatch repair' (MMR-) genes. Immunohistochemical study of lymphocytes showed an absence of the gene products MSH2 and MSH6. Study of the MMR genes revealed a pathogenic germ-line mutation in MSH2. All three patients were satisfied with genetic testing of the MMR-genes as this gave their children and their family members the opportunity to clarify genetic status. HNPCC is a clinical diagnosis, based on family history. As family history taking is often incomplete, the diagnosis is regularly not considered. The following individual criteria can help to recognize a patient at risk for HNPCC: (a) colorectal cancer diagnosed below 50 years of age, (b) second colorectal cancer, (c) a combination of colorectal and endometrial cancer.
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2,338,780 |
Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic.
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Medullary thyroid carcinoma (MTC) occurs as a sporadic form (75%) or as an autosomal dominant inherited familial disorder (25%) called familial MTC (FMTC) or as multiple endocrine neoplasia type 2 (MEN2) syndromes. Germ-line mutations in the rearranged during transfection (RET) proto-oncogene in exons 10, 11, 13, 14, 15 and 16 are known to be a cause of most of the familial forms. In this paper we report molecular genetic testing of 106 families with MTC (358 tested persons) from the Czech Republic in which we directly sequenced these six exons of the RET proto-oncogene. We detected germ-line mutations in 100% of MEN2B families (4/4 families), 90% of MEN2A families (9/10), 40% of FMTC families (4/10) and 7% of apparently sporadic MTC (6/82). Eleven different germ-line mutations were revealed. MEN2B was associated with mutation Met918 Thr in exon 16. In one MEN2B family beside this mutation the Tyr791 Phe was also found, which has not yet been reported. MEN2A was restricted to different mutations in exon 11 (codon 634). In FMTC and 'sporadic' MTC families the mutations in exons 10, 11, 13 and 14 were detected. The genotype/phenotype correlations are given. Genetic testing revealed germ-line mutations in 23 index patients, 24 family members and excluded them in 53 relatives.
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2,338,781 |
The insulin-like growth factor-II receptor gene is associated with type 1 diabetes: evidence of a maternal effect.
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Susceptibility to type 1 diabetes (T1D) is a complex trait, involving several loci. One of these putative loci, insulin-dependent diabetes mellitus-8 (IDDM8) at 6q, has been found to be subject to parental effects, suggesting the involvement of an imprinted gene. IGF-II receptor (IGF2R), the best-studied imprinted gene in the IDDM8 region, encodes the IGF-2 receptor, a protein involved in many biological processes, including immune function and beta-cell regeneration. Mice express only the maternal allele. In humans, the molecular IGF2R imprint (maternal-specific methylation) is present, but it affects expression in only a small subset of individuals. To examine whether IGF2R might contribute to the IDDM8 effect, we examined transmission distortion at several single nucleotide polymorphisms (SNPs) in 404 parent-offspring trios. After correcting for multiple testing, significant distortion was found at only one silent SNP on exon 16 (P = 0.002). SNPs upstream and downstream showed weak linkage disequilibrium and no transmission distortion, localizing the association to a 53-kb block within IGF2R. Interestingly, the exon 16 SNP association was limited to maternally inherited alleles. SLC22A2 and SLC22A3, two genes downstream of IGF2R that are imprinted in the mouse, showed no T1D association. Thus, we present evidence that maternal alleles at an IGF2R polymorphism are associated with T1D. It is thus possible that at some tissue or developmental stage not yet examined, IGF2R is universally imprinted.
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2,338,782 |
Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma.
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More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.
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2,338,783 |
Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors.
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We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperparathyroidism (FIHP). Seven patients with sporadic parathyroid cancers and 35 with parathyroid adenomas with no family history of primary hyperparathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with parathyroid cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic parathyroid cancer. The finding that two of the seven patients with sporadic parathyroid cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.
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2,338,784 |
Solid phase adsorption toxin tracking (SPATT): a new monitoring tool that simulates the biotoxin contamination of filter feeding bivalves.
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A simple and sensitive in situ method for monitoring the occurrence of toxic algal blooms and shellfish contamination events has been developed. The technique involves the passive adsorption of biotoxins onto porous synthetic resin filled sachets (SPATT bags) and their subsequent extraction and analysis. The success of the method is founded on the observation that during algal blooms significant amounts of toxin, including the low polarity lipophilic compounds such as the pectenotoxins and the okadaic acid complex toxins, are dissolved in the seawater. The results of field trials during Dinophysis acuminata and Protoceratium reticulatum blooms are presented. These data prove the concept and demonstrate that the technique provides a means of forecasting shellfish contamination events and predicting the net accumulation of polyether toxins by mussels. As an early warning method it has many advantages over current monitoring techniques such as shellfish-flesh testing and phytoplankton monitoring. In contrast to the circumstantial evidence provided by genetic probe technologies and conventional phytoplankton monitoring methods, it directly targets the toxic compounds of interest. The extracts that are obtained for analysis lack many of the extraneous lipophilic materials in crude shellfish extracts so that many of the matrix problems associated with chemical and biological analysis of these extracts are eliminated. Analyses can confidently target parent compounds only, because analytical and toxicological uncertainties associated with the multiplicity of toxin analogues produced by in vivo biotransformation in shellfish tissues are reduced. Time integrated sampling provides a good simulation of biotoxin accumulation in filter feeders and the high sensitivity provides lengthy early warning and conservative estimates of contamination potential. The technique may reduce monitoring costs and provide improved spatial and temporal sampling opportunities. When coupled with appropriate analytical techniques (e.g. LC-MS/MS multi-toxin screens, ELISA assays, receptor binding assays), the technique has the potential to offer a universal early warning method for marine and freshwater micro-algae toxins.
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2,338,785 |
Cohort analysis of a single nucleotide polymorphism on DNA chips.
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A method has been developed to determine SNPs on DNA chips by applying a flow-through bioscanner. As a practical application we demonstrated the fast and simple SNP analysis of 24 genotypes in an array of 96 spots with a single hybridisation and dissociation experiment. The main advantage of this methodical concept is the parallel and fast analysis without any need of enzymatic digestion. Additionally, the DNA chip format used is appropriate for parallel analysis up to 400 spots. The polymorphism in the gene of the human phenol sulfotransferase SULT1A1 was studied as a model SNP. Biotinylated PCR products containing the SNP (The SNP summary web site: ) (mutant) and those containing no mutation (wild-type) were brought onto the chips coated with NeutrAvidin using non-contact spotting. This was followed by an analysis which was carried out in a flow-through biochip scanner while constantly rinsing with buffer. After removing the non-biotinylated strand a fluorescent probe was hybridised, which is complementary to the wild-type sequence. If this probe binds to a mutant sequence, then one single base is not fully matching. Thereby, the mismatched hybrid (mutant) is less stable than the full-matched hybrid (wild-type). The final step after hybridisation on the chip involves rinsing with a buffer to start dissociation of the fluorescent probe from the immobilised DNA strand. The online measurement of the fluorescence intensity by the biochip scanner provides the possibility to follow the kinetics of the hybridisation and dissociation processes. According to the different stability of the full-match and the mismatch, either visual discrimination or kinetic analysis is possible to distinguish SNP-containing sequence from the wild-type sequence.
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2,338,786 |
Predictive testing for hereditary non-polyposis colorectal cancer: motivation, illness representations and short-term psychological impact.
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This paper describes the motivation, recall of cancer risks, and illness representations of 40 individuals who had a predictive test for hereditary non-polyposis colorectal cancer (HNPCC) as well as the short-term impact of predictive testing by means of a semi-structured interview and self-report questionnaires. The main motives for predictive testing were early detection of cancer, knowledge of the children's risk and reduction of uncertainty. Overall, recall of cancer risks was good. Measurements of illness representations revealed low perceptions of "threat" of cancer and high confidence in the controllability of the disease. Distress was within normal ranges. Distress decreased significantly from pre- to post-test in non-carriers and did not in carriers. It also decreased in individuals for whom "reducing uncertainty" was a very important motive for the test, not in the others. Although part of the carriers did not have colonoscopies, all carriers intended to have regular colonoscopies in the future.
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2,338,787 |
A clinician's guide to hereditary colon cancer.
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Approximately 10% of patients diagnosed with colorectal cancer are at risk for a hereditary form of the disease. At-risk patients can be offered genetic counseling and testing to determine whether they carry a detectable mutation for such a syndrome. If so, this information provides the clinician with valuable data about the patient's risk for other cancers, and what further surveillance and risk reduction options should be incorporated into the management plan. Mutation identification within a family also makes it possible for other family members to learn if they are at risk for the same syndrome. There are many hereditary colorectal cancer syndromes, and the clinician must know what essential information should be elicited from a family history and which patients should be referred for genetic counseling and testing.
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2,338,788 |
[Iron overload disease: recent findings].
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Iron overload diseases are due to a progressive increase in total body iron stores that leads to deposition of iron in parenchymal organs and to subsequent damage to these organs. The commonest inherited form of iron overload is hereditary hemochromatosis (HH), an autosomal recessive disorder affecting the white population. Although in the western world and in northern Europe the majority of cases of HH are associated with an HFE gene mutation (C282Y and H63D), there are families with a familial iron overload disorder in whom neither the C282Y nor the H63D mutations were found. Recently, other forms of HH that are not related to HFE, but are due to mutations in genes coding iron transport proteins (ferroportin-1, TfR2, hepcidin) have been described. The clinical presentation of the disorder is highly variable, depending on the severity of iron overload. In fact, the inappropriate absorption and deposition of dietary iron may result in the development of hepatic and non-hepatic end-organ injury, leading to liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, skin pigmentation and cardiac diseases. HH and its sequelae are preventable with an early diagnosis and treatment. Patients with evidence of iron overload, a family history of HH or other risk factors should be screened by genotype testing for the HFE mutation. Nowadays, HH is recognized as being a complex genetic disease with probable significant environmental and genetic modifying factors, such as hepatitis C virus infection and alcohol abuse, and it has been shown that HFE mutations represent an independent risk factor for fibrosis and cirrhosis in chronic hepatitis C.
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2,338,789 |
Trajectories of psychosis: towards a new social biology of schizophrenia.
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Over the last 2 decades, discourse on the causes of schizophrenia was conducted almost entirely in terms of biological risk factors. This was probably the result of social trends in the research community, and in popular culture, as a wave of techno-optimism promised answers to big human questions in terms of small pixels and even smaller molecules. The human genome project inflated expectations further, and the pharmaceutical industry conspired with the desire of psychiatrists for scientific respectability. 'Social factors', whether at macro-societal or locality/family level, came to be seen as 'fall-out' from biological mechanisms, a kind of padding to our understanding of human disease. But changes are in the wind. New understandings of the influence of social factors on the long-term outcome trajectories of psychosis, their potential role in risks associated with migration, and recent findings from genetic high risk studies, are raising fresh questions about social factors and causation. This paper does not argue that the evidence (yet) is strong. But after 2 decades of often crudely articulated dualism, it is time once again for social experience to be integrated with more sophisticated theory development and hypothesis testing in the search for the causes of schizophrenia.
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2,338,790 |
History and rationale of genetic toxicity testing: an impersonal, and sometimes personal, view.
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Genetic toxicity testing is a necessary and pivotal component of product development and registration. This article traces the historical development and evolution of genetic toxicity testing, and the rationale for such testing, and identifies some of the individuals who played key roles in this process. The evolution of the present test batteries and some of the research and rationales behind the decisions to accept or reject tests are described.
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2,338,791 |
Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study.
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Data addressing the interfamilial heterogeneity of melanoma are limited. In the current study, the authors assessed melanoma risk according to family history of melanoma and other melanoma-associated malignancies and evaluated the familial heterogeneity of melanomas, pancreatic malignancies, and gastrointestinal malignancies.</AbstractText>The authors obtained patient histories of malignancy in first-degree relatives as part of a clinic-based case-control study. The case group included 737 newly diagnosed patients with invasive melanoma, and the control group included 1021 outpatients from clinics at the same medical centers. To assess heterogeneity of risk among families affected by melanoma, a nonparametric method was used to detect extrabinomial variation. In addition, selected patients with melanoma (n=133) were tested for germline mutations in CDKN2A.</AbstractText>The adjusted odds ratio associated with a family history of melanoma was 1.7 (95% confidence interval, 1.1-2.7). Family histories of pancreatic, gastrointestinal, brain, breast, or lymphoproliferative disease did not increase the risk of melanoma significantly. Among case families, significant evidence of familial heterogeneity was found for melanomas, but not for pancreatic or gastrointestinal malignancies. Two mutations in CDKN2A previously associated with melanoma risk were identified among the 133 patients tested in the case group; mutation detection did not differ between families with low and high heterogeneity scores.</AbstractText>Familial heterogeneity testing in the study population did not improve the selection of high-risk families for genetic study. Even in a large case-control study, few families that had multiple members with melanoma were identified, and family members with pancreatic malignancies were rare.</AbstractText>
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2,338,792 |
MSI-testing in hereditary non-polyposis colorectal carcinoma (HNPCC).
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Genomic instability at simple repeated sequences, termed microsatellite instability (MSI), plays an important role in the analysis of sporadic and hereditary colon cancers. In hereditary non-polyposis colorectal cancer syndrome (HNPCC) more than 90% of cases show MSI, whereas only 10-15% of sporadic colorectal cancers do so. Thus, microsatellite analysis is commonly used as the first diagnostic screening test for HNPCC. In 1997, an international collaborative workshop sponsored by the National Cancer Institute (NCI) proposed a set of guidelines for MSI-testing to improve reliability and reproducibility of the analysis as well to allow comparisons between different studies and different laboratories. In this review we assess the value of current protocols for MSI-testing and discuss some diagnostic pitfalls. Our findings support continued use of the MSI marker panel recommended in 1997. Additionally, MSI-testing should be improved by use of microdissection, which helps to identify additional patients with MSI due to enrichment of tumor cells and therefore increased sensitivity. In our view, immunohistochemical staining for mismatch repair protein expression is not a substitute for MSI-analysis but complements MSI screening and helps direct further testing. In summary, MSI-analysis is a highly sensitive and reliable screening method for HNPCC, that requires a well-equipped laboratory as well as an experienced pathologist. Integration of family history and histo-pathological features is also critical.
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2,338,793 |
Identification of HNPCC by molecular analysis of colorectal and endometrial tumors.
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Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is a dominantly inherited syndrome characterized by the development of colorectal cancer, endometrial cancer and other cancers and the presence of microsatellite instability (MSI) in tumors. The Bethesda guidelines have been proposed for the identification of families suspected of HNPCC that require further molecular analysis. We have evaluated the yield of MSI-analysis in a large series of Dutch families suspected of HNPCC. We also analysed whether the loss of mismatch repair (MMR) protein detected by immunohistochemistry (IHC) of colorectal cancer (CRC) and endometrial cancer correlated with the presence of MSI and/or a MMR gene mutation. The results showed that the Bethesda criteria with a few modifications are appropriate to identify families eligible for genetic testing. In addition, we found that MSI and IHC-analysis of CRC using antibodies against MLH1, MSH2, MSH6 and PMS2 proteins are equally effective for identifying carriers of the known MMR gene defects. However, as long as the role of other putative MMR genes in hereditary CRC has not been elucidated, IHC-analysis cannot completely replace MSI. For this reason, we prefer MSI-analysis as first step in families suspected of HNPCC. On the other hand, in families fulfilling the revised Amsterdam criteria in which the probability of detecting a mutation is relatively high, we would recommend IHC as first diagnostic step because the result might predict the specific underlying MMR gene mutation. MSI or IHC-analysis of endometrial cancer alone was found to be less sensitive compared with these tests performed in colorectal cancer. Therefore, probably the best approach in the analysis of this cancer is to perform both techniques. The identification of HNPCC is important as it makes it possible to target effective preventative measures. Our studies showed that MSI and IHC analysis of colorectal and endometrial cancer, are reliable cost-effective tools that can be used to identify patients with HNPCC.
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2,338,794 |
Stable long-term gene correction with low-dose radiation conditioning in murine X-linked chronic granulomatous disease.
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We previously demonstrated that low-dose radiation conditioning impairs murine hematopoietic stem cell function, permitting engraftment of syngeneic fresh and transduced marrow cells. In this study, we directly examined the ability of low-dose radiation conditioning to permit engraftment of transduced long-term repopulating cells in murine X-linked chronic granulomatous disease (X-CGD), which closely mimics the human disease. X-CGD mice conditioned with 160 cGy were transplanted with 20 x 10(6) MSCV-m91Neo-transduced syngeneic X-CGD marrow cells. The presence of oxidase-positive neutrophils in two independent cohorts of transplanted 160-cGy-conditioned X-CGD recipients was determined by nitroblue tetrazolium testing. Transplanted X-CGD mice (n = 9 total) displayed 1-17% oxidase-positive neutrophils 6-16 months post-transplant. Retroviral marking and NADPH-oxidase-positive neutrophils persisted through serial transplantation, verifying that stem cells were transduced. These results establish that low-dose radiation conditioning results in durable engraftment of low but potentially clinically relevant numbers of functionally reconstituted blood cells in a murine model of X-CGD.
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2,338,795 |
Identification of high-risk pancreatic cancer-prone families.
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Pancreatic cancer-prone families provide a unique resource for studying the etiology, natural history, genetics, and treatment of pancreatic cancer. The only effective way of identifying these families is by obtaining a complete family history, since it is not possible to differentiate sporadic pancreatic cancer cases from hereditary cases based on either clinical presentation or features. These families also would benefit greatly from early detection or prevention strategies. Ultimately, this knowledge could be applied to the more common sporadic form of pancreatic cancer, where diagnosis is almost always late, and prognosis remains quite grim.
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2,338,796 |
Genetic counseling for hereditary pancreatitis--the role of molecular genetics testing for the cationic trypsinogen gene, cystic fibrosis and serine protease inhibitor Kazal type 1.
|
The importance of pretest information, using an accredited DNA laboratory and interpreting the genotype on behalf of the patient and their physicians is emphasized. Care with predictive testing and the strong encouragement to involve a specialist genetic counseling service is made. A similar approach to genetic testing should be used when children are involved. Because of the incomplete pickup of PRSS1 mutations, particularly of a limited mutation panel of R122H and N291 (perhaps with A16V), a diagnosis of HP cannot be ruled out by molecular genetic testing alone. The A16V mutation has a reduced penetrance, and its contribution to pancreatitis remains unclear. The advice to patients with genetic forms of pancreatitis is a strong encouragement to avoid smoking, to avoid alcohol, and to remain in contact with clinical and research groups for their follow-up and screening trials for early pancreatic cancer. The remaining issues are of how wide to cast the net of investigation in patients with unexplained pancreatitis, particularly looking for mutations in the CFTR and lower penetrance genes such as PSTI/SPINK1.
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2,338,797 |
The role of cystic fibrosis gene mutations in determining susceptibility to chronic pancreatitis.
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This article reviews current concepts regarding the pathobiology of cystic fibrosis pancreatic disease. It summarizes recent studies on the relationship between CFTR mutations and pancreatitis, and it reviews several unresolved issues in the field.
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2,338,798 |
Serine protease inhibitor Kazal type 1 mutations and pancreatitis.
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In summary, SPINK1 is thought to play an important role in protecting the pancreas against excessive trypsinogen activation. SPINK1 mutations are associated with the development of acute and chronic pancreatitis and have been detected in all forms of chronic pancreatitis. The strong association of mutations in the PRSS1 gene and in the SPINK1 gene with chronic pancreatitis supports the concept of intracellular trypsin activation as an initiating and extremely important step in the development of pancreatitis. The N34S mutation represents the most frequently observed pancreatitis-associated SPINK1 variant. Because the SPINK1 N34S mutation is very common in the general population, it is unlikely that this mutation alone can initiate the development of chronic pancreatitis. Thus, it rather appears that in most patients with SPINK1-associated chronic pancreatitis, this genetic variant acts as disease modifier or within a polygenic model with other yet unidentified genes or environmental cofactors. The possible interaction of mutations in the SPINK1 gene with other pancreatitis-associated susceptibility genes has to be investigated in future research efforts. The most promising candidate gene for such an interaction is the CFTR gene, because genetic alterations within the CFTR gene are also common in the general population and already have been associated with chronic pancreatitis.
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2,338,799 |
Use of TP53 reference materials to validate mutations in clinical tissue specimens by single-strand conformational polymorphism analysis.
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As genetic information moves from basic research laboratories in to the clinical testing environment, there is a critical need for reliable reference materials for the quality assurance of genetic tests. A panel of 12 plasmid clones containing wild-type or point mutations within exons 5-9 have been developed as reference materials for the detection of TP53 mutations.</AbstractText>The goal of this study was to validate the reference materials in providing quality assurance for the detection of TP53 mutations in clinical specimens.</AbstractText>We studied 33 gynecological samples, 11 apparently normal samples and 22 malignant tumors of various origins. Mutations were identified using single-strand conformational polymorphism analysis with both slab gel and capillary electrophoresis. All DNA samples were amplified with fluorescently labeled PCR primers specific for exons 5-9 for mutation detection.</AbstractText>Of the 33 patient samples tested, mutations and polymorphisms were found in six specimens in three of the five exons scanned; no mutations were found in exons 7 or 9. Both a mutation and polymorphism were found in non-malignant specimens from the control group. The mutations were confirmed by DNA sequence analysis of the regions scanned.</AbstractText>Mutations and polymorphisms were detected in the clinical samples. All of the mutations were silent except for one non-conservative mutation in exon 5, codon 181. This study demonstrates the usefulness of the National Institute of Standards and Technology (NIST) TP53 reference panel in TP53 mutation detection in clinical tissue specimens.</AbstractText>
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