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2,339,400 | X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility. | The X-linked sex-determining region Y box 3 (SOX3) gene is expressed in the developing gonads and brain. Sox3-null mice developed according to genetic sex, but the hemizygous null males were hypogonadal, with extensive Sertoli cell vacuo-lization, loss of germ cells, and reduced sperm count. We hypothesized that SOX3 mutations might occur in a subset of infertility patients. Genomic DNA samples from 56 infertile men with idiopathic oligo-azoospermia were screened for SOX3 mutations. Three nucleotide substitutions (609 T-->C, 732 A-->C, and 978 G-->A) were identified, none of which altered the amino acid sequence, suggesting that they are polymorphic variants. The 609 T-->C substitution was in the HMG box, and the two other substitutions were identified within the polyalanine repeat regions. Three patients had 609 T-->C, 2 patients had 609 T-->C and 732 A-->C, and one had 978 G-->A. These data indicate that mutations in the SOX3 gene are not a common cause of male infertility. |
2,339,401 | ACOG committee opinion. Number 298, August 2004. Prenatal and preconceptional carrier screening for genetic diseases in individuals of Eastern European Jewish descent. | Certain autosomal recessive disease conditions are more prevalent in individuals of Eastern European Jewish (Ashkenazi) descent. Previously, the American College of Obstetricians and Gynecologists recommended that individuals of Eastern European Jewish ancestry be offered carrier screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis as part of routine obstetric care. Based on the criteria used to justify offering carrier screening for Tay-Sachs disease, Canavan disease, and cystic fibrosis, the American College of Obstetricians and Gynecologists' Committee on Genetics recommends that couples of Ashkenazi Jewish ancestry also should be offered carrier screening for familial dysautonomia. Individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders. Carrier screening is available for mucolipidosis IV Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher's disease. |
2,339,402 | New molecular targets for treatment of lymphoma. | In recent years, several molecular mechanisms involved in promoting cancer cell survival and growth have been identified. These discoveries helped in designing and testing novel drugs that target specific cellular pathways. In this review, we focus on new molecular targets that are being explored for the treatment of non-Hodgkin's lymphoma and Hodgkin's disease. |
2,339,403 | Genetic comparison of breeding schemes based on semen importation and local breeding schemes: framework and application to Costa Rica.<Pagination><StartPage>1496</StartPage><EndPage>1505</EndPage><MedlinePgn>1496-505</MedlinePgn></Pagination><Abstract><AbstractText>Local breeding schemes for Holstein cattle of Costa Rica were compared with the current practice based on continuous semen importation (SI) by deterministic simulation. Comparison was made on the basis of genetic response and correlation between breeding goals. A local breeding goal was defined on the basis of prevailing production circumstances and compared against a typical breeding goal for an exporting country. Differences in genetic response were <3%, and the correlation between breeding goals was 0.99. Therefore, difference between breeding objectives proved negligible. For the evaluation of genetic response, the current scheme based on SI was evaluated against a progeny testing (PT) scheme and a closed nucleus (CN) breeding scheme, both local. Selection intensities and accuracy of selection were defined according to current population size and reproduction efficiency parameters. When genotype x environment interaction (G x E) was ignored, SI was the strategy with the highest genetic response: 5.0% above the CN breeding scheme and 33.2% above PT. A correlation between breeding values in both countries lower than one was assumed to assess the effect of G x E. This resulted in permanent effects on the relative efficiencies of breeding strategies because of the reduction in the rate of genetic response when SI was used. When the genetic correlation was assumed equal to 0.75, the genetic response achieved with SI was reduced at the same level as local PT. When an initial difference in average genetic merit of the populations was assumed, this only had a temporal effect on the relative ranking of strategies, which is reverted after some years of selection because the rate of change in genetic responses remains unchanged. Given that the actual levels of genetic correlation between countries may be around 0.60, it was concluded that a local breeding scheme based on a nucleus herd could provide better results than the current strategy based on SI.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Vargas</LastName><ForeName>B</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Posgrado Regional en Ciencias Veterinarias Tropicales, Universidad Nacional de Costa Rica, Heredia, Costa Rica.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Arendonk</LastName><ForeName>J A M</ForeName><Initials>JA</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Dairy Sci</MedlineTA><NlmUniqueID>2985126R</NlmUniqueID><ISSNLinking>0022-0302</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001947" MajorTopicYN="N">Breeding</DescriptorName><QualifierName UI="Q000191" MajorTopicYN="N">economics</QualifierName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002417" MajorTopicYN="N">Cattle</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003364" MajorTopicYN="N" Type="Geographic">Costa Rica</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019655" MajorTopicYN="N">Quantitative Trait, Heritable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012098" MajorTopicYN="N">Reproduction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012641" MajorTopicYN="N">Selection, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012661" MajorTopicYN="Y">Semen</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>8</Month><Day>5</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>9</Month><Day>17</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>8</Month><Day>5</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15290999</ArticleId><ArticleId IdType="doi">10.3168/jds.S0022-0302(04)73301-9</ArticleId><ArticleId IdType="pii">S0022-0302(04)73301-9</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">15290806</PMID><DateCompleted><Year>2004</Year><Month>08</Month><Day>24</Day></DateCompleted><DateRevised><Year>2013</Year><Month>06</Month><Day>07</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0362-4331</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2004</Year><Month>Jul</Month><Day>21</Day></PubDate></JournalIssue><Title>The New York times on the Web</Title><ISOAbbreviation>N Y Times Web</ISOAbbreviation></Journal>As gene test menu grows, who gets to choose? | Local breeding schemes for Holstein cattle of Costa Rica were compared with the current practice based on continuous semen importation (SI) by deterministic simulation. Comparison was made on the basis of genetic response and correlation between breeding goals. A local breeding goal was defined on the basis of prevailing production circumstances and compared against a typical breeding goal for an exporting country. Differences in genetic response were <3%, and the correlation between breeding goals was 0.99. Therefore, difference between breeding objectives proved negligible. For the evaluation of genetic response, the current scheme based on SI was evaluated against a progeny testing (PT) scheme and a closed nucleus (CN) breeding scheme, both local. Selection intensities and accuracy of selection were defined according to current population size and reproduction efficiency parameters. When genotype x environment interaction (G x E) was ignored, SI was the strategy with the highest genetic response: 5.0% above the CN breeding scheme and 33.2% above PT. A correlation between breeding values in both countries lower than one was assumed to assess the effect of G x E. This resulted in permanent effects on the relative efficiencies of breeding strategies because of the reduction in the rate of genetic response when SI was used. When the genetic correlation was assumed equal to 0.75, the genetic response achieved with SI was reduced at the same level as local PT. When an initial difference in average genetic merit of the populations was assumed, this only had a temporal effect on the relative ranking of strategies, which is reverted after some years of selection because the rate of change in genetic responses remains unchanged. Given that the actual levels of genetic correlation between countries may be around 0.60, it was concluded that a local breeding scheme based on a nucleus herd could provide better results than the current strategy based on SI. |
2,339,404 | CUBIC: identification of regulatory binding sites through data clustering. | Transcription factor binding sites are short fragments in the upstream regions of genes, to which transcription factors bind to regulate the transcription of genes into mRNA. Computational identification of transcription factor binding sites remains an unsolved challenging problem though a great amount of effort has been put into the study of this problem. We have recently developed a novel technique for identification of binding sites from a set of upstream regions of genes, that could possibly be transcriptionally co-regulated and hence might share similar transcription factor binding sites. By utilizing two key features of such binding sites (i.e. their high sequence similarities and their relatively high frequencies compared to other sequence fragments), we have formulated this problem as a cluster identification problem. That is to identify and extract data clusters from a noisy background. While the classical data clustering problem (partitioning a data set into clusters sharing common or similar features) has been extensively studied, there is no general algorithm for solving the problem of identifying data clusters from a noisy background. In this paper, we present a novel algorithm for solving such a problem. We have proved that a cluster identification problem, under our definition, can be rigorously and efficiently solved through searching for substrings with special properties in a linear sequence. We have also developed a method for assessing the statistical significance of each identified cluster, which can be used to rule out accidental data clusters. We have implemented the cluster identification algorithm and the statistical significance analysis method as a computer software CUBIC. Extensive testing on CUBIC has been carried out. We present here a few applications of CUBIC on challenging cases of binding site identification. |
2,339,405 | Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. | Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model. |
2,339,406 | A powerful strategy to account for multiple testing in the context of haplotype analysis. | Haplotypes--that is, linear arrangements of alleles on the same chromosome that were inherited as a unit--are expected to carry important information in the context of association fine mapping of complex diseases. In consideration of a set of tightly linked markers, there is an enormous number of different marker combinations that can be analyzed. Therefore, a severe multiple-testing problem is introduced. One method to deal with this problem is Bonferroni correction by the number of combinations that are considered. Bonferroni correction is appropriate for independent tests but will result in a loss of power in the presence of linkage disequilibrium in the region. A second method is to perform simulations. It is unfortunate that most methods of haplotype analysis already require simulations to obtain an uncorrected P value for a specific marker combination. Thus, it seems that nested simulations are necessary to obtain P values that are corrected for multiple testing, which, apparently, limits the applicability of this approach because of computer running-time restrictions. Here, an algorithm is described that avoids such nested simulations. We check the validity of our approach under two disease models for haplotype analysis of family data. The true type I error rate of our algorithm corresponds to the nominal significance level. Furthermore, we observe a strong gain in power with our method to obtain the global P value, compared with the Bonferroni procedure to calculate the global P value. The method described here has been implemented in the latest update of our program FAMHAP. |
2,339,407 | Open-nucleus breeding strategies compared with population-wide positive assortative mating: II. Unequal distribution of testing effort. | This study compares population-wide positive assortative mating (PAM) with open-nucleus breeding with an elite and main population when more effort is allocated to parents of the elite. A companion study showed that PAM is advantageous when testing effort is independent of parental value. In the present study,unbalanced testing was imposed by varying the number of crosses or the number of genotypes per cross. These unbalanced alternatives are compared with PAM, where the testing effort was varied so that better parents were mated more frequently. More effort allocated to parents of higher rank increased the additive effect and the additive variance and only slightly altered the group coancestry and inbreeding in the breeding population (BP) compared with completely balanced scenarios. Of particular interest to the breeder, large enhancement of the additive variance in the BP contributed to higher gains in the production population (PP). These simulations demonstrate that population-wide PAM leads to higher genetic gains compared with open-nucleus alternatives at any desired target level of diversity in the PP. This is true for both balanced (part I)and unbalanced distribution of testing effort (part II). |
2,339,408 | Differential qualitative responses to rivastigmine in APOE epsilon 4 carriers and noncarriers. | This retrospective analysis of two double-blind, placebo-controlled studies in patients with mild to moderately severe AD investigated the efficacy of rivastigmine 6-12 mg/day on cognitive outcomes in patients with or without the apolipoprotein (APOE) epsilon4 allele. APOE data were collected from patients who consented to pharmacogenetic testing. Treatment differences within each subgroup were compared, using the Observed Case (OC) population. The APOE epsilon4 and non-APOE epsilon4 subgroups comprised 246 and 121 patients, respectively. Overall, APOE epsilon4 noncarriers showed greater decline than carriers (P<0.05). However, at 26 weeks, placebo-treated APOE epsilon4 patients declined 3.04 points below baseline on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), and rivastigmine-treated patients improved by 1.67 points. Non-APOE epsilon4 placebo-treated patients declined by 4.59 points and rivastigmine-treated patients declined by 0.48 points. Thus, non-APOE epsilon4 carriers showed a less favorable course under either placebo or rivastigmine, but both genotype-defined subgroups showed quantitatively similar responses to therapy (both P<0.05 vs placebo). |
2,339,409 | A novel intronic mutation, 2988G>A, with high predictivity for impaired function of cytochrome P450 2D6 in white subjects. | Individuals with the cytochrome P450 (CYP) 2D6 intermediate metabolizer (IM) phenotype have low residual enzyme activity and compose about 10% to 15% of white populations. Their identification is clinically relevant but remains unsatisfactory because of incomplete characterization of the major allele involved, termed CYP2D6*41 (-1584C, R296C, S486T).</AbstractText>To search for novel mutations, resequencing of the entire CYP2D6 gene was performed in selected individuals. Genotype-phenotype correlation analysis was done in a population sample of 308 white subjects phenotyped with sparteine and previously genotyped for all major alleles.</AbstractText>A total of 16 novel polymorphic positions were identified, of which 7 were located within 2.4 kilobases of previously uncharacterized 2D7-2D6 intergenic sequence and 9 were located within intronic regions. The novel mutation 2988G>A in intron 6 appeared to be specifically associated with the IM phenotype. Further analysis in the population sample demonstrated that 2988G>A was strongly linked to allele *41 but not to any other alleles including *1, *2, *2xN, *4, *6, *7, *8, *9, *10, and *35. The overall frequency of the novel polymorphism was 8.4% in the normal white population. Compared with conventionally determined *41, 2988G>A was shown to have improved predictivity for the IM phenotype. With 2988G>A being taken into account, alleles *1, *2, and *35 (-1584G, V11M, R296C, S486T) were found to be phenotypically equivalent.</AbstractText>CYP2D6 genotyping can be considerably simplified by using 2988G>A as a marker for *41 and by omitting genotyping for the functionally equivalent alleles *2 and *35.</AbstractText> |
2,339,410 | Evolutionary ethics: can values change. | The hypothesis that values change and evolve is examined by this paper. The discussion is based on a series of examples where, over a period of a few decades, new ethical issues have arisen and values have changed. From this analysis it is suggested that there are a series of core values around which most people would agree. These are unlikely to change over long time periods. There are then a series of secondary or derived values around which there is much more controversy and within which differences of view occur. Such changes need to be documented if we are to understand the process involved in the evolution of differences in ethical views. |
2,339,411 | Prenatal smoking and early childhood conduct problems: testing genetic and environmental explanations of the association. | Extensive evidence now supports a statistical association between prenatal smoking and increased risk for antisocial outcomes in offspring. Though this statistical link may signal a causal association, commentators have urged caution in interpreting findings because of the likelihood of confounding.</AbstractText>We used data from the Environmental Risk Longitudinal Twin Study, a representative British sample of 1116 twin pairs studied at ages 5 and 7 years, to assess associations between prenatal smoking and early childhood conduct problems net of the effects of both heritable and environmental risks for child antisocial outcomes.</AbstractText>Prenatal smoking showed a strong, dose-response relationship with child conduct problems at ages 5 and 7 years. Around half of this association was attributable to correlated genetic effects. Mothers who smoked during pregnancy differed from other mothers in a number of ways. They were more likely to be antisocial, had children with more antisocial men, were bringing up their children in more disadvantaged circumstances, and were more likely to have had depression. Controlling for antisocial behavior in both parents, depression in mothers, family disadvantage, and genetic influences, estimates for the effects of prenatal smoking were reduced by between 75% and the entire initial effects.</AbstractText>Observed associations between prenatal smoking and childhood conduct problems are likely to be heavily confounded with other known risks for children's behavioral development. As a result, tests of any causal influence of prenatal smoking must await findings from experimental studies.</AbstractText> |
2,339,412 | Polymorphism of estrogen metabolism genes and cataract. | Cataract is the leading cause of visual impairment in older adults in the world. Age-related lens opacities are common and are frequent causes of loss of vision. The incidence of cataract increases significantly with increasing age in women only. The onset coincides with estrogen deficiency that occurs after menopause. Hormone replacement therapy has proven beneficial to selected postmenopausal women. Estrogen effects on biological system are modulated via the estrogen receptors (ER) and/or estrogen metabolites. Although ER have been detected in ocular tissue, whether ER polymorphism is related to cataract is not known at present. The polymorphisms of estrogen metabolizing enzymes are also related to the serum concentration and activity of estrogen. Polymorphism such as cytochrome P450c17 (A2/A2), cytochrome P450c1A (vt/vt) will result in increased formation of catechol estrogen, while people with catechol-O-methyltransferase (COMT) polymorphism COMT (L/L) will have decreased metabolism of catechol estrogen and decreased level of methoxyestradiol. COMT was also involved in tamoxifen metabolism which may further decrease the activity of COMT in breast cancer patients treated with tamoxifen. It is known that a 4-7% increase in cataract was found in tamoxifen-treated breast cancer patients than non-user. The 7.0% COMT (L/L) genotype in general population corresponded well with the 4-7% of cataract formation in tamoxifen-treated breast cancer patients. Our hypothesis is that breast cancer patients with COMT (L/L) genotype may be at increased risk of cataract formation after tamoxifen treatment. |
2,339,413 | Screening of Y chromosome microdeletion which contains AZF regions in 71 Turkish azoospermic men. | Screening of Y chromosome microdeletion which contains AZF regions in 71 turkish azoospermic men: In 71 Turkish men Y chromosome microdeletions have been studied before intracytoplasmic sperm injection (ICSI). DNA samples were amplified with 18 STS primers of the azoospermia factor (AZF) region on the Y chromosome by using multiplex polymerase chain reaction (PCR). Microdeletions were detected in 4 azoospermic men (5.6 %); one with a deletion in the AZFb region, while the 3 others had a large deletion extending over multiple chromosomal regions (AZFb+c+d and AZFa+b+c+d). In the patients with microdeletion, no spermatogenetic activity could be detected in testis biopsies. This result confirms the idea that Y chromosome microdeletion analysis is important in investigating the possibility of finding sperm in testicular sperm extraction (TESE). Therefore, we point out the importance of genetic testing and counselling regarding Y chromosome microdeletion for couples requesting ICSI. |
2,339,414 | Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors. | The SMARCA4/BRG1 gene product is a component of the SWI-SNF chromatin-remodeling complex and regulates gene expression by disrupting histone-DNA contacts in an ATP-dependent manner. Inactivating mutations of the SMARCA4 gene, on chromosome arm 19p, are present in several human cancer cell lines, including cell lines derived from lung cancers. Interestingly, loss of heterozygosity (LOH) at 19p and absence of the SMARCA4 protein have been reported in lung tumors. To evaluate further the possible contribution of SMARCA4 gene inactivation to lung carcinogenesis, we performed a complete analysis of the SMARCA4 gene to search for (a) point mutations in all 35 coding exons, including an existing splicing variant and the intron-exon boundaries, and (b) abrogation of gene expression through promoter hypermethylation by using the methylation-specific polymerase chain reaction (MSP) assay. We selected genomic DNA from 20 lung primary tumors with LOH on 19p for the screening of point mutations and 10 lung cancer cell lines and 52 lung primary tumors for the MSP analysis. Through our mutational screening, we identified an in-frame and germ-line insertion of 24 bp in exon 4 whose biological relevance is unknown. This variant was not detected in the germ line of the 62 additional individuals analyzed, indicating it is not a common polymorphism. Moreover, two missense alterations were identified in the tumors of 2 patients, a somatic Gly1160Arg mutation and a Ser1176Cys mutation. Neither was present in the germ line of the 51 additional lung cancer individuals tested. Because these mutations lead to substitution of highly conserved amino acids, they may affect the ATPase function of the protein. Finally, no promoter hypermethylation was observed in any lung primary tumor or cancer cell line, indicating that this is not a major mechanism for SMARCA4 inactivation during lung carcinogenesis. In conclusion, our data revealed that somatic point mutations of the SMARCA4 gene are present in a small subset of lung tumors, although mutations affecting the ATPase domain may be a hot-spot for SMARCA4 gene inactivation. We cannot rule out that other mechanisms, such as complete or partial deletions of the SMARCA4 gene, are contributing to the loss of the SMARCA4 protein in lung cancer. |
2,339,415 | SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele. | Sterol regulatory element-binding proteins (SREBPs) are transcription factors involved in cholesterol and fatty acid synthesis. Recently, a polymorphism in the 5'-region of the SREBP-1a gene has been described to be correlated with alterations in the plasma levels of cholesterol. Consequently the relationship between this SREBP-1a gene polymorphism and Alzheimer's disease (AD) alone and in combination with the apolipoprotein E (ApoE) 4 allele was evaluated. No association between SREBP-1a polymorphism alone and AD could be seen. However, in the group of healthy ApoE4 allele carriers, the number of homozygote SREBP-1a DeltaG allele carriers was significantly higher than in AD patients. Cerebrospinal fluid levels of cholesterol were lower in AD patients who were carriers of the SREBP-1a DeltaG allele, and the ratio of 24S-hydroxycholesterol to cholesterol was increased in these probands. Our data suggest a reduced risk of AD in carriers of an ApoE4 allele who are additionally homozygous for the SREBP-1a DeltaG allele, which is possibly due to the influence of SREBP-1a polymorphism on brain cholesterol metabolism. This is the first report on a genetic factor which prevents the deleterious effect of the ApoE4 allele and thus reduces the risk of AD. |
2,339,416 | Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. | Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.</AbstractText>Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.</AbstractText>Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.</AbstractText>Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.</AbstractText> |
2,339,417 | BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. | Heterozygous mutations of the bone morphogenetic protein type II receptor (BMPR-II) gene have been identified in patients with primary pulmonary hypertension. The mechanisms by which these mutations contribute to the pathogenesis of primary pulmonary hypertension are not fully elucidated. To assess the impact of a heterozygous mutation of the BMPR-II gene on the pulmonary vasculature, we studied mice carrying a mutant BMPR-II allele lacking exons 4 and 5 (BMPR-II(+/-) mice). BMPR-II(+/-) mice had increased mean pulmonary arterial pressure and pulmonary vascular resistance compared with their wild-type littermates. Histological analyses revealed that the wall thickness of muscularized pulmonary arteries (<100 mum in diameter) and the number of alveolar-capillary units were greater in BMPR-II(+/-) than in wild-type mice. Breathing 11% oxygen for 3 wk increased mean pulmonary arterial pressure, pulmonary vascular resistance, and hemoglobin concentration to similar levels in BMPR-II(+/-) and wild-type mice, but the degree of muscularization of small pulmonary arteries and formation of alveolar-capillary units were reduced in BMPR-II(+/-) mice. Our results suggest that, in mice, mutation of one copy of the BMPR-II gene causes pulmonary hypertension but impairs the ability of the pulmonary vasculature to remodel in response to prolonged hypoxic breathing. |
2,339,418 | Physical network models. | We develop a new framework for inferring models of transcriptional regulation. The models, which we call physical network models, are annotated molecular interaction graphs. The attributes in the model correspond to verifiable properties of the underlying biological system such as the existence of protein-protein and protein-DNA interactions, the directionality of signal transduction in protein-protein interactions, as well as signs of the immediate effects of these interactions. Possible configurations of these variables are constrained by the available data sources. Some of the data sources, such as factor-binding data, involve measurements that are directly tied to the variables in the model. Other sources, such as gene knock-outs, are functional in nature and provide only indirect evidence about the variables. We associate each observed knock-out effect in the deletion mutant data with a set of causal paths (molecular cascades) that could in principle explain the effect, resulting in aggregate constraints about the physical variables in the model. The most likely settings of all the variables, specifying the most likely graph annotations, are found by a recursive application of the max-product algorithm. By testing our approach on datasets related to the pheromone response pathway in S. cerevisiae, we demonstrate that the resulting model is consistent with previous studies about the pathway. Moreover, we successfully predict gene knock-out effects with a high degree of accuracy in a cross-validation setting. When applying this approach genome-wide, we extract submodels consistent with previous studies. The approach can be readily extended to other data sources or to facilitate automated experimental design. |
2,339,419 | Dejerine-Sottas' neuropathy caused by the missense mutation PMP22 Ser72Leu. | To describe a patient with the Dejerine-Sottas' syndrome due to a de novo Ser72Leu amino acid substitution in the PMP22 protein and summarize the phenotype associated with this frequent mutation.</AbstractText>The proband has a medical history of early onset, severe, and progressive demyelinating neuropathy, accompanied by mild ptosis and limitations of eye movements. Ulnar nerve motor conduction velocities were extremely reduced (2.6 and 2.2 m/s), and the sural nerve biopsy showed onion bulbs and thinly myelinated axons. Duplication of chromosome 17p11.2 was ruled out, and the Ser72Leu substitution was found upon sequencing the PMP22 gene.</AbstractText>The Ser72Leu substitution is being confirmed as the most frequent point mutation in the PMP22 gene. This 'hot spot' should be considered in the strategy of looking for point mutations in the hereditary demyelinating neuropathies.</AbstractText> |
2,339,420 | Inherited forms of renal cell carcinoma. | It is estimated that up to 2% of renal cell cancer (RCC) clusters in families. Several forms of hereditary RCC have been characterized with specific clinical, histopathological, and genetic features. The most common of these is von Hippel-Lindau (VHL) disease caused by mutations in the VHL gene and predisposing to clear cell RCC. Predisposition to papillary RCC is present in hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary papillary renal cell carcinoma (HPRC). Identification of the genetic defects causing these diseases has enlightened the molecular pathogenesis of RCC, and moreover, provided means to improve patient management. Genetic testing enables early diagnosis of the disease, after which individuals at-risk can be guided to regular surveillance. Screening facilitates detection of presymptomatic early tumors broadening treatment options and potentially improving prognosis. Thus, identification of individuals with inherited cancer susceptibility is important as special management of these patients improves disease outcome. The purpose of this review is to provide clues for identification and management of hereditary renal cancer patients in clinical practice. |
2,339,421 | [Exposure and allergy to dust mites in general and working environment in Croatia]. | This paper gives a review of the most important impacts of exposure to dust mites in general and working environment on human health. The Institute for Medical Research and Occupational Health in Zagreb, Croatia, has been investigating the frequency and exposure levels of allergies to pyroglyphid and non-pyroglyphid mites in Croatia for the last 10 years. Investigations were performed in general urban and rural population from the inland and coastal Croatia, and several industrial inland populations occupationally exposed to organic dusts. Mite species and levels of pyroglyphid mites allergens (Der p 1, Der f 1) were established in house dust samples taken from the floors of bedrooms and living rooms and in several industrial dust samples. The frequency of allergies to pyroglyphid mites in general urban population of inland Croatia is about 20%, with significant general indoor exposure to these mites (median value for Der p 1: 0.85 microg/g of dust). General adult population of the coastal region had a significantly higher exposure to pyroglyphid mites (median value for Der p 1: 4.5 microg/g of dust), yet showed a significantly lower frequency of allergies to these mites (about 5%). New studies are necessary to investigate possible genetic and environmental factors involved in the mechanisms which protect coastal population from the development of mite allergy. Acarological and statistical analyses have shown that the high frequency of sensitisation to non-pyroglyphid mites found in the general and working populations of the inland region is not related to environmental exposure to these mites, but to the cross-reactivity between pyroglyphid and non-pyroglyphid mites and to false positive skin reactions in prick testing, particularly to T. putrescentiae. So far, results do not indicate that pyroglyphid mites are occupational allergens in paper-recycling, fish-processing and tobacco-processing. |
2,339,422 | [Current views on allergic diseases]. | Allergic diseases are an increasing health problem in the industrialised and developed countries especially in children and young adult persons. They are considered diseases of modern civilisation. The reported cumulative prevalence of allergic diseases in childhood of 25-30% includes allergic rhinoconjunctivitis, asthma and dermatitis. The reasons for this increasing prevalence are unknown. The main risk factors are genetic predisposition, allergen exposure, environmental pollutants, decreased stimulation of immune system during the critical period of development and lifestyle. Allergic diseases must be treated as common health disorder. They can express themselves in any age groups and in many different organs. IgE antibody is the main connection between involved organs. Specific IgE is still being identified using the 100 years old skin testing method and quantitative immunoenzymatic method in serum. In spite of the permanent improvement of both methods, neither skin reactivity to allergens nor measurable specific IgE necessarily mean a clinically manifested disease. The interpretation of these findings is still in the clinician's domain. Allergic diseases rarely have a fatal outcome, but have a long duration. They need a complex treatment and are a substantial individual and public socio-economic burden. Studies of factors influencing the ontogeny and maturation of the immune system in the early human development as well as studies of interaction between environment and genetic predisposition will provide a new insight in the aetiology of allergic diseases. This rewiev presents curent views on the epidemiology, pathogenesis, diagnosis, therapy and prevention of allergic diseases. |
2,339,423 | The presence of hereditary BRCA1 gene mutations in women with familial breast or ovarian cancer and the frequency of occurrence of these tumours in their relatives. | In 48 women with familial breast cancer as well as in 22 women with familial ovarian cancer, the presence of pathogenic mutations in BRCA1 gene were found in 35.4% and 54.6% of patients, respectively. From the patients with mutations we created two groups: the CaM--probands with breast cancer and CaOv--probands with ovarian cancer. The probands with breast cancer were younger by a mean of five years than the probands with ovarian cancer (p = 0.048).</AbstractText>The PCR-SSCP procedure was used to find mutations in the BRCA1 gene. Fragments suspected of mutation were subjected to nucleotide sequencing.</AbstractText>In the CaM group, which consisted of 17 women with breast cancer, the following mutations in the BRCA1 gene were detected: 5382insC, T300G, 3819del5 and IVS20+60ins12. The probands of the CaM group and their relatives developed a total of 49 breast and ovarian cancers. Among all these tumours the breast cancers of the probands made up 34.7%, the breast cancers of proband relatives made up 57.1% and the ovarian cancers of probands and their relatives made up only 8.2%. The CaOv group consisted of 12 probands with ovarian cancers in whom we detected only two kinds of mutations: 5382insC and 185delAG. The probands of the CaOv group and their relatives developed a total of 38 ovarian and breast cancers. Among all these tumours the ovarian cancers of the probands made up 31.6%, the ovarian cancers of their relatives made up 34.2% and the breast cancers of the relatives 34.2% of tumours. In the probands with breast or ovarian cancer the predominant mutation was 5382insC--in the BRCA1 gene detected in 76.5%, and 91.7%, respectively. Despite the predominant presence of the same mutation in probands from both groups the ratio of the number of breast cancers to the number of ovarian cancers in their relatives differed significantly (p = 0.0003).</AbstractText>This data shows that the presence of the 5382insC mutation in the BRCA1 gene is not always associated with the development of ovarian cancer. It is very likely that the development of ovarian cancer requires some additional factor, which was common among the familial ovarian cancer patients, and was almost inexistent among the familial breast cancer patients. On the other hand, the development of ovarian cancer at a later age than breast cancer in probands suggests that some factors exist which slow down the development of ovarian cancer or which accelerate the development of breast cancer.</AbstractText> |
2,339,424 | Translating genetics leaflets into languages other than English: lessons from an assessment of Urdu materials. | Genetic counselors frequently counsel clients whose first language is not English, relying on interpreters and on supplementary translated written material. This paper highlights factors that counselors need to consider before using or commissioning translated leaflets. It is based on an assessment of leaflets translated into Urdu, the national language of Pakistan, which are available through U.K. genetics clinics for use with Pakistani-origin clients. The 2 authors, who know Urdu as their 2nd and 1st languages respectively, independently read each leaflet, checking for accuracy of information, ease of reading and understanding, cultural sensitivity, and contact details for Urdu-speaking professionals. There were factual errors and confusing or very difficult text in all leaflets; some leaflets also contained culturally insensitive messages that could alienate users of genetics services. The paper discusses the reasons for these pitfalls and makes recommendations to guide the future production of translated genetics leaflets. |
2,339,425 | Exploring the public understanding of basic genetic concepts. | It is predicted that the rapid acquisition of new genetic knowledge and related applications during the next decade will have significant implications for virtually all members of society. Currently, most people get exposed to information about genes and genetics only through stories publicized in the media. We sought to understand how individuals in the general population used and understood the concepts of "genetics" and "genes." During in-depth one-on-one telephone interviews with adults in the United States, we asked questions exploring their basic understanding of these terms, as well as their belief as to the location of genes in the human body. A wide range of responses was received. Despite conversational familiarity with genetic terminology, many noted frustration or were hesitant when trying to answer these questions. In addition, some responses reflected a lack of understanding about basic genetic science that may have significant implications for broader public education measures in genetic literacy, genetic counseling, public health practices, and even routine health care. |
2,339,426 | Patient satisfaction with cancer genetic counseling: a psychometric analysis of the Genetic Counseling Satisfaction Scale. | Satisfaction is an important patient reported outcome of genetic counseling, as it is one of the elements used by professional organizations and healthcare accrediting bodies to determine the quality of professional work. However, empirical research on patient satisfaction with genetic counseling has been limited, partly due to the lack of standardized measures available to assess this construct. The purpose of this study was to conduct a psychometric analysis of a new satisfaction measure, the Genetic Counseling Satisfaction Scale (GCSS), within a sample of women participating in a no-cost cancer genetic counseling and testing program. The sample consisted of 61 women undergoing counseling and testing for hereditary breast-ovarian cancer risk (BRCA1/2 testing) who completed the GCSS following pretest counseling. The results suggest that the GCSS was reliable (Cronbach's coefficient alpha = 0.90) and that participants were highly satisfied with the care they received. In addition, there were no differences in satisfaction between cancer genetic counseling and prenatal counseling participants (based on preexisting norms), and satisfaction did not vary by sociodemographic characteristics. Implications and recommendations are discussed. |
2,339,427 | Enhancing the readability of materials describing genetic risk for breast cancer. | The number of individuals contemplating genetic testing is increasing, but the current materials and overall subject matter remain complex and not easily understood by many. The goal of this project was to evaluate efforts to revise and increase the readability of an existing information packet describing genetic risk for breast cancer.</AbstractText>Evaluation was conducted in two stages through two related studies. In Study 1, a focus group of multiethnic breast cancer survivors was assembled to obtain feedback on images included in the revised breast cancer genetics information packet. In Study 2, African American adult students in a literacy program evaluated the revised images (based on the feedback of the focus group in Study 1) and text of the information packet and provided ratings on readability, format, and appearance.</AbstractText>Responses from Study 1 participants suggested that some of the images created for the packet needed to be clearer in the concepts they were intended to convey. In Study 2, ratings of adult learners suggested difficulty with word comprehension in spite of the inclusion of definitions and a glossary. The reading level achieved was markedly lower than the college reading level required by the original information packet and other patient-directed cancer genetics materials.</AbstractText>Although efforts to clarify written materials in order to better serve patients with low literacy received generally favorable responses, continued efforts to create more user-friendly patient education materials are warranted.</AbstractText> |
2,339,428 | Cancer genetics knowledge and beliefs and receipt of results in Ashkenazi Jewish individuals receiving counseling for BRCA1/2 mutations. | Genetic counseling for BRCA1 and BRCA2 mutations (mutations associated with increased risk of breast-ovarian cancer) endeavors to communicate information that will help individuals make informed decisions regarding genetic testing.</AbstractText>This repeated-measures study examined cancer genetics knowledge and beliefs before and after counseling and their relationship to receipt of results for BRCA1/2 mutations in 120 highly educated Ashkenazi Jewish individuals.</AbstractText>A repeated-measures analysis examined change in knowledge and beliefs regarding personal behavior, mechanisms of cancer inheritance, meaning of a positive result, practitioner knowledge, frequency of inherited cancer, and meaning of a negative result from pre- to post-counseling with the between subjects variables of education (with/without graduate training) and personal history of breast or ovarian cancer (yes/no), and risk of having a mutation entered as a covariate. Mechanisms of cancer inheritance, meaning of a positive result, and practitioner knowledge increased from pre- to post-counseling. Those with graduate training had higher ratings of mechanisms of cancer inheritance ratings and lower ratings of frequency of inherited cancers than those without. Mann-Whitney U tests found those testing had higher ratings in mechanisms of cancer inheritance, specifically in the association of multiple primary cancers with hereditary cancer, than those not testing.</AbstractText>Genetic counseling is helpful in improving overall knowledge of cancer genetics even for highly educated individuals. Particular areas of knowledge improvement should be explored in relation to receipt of results, especially to further elucidate the relationship of knowledge of the association of multiple primary cancers with hereditary cancer to receipt of test results.</AbstractText> |
2,339,429 | Adenovirus expressing a bioluminescence reporter gene and cMAGI cell assay for the detection of HIV-1. | We report a fast, highly sensitive method for detecting and testing drug resistance of M-tropic and T-tropic laboratory and primary HIV-1 isolates. cMAGI cells are infected with an adenovirus vector harboring the luciferase reporter gene controlled by HIV-1 Tat-responsive element, TAR. HIV-1 Tat production by HIV-1 chronically infected cells, or by cMAGI cells as early as two days after being acutely infected with HIV-1, is readily monitored in the presence or absence of antiviral drugs. This method is more sensitive than HIV-1 Tat dependant production of beta-galactosidase in the cMAGI cells. The fast answer, ease and sensitivity as well as the possibility of using this method in high throughput screening, makes it an very attractive tool for phenotypic detection of HIV-1 in clinical samples as well as a sensitive assay for monitoring drug resistant HIV-1 variants. This method can also be used for discovery of novel anti HIV-1 drugs. |
2,339,430 | Primer design and marker clustering for multiplex SNP-IT primer extension genotyping assay using statistical modeling. | The optimization of the primer design is critical for the development of high-throughput SNP genotyping methods. Recently developed statistical models of the SNP-IT primer extension genotyping reaction allow further improvement of primer quality for the assay.</AbstractText>Here we describe how the statistical models can be used to improve primer design for the assay. We also show how to optimize clustering of the SNP markers into multiplex panels using statistical model for multiplex SNP-IT. The primer set failure probability calculated by a model is used as a minimization function for both primer selection and primers clustering. Three clustering algorithms for the multiplex genotyping SNP-IT assay are described and their relative performance is evaluated. We also describe the approaches to improve the speed of primer design and clustering calculations when using the statistical models. Our clustering decreases the average failure probability of the marker set by 7-25%. The experimental marker failure rate in the multiplex reaction was reduced dramatically and success rate can be achieved as high as 96%.</AbstractText>The primer design using statistical models is freely available from www.autoprimer.com.</AbstractText> |
2,339,431 | The Australian joint inquiry into the Protection of Human Genetic Information. | The Australian Law Reform Commission (ALRC) and the Australian Health Ethics Committee are currently engaged in an inquiry into the Protection of Human Genetic Information. In particular, the Attorney-General and the Minister for Health and Ageing have asked us to focus, in relation to human genetic information and tissue samples, on how best to ensure world's best practice in relation to: privacy protection; protection against unlawful discrimination; and the maintenance of high ethical standards in medical research and clinical practice. While initial concerns and controversies have related mainly to aspects of medical research (e.g. consent; re-use of samples) and access to private insurance coverage, relevant issues arise in a wide variety of contexts, including: employment; medical practice; tissue banks and genetic databases; health administration; superannuation; access to government services (e.g. schools, nursing homes); law enforcement; and use by government authorities (e.g. for immigration purposes) or other bodies (e.g. by sports associations). Under the Australian federal system, it is also the case that laws and practices may vary across states and territories. For example, neonatal genetic testing is standard, but storage and retention policies for the resulting 'Guthrie cards' differ markedly. Similarly, some states have developed highly linked health information systems (e.g. incorporating hospitals, doctors' offices and public records), while others discourage such linkages owing to concerns about privacy. The challenge for Australia is to develop policies, standards and practices that promote the intelligent use of genetic information, while providing a level of security with which the community feels comfortable. The inquiry is presently reviewing the adequacy of existing laws and regulatory mechanisms, but recognizes that it will be even more important to develop a broad mix of strategies, such as community and professional education, and the development of official standards and industry codes that reflect emerging international best practice in the area. |
2,339,432 | Genome-wide discovery of loci influencing chemotherapy cytotoxicity. | Little is known about the heritability of chemotherapy activity or the identity of genes that may enable the individualization of cancer chemotherapy. Although numerous genes are likely to influence chemotherapy response, current candidate gene-based pharmacogenetics approaches require a priori knowledge and the selection of a small number of candidate genes for hypothesis testing. In this study, an ex vivo familial genetics strategy using lymphoblastoid cells derived from Centre d'Etude du Polymorphisme Humain reference pedigrees was used to discover genetic determinants of chemotherapy cytotoxicity. Cytotoxicity to the mechanistically distinct chemotherapy agents 5-fluorouracil and docetaxel were shown to be heritable traits, with heritability values ranging from 0.26 to 0.65 for 5-fluorouracil and 0.21 to 0.70 for docetaxel, varying with dose. Genome-wide linkage analysis was also used to map a quantitative trait locus influencing the cellular effects of 5-fluorouracil to chromosome 9q13-q22 [logarithm of odds (LOD) = 3.44], and two quantitative trait loci influencing the cellular effects of docetaxel to chromosomes 5q11-21 (LOD = 2.21) and 9q13-q22 (LOD = 2.73). Finally, 5-fluorouracil and docetaxel were shown to cause apoptotic cell death involving caspase-3 cleavage in Centre d'Etude du Polymorphisme Humain lymphoblastoid cells. This study identifies genomic regions likely to harbor genes important for chemotherapy cytotoxicity using genome-wide linkage analysis in human pedigrees and provides a widely applicable strategy for pharmacogenomic discovery without the requirement for a priori candidate gene selection. |
2,339,433 | Divergence of conserved non-coding sequences: rate estimates and relative rate tests. | In many eukaryotic genomes only a small fraction of the DNA codes for proteins, but the non-protein coding DNA harbors important genetic elements directing the development and the physiology of the organisms, like promoters, enhancers, insulators, and micro-RNA genes. The molecular evolution of these genetic elements is difficult to study because their functional significance is hard to deduce from sequence information alone. Here we propose an approach to the study of the rate of evolution of functional non-coding sequences at a macro-evolutionary scale. We identify functionally important non-coding sequences as Conserved Non-Coding Nucleotide (CNCN) sequences from the comparison of two outgroup species. The CNCN sequences so identified are then compared to their homologous sequences in a pair of ingroup species, and we monitor the degree of modification these sequences suffered in the two ingroup lineages. We propose a method to test for rate differences in the modification of CNCN sequences among the two ingroup lineages, as well as a method to estimate their rate of modification. We apply this method to the full sequences of the HoxA clusters from six gnathostome species: a shark, Heterodontus francisci; a basal ray finned fish, Polypterus senegalus; the amphibian, Xenopus tropicalis; as well as three mammalian species, human, rat and mouse. The results show that the evolutionary rate of CNCN sequences is not distinguishable among the three mammalian lineages, while the Xenopus lineage has a significantly increased rate of evolution. Furthermore the estimates of the rate parameters suggest that in the stem lineage of mammals the rate of CNCN sequence evolution was more than twice the rate observed within the placental amniotes clade, suggesting a high rate of evolution of cis-regulatory elements during the origin of amniotes and mammals. We conclude that the proposed methods can be used for testing hypotheses about the rate and pattern of evolution of putative cis-regulatory elements. |
2,339,434 | Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. | Vitamin D receptor (VDR) polymorphisms have been associated with several immune-related diseases, and VDR and vitamin D itself modulate T cell differentiation. VDR maps to chromosome 12q, near a region commonly linked to asthma. We evaluated VDR as part of a 12q positional candidate survey, and in response to observations of VDR polymorphism associations with asthma and atopy in a founder population of Quebec. Twenty-eight loci in 7 positional candidates (7 in VDR) were genotyped in 582 families. Whereas other candidates demonstrated no association, the VDR ApaI polymorphism demonstrated significant transmission distortion, with undertransmission of the C allele in a ratio of 4:5 (p = 0.01). This association was most prominent in girls, in whom distortion was more marked (p = 0.009). Sex-specific associations between multiple VDR polymorphisms and immunoglobulin E levels were also observed (p = 0.006-0.01). Asthma associations were replicated in a second cohort (517 females with asthma and 519 matched control subjects): 4 of 6 VDR variants demonstrated significant association (p = 0.02-0.04). The direction of association in this second cohort was opposite to the effects seen in the trios, but similar to findings in the Quebec study. These results suggest that VDR influences asthma and allergy susceptibility in a complex manner. |
2,339,435 | Discovery of induced point mutations in maize genes by TILLING. | Going from a gene sequence to its function in the context of a whole organism requires a strategy for targeting mutations, referred to as reverse genetics. Reverse genetics is highly desirable in the modern genomics era; however, the most powerful methods are generally restricted to a few model organisms. Previously, we introduced a reverse-genetic strategy with the potential for general applicability to organisms that lack well-developed genetic tools. Our TILLING (Targeting Induced Local Lesions IN Genomes) method uses chemical mutagenesis followed by screening for single-base changes to discover induced mutations that alter protein function. TILLING was shown to be an effective reverse genetic strategy by the establishment of a high-throughput TILLING facility and the delivery of thousands of point mutations in hundreds of Arabidopsis genes to members of the plant biology community.</AbstractText>We demonstrate that high-throughput TILLING is applicable to maize, an important crop plant with a large genome but with limited reverse-genetic resources currently available. We screened pools of DNA samples for mutations in 1-kb segments from 11 different genes, obtaining 17 independent induced mutations from a population of 750 pollen-mutagenized maize plants. One of the genes targeted was the DMT102 chromomethylase gene, for which we obtained an allelic series of three missense mutations that are predicted to be strongly deleterious.</AbstractText>Our findings indicate that TILLING is a broadly applicable and efficient reverse-genetic strategy. We are establishing a public TILLING service for maize modeled on the existing Arabidopsis TILLING Project.</AbstractText> |
2,339,436 | Outcome of five years of accelerated surveillance in patients at high risk for inherited breast/ovarian cancer: report of a phase II trial. | To assess the outcome of accelerated patient surveillance in patients at high risk for inherited breast or ovarian cancer.</AbstractText>Using stringent inclusion criteria, 57 high-risk patients (7 positive for BRCA1/2 mutations, 39 mutation negative, and 11 unaffected) were recruited from a genetic testing protocol for inherited breast/ovarian cancer and were followed for 5 years (192.5 total patient years). Patients received twice annual physical examinations, imaging studies, measurement of CA125 and CA15-3, psychometric measurements, and unstructured interviews by a psychologist.</AbstractText>When mutation (+) and mutation (-) patients were compared, there were no significant differences in the development of disease metastasis, recurrence, or new cancers. No unaffected patients developed cancer. Management of osteoporosis, sexual function, and psychological distress were major concerns.</AbstractText>Our data suggest that all patients with remarkable family history, regardless of their mutation status, may be at substantially increased risk for disease progression and development of new cancers, which is often not ovarian or recurrent breast cancer. Although prophylactic surgery is important in decreasing cancer recurrence in mutation carriers, increased surveillance with physical examinations and psychological support is also valuable and acceptable to such high-risk patients.</AbstractText> |
2,339,437 | [BRCA1 and BRCA2 have reached the clinical medicine. The 10-year old finding of the genetic mutation makes it now possible to prevent breast cancer]. | Increased knowledge of breast cancer genetics has improved the possibilities to predict the future risk of a woman to be diagnosed with breast cancer. In certain families, presymptomatic testing of breast cancer susceptibility genes may be offered, leading to an even more accurate individual risk prediction. As a result, advice regarding follow-up and risk reducing measures may be given to the individuals with the highest risks of cancer. Preventive surgery drastically reduces the risk of having breast or ovarian cancer respectively. The value of increased controls in hereditary high risk women is insufficiently investigated. Further studies are warranted to elucidate the efficacy of chemoprevention in women at a very high risk of breast cancer, e.g. mutation carriers of BRCA1 and BRCA2. |
2,339,438 | Social contract theory and just decision making: lessons from genetic testing for the BRCA mutations. | Decisions about funding health services are crucial to controlling costs in health care insurance plans, yet they encounter serious challenges from intellectual property protection--e.g., patents--of health care services. Using Myriad Genetics' commercial genetic susceptibility test for hereditary breast cancer (BRCA testing) in the context of the Canadian health insurance system as a case study, this paper applies concepts from social contract theory to help develop more just and rational approaches to health care decision making. Specifically, Daniel's and Sabin's "accountability for reasonableness" is compared to broader notions of public consultation, demonstrating that expert assessments in specific decisions must be transparent and accountable and supplemented by public consultation. |
2,339,439 | Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: a randomized controlled trial. | As the availability of and demand for genetic testing for hereditary cancers increases in primary care and other clinical settings, alternative or adjunct educational methods to traditional genetic counseling will be needed.</AbstractText>To compare the effectiveness of a computer-based decision aid with standard genetic counseling for educating women about BRCA1 and BRCA2 genetic testing.</AbstractText>Randomized controlled trial conducted from May 2000 to September 2002.</AbstractText>Outpatient clinics offering cancer genetic counseling at 6 US medical centers enrolled 211 women with personal or family histories of breast cancer.</AbstractText>Standard one-on-one genetic counseling (n = 105) or education by a computer program followed by genetic counseling (n = 106).</AbstractText>Participants' knowledge, risk perception, intention to undergo genetic testing, decisional conflict, satisfaction with decision, anxiety, and satisfaction with the intervention. Counselor group measures were administered at baseline and after counseling. Computer group measures were administered at baseline, after computer use, and after counseling. Testing decisions were assessed at 1 and 6 months. Outcomes were analyzed by high vs low risk of carrying a BRCA1 or BRCA2 mutation.</AbstractText>Both groups had comparable demographics, prior computer experience, medical literacy, and baseline knowledge of breast cancer and genetic testing, and both counseling and computer use were rated highly. Knowledge scores increased in both groups (P<.001) regardless of risk status, and change in knowledge was greater in the computer group compared with the counselor group (P =.03) among women at low risk of carrying a mutation. Perception of absolute risk of breast cancer decreased significantly after either intervention among all participants. Intention to undergo testing decreased significantly after either intervention among low-risk but not high-risk women. The counselor group had lower mean scores on a decisional conflict scale (P =.04) and, in low-risk women, higher mean scores on a satisfaction-with-decision scale (P =.001). Mean state anxiety scores were reduced by counseling but were within normal ranges for both groups at baseline and after either intervention, regardless of risk status.</AbstractText>An interactive computer program was more effective than standard genetic counseling for increasing knowledge of breast cancer and genetic testing among women at low risk of carrying a BRCA1 or BRCA2 mutation. However, genetic counseling was more effective than the computer at reducing women's anxiety and facilitating more accurate risk perceptions. These results suggest that this computer program has the potential to stand alone as an educational intervention for low-risk women but should be used as a supplement to genetic counseling for those at high risk.</AbstractText> |
2,339,440 | Identifying the susceptibility gene(s) in a set of trait-linked genes using genotype data. | There are generally three steps to isolate a disease linkage-susceptibility gene: genome-wide scan, fine mapping, and, last, positional cloning. The last step is time consuming and involves intensive laboratory work. In some cases, fine mapping cannot proceed further on a set of markers because they are tightly linked. For years, genetic statisticians have been trying different ways to narrow the fine-mapping results to provide some guidance for the next step of laboratory work. Although these methods are practical and efficient, most of them are based on IBD data, which usually can be inferred only from the genotype data with some uncertainty. The corresponding methods thus have no greater power than one using genotype data directly. Also, IBD-based methods apply only to relative pair data. Here, using genotype data, we have developed a statistical hypothesis-testing method to pinpoint a SNP, or SNPs, suspected of responsibility for a disease trait linkage among a set of SNPs tightly linked in a region. Our method uses genotype data of affected individuals or case-control studies, which are widely available in the laboratory. The testing statistic can be constructed using any genotype-based disease-marker disequilibrium measure and is asymptotically distributed as a chi-square mixture. This method can be used for singleton data, relative pair data, or general pedigree data. We have applied the method to simulated data as well as a real data set; it gives satisfactory results. |
2,339,441 | Ethical implications of predictive DNA testing for hereditary breast cancer. | Predictive medicine offers the possibility of detecting many common diseases that have a genetic basis, such as cancer; however, a genetic alteration might only indicate susceptibility to, not certainty of, disease. Whereas means for identifying a greater susceptibility to disease have been developed, effective interventions have progressed much more slowly. Awareness of one's susceptibility to disease without an actual possibility of intervention can lead to an unacceptable use of such information, or have a dramatic psychological impact on the person involved. Are the risks connected with the knowledge of susceptibility to genetic disease proportional to the benefits that such knowledge may provide? Does the knowledge of one's genetic condition constitute a service to the individual and society, or is this predominantly harmful for the person involved? The problem is vast, and involves medical, psychological, social, political and ethical dilemmas. These dilemmas, common to all predictive medicine, are most evident in predictive DNA testing for hereditary breast cancer. In our analysis, we will first examine the ethical values involved in genetic testing, highlighting the special ethical issues raised by predictive DNA testing for hereditary breast cancer. Next we will deal with genetic counseling, which, in our opinion, is the 'ethos' for ethically justifying predictive DNA testing. |
2,339,442 | Genetic medicine: the balance between science and morality. | This article explores the relationship between science and morality with respect to the major changes that genetic knowledge has induced in medicine, as well as in many other spheres of our lives. The following themes are treated: (i) the influence of genetic knowledge on the concepts of normalcy and diversity with respect to health; (ii) the influence of genetic knowledge on the concept of responsibility; (iii) the reciprocal influence of pre-existing biases and genetic knowledge; (iv) the influence of genetic knowledge on the concept of community; and (v) the influence of genetic knowledge on autonomy and trust in the patient-doctor relationship. The article does not wish to be prescriptive, but rather to raise open questions. The key philosophical question is to what extent human beings benefit from predictions about the future. The role attributed to genetics is largely overestimated. Genetic knowledge can be perceived as enhancing the control that individuals have on their lives, or as paralyzing the decision process of an individual who may feel predestined to a serious disease. In the case of breast and ovarian cancer, the probabilistic nature of genetics is especially relevant, given the relatively low penetrance of BRCA mutations. "Future things: not our domain. But in this today which unravels in front of us, what shall we do?" (Sophocles, Antigones). |
2,339,443 | Awareness of breast cancer genetics and interest in predictive genetic testing: a survey of a southern Italian population. | Before starting a molecular screening program for breast cancer risk and in order to develop ad hoc educational strategies, a population survey in Apulia, Italy, was performed to gather information on women's awareness of breast cancer genetics and their attitude toward genetic testing for breast cancer risk.</AbstractText>A consecutive series of 677 healthy women with or without a family history of breast cancer, who attended the outpatient clinics of Lega Italiana per la Lotta contro i Tumori in Bari, Italy, for preventive visits, were asked to complete a 20-item questionnaire on socio-demographics, risk perception, psychological characteristics and interest in genetic testing for breast cancer predisposing genes.</AbstractText>Most women (77%) reported knowing something about the genetics of breast cancer; only 7% of the women were not interested at all in genetic testing. These figures were not significantly different for women with or without a family history of breast cancer. The two most frequently cited reasons for being interested in genetic testing, accounting for more than 50% of collected responses, were 'to learn about your children's risk' and 'to help advance research'. On multiple logistic regression analysis, only older age [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.3-2.9] was associated with women's knowledge of genetic testing. Moreover, marital status (OR 4.0; 95% CI 1.1-14.6) and thinking of cancer (OR 2.2; 95% CI 1.0-4.7) independently predicted the interest in having genetic testing.</AbstractText>Southern Italian women seem highly interested in genetic testing for breast cancer risk. However, their expectations mainly regard their concerns about their children or their altruistic need to help research rather than the idea of a direct clinical benefit. The great interest of the women in genetic testing probably reflects their inappropriate knowledge of the information that genetic testing can provide for breast cancer risk analysis.</AbstractText>Copyright 2004 European Society for Medical Oncology</CopyrightInformation> |
2,339,444 | Intensive radiologic surveillance: a focus on the psychological issues. | Although women who carry BRCA1 or BRCA2 mutations have up to an 85% lifetime risk of breast cancer, the majority choose to forego prophylactic mastectomy, which has been proven to markedly lower breast cancer mortality, and opt for lifelong intensive surveillance. Whether surveillance lowers breast cancer mortality in these women is unknown. However, in a formal survey of 34 of these women, 82% indicated a strong belief in the ability of surveillance to find breast cancer at a stage when it is still curable. Since 1997 we have been conducting a study to compare the sensitivity of breast magnetic resonance imaging (MRI), ultrasound, mammography and clinical breast examination (CBE) in women at high risk for hereditary breast cancer. Breast cancer incidence rates have been even higher than predicted for this population. The addition of MRI and ultrasound to conventional surveillance with mammography and CBE significantly improves sensitivity, but at the expense of decreased specificity. Two years ago we began a formal study of distress and breast cancer anxiety. A sample of 25 new and ongoing participants in the surveillance study have completed the Hospital Anxiety and Depression Scale together with the Breast Cancer Worry Scale, up to six times per year over a 2-year period. To date there has been no evidence of any impact of intensive surveillance, including false-positive studies, on anxiety, depression or breast cancer worry. |
2,339,445 | Genetic testing and breast cancer: the women's point of view. | Breast cancer is the most common cancer among women in Western countries (130,000 cases per year in Europe) and accounts for 20-25% of all malignancies in European women. In the past few years medical journals have focused greater attention on the quality and quantity of information provided to consumers; there is a general consensus amongst physicians on the importance of having better informed consumers. This change in attitude is influencing greatly the physician-patient relationship and political decisions. Breast cancer associations, like the National Breast Cancer Coalition in the USA or EUROPA DONNA, the European Breast Cancer Coalition in Europe, have pushed for involvement in the discussion of any phase of illness, and have a particular interest in preventive medicine. The identification of high-risk women by genetic testing for BRCA1 and BRCA2 mutations is largely debated, in particular regarding patient counseling, and psychosocial and legislative support. This article reports the different points of view raised by women's movements, so that useful suggestions may be provided to improve breast cancer prevention modalities. |
2,339,446 | Decisions and outcomes of genetic testing for inherited breast cancer risk. | Since the discovery of breast cancer susceptibility genes and the availability of genetic testing, a substantial amount of research has been conducted to evaluate rates of genetic test acceptance and to understand the psychological and behavioral impact of BRCA1 and BRCA2 (BRCA1/2) genetic test results. This article explores findings related to genetic test acceptance for inherited breast cancer risk and the impact of genetic test results on psychological functioning, cancer prevention and control behaviors, and family communication about genetic testing. Overall, rates of genetic test acceptance were lower than anticipated based on interest in genetic testing reported in early research. While there is limited evidence that genetic testing generates adverse psychological effects, receiving positive BRCA1/2 test results may cause emotional reactions and concerns that are specific to such results. Although early reports suggested that receiving positive BRCA1/2 test results may have a limited impact on cancer screening or prevention behaviors, recent studies have shown that genetic testing for inherited breast cancer risk may increase screening behaviors among mutation carriers. However, utilization of some screening tests remains low among mutation carriers. Additional studies are needed to identify subgroups of participants in genetic testing who may be vulnerable to experiencing testing-specific concerns, and to evaluate the effects of interventions designed to promote behavioral change and address other concerns that may be generated by receiving positive BRCA1/2 test results. |
2,339,447 | External quality assessment for mutation detection in the BRCA1 and BRCA2 genes: EMQN's experience of 3 years. | The European Molecular Genetics Quality Network (EMQN) was formed in order to improve external quality assessment for molecular genetic testing in Europe. From 1999 to 2002 it received funding from the European Union under the Standards, Measurement and Testing programme (contract no. SMT4-CT98-7515). Since then, its maintenance has been supported through subscription of the participants, and it has been coordinated by the National Genetic Reference Laboratory at Manchester, UK (Rob Elles and Simon Patton; www.emqn.org).</AbstractText>Among other external quality assessment (EQA) schemes, EMQN has provided an EQA scheme for mutation detection in the breast cancer genes, BRCA1 and BRCA2, designed to cover the two important aspects of genetic testing: (i) genotyping and (ii) interpretation and reporting of results. The fourth full scheme was completed in 2003, with data evaluation pending for the 47 participants.</AbstractText>Analysis of genotyping data has pinpointed two main types of errors: (i) missing a mutation (in nine of the 17 false results a normal sequence was reported); and (ii) description of the observed sequence change by an incorrect nomenclature. Compared with the more technical process of genotyping, the writing of reports displayed a much wider variation between laboratories.</AbstractText>From the reported data it is clear that external quality control should become an integral part of quality assessment in the laboratory, thus contributing to maintaining confidence in the reliability of genetic testing among patients and health professionals.</AbstractText>Copyright 2004 European Society for Medical Oncology</CopyrightInformation> |
2,339,448 | Genetic alterations in hereditary breast cancer. | Genetic linkage studies have led to the identification of highly penetrant genes as the possible cause of inherited cancer risk in many cancer-prone families. Most women with a family history of breast/ovarian cancer have tumors characterized by alterations in particular genes, mainly BRCA1 and BRCA2, but also CHK2, ATM, STK11 and others. This paper examines the BRCA1 and BRCA2 genes, focusing on the Italian pattern of mutations. The function of these two genes, classified as tumor suppressors, is linked with key metabolic mechanisms such as DNA damage repair, regulation of gene expression and cell cycle control. The pathological BRCA allelic variants may cause alteration of protein function, transcriptional activity and DNA repair; accumulation of the defects leads to widespread chromosome instability that may be directly responsible for cancer formation. In fact, mutations in BRCA1 and BRCA2, conferring a highly increased susceptibility to breast and ovarian cancer, do not lead to cancer by themselves. The current consensus is that these are 'caretaker' genes, which, when inactivated, allow other genetic defects to accumulate. The nature of these other molecular events may define the pathway through which BRCA1 and BRCA2 act. The BRCA mutation spectrum is complex, and the significance of most nucleotide alterations is difficult to understand. Moreover, the mutation pattern seems to be related to ethnicity. The Italian Consortium of Hereditary Breast and Ovarian Cancer has reviewed 1758 families; 23% have been found to be carriers of pathogenetic mutations in BRCA1 or BRCA2. Founder mutations have been described in geographically restricted areas of Italy; a regional founder effect has been demonstrated in Italy for the mutations BRCA1 5083del19 and BRCA2 8765delAG, and a probable new founder mutation has been characterized in Tuscany. The presence of founder mutations has practical implications for genetic testing. |
2,339,449 | Preliminary estimate for the second-trimester maternal serum screening detection rate of the 45,X karyotype using alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin. | To estimate the detection rate for 45,X pregnancies through second-trimester screening using maternal serum alpha-fetoprotein, human chorionic gonadotropin and unconjugated estriol.</AbstractText>Twenty-two cases of 45,X were ascertained through a cytogenetics database and an additional 51 cases were identified through publications. Serum analyte concentrations were reviewed for cases with fetal hydrops, cystic hygroma alone, and no evidence of edema. Using the statistical characteristics of this sample of affected pregnancies, computer simulations were carried out to determine the proportion of 45,X pregnancies that should be screen-positive for Down syndrome and trisomy 18. The extent to which additional cases of 45,X might be identified using a protocol specifically designed to detect 45,X pregnancies was also estimated.</AbstractText>Approximately 54% of all 45,X pregnancies should be identifiable through screening for Down syndrome and trisomy 18. The detection rate for cases with hydrops and/or cystic hygroma was 60%, and without edema 33%. If offered with screening for Down syndrome and trisomy 18, 45,X screening could identify approximately 7% more of the affected pregnancies with an incremental rise of 0.2% in the false-positive rate.</AbstractText>A screening algorithm for 45,X could be developed. However, the number of additional affected pregnancies identified would appear to be too small to justify this screening.</AbstractText> |
2,339,450 | The changing face of gastroschisis and omphalocele in southeast Georgia. | To document trends in the clinical characteristics of gastroschisis and omphalocele in southeast Georgia, USA, from 1994 to 2002.</AbstractText>All babies with an abdominal wall defect in a 19-county region were referred to one Perinatal Center for genetic counseling, level II ultrasound scans, pregnancy follow-up and delivery. Karyotyping was offered for omphalocele, advanced maternal age, family history predisposing to aneuploidy, and gastroschisis with an additional anomaly.</AbstractText>There were 64 patients, 34 with gastroschisis and 30 with omphalocele. From 1994 to 2002, the birth prevalence of gastroschisis was 1:3600 and omphalocele 1:3400, but from 2000 to 2002, gastroschisis increased to 1:1667, while omphalocele increased to only 1:2709. Gender distribution was different: for gastroschisis the M:F ratio was 1:2.1; for omphalocele the ratio was 1.7:1. In the patients with omphalocele, 90% had an amniocentesis and 9/27 were aneuploid: five had trisomy 18, three had trisomy 13 and one had trisomy 21. Seventy-six per cent of the patients with omphalocele had associated anomalies, but only 17.6% of those with gastroschisis. Mothers whose babies had gastroschisis showed a trend to progressively younger age, while no such trend was observed among mothers whose babies had omphalocele.</AbstractText>The birth prevalence of abdominal wall defects in general is increasing, but more notably for gastroschisis. Maternal age continues to decrease for gastroschisis. In the study population, gender distribution showed a statistically significant variation between the defects.</AbstractText> |
2,339,451 | Ataxia-telangiectasia, an evolving phenotype. | Ataxia-telangiectasia (A-T) is a progressive neurodegenerative disorder, with onset in early childhood and a frequency of approximately 1 in 40,000 births in the United States. A-T is seen among all races and is most prominent among ethnic groups with a high frequency of consanguinity. The syndrome includes: progressive cerebellar ataxia, dysarthric speech, oculomotor apraxia, choreoathetosis and, later, oculocutaneous telangiectasia. Immunodeficiency with sinopulmonary infections, cancer susceptibility (usually lymphoid), and sensitivity to ionizing radiation are also characteristic. Laboratory findings include: (1) elevated alphafetoprotein (AFP), (2) cerebellar atrophy on magnetic resonance imaging, (3) reciprocal translocations between chromosomes 7 and 14 in lymphocytes, (4) absence or dysfunction of the ATM protein, (5) radiosensitivity, as demonstrated by colony survival assay (CSA), and (6) mutations in the ATM gene. The latter are usually truncating or splicing mutations; approximately 10% are missense mutations. Mutations are found across the entire gene. Almost all recurring mutations are found on unique haplotypes that represent founder effects and ancestral relationships between patients. In addition to radiosensitivity and sensitivity to radiomimetic chemicals, the phenotype of A-T cells includes defective damage-induced activation of the cell cycle checkpoints at G1, S and G2/M. With the aid of molecular testing, A-T can now be distinguished from other autosomal recessive cerebellar ataxias (ARCAs) such as Friedreich ataxia, Mre11 deficiency (AT-like disease), and the oculomotor apraxias 1 (aprataxin deficiency) and 2 (senataxin deficiency). Other "A-T variants" include: (1) Nijmegen breakage syndrome (NBS) or nibrin/Nbs1 deficiency, with microcephaly and mental retardation but without ataxia, apraxia, or telangiectasia, and 2) A-T(Fresno), a phenotype that combines features of both NBS and A-T, with mutations in the ATM gene. The term "A-T variant" has a diminishing usefulness. |
2,339,452 | Evaluation of DNA intercalation potential of pharmaceuticals and other chemicals by cell-based and three-dimensional computational approaches. | To what extent noncovalent chemical-DNA interactions, in particular weak nonbonded DNA intercalation, contribute to genotoxic responses in mammalian cells has not been fully elucidated. Moreover, with the exception of predominantly flat, multiple-fused-ring structures, our ability to predict intercalation ability of novel compounds is nearly completely lacking. Computational programs such as DEREK and MCASE recognize primarily those molecules that can form irreversible covalent adducts with DNA since their learning sets, for the most part, have not been populated by compounds for which a relationship between noncovalent interaction and genotoxicity exists. We describe here a novel three-dimensional (3D) computational DNA-docking model for prediction of DNA intercalative activity of molecules with both classical and nonclassical intercalating structures. The 3D docking results show a remarkable concordance with results obtained from testing these molecules directly in the Chinese hamster V79 cell-based bleomycin amplification system suggesting that either or both of these approaches may have utility in defining noncovalent chemical-DNA interactions. The ability to predict and/or demonstrate cellular DNA intercalation of novel molecules may well provide fresh insights into the nature and mechanistic basis of structurally unexpected genotoxicity observed during safety testing. |
2,339,453 | Fate of the first polar bodies in mouse oocytes. | Both nuclear transfer and intracytoplasmic sperm injection (ICSI) practice necessitates studies on the spatial relationship between the MII spindle and the first polar bodies (FPB). Although recent observations have shown that the FPB position does not predict accurately the location of the meiotic spindle in metaphase II oocytes of monkey, hamster, and human, detailed studies on FPB deviation and its affecting factors are lacking. Since polar bodies can be used for genetic testing and oocyte quality grading, their life span under different conditions should be studied. The timing of formation and degeneration and the position relative to the MII spindle of the FPB and the factors affecting FPB deviation and degeneration during in vivo and in vitro aging of both in vivo and in vitro matured mouse oocytes were investigated in this study. Mice of the Kun-ming breed were used, and the intact and degenerated FPB were identified through microscopic morphology in combination with propidium iodide (PI) exclusion test and the chromosomes visualized by Hoechst staining. Results are summarized as follows: (i) oocytes started FPB extrusion at 8 hr after the onset of in vivo or in vitro maturation, but the number of FPB reached maximum much later in vitro (14 hr of culture) than in vivo (10 hr post hCG). (ii) Some FPB began to degenerate before ovulation and around 70% became degenerated within 6 hr after maximal nuclear maturation both in vivo and in vitro; they disappeared faster during in vivo than in vitro aging but turned from intact to degenerated at a similar tempo. (iii) Some FPB began to deviate from the MII spindle 10 hr after hCG injection or in vitro culture and the distance between FPB and the spindle increased with time during both in vivo and in vitro aging. (iv) FPB deviated more slowly in the in vitro matured oocytes than in in vivo matured. (v) Denudation performed after FPB extrusion markedly enhanced its deviation. (vi) The perivitelline space (PVS) increased with time during maturation and aging in vivo and in vitro and the values of PVS and the percentages of FPB adjacent to the spindle were significantly negatively correlated. (vii) Cytochalasin B and colchicine had no effect on FPB deviation. (viii) None of the more than 3,500 FPBs observed was found to be dividing or have divided into two cells at any time points before or after ovulation or in vitro maturation. Our results were consistent with the possibility that the displacement of the FPB was a time- and PVS-dependent process, indicating that PVS would increase with time and its formation and enlargement would facilitate the lateral displacement of the degenerating FPB. |
2,339,454 | Comparison between various strategies for the disease-gene mapping using linkage disequilibrium analyses: studies on adenine phosphoribosyltransferase deficiency used as an example. | Recently, linkage disequilibrium analyses have been used to detect disease-causing loci based on the common disease-common variant hypothesis. To see what methods can effectively identify the genes, we have to apply them to the practical data obtained from the human population. We extensively performed linkage disequilibrium and haplotype analyses on adenine phosphoribosyltransferase ( APRT) genes in both control and deficient subjects. To examine the power to detect disease-causing loci, we analyzed SNPs, STRPs, and VNTR within and around the APRT gene. When only SNPs were used, P values did not necessarily show significant difference, even at loci close to the mutation site for APRT*J that is exclusively observed among Japanese. However, the examination of the same samples with haplotypes based on the haplotype block data gave sufficient significance. In the case of STRP and VNTR, some single-marker loci showed significant difference. Our study suggested that the use of haplotype analysis based on the haplotype-block structure is more powerful than single-marker locus analysis for the detection of disease-related loci. |
2,339,455 | Open-nucleus breeding strategies compared with population-wide positive assortative mating: I. Equal distribution of testing efforts. | Positive assortative mating (PAM) can enhance the additive genetic variance in a breeding population(BP). This increases the potential for gains in the production population (PP, selected subset of the BP) for recurrent selection programs in forest trees. The assortment of mates can be either: (1) by individual tree rank across the whole BP (PAM), or (2) trees of similar rank can be merged into larger hierarchical groups and then mated randomly within group ("open"-nucleus breeding,NB). The objective of this study was to compare PAM and NB in quantitative terms. The NB simulation model assumed two tiers (nucleus, main) with unrestricted migration between the tiers. Clonal tests were used to predict breeding values and test resources per mate were kept constant for all mates. Both gain and diversity were combined into a single selection criterion, "group-merit selection." Alternatives were compared over five breeding cycles by considering genetic gain and diversity in a selected PP established in a seed orchard. The assortment of mates in both alternatives enhanced additive variance and increased the additive effect in the BP, leading to additional gain in the PP. Gains generated under PAM always exceeded gains under NB. Thus, the main message from this study is that PAM in both the short- and long-term results in more gain at any target level of diversity in the PP (the breeder's target) than is achieved by the NB alternative. The optimum size of the nucleus varies with the desired level of seed orchard diversity. At lower target diversity, smaller nucleus sizes are favorable, while larger sizes result in more gain when seed orchard diversity is considered more important. |
2,339,456 | Fragile X premutation alleles in SCA, ET, and parkinsonism in an Asian cohort. | Among 367 subjects, the authors analyzed 167 patients with essential tremor, sporadic progressive cerebellar ataxia, multiple-system atrophy, and atypical parkinsonism and 200 healthy control subjects for FMR1 premutation alleles. None of the subjects carried alleles within the premutation range. These findings suggest that in the absence of other supportive clinical or imaging features, the cost-effectiveness of routine fragile X tremor/ataxia syndrome screening in this Asian cohort with movement disorders was low. |
2,339,457 | DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. | Genetic associations between type 1 diabetes and alleles at the HLA class II locus DPB1 have been previously reported. Observed associations could be due to variation in the DPB1 locus itself or to linkage disequilibrium (LD) between DPB1 alleles and other susceptibility loci. One measure of whether the association of an allele with a disease reflects a true effect of the locus or is simply due to LD is the observation of that association in multiple ethnic groups. Previous type 1 diabetes associations have been reported for DPB1*0301 and DPB1*0202 (predisposing) and for DPB1*0402 (protective). In this study, results are reported from testing these associations in three different sample sets: 1) Puerto Rican case and control subjects, 2) Mexican-American simplex families, and 3) high-risk (DR3/DR4) individuals with and without an affected relative. DPB1*0301 was associated in all three groups, even after accounting for LD with DRB1-DQB1. DPB1*0202 and DPB1*0402 were positively and negatively associated, respectively, in two of the three populations. These results suggest that the observed DPB1 associations, especially that of the DPB1*0301 allele, with type 1 diabetes are likely to be true associations. This supports the concept that multiple genes in the HLA region can affect type 1 diabetes susceptibility. |
2,339,458 | Lack of association between Connexin 31 (GJB3) alterations and sensorineural deafness in Austria. | Mutations in the gap junction protein beta 3 (GJB3) gene encoding Connexin 31 (Cx31) are known to cause autosomal inherited sensorineural deafness, erythrokeratodermia and neuropathy. The role of Cx31 mutations has not been described in familial cases of non-syndromic hearing impairment (NSHI) in central European populations. To identify mutations in the Austrian population, highly selected familial (n=24) and sporadic (n=21) cases of isolated NSHI were screened by analysis of the complete coding sequence of Cx31, after exclusion of a common Cx26 causing deafness. Three different variations occurring in a total of 37% of all cases were identified. A C94T (R32W) missense mutation was seen in 4.4% of cases and two silent alterations C357T and C798T were detected in 8.9% and 24.4% of cases exclusively in a heterozygous pattern. No correlation between Cx31 alterations and deafness was found. To investigate the role of heterozygous Cx31 variations for a possibly combination allelic disease inheritance with Cx26 mutations as shown for Connexin 30 and Connexin 26, patients with Cx26 variations were tested. Our data suggest that Cx31 alterations are common but have no or a low genetic relevance in the Austrian hearing impaired population with or without Cx26 alterations. |
2,339,459 | Delayed non-matching to position performance in aged hybrid Fischer 344 x brown Norway rats: a longitudinal study. | In this study, the effects of aging on the performance in a delayed non-matching to position (DNMTP) task were investigated longitudinally in hybrid Fischer 344 x Brown Norway rats. The rats were first trained to perform the task. Subsequently, their performance was assessed monthly from 28 to 34 months of age. The measures of responding on the DNMTP schedule did not decrease in the course of the study. After the last DNMTP test, choline acetyltransferase (ChAT) activity and glial fibrillary acidic protein (GFAP) content were measured in frontal cortex and hippocampus. We found that higher levels of GFAP in the frontal cortex, but not hippocampus, were associated with a poorer performance in the DNMTP task. Our findings support the notion that repeated testing prevents the age-related decline in cognitive functions that has been reported in cross-sectional studies. Pathology of the frontal cortex seems to predict a faster rate of forgetting in aging rats. |
2,339,460 | Non-invasive screening of fragile X syndrome A using urine and hair roots. | The diagnosis of fragile X A syndrome (FRAXA) during childhood depends largely on DNA-based diagnostic tests due to the lack of the specific clinical features. To determine a non-invasive screening method for fragile X syndrome, we studied the method of DNA-based diagnosis using urine or hair roots instead of routinely used peripheral blood cells. The amplification of repeat-containing alleles of FMR-1 by PCR using Pfu polymerase was applied on DNA extracted from urine sediments or hair roots of 50 and 28 normal individuals, respectively. Consistent amplification of repeat-containing DNA fragments of normal size to ethidium-visible quantities were obtained in 92% (46/50) of urine samples and 100% (28/28) of hair roots. No bands of normal size or abnormal or artificial smears were detected in two male FRAXA patients. No female samples were examined in the present study because the separation of two alleles was unsatisfactory on agarose gels with DNA from blood samples. Our results indicate that the use of hair roots in a DNA-based test constitutes a rapid, simple and less-invasive screen to diagnose males with FRAXA. |
2,339,461 | Analysis of childhood absence epilepsy using haplotype-based haplotype relative risk and transmission disequilibrium test. | The authors performed haplotype-based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analysis of childhood absence epilepsy in 30 trios families, using gene typing technology based on microsatellite polymorphic marker. The five microsatellite DNA markers (D8S554, D8S1753, D8S534, D8S1100, D8S1783) used in the study are on chromosome 8q24. HHRR shows D8S554(4) (chi2 = 5.939, P < 0.05), D8S1100(3) (chi2 = 5.081, P < 0.05), D8S1783(6) (chi2 = 4.308, P < 0.05), TDT shows D8S554(4) (chi2 = 4.455, P < 0.05), D8S1783(6) (chi2 = 4, P < 0.05), some signs of association and disequilibrium between these loci and CAE. A suspected association of childhood absence epilepsy in the Chinese population to chromosome 8q24 has been proposed. In addition, it is hypothesized that the CAE gene might have a genetic heterogeneity in the population from a different race. |
2,339,462 | Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. | Autism, a childhood neuropsychiatric disorder with a strong genetic component, is currently the focus of considerable attention within the field of human genetics as well many other medical-related disciplines. A recent study has implicated two X-chromosomal neuroligin genes, NLGN3 and NLGN4, as having an etiological role in autism, having identified a frameshift mutation in one gene and a substitution mutation in the other, segregating in multiplex autism spectrum families (Jamain et al. [2003: Nat Genet 34:27-29]). The function of neuroligin as a trigger for synapse formation would suggest that such mutations would likely result in some form of pathological manifestation. Our own study, screening a larger sample of 196 autism probands, failed to identify any mutations that would affect the coding regions of these genes. Our findings suggest that mutations in these two genes are infrequent in autism. |
2,339,463 | Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample. | Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study. |
2,339,464 | Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients. | A hemizygous deletion of the q11 band on chromosome 22 occurs in 1 of every 5,950 live births (0.017%). The deletion is mediated by low copy repeats (LCRs) flanking this locus. Presence of the deletion is associated with variable phenotypic expression, which can include distinctive facial dysmorphologies, congenital heart disease and learning disabilities. An unusually high percentage of individuals with this deletion (25-30%) have been described to develop schizophrenia or schizoaffective disorder. In previous studies, the prevalence of the 22q11 deletion in patients with schizophrenia was found to be approximately 2% in Caucasian adults and 6% in childhood-onset cases. Both these frequencies represent a dramatic increase from the prevalence of the deletion in the general population. In this study, we investigate the occurrence of the 22q11 deletion in an independent sample of schizophrenic patients of Afrikaner origin. We first ascertained a sample of 85 patients who meet full diagnostic criteria for schizophrenia for presence of two or more of the clinical features associated with presence of the 22q11 deletion. A group of six patients (7%) met these criteria. This group was subjected to fluorescent in situ hybridization (FISH) and presence of the 22q11 deletion was confirmed for two subjects. Our study therefore confirms the previously reported rate of 2% frequency of the 22q11 deletion in adult schizophrenic patients and provides a two-stage screening protocol to identify these patients. |
2,339,465 | Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. | Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C-->T, PRODH*1482C-->T, PRODH*1483A-->G, PRODH*1766A-->G, PRODH*1852G-->A PRODH*1945T-->C, two of which (PRODH*1483A-->G and PRODH*1852G-->A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T-->C and PRODH*1852G-->A (Global P = 0.006), and PRODH*1852G-->A and PRODH*1766A-->G (Global P = 0.01) which include one of the newly identified markers. After six-fold Bonferroni correction for multiple testing the PRODH*1945T-C/PRODH*1852G-A haplotypes remained significant. This is a sub-haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3' region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia. |
2,339,466 | [Integrated population genetic and medical genetic study of two raions of the Tver oblast]. | An integrated medical genetic an population genetic study has been performed in two raions (administrative districts) of the Tver oblast (region) of Russia: the Udomlya raion located in the zone affected by the Kalininskaya Nuclear Power Plant and the Ostashkov raion, which served as a control district. No significant differences has been found with respect to the genetic parameters studied. The values of these parameters in the populations of the town of Udomlya, the town of Ostashkov, the Udomlya raion, and the Ostashkov raion, respectively, are the following: random inbreeding, 0.00006, 0.00011, 0.000167, and 0.000366; endogamy index, 0.05, 0.43, 0.30, and 0.42; local inbreeding, 0.0003, 0.00045, 0.0009, and 0.0011; the degree of isolation by distance, 0.0003, 0.00045, 0.0009, and 0.0005; sigma, 2098, 1338, 1473, and 1189; the load of autosomal dominant (AD) diseases, 0.71, 0.92, 0.92, and 1.37; the load of autosomal recessive (AR) diseases, 0.68, 0.69, 0.67, and 0.82; and the load of X-linked diseases, 0.18, 0.64, 0.83, and 0.27. |
2,339,467 | The future of association studies: gene-based analysis and replication. | Historically, association tests were limited to single variants, so that the allele was considered the basic unit for association testing. As marker density increases and indirect approaches are used to assess association through linkage disequilibrium, association is now frequently considered at the haplotypic level. We suggest that there are difficulties in replicating association findings at the single-nucleotide-polymorphism (SNP) or the haplotype level, and we propose a shift toward a gene-based approach in which all common variation within a candidate gene is considered jointly. Inconsistencies arising from population differences are more readily resolved by use of a gene-based approach rather than either a SNP-based or a haplotype-based approach. A gene-based approach captures all of the potential risk-conferring variations; thus, negative findings are subject only to the issue of power. In addition, chance findings due to multiple testing can be readily accounted for by use of a genewide-significance level. Meta-analysis procedures can be formalized for gene-based methods through the combination of P values. It is only a matter of time before all variation within genes is mapped, at which point the gene-based approach will become the natural end point for association analysis and will inform our search for functional variants relevant to disease etiology. |
2,339,468 | Gastrointestinal polyps and polyp syndromes in adolescents. | Although gastrointestinal polyps are more common in the first decade of life than during adolescence, underlying genetic polyposis syndromes are more likely in adolescents. In the past decade, the discovery of gene defects associated with polyposis syndromes has improved classification of these disorders, assisted in the stratification of cancer risk, and permitted more precise diagnosis. Genetic testing is now clinically available for the gene defects that occur in familial adenomatous polyposis coli, Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome. This review outlines clinical features, genetics, and management strategies for the major polyposis syndromes that affect adolescents. |
2,339,469 | Amelogenesis imperfecta in a new animal model--a mutation in chromosome 5 (human 4q21). | Candidate genes for amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are located on 4q21 in humans. We tested our hypothesis that mutations in the portion of mouse chromosome 5 corresponding to human chromosome 4q21 would cause enamel and dentin abnormalities. Male C3H mice were injected with ethylnitrosourea (ENU). Within a dominant ENU mutagenesis screen, a mouse mutant was isolated with an abnormal tooth enamel (ATE) phenotype. The structure and ultrastructure of teeth were studied. The mutation was located on mouse chromosome 5 in an interval of 9 cM between markers D5Mit18 and D5Mit10. Homozygotic mutants showed total enamel aplasia with exposed dentinal tubules, while heterozygotic mutants showed a significant reduction in enamel width. Dentin of mutant mice showed a reduced content of mature collagen cross-links. We were able to demonstrate that a mutation on chromosome 5 corresponding to human chromosome 4q21 can cause amelogenesis imperfecta and changes in dentin composition. |
2,339,470 | Effects of the Enterococcus faecalis hypR gene encoding a new transcriptional regulator on oxidative stress response and intracellular survival within macrophages. | In order to identify regulators of the oxidative stress response in Enterococcus faecalis, an important human pathogen, several genes annotated as coding for transcriptional regulators were inactivated by insertional mutagenesis. One mutant, affected in the ef2958 locus (designated hypR [hydrogen peroxide regulator]), appeared to be highly sensitive to oxidative challenge caused by hydrogen peroxide. Moreover, testing of the hypR mutant by using an in vivo-in vitro macrophage infection model resulted in a highly significant reduction in survival compared to the survival of parent strain JH2-2. Northern blot analyses were carried out with probes specific for genes encoding known antioxidant enzymes, and they showed that the ahpCF (alkyl hydroperoxide reductase) transcript was expressed less in mutant cells. Mobility shift protein-DNA binding assays revealed that HypR regulated directly the expression of hypR itself and the ahpCF operon. Our combined results showed that HypR appeared to be directly involved in the expression of ahpCF genes under oxidative stress conditions and suggested that this regulator could contribute to the virulence of E. faecalis. |
2,339,471 | C-reactive protein genotypes affect baseline, but not exercise training-induced changes, in C-reactive protein levels. | The goal of this study is to determine whether C-reactive protein (CRP) gene variants affect baseline and training-induced changes in plasma CRP levels.</AbstractText>Sixty-three sedentary men and women aged 50 to 75 years old underwent baseline testing (Vomax, body composition, CRP levels). They repeated these tests after 24 weeks of exercise training while on a low-fat diet. The CRP +219G/A variant significantly associated with CRP levels before and after training after accounting for the effects of demographic and biological variables. CRP -732A/G genotype was significantly related on a univariate basis to CRP levels after training. The CRP +29T/A variant did not affect CRP levels before or after training. In regression analyses, the +219 and -732 variants each had significant effects on CRP levels before and after training. Subjects homozygous for the common A/G -732/+219 haplotype exhibited the highest CRP levels, and having the rare allele at either site was associated with significantly lower CRP levels. CRP levels decreased significantly with training (-0.38+/-0.18 mg/L; P=0.03). However, none of the CRP variants was associated with the training-induced CRP changes.</AbstractText>CRP +219G/A and -732A/G genotypes and haplotypes and exercise training appear to modulate CRP levels. However, training-induced CRP reductions appear to be independent of genotype at these loci.</AbstractText> |
2,339,472 | Testing for microevolution in body size in three blue tit populations. | Quantifying the genetic variation and selection acting on phenotypes is a prerequisite for understanding microevolutionary processes. Surprisingly, long-term comparisons across conspecific populations exposed to different environments are still lacking, hampering evolutionary studies of population differentiation in natural conditions. Here, we present analyses of additive genetic variation and selection using two body-size traits in three blue tit (Parus caeruleus) populations from distinct habitats. Chick tarsus length and body mass at fledging showed substantial levels of genetic variation in the three populations. Estimated heritabilities of body mass increased with habitat quality. The poorer habitats showed weak positive selection on tarsus length, and strong positive selection on body mass, but there was no significant selection on either trait in the good habitat. However, there was no evidence of any microevolutionary response to selection in any population during the study periods. Potential explanations for this absence of a response to selection are discussed, including the effects of spatial heterogeneity associated with gene flow between habitats. |
2,339,473 | Serum amino acids in patients with mutations in the hepatocyte nuclear factor-1 alpha gene. | Knockout mice lacking both copies of the hepatocyte nuclear factor 1 (HNF1) gene have altered serum levels of amino acids and generalized aminoaciduria. The aim of our study was to test whether alterations in serum amino acid levels were found in patients with mutations in the hepatocyte nuclear factor-1 alpha (HNF-1alpha) gene compared with controls.</AbstractText>Fasting serum from 20 patients with HNF-1alpha mutations and 20 age, sex and body mass index-matched controls was analysed for 16 amino acids. Means were compared between the two groups and Z scores calculated.</AbstractText>There was no significant difference between patients with HNF-1alpha mutations and controls in serum levels of phenylalanine, arginine, citrulline or lysine as suggested by knockout mice models. Although serum levels of eight amino acids were different in the two groups, these were not significant after Bonferroni correction.</AbstractText>The alterations in serum amino acid levels seen in mice models are not seen in patients with mutations in the HNF-1alpha gene. This suggests differences in mouse and man in the regulation of amino acid transport and has not provided us with a phenotypic marker to use before confirmatory genetic testing.</AbstractText>Copyright 2004 Diabetes UK</CopyrightInformation> |
2,339,474 | Informed consent when taking genetic decisions. | Developments in genetics with diagnostic, pre-symptomatic and predictive testing involve significant changes in the decision-making process, because of the complexity of genetic information and the difficulty related to understanding the causes and mechanism of genetic diseases, ethical, psychological and social implications (psychological stress, anxiety, discrimination in employment and assurance, difficulties in interpersonal relationship), and indirect involvement of third parties. When taking genetic decisions, the patient should receive all the information about the objective and the type of the test, the hypothetical risk, the possibility of obtaining unexpected results, possible psycho-physical repercussion, and means of support for the long time that might pass between the diagnostic predictions and the possible onset of the disease: genetic counseling is a complex but essential operation for acquiring the informed consent of the patient. The outlined peculiarities of the process for informed consent in genetics requires the adequate training of medical personnel to manage the relationship with the patient in these complex cases. |
2,339,475 | Clonal lymphocytes in persons without known chronic lymphocytic leukemia (CLL): implications of recent findings in family members of CLL patients. | Several genetic abnormalities have been characterized in chronic lymphocytic leukemia (CLL) but these are predominantly secondary events and the initiating phenomena in the etiology of the disease are yet to be established. Studies of inherited susceptibility have identified the early oncogenic events in both familial and "sporadic" forms of several malignant disorders, and this may also be possible in CLL. However, the utility of linkage analysis in identifying a predisposition locus for the disease is limited because large multigenerational families segregating CLL are rare, while the more frequent small nuclear CLL families contain insufficient numbers of affected individuals. The power to detect predisposition gene(s) could be greatly increased by extending the number of affected individuals within a particular family, for example, by identifying family members with subclinical levels of disease. High-sensitivity flow cytometry techniques, developed to monitor disease in CLL patients undergoing treatment, have allowed accurate enumeration of subclinical levels of CLL cells in healthy individuals from the general population and CLL families. Emerging evidence confirms the phenotypic, genotypic, and clinical associations between the aberrant cells in healthy individuals and those in CLL patients. The data suggest that inherited factors increase the susceptibility to both indolent and aggressive CLL, and they provide unbiased demonstration that the age of onset in CLL families is younger than in the general population. |
2,339,476 | Adenovirus hexon T-cell epitope is recognized by most adults and is restricted by HLA DP4, the most common class II allele. | The immunogenicity of adenovirus (Ad) vectors is enhanced by virus-specific memory immune responses present in most individuals as a result of past exposure to these ubiquitous pathogens. We previously identified the first human T-cell epitope from the major capsid protein hexon, H910-924, and found that it is highly conserved among different Ad serotypes. Memory/effector T-cell responses to H910-924 were detected in 14 of 18 (78%) healthy adults by an interferon-gamma ELISPOT assay. Hexon peptide-specific CD4 T-cell lines were generated from three HLA-typed donors and analyzed using a panel of HLA homozygous B-cell lines and monoclonal antibodies to HLA class II loci. These studies reveal that the hexon epitope is restricted by HLA DP4, a class II allele present in 75% of the population. Analysis of overlapping peptides and peptides with single residue mutations identified a HLA DP4-binding motif. Additionally, antibodies to the hexon peptide were detected in all donor sera by dot blot assay and ELISA. Therefore, most individuals exhibit both memory B- and T-cell responses to this highly conserved epitope on hexon, an obligate component of all Ad vectors, including 'gutted' vectors. These data suggest that current strategies for the use of Ad gene therapy vectors will not evade memory immune responses to Ad. |
2,339,477 | Hsp90: an emerging target for breast cancer therapy. | Rapidly evolving insights into the specific molecular genetic abnormalities that drive the growth and metastasis of breast cancer have led to the development of targeted therapeutics that do not rely on the generalized disruption of DNA metabolism and cell division for activity. Of particular interest are inhibitors of cellular signal transduction pathways involving tyrosine kinases as well as selective modulators of steroid hormone signaling, histone acetylation, angiogenesis and tumor cell apoptosis. Unique within this array of promising new agents, however, are compounds that target heat shock protein 90 (Hsp90). This molecular chaperone associates with a distinct, but surprisingly diverse, set of proteins that are referred to as Hsp90 client proteins. Hsp90 binds to these clients, and plays a key role in regulating their stability and function. Many of the proteins chaperoned by Hsp90 are involved in breast cancer progression and resistance to therapy, including the estrogen receptor, receptor tyrosine kinases of the erbB family, Akt, and mutant p53. Several small molecule inhibitors of Hsp90 have been identified that can deplete cellular levels of multiple oncogenic client proteins simultaneously by enhancing their ubiquitination and proteasome-mediated degradation. The activity of Hsp90 inhibitors has been well validated in preclinical breast cancer models, both in single-agent studies and in combination with conventional chemotherapy. One of these inhibitors, 17-allylamino, 17-demethoxygeldanamycin (17-AAG, NSC 330507) has recently completed phase I testing. The agent was well tolerated at drug exposures that were shown to cause modulation of Hsp90 client protein levels. Given the redundancy and complexity of the molecular abnormalities present in most breast cancers, the ability of Hsp90 inhibitors to alter the activity of multiple oncogenic targets may prove of unique therapeutic benefit. |
2,339,478 | Long-range (17.7 kb) allele-specific polymerase chain reaction method for direct haplotyping of R117H and IVS-8 mutations of the cystic fibrosis transmembrane regulator gene. | Genotyping of genetic polymorphisms is widely used in clinical molecular laboratories to confirm or predict diseases due to single locus mutations. In contrast, very few molecular methods determine the phase or haplotype of two or more mutations that are kilobases apart. In this report, we describe a new method for haplotyping based on long-range allele-specific PCR. Reaction conditions were established to circumvent the incompatibility of using allele-specific primers and a polymerase with proofreading activity. Haplotypes are determined by post-PCR analysis using different detection methods. The clinical application presented here directly determines the phase of two mutations separated by 17.7 kilobases in the cystic fibrosis transmembrane conductance regulator gene. Each mutation, the missense mutation R117H in exon 4 and the 5T polymorphism in intron 8 (IVS-8), have mild phenotypic effect unless they are present on the same chromosome (in cis). If an individual is heterozygous for both R117H and the IVS-8 5T variant, cis/trans testing is required to completely interpret results. The molecular method presented here bypasses the need to perform family studies to establish haplotypes. We propose use of this assay as a reflex clinical test for R117H- 5T-positive samples. |
2,339,479 | Test of linkage and/or association between the estrogen receptor alpha gene with bone mineral density in Caucasian nuclear families. | Extensive studies have been performed on the association between the estrogen receptor alpha (ER-alpha) gene and bone mineral density (BMD). Despite considerable efforts, the studies using limited markers and relatively small sample size have yielded largely inconsistent results. In this study, 1873 Caucasian subjects from 405 nuclear families containing 1512 sib pairs were recruited. BMD at the lumbar spine (LS) and femoral neck (FN) was measured by dual-energy X-ray absorptiometry (DXA). Seven single-nucleotide polymorphisms (SNPs) spanning from exon 1 to 8 in the ER-alpha gene were genotyped. The program QTDT (quantitative transmission disequilibrium test) was applied to test linkage and/or association of the ER-alpha gene and BMD variation using individual SNP markers and reconstructed haplotypes. Linkage disequilibrium (LD) was generally detected for SNPs in the ER-a gene (P < 0.05). Associations were observed between SNP rs932477 and FN BMD (P = 0.028), and between the most predominant three-marker haplotype (GCG) containing SNP rs932477 and FN BMD (P = 0.010). Within-family association (present only with both linkage and association) between SNP rs2228480 (G2014A) and FN BMD (P = 0.015) was observed. The most predominant seven-SNP haplotype (TCGCGGG) was associated with higher LS BMD (P = 0.015). However, after correction for multiple testing, these associations did not reach statistical significance. Denser markers may be necessary to better define the relationship between the ER-alpha gene and BMD variation in our sample. |
2,339,480 | Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency. | We report a family in which the normal pattern of X-linked inheritance of hemophilia B (Factor IX deficiency) is complicated by mosaicism in the proband's maternal grandfather. The proband, an infant with severe Factor IX deficiency, was initially thought to be a sporadic case. Testing of other family members identified his mother as a carrier of the disorder, and his asymptomatic maternal grandfather as having very mild FIX deficiency. The causative familial mutation was identified as a two base pair deletion (AG within codons 134-135) in the Factor IX gene. The grandfather was shown to be "heterozygous" for the deletion. Karyotype analysis confirmed him to be 46XY thereby ruling out Klinefelter syndrome. The proband's aunt, who as the daughter of a man with hemophilia is theoretically an obligate carrier, was found not to carry this familial mutation, and thus not to be a carrier of hemophilia B. The grandfather must therefore be an X chromosome somatic and germline mosaic, with consequent segregation of the affected and non-affected Factor IX genes. This observation underlines the importance of confirming carrier status even in those individuals assumed to be obligate carriers, and has implications for genetic counseling. |
2,339,481 | Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. | Large exploratory studies, including candidate-gene-association testing, genomewide linkage-disequilibrium scans, and array-expression experiments, are becoming increasingly common. A serious problem for such studies is that statistical power is compromised by the need to control the false-positive rate for a large family of tests. Because multiple true associations are anticipated, methods have been proposed that combine evidence from the most significant tests, as a more powerful alternative to individually adjusted tests. The practical application of these methods is currently limited by a reliance on permutation testing to account for the correlated nature of single-nucleotide polymorphism (SNP)-association data. On a genomewide scale, this is both very time-consuming and impractical for repeated explorations with standard marker panels. Here, we alleviate these problems by fitting analytic distributions to the empirical distribution of combined evidence. We fit extreme-value distributions for fixed lengths of combined evidence and a beta distribution for the most significant length. An initial phase of permutation sampling is required to fit these distributions, but it can be completed more quickly than a simple permutation test and need be done only once for each panel of tests, after which the fitted parameters give a reusable calibration of the panel. Our approach is also a more efficient alternative to a standard permutation test. We demonstrate the accuracy of our approach and compare its efficiency with that of permutation tests on genomewide SNP data released by the International HapMap Consortium. The estimation of analytic distributions for combined evidence will allow these powerful methods to be applied more widely in large exploratory studies. |
2,339,482 | Testing small clutch size models with Daphnia. | Life-history theory predicts that for small clutches, variance in egg size (between individuals) should decrease in a predictable invariant manner as clutch size increases. To test this, we studied Daphnia magna at 350 different food treatments and recorded the number of eggs and the volume of each egg for their first clutch. As predicted, we found that the relationship between clutch size and resources devoted to reproduction was linear, variance in egg volume decreased with increasing clutch size, and resources were shared relatively equally between the eggs in a clutch. However, we found that the rate at which the range of egg volumes decreased with clutch size was slower than predicted. We discuss possible explanations for this discrepancy, including a lower limit on the volume of eggs that are produced and selection for smaller eggs when food is abundant. Consistent with this, we found that mean egg volume decreased with increasing clutch size. |
2,339,483 | Parallel evolution and inheritance of quantitative traits. | Parallel phenotypic evolution, the independent evolution of the same trait in closely related lineages, is interesting because it tells us about the contribution of natural selection to phenotypic evolution. Haldane and others have proposed that parallel evolution also results from a second process, the similarly biased production of genetic variation in close relatives, an idea that has received few tests. We suggest that influence of shared genetic biases should be detectable by the disproportionate use of the same genes in independent instances of parallel phenotypic evolution. We show how progress in testing this prediction can be made through simple tests of parallel inheritance of genetic differences: similar additive, dominance, and epistasis components in analysis of line means and similar effective numbers of loci. We demonstrate parallel inheritance in two traits, lateral plate number and body shape, in two lineages of threespine stickleback that have adapted independently to freshwater streams on opposite sides of the Pacific Ocean. Notably, reduction of plate number in freshwater involves a substitution at the same major locus in both lineages. Our results represent only a first step in the study of the genetics of parallel phenotypic evolution in sticklebacks. Nevertheless, we have shown how such studies can be employed to test the genetic hypothesis of parallel evolution and how study of parallel evolution might yield insights into the roles of both selection and genetic constraint in phenotypic evolution. |
2,339,484 | Multimedia messages in genetics: design, development, and evaluation of a computer-based instructional resource for secondary school students in a Tay Sachs disease carrier screening program. | Tay Sachs disease is a recessively inherited neurodegenerative disorder, for which carrier screening programs exist worldwide. Education for those offered a screening test is essential in facilitating informed decision-making. In Melbourne, Australia, we have designed, developed, and evaluated a computer-based instructional resource for use in the Tay Sachs disease carrier screening program for secondary school students attending Jewish schools. The resource entitled "Genetics in the Community: Tay Sachs disease" was designed on a platform of educational learning theory.</AbstractText>The development of the resource included formative evaluation using qualitative data analysis supported by descriptive quantitative data. The final resource was evaluated within the screening program and compared with the standard oral presentation using a questionnaire. Knowledge outcomes were measured both before and after either of the educational formats.</AbstractText>Data from the formative evaluation were used to refine the content and functionality of the final resource. The questionnaire evaluation of 302 students over two years showed the multimedia resource to be equally effective as an oral educational presentation in facilitating participants' knowledge construction.</AbstractText>The resource offers a large number of potential benefits, which are not limited to the Tay Sachs disease carrier screening program setting, such as delivery of a consistent educational message, short delivery time, and minimum financial and resource commitment. This article outlines the value of considering educational theory and describes the process of multimedia development providing a framework that may be of value when designing genetics multimedia resources in general.</AbstractText> |
2,339,485 | Genetic information leaflets: influencing attitudes towards genetic testing. | This article explores how a "neutral" genetics information leaflet influenced people's attitudes to be more positive toward predictive genetic testing. This is of concern, given the desire within clinical genetics and population based testing to provide information that informs choice without directing toward, or against, testing.</AbstractText>Four studies are reported. The first two investigated presentation (glossy and colored vs. black and white), and method of reading (read only vs. read followed by probing questions). The second two investigated content, using "think aloud," "card sort," and delayed recall tasks.</AbstractText>Those receiving a glossy leaflet expressed more positive attitudes and more interest in undergoing testing than those receiving a black and white leaflet, and those who were asked questions about what they had read were more positive about genetic testing than those who only read the leaflet. Recall one week later varied from 72% to 28%, depending on type of information. Information that described the advantages of genetic testing or discussed genes and genetic testing in relation to disease were well recalled and rated positively. Attitudes toward information ranged from 100% positive (e.g., what diseases genetic tests are available for) to 0% positive (e.g., the meaning of a positive result).</AbstractText>These results show that quite small changes within a leaflet can change attitudes toward genetic testing. This is of concern, given the association between attitudes toward a behavior and undergoing that behavior. The form, method of presentation, and content of genetic information leaflets should be evaluated for impact on attitude and decisions before they are used clinically.</AbstractText> |
2,339,486 | Genetic testing for alpha1-antitrypsin deficiency. | The Alpha Coded Testing Study investigated the risks, benefits, and psychological impact of home genetic testing for alpha1-antitrypsin deficiency.</AbstractText>In the study, 996 adult individuals requested and returned a home-administered, confidential, fingerstick blood test.</AbstractText>Individuals highly rated the benefits of establishing a diagnosis (82%), helping family members (86%), and anticipating peace of mind (79%). 78% of 239 current smokers reported a high likelihood of smoking cessation if diagnosed with AATD. After testing, more than 60% indicated that they would share the results with family and physicians but < 30% would share results with insurance companies.</AbstractText>Confidential home testing for genetic disorders requires a comprehensive program of participant support.</AbstractText> |
2,339,487 | Who seeks genetic susceptibility testing for Alzheimer's disease? Findings from a multisite, randomized clinical trial. | Alzheimer's disease, for which one form of the apolipoprotein E (APOE) genotype is a risk factor, provides a paradigm in which to examine response to susceptibility testing for common, complex diseases. This study's main purposes were to estimate interest in such testing and to examine demographic predictors of study participation.</AbstractText>In this 3-site, randomized clinical trial (RCT), the intervention was a risk assessment program wherein genetic counselors educated adult children of AD patients about lifetime risk of disease based on their gender, family history, and APOE genotype. Two groups of participants were followed from initial contact to RCT enrollment: those who were systematically contacted through research registries, and those who were self-referred.</AbstractText>Of 196 systematically contacted participants, 47, or 24%, progressed from initial contact to RCT enrollment. These participants were more likely to be below age 60 (adjusted OR = 3.83, P < 0.01) and college educated (adjusted OR = 3.48, P < 0.01). Of 179 self-referred participants, 115, or 64%, progressed from initial contact to RCT enrollment. Most self-referred participants had a college education and were female (79%).</AbstractText>In the first RCT to examine genetic susceptibility testing for AD, uptake rates were sufficiently high to merit concern that future test demand may strain available education and counseling resources. Findings suggest that susceptibility testing for AD may be of particular interest to women, college educated persons, and persons below age 60.</AbstractText> |
2,339,488 | Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. | Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a relatively common, underdiagnosed autosomal-dominant disorder of arteriovenous malformations and telangiectases. DNA testing for hereditary hemorrhagic telangiectasia has recently become available in North America, making presymptomatic screening available to relatives with a positive molecular diagnosis. This now enables practitioners to prevent catastrophic complications of undiagnosed pulmonary and CNS arteriovenous malformations and eliminates the need to radiographically screen all at-risk relatives shown to be unaffected by molecular testing. We review the clinical aspects of hereditary hemorrhagic telangiectasia, describe the indications, benefits, and limitations of molecular diagnostic testing for hereditary hemorrhagic telangiectasia, and provide a molecular genetics summary to facilitate genetic counseling before and after DNA testing for this complex disorder. |
2,339,489 | Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. | Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Oncogenes refer to those genes whose alterations cause gain-of-function effects, while tumor suppressor genes cause loss-of-function effects that contribute to the malignant phenotype. The effects of these alterations are complex due to the high number of changes in a typical case of breast cancer and the interactions of the biological pathways involved. This review focuses on the more common abnormalities in oncogenes and tumor suppressor genes in human breast cancer and their known associations with clinical outcome in terms of tumor classification, prognosis, and response to specific therapies. A better understanding of these relationships has led to new therapeutic applications. Agents that target oncogenes and their associated pathways are now in clinical use, with many more undergoing preclinical and clinical testing. The availability of antibodies, small synthetic molecules, cyotokines, gene therapy techniques, and even natural compounds that are screened for specific biological properties has greatly increased the number of candidate drugs. Nevertheless, clinical successes have been limited because of the redundancy of many cancer-related pathways as well as the high degree of variability in genotype and phenotype among individual tumors. Likewise, strategies to replace tumor suppressor gene functions face numerous technical hurdles. This review summarizes the current achievements and future prospects for the therapeutic targeting of oncogenes and tumor suppressor genes and new technology to better classify tumors and accurately predict responses to standard and novel agents. |
2,339,490 | Hereditary pancreatitis in a family of Aboriginal descent. | Hereditary pancreatitis is an autosomal dominant condition characterized by recurrent episodes of acute pancreatitis, usually starting in childhood. We present a family who was ascertained when an 11-year-old girl presented with an episode of acute pancreatitis. Her father and other family members had also had recurrent bouts of acute pancreatitis. Genetic testing revealed a pathogenic mutation in the cationic trypsinogen gene in the proband, her father and her paternal grandmother. As far as we are aware, this is the first Aboriginal kindred with mutation-proven hereditary pancreatitis. Hereditary pancreatitis is an important differential diagnosis to consider in a patient with recurrent episodes of acute pancreatitis with no obvious precipitating cause. This family is of Aboriginal descent and the implications of the family's background are also discussed when considering the aetiology of the condition. We emphasize the need to ascertain a full family history from patients with a history of repeated episodes of acute pancreatitis and also emphasize the need to avoid ethnic stereotypes when assessing patients. |
2,339,491 | Genetic diversity in German draught horse breeds compared with a group of primitive, riding and wild horses by means of microsatellite DNA markers. | We compared the genetic diversity and distance among six German draught horse breeds to wild (Przewalski's Horse), primitive (Icelandic Horse, Sorraia Horse, Exmoor Pony) or riding horse breeds (Hanoverian Warmblood, Arabian) by means of genotypic information from 30 microsatellite loci. The draught horse breeds included the South German Coldblood, Rhenish German Draught Horse, Mecklenburg Coldblood, Saxon Thuringa Coldblood, Black Forest Horse and Schleswig Draught Horse. Despite large differences in population sizes, the average observed heterozygosity (H(o)) differed little among the heavy horse breeds (0.64-0.71), but was considerably lower than in the Hanoverian Warmblood or Icelandic Horse population. The mean number of alleles (N(A)) decreased more markedly with declining population sizes of German draught horse breeds (5.2-6.3) but did not reach the values of Hanoverian Warmblood (N(A) = 6.7). The coefficient of differentiation among the heavy horse breeds showed 11.6% of the diversity between the heavy horse breeds, as opposed to 21.2% between the other horse populations. The differentiation test revealed highly significant genetic differences among all draught horse breeds except the Mecklenburg and Saxon Thuringa Coldbloods. The Schleswig Draught Horse was the most distinct draught horse breed. In conclusion, the study demonstrated a clear distinction among the German draught horse breeds and even among breeds with a very short history of divergence like Rhenish German Draught Horse and its East German subpopulations Mecklenburg and Saxon Thuringa Coldblood. |
2,339,492 | Down syndrome with an unusual etiology: case report and review. | To present the genetic etiology of an unusual case of Down syndrome, arising from translocation of chromosome 21 to chromosome 9; to discuss advanced genetic diagnostic techniques, focusing on how pinpointing a specific genetic mistake can influence treatment and outcome; and to review the role of the nurse practitioner (NP) in caring for families of children with Down syndrome.</AbstractText>Case report, literature review, and advanced genetic techniques.</AbstractText>NPs often answer patient questions regarding genetic abnormalities and risk factors for transmission of genetic errors to offspring. Advanced genetic analysis allows for the diagnosis of unusual causes of common genetic disorders. The ability to identify a specific genetic mistake and to predict the scope of its effect on an individual offers health care providers the opportunity to develop a case-by-case plan of care.</AbstractText>NPs have a responsibility to be informed about the processes involved in the transmission of genetic errors and about the subtleties of various expressions of a genetic disorder. The availability of new genetic-testing techniques allows NPs to individualize patient care and family teaching.</AbstractText> |
2,339,493 | [Cancer genetic counseling as it pertains to gynaecologic oncology: general considerations in hereditary tumors]. | One of the most remarkable discoveries during the last two decades is that cancer is a genetic disease, which develops in a stepwise fashion including many gene mutations. The nature of hereditary tumours has also been elucidated, with recognised inherited germline gene mutations predisposing cancer development. These are called cancer susceptibility gene mutations and mostly involve tumour suppressor genes, occasionally oncogenes, genes of the apoptosis pathway and DNA repair. As a result, cancer genetic counselling centres have been established with the objectives of identifying persons at high-risk for cancer development. In addition, activities of these centres may involve applied genetics, mostly in research setting. The major steps in cancer genetic counselling in terms of hereditary tumours include: 1. identifying at risk patients, e.g. gene mutation carriers, 2. proper counselling with full information regarding the benefits and disadvantages of DNA testing, and 3. preventive measures including screening, early detection and prophylactic surgery, drug treatment etc. In this review, the natural history and clinical characteristics of hereditary tumours are outlined, as well as, the major considerations of cancer genetic counselling are discussed. |
2,339,494 | Pharmacogenomics in breast cancer: current trends and future directions. | Pharmacogenomics is the study of genetic variations between individuals to predict the risk of toxic side effects and the probability that a patient will respond to single- or multidrug chemotherapy. Breast cancer remains one of the most common cancers among women worldwide and is second only to lung cancer in cancer-related death. A better understanding of the mechanisms of initiation and progression of breast cancer is needed for early diagnosis and development of better therapeutic methodologies. Differences in cancer patients' responses to chemotherapy have often been attributed to pathogenesis and severity of the disease, drug interactions, patient's age, gender, nutritional status, organ functions and tumor biology. It is now well recognized that genetic variations in drug target genes, disease pathway genes and drug metabolizing enzymes can have greater influence on drug efficacy and toxicity. In addition, germline variants can be used to study breast cancer susceptibility, as well as the variable response to both drug and radiation therapy used in the treatment of breast cancer. This review discusses clinically relevant individual gene variations that influence breast cancer susceptibility and cancer therapy, as well as the microarray-based expression profiling studies that have great potential in cancer pharmacogenomics in terms of tumor classification, drug and biomarker discovery and drug efficacy testing. |
2,339,495 | Survey of colorectal cancer screening practices in a large Canadian urban centre. | Colorectal carcinoma (CRC) is an ideal tumour for population-based screening policies. Screening guidelines are based on differing levels of evidence and opinion. The objective of this study was to determine current CRC screening practices in Alberta.</AbstractText>A questionnaire was mailed to all family physicians, gastroenterologists, general and colorectal surgeons, and general internal medicine specialists in a large Canadian urban centre. Results tabulated included response rate, specialty, presence/absence of a screening policy, and policy type.</AbstractText>The 922 surveys mailed resulted in a 61% response rate. Among the responses, 58% (95% confidence interval [CI] 53.6%-62.6%) of physicians recommended screening to healthy individuals without a family history of CRC, and 96% (CI 94.7%-98%; p < 0.0001) to those with a family history. For patients without a family history of CRC, the majority of physicians chose the age of 50 to initiate screening (63%) by fecal occult blood testing (79%) or, less frequently, colonoscopy (26%). Screening frequency varied by the modality used. In individuals with a family history of CRC, most physicians initiated screening prior to the index case (45%) or by age 40 (31%), mostly with colonoscopy (84%); screening frequency varied mainly by modality.</AbstractText>Despite the evidence supporting CRC screening in all persons at average risk, only 58% of physicians currently recommend screening to patients with no family history of CRC. Fecal occult blood testing was recommended most frequently in this subgroup, whereas most physicians screen people with a family history of CRC via colonoscopy, suggesting that they believe it to be a superior screening modality. As this looks to be the trend in practice, a randomized controlled trial comparing fecal occult testing with screening colonoscopy is needed.</AbstractText> |
2,339,496 | Clinical presentation of 13 patients with subtelomeric rearrangements and a review of the literature. | To re-examine the potential clinical indications for subtelomeric FISH testing and to provide additional cases to the growing literature on subtelomeric abnormalities and their genotype-phenotype correlations, we present a single center case series of 13 patients with chromosomal abnormalities detected by subtelomeric FISH testing over a 21 month period. The most common abnormality involved chromosome 1p (23%). Partial monosomy was present in 69% of the patients, complex rearrangements in 23%, and partial trisomy in 8%. The mean time from first normal karyotype to positive subtelomeric FISH result was 3.8 years (n = 11, median 3.5 years, range: 6 months-10 years). One patient had an abnormal high resolution karyotype recognized retrospectively, and two other patients had abnormal karyotypes that were fully deciphered only after subtelomeric FISH analysis. Eighty five percent of cases occurred de novo. The subtelomeric FISH results were useful for adjusting the recurrence risks and helping to focus medical screening and monitoring. The results impacted family planning and satisfied families in search of a diagnosis. Our findings support the use of subtelomeric FISH analysis as a second tier test in patients suspected of having a chromosomal abnormality with a normal karyotype. Potential benefits of subtelomeric FISH testing include faster time to diagnosis, better informed patient prognosis, and more accurate genetic counseling. |
2,339,497 | Breast cancer genetics: unsolved questions and open perspectives in an expanding clinical practice. | Breast cancer is the most common cause of cancer death in the United Kingdom, with a lifetime risk of one in nine in women. Only 5-10% of all cancers is thought to be due to strongly penetrant inherited predisposing genes, such as BRCA1 and BRCA2. However, other less penetrant genes, including some autosomal recessive genes, are likely to be of etiological importance in other families. This review addresses the current knowledge of breast cancer susceptibility genes and explores the possibilities for future developments. Features of tumor pathology, prognosis, and the scope for targeted treatments in mutation carriers are discussed, and the management of known carriers and those at increased risk for developing breast cancer are evaluated. Genetic testing for cancer susceptibility may become widely available in the future, and has important ethical and management implications. |
2,339,498 | Adult height distribution in subjects born small for gestational age. | The aim of the study was to investigate the post-natal growth of subjects born small for gestational age (SGA) by describing adult height distribution and by testing the effects of parental, neonatal and pregnancy-related parameters on the risk for adult short stature. The study population was made of adults selected on birth data from a maternity registry and born either small (SGA, n = 734, birth weight < 10th percentile) or appropriate for gestational age (AGA, n = 886, 25th < birth weight < 75th percentile) in whom anthropometric parameters were measured at 22 years of age. The SGA group demonstrated significantly reduced body size in comparison to the AGA group with a mean loss of 0.7 standard deviation (SD) in adult height. The frequency of adult short stature (< -2 SD) was 10.3% in the SGA group vs. 2.4% in the AGA group (p = 0.0001), adult height < -2.5 SD was observed in only 3.7% of the SGA group. Maternal (OR = 0.31 (0.16-0.62), p = 0.0001) and paternal (OR = 0.45 (0.31-0.67), p = 0.0001) heights and subjects birth length (OR = 0.78 (0.62-0.99), p = 0.04) significantly influenced the risk of adult short stature. In summary, post-natal growth defect remains moderate in the majority of subjects born SGA and < 4% only will end up with severe short stature requiring GH therapy according to most current recommendations. The role of parental height and birth length suggests that adult short stature in SGA subjects results at least in some cases from a familial and likely genetic growth disorder with antenatal onset. |
2,339,499 | Reconstructing phylogeny by quadratically approximated maximum likelihood. | Maximum likelihood (ML) for phylogenetic inference from sequence data remains a method of choice, but has computational limitations. In particular, it cannot be applied for a global search through all potential trees when the number of taxa is large, and hence a heuristic restriction in the search space is required. In this paper, we derive a quadratic approximation, QAML, to the likelihood function whose maximum is easily determined for a given tree. The derivation depends on Hadamard conjugation, and hence is limited to the simple symmetric models of Kimura and of Jukes and Cantor. Preliminary testing has demonstrated the accuracy of QAML is close to that of ML. |
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