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2,338,500 |
Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study.
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Efavirenz is an effective antiretroviral agent, but central nervous system side effects occur commonly, and population (racial) differences in pharmacokinetics and response have been reported. Efavirenz is metabolized by cytochrome P4502B6 (CYP2B6). We investigated whether polymorphisms in CYP2B6, CYP3A4, CYP3A5, and MDR1 were associated with efavirenz central nervous system side effects and pharmacokinetics.</AbstractText>Twenty-four week cohort from a randomized study.</AbstractText>Adult AIDS Clinical Trials Group study A5097s examined relationships between central nervous system side effects and efavirenz plasma concentration-time profiles in HIV-infected subjects. Efavirenz plasma pharmacokinetics were estimated by a population-based method. Central nervous system symptoms were assessed by questionnaires and neuropsychological testing.</AbstractText>Study subjects included 89 (57%) European-Americans, 50 (32%) African-Americans, and 15 (10%) Hispanics. The CYP2B6 T/T genotype at position 516 (GlnHis) was more common in African-Americans (20%) than in European-Americans (3%), and was associated with greater efavirenz plasma exposure (P < 0.0001). The median efavirenz [area-under-the-curve] (0-24 h) according to G/G, G/T, and T/T genotype was 44 (n = 78), 60 (n = 60), and 130 (n = 14) mug.h/ml, respectively (P < 0.0001). The CYP2B6 G516T genotype was also associated with central nervous system symptoms at week 1 (P = 0.036). Analysis of DNA from other subjects confirmed population differences in frequency of the G516T variant. No associations were apparent with the other polymorphisms studied.</AbstractText>A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater efavirenz plasma exposure during HIV therapy. Inter-individual differences in metabolism may, in part, explain susceptibility to efavirenz central nervous system side effects.</AbstractText>
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2,338,501 |
Safety and immunogenicity of adenovirus-vectored nasal and epicutaneous influenza vaccines in humans.
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The increasing number and density of the human population, the emergence of lethal influenza strains, and the potential use of designer influenza virus as a bioweapon, collectively highlight a critical need for more rapid production of influenza vaccines and less invasive means of delivery. We have developed a nonreplicative adenovirus-vectored influenza vaccine that can be produced without the prerequisite of growing influenza virus. This new class of vaccines can be administered as a nasal spray or skin patch by personnel without medical training. We report here that adenovirus-vectored nasal and epicutaneous influenza vaccines were well tolerated by human volunteers. The nasal vaccine was more potent than its epicutaneous counterpart under the adjuvant-free experimental condition. These results provide the foundation for further human testing of needleless vectored vaccines as promising alternatives to current vaccines.
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2,338,502 |
Populational genetic structure of free-living maned wolves (Chrysocyon brachyurus) determined by proteic markers.
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Electrophoretic analysis of presumptive twenty gene loci products was conducted in hemolisates and plasma samples of twenty-eight maned wolves (Chrysocyon brachyurus) from an area in northeastern São Paulo State, Brazil. The area sampled was divided into three sub-areas, with the Mogi-Guaçu and Pardo rivers regarded as barriers to the gene flow. The polymorphism degree and heterozygosity level (intralocus and average) estimated in this study were similar to those detected by other authors for maned wolves and other species of wild free-living canids. The samples of each sub-area and the total sample exhibited genotype frequencies consistent with the genetic equilibrium model. The values of the F-statistics evidenced absence of inbreeding and population subdivision and, consequently, low genetic distances were found among the samples of each area.
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2,338,503 |
Visualizing the laboratory mouse: capturing phenotype information.
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A concerted effort to develop myriad new phenotypic alleles through mutagenesis programs presents new challenges for the biomedical community and for the informatics infrastructure needed to support this work. To handle and co-ordinate large programs of treatment, breeding, and sequential or longitudinal testing for a variety of obvious and subtle traits requires sophisticated data management software. Further, trait analyses, heritability testing, and animal availability and status must be captured and disseminated to the wider community. The Mouse Genome Database (MGD) will serve as the central integration point for the various mutagenesis programs, registering new alleles, providing accession identifiers, and capturing phenotypic descriptions. In addition, MGD will provide public access to unified searches over all alleles with links to the centres of origin for detailed testing data.
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2,338,504 |
Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD.
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Using a classical twin design study, we estimated the genetic contribution to liability of wrist fracture in women to be statistically and clinically significant. BMD is highly heritable, but statistical models showed very little overlap of shared genes between the two traits.</AbstractText>Studies have observed contradictory evidence for genetic effects influencing the outcome of osteoporotic fracture, in part because of the methodological problems involved in analyzing age-related "censored" outcomes. Although a shared genetic etiology is often assumed between fracture and low BMD, this has not been shown to be the case.</AbstractText>In a study of 6570 white healthy female volunteer twins between 18 and 80 years of age, we identified and validated 220 nontraumatic wrist fracture cases. From this we estimated the population prevalence, case-wise twin concordance, heritability in liability to wrist fracture (WF), and the genetic contribution to WFs controlling for age by analyzing the survival outcome using generalized linear mixed models implemented in Winbugs software. We included forearm BMD as a co-variate in some of the models to test whether there is a shared genetic etiology between WFs and BMD.</AbstractText>The prevalence of WFs in women was estimated to be 3.3% with a case-wise concordance in monozygotic twins of 0.28 and 0.11 in dizygotic twins. The additive polygenic heritability in liability was approximately 54%, and a significant genetic etiology was confirmed by analyzing WFs as a survival outcome. The magnitude of the genetic influence on risk of WFs reduced very little when BMD was included as a co-variate in the survival analysis model.</AbstractText>There is an important genetic contribution to the risk of WFs, but for the most part, these genes are unlikely to play a direct etiological role in the development of low BMD. If these results are confirmed for other sites, fracture and low BMD will have their own specific genetic risk factors that are unlikely to be shared between the two traits. This has important clinical and research implications.</AbstractText>
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2,338,505 |
Improved statistical tests for differential gene expression by shrinking variance components estimates.
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Combining information across genes in the statistical analysis of microarray data is desirable because of the relatively small number of data points obtained for each individual gene. Here we develop an estimator of the error variance that can borrow information across genes using the James-Stein shrinkage concept. A new test statistic (FS) is constructed using this estimator. The new statistic is compared with other statistics used to test for differential expression: the gene-specific F test (F1), the pooled-variance F statistic (F3), a hybrid statistic (F2) that uses the average of the individual and pooled variances, the regularized t-statistic, the posterior odds statistic B, and the SAM t-test. The FS-test shows best or nearly best power for detecting differentially expressed genes over a wide range of simulated data in which the variance components associated with individual genes are either homogeneous or heterogeneous. Thus FS provides a powerful and robust approach to test differential expression of genes that utilizes information not available in individual gene testing approaches and does not suffer from biases of the pooled variance approach.
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2,338,506 |
Strategies and methods for research on sex differences in brain and behavior.
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Female and male brains differ. Differences begin early during development due to a combination of genetic and hormonal events and continue throughout the lifespan of an individual. Although researchers from a myriad of disciplines are beginning to appreciate the importance of considering sex differences in the design and interpretation of their studies, this is an area that is full of potential pitfalls. A female's reproductive status and ovarian cycle have to be taken into account when studying sex differences in health and disease susceptibility, in the pharmacological effects of drugs, and in the study of brain and behavior. To investigate sex differences in brain and behavior there is a logical series of questions that should be answered in a comprehensive investigation of any trait. First, it is important to determine that there is a sex difference in the trait in intact males and females, taking into consideration the reproductive cycle of the female. Then, one must consider whether the sex difference is attributable to the actions of gonadal steroids at the time of testing and/or is sexually differentiated permanently by the action of gonadal steroids during development. To answer these questions requires knowledge of how to assess and/or manipulate the hormonal condition of the subjects in the experiment appropriately. This article describes methods and procedures to assist scientists new to the field in designing and conducting experiments to investigate sex differences in research involving both laboratory animals and humans.
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2,338,507 |
Genetic consequences of many generations of hybridization between divergent copepod populations.
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Crosses between populations of the copepod Tigriopus californicus typically result in outbreeding depression. In this study, replicate hybrid populations were initiated with first generation backcross hybrids between two genetically distinct populations from California: Royal Palms (RP) and San Diego (SD). Reciprocal F(1) were backcrossed to SD, resulting in expected starting frequencies of 25% RP/75% SD nuclear genes on either a pure RP cytoplasmic or a pure SD cytoplasmic background. After 1 year of hybridization (up to 15 generations), seven microsatellite loci were scored in two replicates on each cytoplasmic background. Frequencies of the rarer RP alleles increased significantly in all four replicates, regardless of cytoplasmic source, producing a mean hybridity of 0.97 (maximum = 1), instead of the expected 0.50. Explicit tests for heterozygote excess across loci and replicates showed significant deviations. Only the two physically linked markers showed linkage disequilibrium in all replicates. Subsequent fitness assays in parental populations and early generation hybrids revealed lower fitness in RP than SD, and significant F(2) breakdown. Computer simulations showed that selection must be invoked to explain the shift in allele frequencies. Together, these results suggest that hybrid inferiority in early generations gave way to hybrid superiority in later generations.
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2,338,508 |
On the estimation of genome-wide heterozygosity using molecular markers.
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Coltman and Slate (2003) recently performed a meta-analysis on studies that investigated the association between genetic variation at microsatellite loci and phenotypic trait variation. One factor not explicitly addressed in their meta-analysis is the actual estimation of genome-wide heterozygosity via molecular markers. Many authors still associate marker-estimated heterozygosity with genome-wide heterozygosity, despite allozyme-based evidence that such correlations are usually very weak or nonexistent. Here, we show that genome-wide heterozygosity is poorly estimated not only by allozymes but also by microsatellite loci and by single-nucleotide polymorphisms (SNPs). Thus, associations between fitness (or other phenotypes) and heterozygosity should be established firmly on causative factors and not on simple correlations.
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2,338,509 |
Psychiatric and neuropsychological characterization of Pallister-Hall syndrome.
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Pallister-Hall syndrome (PHS) is a rare, single-gene, malformation syndrome that includes central polydactyly, hypothalamic hamartoma, bifid epiglottis, endocrine dysfunction, and other anomalies. The syndrome has variable clinical manifestations and is inherited in an autosomal dominant pattern. We sought to determine whether psychiatric disorders and/or neuropsychological impairment were characteristic of PHS. We prospectively conducted systematic neuropsychiatric evaluations with 19 PHS subjects ranging in age from 7 to 75 years. The evaluation included detailed clinical interviews, clinician-rated and self-report instruments, and a battery of neuropsychological tests. Seven of 14 adult PHS subjects met diagnostic criteria for at least one DSM-IV Axis I disorder. Three additional subjects demonstrated developmental delays and/or neuropsychological deficits on formal neuropsychological testing. However, we found no characteristic psychiatric phenotype associated with PHS, and the frequency of each of the diagnoses observed in these subjects was not different from that expected in this size sample. The overall frequency of psychiatric findings among all patients with PHS cannot be compared to point prevalence estimates of psychiatric disease in the general population because of biased ascertainment. This limitation is inherent to the study of behavioral phenotypes in rare disorders. The general issue of psychiatric evaluation of rare genetic syndromes is discussed in light of this negative result.
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2,338,510 |
FMR1 alleles in Tasmania: a screening study of the special educational needs population.
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The distribution of fragile X mental retardation-1 (FMR1) allele categories, classified by the number of CGG repeats, in the population of Tasmania was investigated in 1253 males with special educational needs (SEN). The frequencies of these FMR1 categories were compared with those seen in controls as represented by 578 consecutive male births. The initial screening was based on polymerase chain reaction analysis of dried blood spots. Inconclusive results were verified by Southern analysis of a venous blood sample. The frequencies of common FMR1 alleles in both samples, and of grey zone alleles in the controls, were similar to those in other Caucasian populations. Consistent with earlier reports, we found some (although insignificant) increase of grey zone alleles in SEN subjects compared with controls. The frequencies of predisposing flanking haplotypes among grey zone males FMR1 alleles were similar to those seen in other Caucasian SEN samples. Contrary to expectation, given the normal frequency of grey zone alleles, no premutation (PM) or full mutation (FM) allele was detected in either sample, with only 15 fragile X families diagnosed through routine clinical admissions registered in Tasmania up to 2002. An explanation of this discrepancy could be that the C19th founders of Tasmania carried few PM or FM alleles. The eight to ten generations since white settlement of Tasmania has been insufficient time for susceptible grey zone alleles to evolve into the larger expansions.
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2,338,511 |
Assessing ethnicity in preconception counseling: genetics--what nurse practitioners need to know.
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To define and discuss five genetic disorders--Tay-Sachs, sickle cell anemia, Canavan's disease, thalassemia, and cystic fibrosis (CF)--and to explain the importance of the nurse practitioner's (NP's) assessment of clients' ethnicity during preconception counseling, which should address these genetic conditions.</AbstractText>Review of literature from professional journals, professional organizations' Web sites, guidelines from the American College of Obstetricians and Gynecologists, the National Institute of Health Consensus Statement, and the authors' professional clinical experience.</AbstractText>The goal of preconception counseling is to identify potential or actual medical, psychological, or social conditions that may affect the mother or fetus. NPs are often the health care providers that initiate preconception counseling to women in varied primary care settings. NPs must be familiar with ethnicity-related inheritable conditions in order to provide appropriate client information and education and to implement testing and, when needed, referral for genetic counseling to individuals and families at risk for genetic disorders such as Tay-Sachs, Canavan's disease, CF, sickle cell anemia, and thalassemia.</AbstractText>NPs providing health care to women of child-bearing age should assess the client's use of contraception and intent for future pregnancy. Preconception counseling when indicated should be initiated to all women to increase their potential for healthy pregnancy outcomes. Although a comprehensive personal, family, medical, and psychosocial history and initiation of folic acid are the mainstays of preconception counseling, assessment for risk of ethnicity-related genetic conditions must also be included in prepregnancy health care.</AbstractText>
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2,338,512 |
Identification of differentially regulated genes during elongation and early implantation in the ovine trophoblast using complementary DNA array screening.
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Following hatching, pre-elongated conceptuses undergo elongation by intense proliferation, until implantation. We investigated the changes in gene expression associated with these physiological events using human cDNA arrays containing 2370 known genes. Comparison of pre-elongated, elongated, and implanting trophoblasts allowed the determination of 313 expressed genes, 63 of which were differentially regulated. These were classified into four functional families. Pre-elongated trophoblasts were characterized by preferential expression of genes involved in protein trafficking, whereas only latter developmental stages expressed cell signaling genes and receptors. Among the 63 developmentally regulated genes, four exhibited the highest levels of expression (TMSB10, CTNNA1, NMP1, and CX3CL1). Each of these also represents a functional family and display a specific expression pattern. One of them, CX3CL1 (CX3C chemokine, also known as fractalkine), is a chemokine that seems to have potential importance in trophoblast development, and which deserves further clarification of its role in implantation.
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2,338,513 |
Heritability of insulin secretion, peripheral and hepatic insulin action, and intracellular glucose partitioning in young and old Danish twins.
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The etiology of type 2 diabetes is multifactorial, including genetic as well as pre- and postnatal factors that influence several different defects of glucose homeostasis, primarily in muscle, beta-cells, and liver. In the present twin study, we report heritability estimates (h(2)) for measures of insulin secretion, insulin resistance, hepatic glucose production (HGP), and intracellular glucose partitioning using gold standard methods (euglycemic-hyperinsulinemic clamp technique, tritiated glucose infusion, indirect calorimetry, and intravenous glucose tolerance testing) among 110 younger (22-31 years of age) and 86 older (57-66 years of age) twins. To obtain a valid estimate of beta-cell function, insulin secretion was adjusted for the individual degree of insulin action (disposition index). In both age-groups there was a major genetic component in the etiology of insulin secretion that was statistically significantly higher among older twins (young h(2) = 0.75 [0.55-0.86] and old h(2) = 0.84 [0.69-0.92], P < 0.05). The heritability estimates for peripheral insulin sensitivity (young h(2) = 0.53 [0.28-0.71] and old h(2) = 0.55 [0.20-0.76]) and nonoxidative glucose metabolism (young h(2) = 0.50 [0.32-0.64] and old h(2) = 0.48 [0.04-0.72]) were similar in younger and older twins, supporting the notion of both genetic and environmental etiological factors in the control of insulin action and nonoxidative glucose metabolism. The results suggested that HGP was predominantly controlled by nongenetic factors in both young and old twins. In conclusion, we provide further evidence for a role of genes in controlling insulin secretion, insulin action, and nonoxidative glucose metabolism. The relative contribution of genes versus environment on in vivo insulin secretion exhibited an age dependency with a slightly greater relative impact of genes among older as compared with younger twins.
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2,338,514 |
Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation.
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The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited ante-mortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were -35.2 ml/year (3.23% decrease per year) and +20.75 ml/year (16.93% increase per year) for the proband, and -30.75 ml/year (2.77% decrease per year) and +5.01 ml/year (3.11% increase per year) for the proband's sister. In conclusion, the mutation in these siblings may have arisen during oogenesis in the mother and probably represents germline mosaicism. Although both patients have exhibited the typical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsychological profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain volume and ventricular volume between the two patients are quite different. These findings have implications for future drug trial development in FTDP-17 and the sporadic tauopathies.
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2,338,515 |
Medical management of childhood hearing loss.
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Hearing loss in children is common. Advances in the identification of infectious diseases at birth or in utero, genetic testing, and diagnostic imaging now permit many infants and children to be identified and treated sooner. Treatment and rehabilitation should be instituted early so that the effects of hearing loss on communication are minimized and the child's social and academic skills maximized. CHL can usually be managed medically or surgically with subsequent return to normal or near normal hearing. Children with SNHL, and their future hearing will benefit from new antiviral agents, less antibiotics, ototoxic more focused chemotherapy, and possibly genetic therapy. Digital and programmable hearing aids, more accessible FM systems, cochlear implants, and bone-anchored hearing aids provide significant rehabilitation potential for children with even very significant hearing losses. Early identification and prevention, however, remain the best strategies to combat hearing loss in children.
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2,338,516 |
Genomewide scan for affective disorder susceptibility Loci in families of a northern Swedish isolated population.
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We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers approximately 8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) >/=2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples approximately 10 generations ago. In this approximately 10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region.
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2,338,517 |
The strength of indecisiveness: oscillatory behavior for better cell fate determination.
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Oscillatory behavior is very common in many cellular responses. Recently, two pathways involved in response to cell stress, the p53 and nuclear factor kappa B signaling pathways, have been found to show oscillatory behavior. At first sight, there would seem to be no reason for signaling pathways of this type to require oscillations. Recent single-cell studies indicate that oscillatory behavior may be used to allow repeated testing for the continued existence of a signal. I argue that oscillations increase cellular response sensitivity and flexibility by allowing the cell to integrate the results of many periodical evaluations of the signal before making an eventual decision about cell fate, thus reducing the risk of premature commitment.
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2,338,518 |
Methodological aspects of the genetic dissection of gene expression.
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Dissection of the genetics underlying gene expression utilizes techniques from microarray analyses as well as quantitative trait loci (QTL) mapping. Available QLT mapping methods are not tailored for the highly automated analyses required to deal with the thousand of gene transcripts encountered in the mapping of QTL affecting gene expression (sometimes referred to as eQTL). This report focuses on the adaptation of QTL mapping methodology to perform automated mapping of QTL affecting gene expression.</AbstractText>The analyses of expression data on > 12,000 gene transcripts in BXD recombinant inbred mice found, on average, 629 QTL exceeding the genome-wide 5% threshold. Using additional information on trait repeatabilities and QTL location, 168 of these were classified as 'high confidence' QTL. Current sample sizes of genetical genomics studies make it possible to detect a reasonable number of QTL using simple genetic models, but considerably larger studies are needed to evaluate more complex genetic models. After extensive analyses of real data and additional simulated data (altogether > 300,000 genome scans) we make the following recommendations for detection of QTL for gene expression: (1) For populations with an unbalanced number of replicates on each genotype, weighted least squares should be preferred above ordinary least squares. Weights can be based on repeatability of the trait and the number of replicates. (2) A genome scan based on multiple marker information but analysing only at marker locations is a good approximation to a full interval mapping procedure. (3) Significance testing should be based on empirical genome-wide significance thresholds that are derived for each trait separately. (4) The significant QTL can be separated into high and low confidence QTL using a false discovery rate that incorporates prior information such as transcript repeatabilities and co-localization of gene-transcripts and QTL. (5) Including observations on the founder lines in the QTL analysis should be avoided as it inflates the test statistic and increases the Type I error. (6) To increase the computational efficiency of the study, use of parallel computing is advised. These recommendations are summarized in a possible strategy for mapping of QTL in a least squares framework.</AbstractText>The software used for this study is available on request from the authors.</AbstractText>
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2,338,519 |
Human immunodeficiency virus type 1 clade B superinfection: evidence for differential immune containment of distinct clade B strains.
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Sequential infection with different strains of human immunodeficiency virus type 1 (HIV-1) is a rarely identified phenomenon with important implications for immunopathogenesis and vaccine development. Here, we identify an individual whose good initial control of viremia was lost in association with reduced containment of a superinfecting strain. Subject 2030 presented with acute symptoms of HIV-1 infection with high viremia and an incomplete seroconversion as shown by Western blotting. A low set point of viremia (approximately 1,000 HIV-1 copies/ml) was initially established without drug therapy, but a new higher set point (approximately 40,000 HIV-1 copies/ml) manifested about 5 months after infection. Drug susceptibility testing demonstrated a multidrug-resistant virus initially but a fully sensitive virus after 5 months, and an analysis of pol genotypes showed that these were two phylogenetically distinct strains of virus (strains A and B). Replication capacity assays suggested that the outgrowth of strain B was not due to higher fitness conferred by pol, and env sequences indicated that the two strains had the same R5 coreceptor phenotype. Delineation of CD8+-T-lymphocyte responses against HIV-1 showed a striking pattern of decay of the initial cellular immune responses after superinfection, followed by some adaptation of targeting to new epitopes. An examination of targeted sequences suggested that differences in the recognized epitopes contributed to the poor immune containment of strain B. In conclusion, the rapid overgrowth of a superinfecting strain of HIV-1 of the same subtype raises major concerns for effective vaccine development.
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2,338,520 |
Neutralizing antibodies elicited by immunization of monkeys with DNA plasmids and recombinant adenoviral vectors expressing human immunodeficiency virus type 1 proteins.
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Immunization with recombinant serotype 5 adenoviral (rAd5) vectors or a combination of DNA plasmid priming and rAd5 boosting is known to elicit potent immune responses. However, little data exist regarding these immunization strategies and the development of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies. We used DNA plasmids and rAd5 vectors encoding the HIV-1 89.6P or chimeric HxB2/BaL envelope glycoprotein to immunize macaque monkeys. A single rAd5 immunization elicited anti-Env antibody responses, but there was little boosting with subsequent rAd5 immunizations. In contrast, rAd5 boosting of DNA-primed monkeys resulted in a rapid rise in antibody titers, including the development of anti-HIV-1 neutralizing antibodies. The potency and breadth of neutralization were evaluated by testing plasma against a panel of 14 clade B primary isolates. Moderate levels of plasma neutralizing activity were detected against about one-third of the viruses tested, and immunoglobulin G fractionation demonstrated that virus neutralization was antibody mediated. After a challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P), an anamnestic neutralizing antibody response was observed, although the breadth of the response was limited to the subset of viruses that were neutralized after the primary immunization. These data are the first detailed description of the anti-HIV-1 neutralizing antibody response in nonhuman primates elicited by DNA and rAd5 immunization. In addition to the well-established ability of DNA priming and rAd5 boosting to elicit potent anti-HIV-1 cellular immune responses, this immunization strategy elicits anti-HIV-1 neutralizing antibodies and therefore can be used to study novel Env immunogens designed to elicit more potent neutralizing antibodies.
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2,338,521 |
The current clinical value of genomic instability.
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Clinical Oncologists have largely ignored the debate over genetic instability in human cancers. It is clear that genetic lesions themselves provide valuable information in the treatment of patients with cancer and those genetic lesions can be exploited successfully as therapeutic targets. Whether the mechanisms resulting in the accumulation of genetic lesions can be translated and used clinically remains to be seen.
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2,338,522 |
MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study.
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Elevated homocysteine level is an independent risk factor for ischemic stroke, thrombotic and cardiovascular diseases. The enzyme methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating the levels of homocysteine. A C677T mutation in this gene results in reduced activity. Sixty-nine patients with arterial stroke, six patients with venous stroke (confirmed by computed tomography and/or magnetic resonance imaging) with hyperhomocysteinemia were selected for the study. Forty-nine subjects with no past history of stroke served as controls. MTHFR genotypes were determined by PCR using specific primers, followed by restriction digestion and gel analysis. The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the patients with arterial stroke was 1.4% (one of 69) and 31.88% (21 of 69), respectively. There frequency was 16.6% (one of six) and 33.3% (two of six) in venous stroke. The genotyping results from controls showed that there was only one heterozygote out of the 49 studied (2.08%). There was a significant difference between the control and the patient groups. Odds ratio for the probability of the C677T MTHFR gene mutation in the patients versus control group was 22.29 (95% CI 4.89-98.8). This indicates that C677T MTHFR mutation is strongly associated with arterial stroke especially in young adults. MTHFR allele evaluation will help in preventing/reducing morbidity caused by stroke.
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2,338,523 |
Optic neuritis, multiple sclerosis and human leukocyte antigen: results of a 4-year follow-up study.
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In the present study the relation between human leukocyte antigen (HLA), optic neuritis (ON) and multiple sclerosis (MS) has been investigated in 56 Iranian patients (46 females and 10 males). HLA-A and -B typing by microlymphocytotoxicity method and HLA-DRB, DQA and DQB by polymerase chain reaction based on sequence specific primers method was performed for the selected patients with ON. The diagnosis of clinically defined MS (CDMS) was confirmed in 15 of them (26.7%) during their follow-up. HLA-A24 was significantly higher in ON patients, whilst A23, A26, and A30 showed a significant decrease in these patients. HLA-A10 and A26 were absent in CDMS patients and A2 and A11 were significantly decreased in ON and CDMS patients. HLA-B5, B51, B38, B27, and B35 were significantly increased in ON patients compared with control subjects. HLA-B44, B16 and B38 alleles were not present in CDMS patients. Regarding DR locus, the frequency of HLA-DRB1*15 and DRB1*04 has been increased in CDMS patients, whilst the frequency of HLA-DRB1*07 and *11 was much higher in ON patients. In DQA region, the most frequent allele in the MS patients was DQA1*0102, which was significantly higher than ON patients, and control group. The frequency of DQA1*0103 was significantly increased in both patients group. In DQB1, the frequency of DQB1*0602 increased significantly in the MS patients. In conclusion existence of common genetic basis for early manifestations of MS could be suggested.
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2,338,524 |
HLA class II allele typing using DNA obtained from human fingernail clipping material.
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Obtaining deoxyribonucleic acid (DNA), is the starting point for most genetic analysis. Nail material constitutes a source of DNA of easy access. This communication reports DNA extraction from fresh nail clipping material, by a combined extraction method, and its use in the typing of HLA-class II genes. Nail clipping material can be considered a convenient material for genetic analysis.
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2,338,525 |
The history of a nearctic colonization: molecular phylogenetics and biogeography of the Nearctic toads (Bufo).
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Previous hypotheses of phylogenetic relationships among Nearctic toads (Bufonidae) and their congeners suggest contradictory biogeographic histories. These hypotheses argue that the Nearctic Bufo are: (1) a polyphyletic assemblage resulting from multiple colonizations from Africa; (2) a paraphyletic assemblage resulting from a single colonization event from South America with subsequent dispersal into Eurasia; or (3) a monophyletic group derived from the Neotropics. We obtained approximately 2.5 kb of mitochondrial DNA sequence data for the 12S, 16S, and intervening valine tRNA gene from 82 individuals representing 56 species and used parametric bootstrapping to test hypotheses of the biogeographic history of the Nearctic Bufo. We find that the Nearctic species of Bufo are monophyletic and nested within a large clade of New World Bufo to the exclusion of Eurasian and African taxa. This suggests that Nearctic Bufo result from a single colonization from the Neotropics. More generally, we demonstrate the utility of parametric bootstrapping for testing alternative biogeographic hypotheses. Through parametric bootstrapping, we refute several previously published biogeographic hypotheses regarding Bufo. These previous studies may have been influenced by homoplasy in osteological characters. Given the Neotropical origin for Nearctic Bufo, we examine current distributional patterns to assess whether the Nearctic-Neotropical boundary is a broad transition zone or a narrow boundary. We also survey fossil and paleogeographic evidence to examine potential Tertiary and Cretaceous dispersal routes, including the Paleocene Isthmian Link, the Antillean and Aves Ridges, and the current Central American Land Bridge, that may have allowed colonization of the Nearctic.
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2,338,526 |
Short- and long-term impact of receiving genetic mutation results in women at increased risk for hereditary breast cancer.
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Forty-seven unaffected women from high-risk breast cancer families who had received results for hereditary breast/ovarian predisposition genes between 1 month and 5 years ago were interviewed regarding their experiences. Women responded to open-ended questions. The initial emotional turmoil reported by most was generally short lived. However, the impact of genetic testing went beyond the individual to the extended family and social context, particularly in the short-term. A common theme was the difficulty associated with divulging a result to family members, who were also adjusting to their own result. The majority of carriers reported advantages that were both physical (options for surveillance programs and prophylactic surgery) and emotional (reduced uncertainty, increased awareness of options and knowledge about risk, preparation time). Most carriers reported no change in lifestyle although some reported discovering their mutation status as a positive life-changing experience. Implications for genetic counseling and further research are discussed.
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2,338,527 |
Preimplantation genetic diagnosis for Niemann-Pick disease type B.
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Acid sphingomyelinase (ASM) deficient Niemann-Pick disease (NPD) is an autosomal recessive disorder caused by mutations in the ASM gene (SMPD1). More than 70 different mutations have been reported in this gene. NPD type B is the most common type in Saudi Arabia with a frequency of 1:40 000 to 1:100 000. The phenotype of Saudi Type B patients is more severe than patients reported from the West. Two mutations specific to Saudi patients have been inherited in the SMPD1 gene. Given the difficult management of the disease, we opted for a preventive approach to the suffering families by screening the whole SMPD1 gene for mutations followed by Preimplantation Genetic Diagnosis (PGD).</AbstractText>The family suffering from NPD-B underwent mutation screening for the entire SMPD1 gene followed by PGD using nested PCR and sequencing.</AbstractText>A novel mutation in a family suffering from the same severe NPD-B phenotype is described in this report (W533R). After PGD, a singleton pregnancy ensued after transfer of one heterozygous and one normal embryo. Postnatal DNA testing of the newborn showed a normal homozygous genotype.</AbstractText>This report reveals a new SMPD1 mutation responsible for similar Saudi severe phenotype, and the prevention of this disorder by PGD.</AbstractText>Copyright (c) 2004 John Wiley & Sons, Ltd.</CopyrightInformation>
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2,338,528 |
Genotoxicity testing of Plantago major extracts in somatic cells of Drosophila melanogaster.
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Plantago major is used in many parts of the world for the treatment of diseases and to promote the healing of wounds. In the present study, the somatic mutation and recombination test (SMART) in Drosophila melanogaster was used to evaluate the genotoxic activity of an aqueous extract of P. major. The following Drosophila crosses were made: standard (ST) cross, in which virgin flare females (flr3/TM3, Bds) were mated with mwh/mwh males, and high-bioactivation (HB) cross, in which virgin ORR females (ORR/ORR; flr3/TM3, Bds) were mated with mwh/mwh males. Each cross produced two types of descendents, marker-transheterozygous (MH) (mwh +/+ flr3) and balancer-heterozygous (BH) (mwh +/+ TM3, Bds) flies. Three-day-old larvae of both types of descendents were treated with undiluted and diluted (1:1 and 1:2 in water) aqueous extracts of P. major. The extracts were genotoxic in both crosses, producing similar induced frequencies in ST and HB flies. Comparison of the frequencies of wing spots in the BH and MH descendents indicated that recombination was a major response. The results indicate that, under these experimental conditions, aqueous extracts of P. major are genotoxic (recombinagenic).
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2,338,529 |
Examination of candidate genes in language disorder: a model of genetic association for treatment studies.
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The purpose of this review is to provide a model for studying genetic association of response to intervention in child language disorders. In addition to a theoretical overview and review of different approaches to studying candidate genes, a specific methodology for completing this type of analysis is presented. The goal of the analysis is to provide detail beyond simple broad phenotyping for affected and nonaffected individuals and to take advantage of data yielded from concise behavioral phenotyping often available in treatment studies.
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2,338,530 |
Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21.
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Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.
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2,338,531 |
[Identification of two heterozygous mutations in the SLC26A4/PDS gene in a family with Pendred-syndrome].
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Pendred-syndrome is an autosomal recessive disease that is classically characterised by sensorineural hearing loss and enlargement of the thyroid gland. The gene SLC26A4/PDS for the pendred-syndrome has been localised by linkage analysis on chromosome 7q31. This protein is expressed in the inner ear, thyroid gland, kidney and placenta. Functional analysis in Xenopus laevis oocytes revealed that it acts as an iodide/chloride and chloride/formate exchanger.</AbstractText>Each of the exons and flanking splice regions of the SLC26A4/PDS gene was analysed by direct sequencing.</AbstractText>In the involved family two heterozygous mutations could be detected which results by combination in hearing loss and deafness.</AbstractText>By evidences of familial background in hearing loss and thyroid disorder it is reasonable to analyse the PDS gene for mutation to have early the possibility for medical care of linguistic development through hearing aid or CI-implantation.</AbstractText>
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2,338,532 |
[Medullary thyroid carcinoma: clinical and oncological features and treatment].
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Medullary carcinoma of the thyroid (MTC) may be sporadic or may occur on a hereditary basis. Hereditary MTC can occur either alone -- familial MTC (FMTC) -- or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B) or other forms. Germ-line mutations in RET cause MEN 2. Genetic testing, now available, forms the basis for MTC screening procedures. In the past few years, several genotype-phenotype correlations have focused on the relationship between specific mutations and different MEN 2 syndrome variants. Differences in dimerization induction intensities are a reasonable explanation for the phenotypes resulting from mutations of the different cysteines. Here we described the molecular mechanisms, diagnose and treatment as well as our experience on the management of this rare form of thyroid cancer.
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2,338,533 |
Refining the Amsterdam Criteria and Bethesda Guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic.
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Hereditary nonpolyposis colon cancer (HNPCC) is a Mendelian dominant syndrome of bowel, endometrial, and other cancers and results from germline mutations in mismatch repair (MMR) genes. HNPCC is now best diagnosed on molecular grounds using MMR mutation screening, aided by microsatellite instability (MSI) and immunohistochemistry in tumors. Selection of families for molecular investigation of HNPCC is usually based on suboptimal methods (Amsterdam Criteria or Bethesda Guidelines), but these can be improved using additional clinical data (mean ages of affected persons and presence of endometrial cancer) in a quantitative model.</AbstractText>We have verified the performance of the Wijnen model and have shown that it remains valid when HNPCC is diagnosed using mutation screening, MSI, and immunohistochemistry. We have also set up and verified our own models (Amsterdam-plus and Alternative), which perform at least as well as the Wijnen model.</AbstractText>The Amsterdam-plus model improves on the Amsterdam Criteria by using five extra variables (numbers of colorectal and endometrial cancers in the family, number of patients with five or more adenomas, number with more than one primary cancer of the colorectum or endometrium, and mean age of presentation) and performs better than the Wijnen model. The Alternative model avoids the need to evaluate the Amsterdam Criteria and performs nearly as well as the other models.</AbstractText>We believe that a quantitative model, such as the Amsterdam-plus model, should be the first choice for selecting families or patients for evaluation of HNPCC using molecular tests. We present an algorithm for this process.</AbstractText>
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2,338,534 |
Detection of C-erb B2 gene amplification in bilharzial associated bladder cancer using fluorescence in situ hybridization.
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Gene amplifications are common events in different tumor types and may confer diagnostic, prognostic, or therapeutic information for patient management. Fluorescence in situ hybridization (FISH) represents a standard methodologic approach for testing for this genetic alteration, as it is rapid, reproducible and extremely reliable in detecting presence of C-erb-B2 gene amplification for clinical utility.</AbstractText>In this study, FISH is used in a series of archival human bilharzial bladder cancer specimens to evaluate for the presence of cerbB-2 gene alterations in the most common malignant tumor in bilharzial endemic areas, e.g., Egypt and some other countries. The study included 40 cases, 30 males and 10 females. Their ages ranged between 30 years and 76 years (median: 51 years). Twenty-one cases had squamous cell carcinoma, 16 had transitional cell carcinoma, two had adenocarcinoma, and one case had undifferentiated carcinoma.</AbstractText>Thirteen out of 40 tumor samples (32.5%) show evidence of true C-erb-B2 gene amplification. Of the remaining samples, 24 (60%) show no gene amplification and three (7.5%) fall into the borderline category with a ratio between one and two C-erb-B2 genes/cell relative to chromosome 17 centromeres. No evidence of chromosome 17 polysomy was found in any cases scored as single copy with the C-erb-B2 probe.</AbstractText>No significant association was found between gene amplification and any of the tested clinicopathologic parameters or tumor recurrence except for tumor grade where higher tumor grades tended to be associated with more C-erb-B2 gene amplification (P = 0.01) thus reflecting more tumor aggressiveness. So, the amplification of C-erb-B2 in bilharzial associated bladder cancer is probably not independently related to clinical outcome of patients.</AbstractText>
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2,338,535 |
Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy.
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Nine patients with Duchenne or Becker muscular dystrophy were injected via the radialis muscle with a full-length human dystrophin plasmid, either once with 200 or 600 microg of DNA or twice, 2 weeks apart, with 600 microg of DNA. In the biopsies taken 3 weeks after the initial injection, the vector was detected at the injection site in all patients. Immunohistochemistry and nested reverse transcription-polymerase chain reaction indicated dystrophin expression in six of nine patients. The level of expression was low (up to 6% weak, but complete sarcolemmal dystrophin staining, and up to 26% partial sarcolemmal labeling). No side effects were observed, nor any cellular or humoral anti-dystrophin responses. These results suggest that exogenous dystrophin expression can be obtained in Duchenne/Becker patients after intramuscular transfer of plasmid, without adverse effects, hence paving the way for future developments in gene therapy of hereditary muscular diseases.
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2,338,536 |
Trisomy 3 may predict a poor response of gastric MALT lymphoma to Helicobacter pylori eradication therapy.
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To investigate the relation of the response to Helicobacter pylori eradication therapy to the depth of tumor invasion and chromosome abnormalities in patients with mucosa-associated lymphoid tissue (MALT) lymphoma and to determine the clinical value of aneuploidy.</AbstractText>We studied 13 patients with localized gastric MALT lymphoma of stage E1. Before eradication therapy, the depth of tumor invasion was assessed by endoscopic ultrasonography in 8 patients and by endoscopic examination and gastrointestinal series in the remaining patients. To detect chromosomal abnormalities, paraffin-embedded tissue sections of diagnostic biopsy specimens underwent tissue-fluorescence in situ hybridization (FISH), using chromosome-specific alpha-satellite DNA probes for chromosomes 3,7,12, and 18 and YAC clones for t(11;18)(q21;q21).</AbstractText>Seven of the 13 patients had complete regression (CR) in response to H pylori eradication therapy. No patient with CR had submucosal tumor invasion. Trisomy 18 was seen in 1 patient with CR, and both trisomies 12 and 18 were present in another patient with CR. All patients with no response or progressive disease had deep submucosal tumor invasion and showed t(11;18)(q21;q21) or trisomy 3. Trisomy 7 was not detected in this series of patients.</AbstractText>The depth of tumor invasion is an accurate predictor of the response of stage E1 MALT lymphoma to H pylori eradication therapy and is closely associated with the presence of chromosomal abnormalities. Trisomy 3 may predict the aggressive development of MALT lymphoma.</AbstractText>
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2,338,537 |
Treatment of multi-focal colorectal carcinoma metastatic to the liver of immune-competent and syngeneic rats by hepatic artery infusion of oncolytic vesicular stomatitis virus.
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Viruses that replicate selectively in cancer cells hold considerable promise as novel therapeutic agents for the treatment of malignancy. We report an orthotopic model of multi-focal colorectal cancer (CRC) metastases in the livers of syngeneic and immune-competent rats, which permitted rigorous testing of oncolytic virus vectors as novel therapeutic agents through hepatic arterial infusion for efficacy and safety. Vesicular stomatitis virus (VSV) is a negative-strand RNA virus with intrinsic oncolytic specificity due to attenuated anti-viral responses in many tumors. After administration at the maximum tolerated dose, the recombinant VSV vector gained access to multi-focal hepatic CRC lesions that led to tumor-selective viral replication and oncolysis. No relevant vector-associated toxicities were noted and in particular, no damage to the hepatic parenchyma was seen. Moreover, the survival rate of vector-treated rats was significantly improved over that of animals in the control treatment group (p = 0.015). Our results demonstrate that hepatic arterial administration of oncolytic VSV is both effective and safe in an immune-competent and syngeneic rat model of multi-focal CRC liver metastasis, suggesting that it can be developed into an effective therapeutic modality in patients in the future.
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2,338,538 |
Recognizing the clinical features of Trisomy 13 syndrome.
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Recognition of the clinical features of Trisomy 13 syndrome, a common autosomal trisomy, provides the basis for diagnostic testing and counseling of families. This article provides a systematic guide to physical assessment and photographs to enhance recognition of this genetic disorder. The principles of numerical chromosomal abnormalities as related to trisomies are reviewed. An abnormal development of the forebrain, holoprosencephaly, is the most common cranial abnormality in infants with Trisomy 13. The embryology and implications of holoprosencephaly are described. A discussion of antenatal diagnosis of Trisomy 13 and delivery room management is also provided. The diagnosis of Trisomy 13 is confirmed antenatally or after delivery with genetic testing. Prognosis of infants with Trisomy 13 and implications for the infants development are described.
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2,338,539 |
Rapid detection of VHL exon deletions using real-time quantitative PCR.
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Various types of mutations exist that exert an effect on the normal function of a gene. Among these, exon/gene deletions often remain unnoticed in initial mutation screening. Until recently, no fast and efficient methods were available to detect this type of mutation. Molecular detection methods for gene copy number changes included Southern blot (SB) and fluorescence in situ hybridisation, both with their own intrinsic limitations. In this paper, we report the development and application of a fast, sensitive and high-resolution method for the detection of single exon or larger deletions in the VHL gene based on real-time quantitative PCR (Q-PCR). These deletions account for approximately one-fifth of all patients with the von Hippel-Lindau syndrome, a dominantly inherited highly penetrant familial cancer syndrome predisposing to specific malignancies including phaeochromocytomas and haemangioblastomas. Our VHL exon quantification strategy is based on SYBR Green I detection and normalisation using two reference genes with a normal copy number, that is, ZNF80 (3q13.31) and GPR15 (3q12.1). Choice of primer sequences and the use of two reference genes appears to be critical for accurate discrimination between 1 and 2 exon copies. In a blind Q-PCR study of 29 samples, all 14 deletions were detected, which is in perfect agreement with previously determined SB results. We propose Q-PCR as the method of choice for fast (within 3.5 h), accurate and sensitive (ng amount of input DNA) exon deletion screening in routine DNA diagnosis of VHL disease. Similar assays can be designed for deletion screening in other genetic disorders.
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2,338,540 |
A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans.
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Recent research has implicated the endogenous opioid system in the development of alcohol use disorders. The A118G polymorphism of the OPRM1 gene has been shown to confer functional differences to mu-opioid receptors, such that the G variant binds beta-endorphin three times more strongly than the A variant. The goal of this study was to test whether the A118G polymorphism is associated with sensitivity to the effects of alcohol.</AbstractText>Participants who were either homozygous for the A allele (n = 23) or heterozygous (n = 15) received intravenous doses of alcohol designed to reach three target levels of breath alcohol concentration: 0.02, 0.04, and 0.06. The testing procedure consisted of measures of subjective intoxication, stimulation, sedation, and mood states at baseline and at each of the three target breath alcohol concentrations.</AbstractText>The results suggested that individuals with the G allele reported higher subjective feelings of intoxication, stimulation, sedation, and happiness across trials as compared with participants with the A allele. Furthermore, participants with the G allele were almost three times more likely to report a positive family history of alcohol use disorders than participants with the A allele.</AbstractText>These findings may help to explain previous research suggesting that naltrexone is more effective among individuals with the G allele. A medication that reduces feelings of euphoria after alcohol consumption may be more successful among individuals with a genetic predisposition to greater feelings of euphoria after consuming alcohol.</AbstractText>
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2,338,541 |
Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.
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To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism.</AbstractText>CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring <or= 1.5 mg warfarin per day and with apparently homozygous wild-type or heterozygous CYP2C9*2 genotypes were screened for novel polymorphisms by single-strand conformational polymorphism analysis. PCR-based genotyping assays for novel upstream and other known polymorphisms were used to screen a larger patient population of known CYP2C9*2 and *3 genotype requiring a range of warfarin doses.</AbstractText>Polymorphisms at eight different upstream sites were found, five of which were already described. We found that the majority of the upstream polymorphisms were in complete linkage disequilibrium with previously described coding region polymorphisms. However, two polymorphisms, T-1188C and the novel DeltaG-2664DeltaT-2665, occurred both in individuals who were otherwise wild-type and in individuals positive for coding region polymorphisms. Evidence for 11 haplotypes, including 8 with frequencies >or= 0.01, was obtained. In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or DeltaG-2664DeltaT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant. Dose requirements in CYP2C9*11 heterozygotes were not statistically significantly different from homozygous wild-type individuals.</AbstractText>The coding region non-synonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 alleles are the major CYP2C9-related factor affecting warfarin dose in UK Caucasians. Upstream CYP2C9 polymorphisms do not appear to be important independent determinants of dose requirement.</AbstractText>
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2,338,542 |
Multiple endocrine neoplasia syndrome: genetic basis for clinical management.
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Multiple endocrine neoplasia (MEN) types 1 and 2 are rare hereditary cancer syndromes expressing a variety of mainly endocrine neoplasias. Improved understanding of the molecular and clinical genetics associated with these lesions will likely enhance the diagnosis and treatment of patients with these diseases.</AbstractText>The MEN1 gene causing MEN1 is a tumor suppressor gene and seems to act as a regulator of the transcriptional machinery. Novel genetic and diagnostic modalities tend to identify neoplastic lesions at an earlier stage, potentially improving outcome and quality of life. Improved understanding of genotype-phenotype correlations in MEN2, caused by a mutation in the RET oncogene, may enable a more individualized treatment for these patients.</AbstractText>Recent advances in molecular pathology, diagnosis, and management of patients with MEN1 and MEN2 are reviewed.</AbstractText>
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2,338,543 |
Quantitative analysis of SMN1 gene and estimation of SMN1 deletion carrier frequency in Korean population based on real-time PCR.
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Spinal muscular atrophy (SMA) is an autosomal recessive disorder, caused by homozygous absence of the survival motor neuron gene (SMN1) in approximately 94% of patients. Since most carriers have only one SMN1 gene copy, several SMN1 quantitative analyses have been used for the SMA carrier detection. We developed a reliable quantitative real-time PCR with SYBR Green I dye and studied 13 patients with SMA and their 24 parents, as well as 326 healthy normal individuals. The copy number of the SMN1 gene was determined by the comparative threshold cycle (Ct) method and albumin was used as a reference gene. The homozygous SMN1 deletion ratio of patients was 0.00 and the hemizygous SMN1 deletion ratio of parents ranged from 0.39 to 0.59. The deltadelta Ct ratios of 7 persons among 326 normal individuals were within the carrier range, 0.41-0.57. According to these data, we estimated the carrier and disease prevalence of SMA at 1/47 and 1/8,496 in Korean population, respectively. These data indicated that there would be no much difference in disease prevalence of SMA compared with western countries. Since the prevalence of SMA is higher than other autosomal recessive disorders, the carrier detection method using real-time PCR could be a useful tool for genetic counseling.
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2,338,544 |
Alpha-adducin Gly460Trp polymorphism and essential hypertension in Korea.
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Previous studies have suggested that the Gly460Trp polymorphism of the alpha-adducin gene (ADD-1) is associated with salt sensitivity and primary hypertension. The results of linkage or association studies of ADD-1 of different populations are controversial. This study investigated the relationship between the Gly460Trp polymorphism of ADD-1 and essential hypertension in a Korean population. The subjects (n=903) were participants in a population-based study in Jangseong County, Korea. The Gly460Trp polymorphism of ADD-1 was determined using a polymerase chain reaction method. The frequency of the 460Trp allele was 59.4% in normotensives and 61.1% in hypertensives (p=0.523). The frequencies of the genotypes did not differ significantly between the hypertensive and normotensive groups (16.3% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in normotensives; 16.2% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in hypertensives; p=0.928). After adjusting for other risk factors, Gly/Trp and Trp/Trp were not associated with hypertension (OR 1.00, 95% CI 0.65-1.53, Gly/Trp vs. Gly/Gly; OR 1.22, 95% CI 0.79-1.90, Trp/Trp vs. Gly/Gly). These findings suggest that the Gly460Trp polymorphism of ADD-1 is not associated with hypertension.
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2,338,545 |
Rapid second-tier molecular genetic analysis for congenital adrenal hyperplasia attributable to steroid 21-hydroxylase deficiency.
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Neonatal screening for steroid 21-hydroxylase (CYP21) deficiency is performed to identify congenital adrenal hyperplasia (CAH). The immunologic assay for 17alpha-hydroxyprogesterone (17-OHP) has a high rate of false positives. We assessed the potential for increasing the specificity for CAH by use of a second step involving analysis of the CYP21 gene.</AbstractText>Between January 1999 and December 2003, a total of 810,000 newborns were screened. Of these, 7920 had to be retested because their 17-OHP values were above the cutoff of the assay. Sixty-one had positive 17-OHP values in their recall samples and were diagnosed as having CAH. We used a rapid assay for common mutations of the CYP21 gene to analyze these 61 samples. In a prospective study, 198 consecutive samples that had increased 17-OHP and 100 samples that had normal 17-OHP concentrations were genotyped.</AbstractText>Fifty-nine of 61 cases diagnosed as having CAH were confirmed genetically as CYP21 deficiencies. One patient had a 3beta-hydroxysteroid dehydrogenase deficiency, and one patient carried no CYP21 mutations. The 198 increased 17-OHP results were designated as false positives after immunologic testing of recall samples. None of these samples exhibited the genetic pattern consistent with CYP21 deficiency.</AbstractText>If samples with increased 17-OHP values were screened genetically, the number of retests would decrease by approximately 90%, but the overall sensitivity of CAH screening would remain the same. Adding a second-tier genetic step would require a modest increase in costs, but is counterbalanced by fewer recalls, less clinical follow-up, and a reduction in unnecessary worry for families.</AbstractText>
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2,338,546 |
The Wilms' tumor gene WT1 is a common marker of progenitor cells in fetal liver.
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It is well known that the Wilms' tumor gene WT1 plays an important role in cell proliferation and differentiation, and in organ development. In this study, to examine the role of the WT1 gene in lineage determination, fetal liver cells from LacZ-transgenic mice, in which WT1 expression was marked by the expression of the LacZ gene driven by WT1 promoter, were FACS-sorted according to LacZ expression of high (LacZ(++)) or undetectable (LacZ(-)) levels, which paralleled endogenous WT1 expression levels. LacZ(++) fetal liver cells were enriched by hepatocyte and endothelial progenitor cells. These results indicated that WT1 expression is a common marker of both hepatocyte and endothelial progenitors. These results also implied a role of the WT1 gene in lineage determination.
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2,338,547 |
Oligonucleotide array for detection of common severe determinants of alpha thalassemia.
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A simple and an efficient oligonucleotide array was developed to identify common severe determinants of alpha (alpha) thalassemia. A total of 14 probes were designed to detect the most frequently three deletions (-alpha(3.7), -alpha(4.2), -(SEA)) and two non-deletions (alpha(Quong Sze), alpha(Constant Spring)). PCR products were amplified from human genomic DNA and allowed to hybridize with the oligonucleotide array. Hybridization was detected by fluorescence scanning, and alpha globin genotypes were assigned by quantitative analysis of the hybridization results. The efficiency and specificity of identifying alpha globin genotypes using the oligonucleotide arrays was evaluated by blinded analysis of 690 samples from unrelated individuals. The oligonucleotide array method described in this paper provides unambiguous detection of complex combinations of heterozygous, compound heterozygous and homozygous alpha thalassemia genotypes. The experimental results demonstrate that this methodological approach may be applied for screening and for hemological diagnosis in population at large.
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2,338,548 |
A power law global error model for the identification of differentially expressed genes in microarray data.
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High-density oligonucleotide microarray technology enables the discovery of genes that are transcriptionally modulated in different biological samples due to physiology, disease or intervention. Methods for the identification of these so-called "differentially expressed genes" (DEG) would largely benefit from a deeper knowledge of the intrinsic measurement variability. Though it is clear that variance of repeated measures is highly dependent on the average expression level of a given gene, there is still a lack of consensus on how signal reproducibility is linked to signal intensity. The aim of this study was to empirically model the variance versus mean dependence in microarray data to improve the performance of existing methods for identifying DEG.</AbstractText>In the present work we used data generated by our lab as well as publicly available data sets to show that dispersion of repeated measures depends on location of the measures themselves following a power law. This enables us to construct a power law global error model (PLGEM) that is applicable to various Affymetrix GeneChip data sets. A new DEG identification method is therefore proposed, consisting of a statistic designed to make explicit use of model-derived measurement spread estimates and a resampling-based hypothesis testing algorithm.</AbstractText>The new method provides a control of the false positive rate, a good sensitivity vs. specificity trade-off and consistent results with varying number of replicates and even using single samples.</AbstractText>
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2,338,549 |
Full-field ERG, multifocal ERG and multifocal VEP in patients with retinitis pigmentosa and residual central visual fields.
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To evaluate (with three different electrophysiological methods) the residual retinal function in a selected group of patients with retinitis pigmentosa and remaining small central visual fields.</AbstractText>Fourteen patients from several different genetic subgroups, who had been followed with visual acuity and visual field testing for periods up to 32 years, were examined. Ophthalmological examination included full-field electroretinography (ERG), multifocal electroretinography (mfERG) and multifocal visual evoked potential (mfVEP).</AbstractText>The ERGs were severely reduced in all patients. The mfERGs demonstrated the residual central retinal function in five of the patients. The mfVEPs showed measurable amplitudes centrally in most of the patients. The follow-up examinations demonstrated the slowly progressive course of the disease with preservation or only slight further loss of visual fields over a period of 7-32 years.</AbstractText>Patients with retinitis pigmentosa may not always follow the typical natural course with progressive loss of visual fields, which may in some patients remain unaffected over several decades. Multifocal ERG and mfVEP may be clinically useful for evaluating remaining visual function in these patients.</AbstractText>
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2,338,550 |
Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas.
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Genetic alterations of PI3K (phosphoinositide 3-kinase) subunits have been documented in a number of tumor types, with increased PI3K activity linked to gene amplification and mutation of catalytic subunits, as well as mutations of regulatory subunits. Among high grade gliomas, activation of the PI3K-AKT signaling pathway through loss of PTEN function is common. We therefore investigated whether genetic alteration of class IA PI3Ks might provide a mechanism for deregulation of this pathway in glioblastomas. We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR-SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits. FISH revealed frequent balanced copy number increases of both PIK3CA and PIK3CD, and one case showed an extra copy limited to PIK3CA. One glioblastoma exhibited a 9-bp deletion that encompassed the exon-intron junction of exon 12 of PIK3R1, documenting for the first time a mutation within a PI3K regulatory subunit in human glioblastoma. This deletion would be predicted to yield a truncated protein that lacks the inhibitory domain, resulting in increased PI3K activity. Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation. These results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating the PI3K-AKT signaling pathway independently of PTEN mutation.
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2,338,551 |
Analyzing the process and content of genetic counseling in familial breast cancer consultations.
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A detailed examination of the process of genetic counseling has been identified as a priority area for research by previous authors. This multicenter longitudinal study examined the process and content of genetic counseling in initial consultations with women from high-risk breast cancer families. One hundred and fifty-eight consultations with women unaffected and affected with breast cancer were audio taped and transcribed verbatim. A detailed coding system was developed. Clinical geneticists and genetic counselors demonstrated consistently good practice in giving detailed information on essential aspects related to familial breast cancer such as screening and management, genetic testing, breast cancer genetics, and prophylactic surgery. Eliciting emotional concerns and facilitating communication were found to be inconsistently present. As clinical practice guidelines and the general communication literature emphasize the importance of these factors, this is an area where training in or self-monitoring of such behaviors may assist consultants to further develop these skills.
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2,338,552 |
The interface between the practice of medical genetics and human genetic research: what every genetic counselor needs to know.
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Genetic counselors have historically used human genetic research as an advanced information resource for their patients. Most commonly, this has been via access to information provided by gene identification studies in advance of commercial testing. More recently genetic counselors have been participating in human genetic research studies as part of the investigative team. This review provides a framework to help genetic counselors in research and clinical practice understand the historical perspectives, ethical principles, and federal regulations that govern the current practice of human subject research. Special consideration is given to the IRB process and unique issues in human genetic research. This overview is intended to help improve the ability of genetic counselors to act as advocates for their patients.
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2,338,553 |
The decision to test in women receiving genetic counseling for BRCA1 and BRCA2 mutations.
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Functions of genetic counseling include provision of risk information and provision of support in an effort to assist with decision making. This study examines (1) the relationship among intentions to test, self-reported provision of blood sample, and receipt of test results; (2) the impact of genetic counseling on distress specific to gene status, perceived risk of developing breast and ovarian cancer in the context having BRCA1/2 mutations (mutations predisposing to increased risk of breast-ovarian cancer), and perceived risk factors for breast cancer; and (3) the clinical profile of those receiving/not receiving results. Intentions to test for BRCA1/2 mutations, self-reported provision of blood sample immediately after counseling, and receipt of test results were statistically different but highly correlated, and intentions to test increased from pre- to postcounseling. A repeated measures ANOVA found distress specific to gene status and perceived risk factors decreased from pre- to postcounseling. Further, two clinical profiles of consultands emerged: (1) those receiving results with change in intentions to test having lower levels of distress and (2) those not receiving results and those receiving results with no change in intentions to test with higher levels of distress. Our findings are consistent with the function of genetic counseling-to provide information and support to those with familial cancer, as well as to assist in decision making. The provision of support is important as distress specific to gene status may impede flexible decision making about genetic testing.
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2,338,554 |
Decision making with uncertain information: learning from women in a high risk breast cancer clinic.
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Patients and practitioners may believe that clinically validated laboratory tests provide definitive information. Genetic counselors know this is not always so, and the possibility of inconclusive genetic test results is often discussed in the pretest counseling session. This added discussion topic prolongs the process of genetic counseling, but if there is inadequate patient understanding, patient frustration may be high when receiving a result of uncertain significance, and patients may make decisions about subsequent medical management based on incorrect assumptions. For patients/participants in a research setting, where the clinical validity of testing may be unclear, some patients/participants may still want to use test results to influence their medical management. This paper presents findings from a qualitative study wherein 15 women from the High Risk Breast Cancer Clinic at Utah's Huntsman Cancer Institute discussed how uncertainty regarding results affected their decision making. The women were randomly selected from 3 categories--women with test results of uncertain significance; women without cancer who have a mutation; and women who are members of high-risk families, but for whom no mutation was found. Study findings will be used in future studies to better understand how to improve communication regarding uncertain results, especially in a research environment.
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2,338,555 |
Family environments of women seeking BRCA1/BRCA2 genetic mutation testing: an exploratory analysis.
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Although there is some understanding of the shared characteristics and predictors of psychological distress of women participating in hereditary breast and ovarian cancer registries, these same characteristics are only beginning to be identified in research on community women seeking genetic testing for BRCA1/BRCA2 gene mutations. This study provides an initial exploration of characteristics associated with family environments for 51 community women waiting to receive such genetic testing results. Thirty-four of the 36 women classified on family environment type of the Family Environment Scale (FES) were from Personal Growth-Oriented families. Comparisons of women with and without personal cancer histories resulted in a trend for women with personal cancer histories to be classified as from Independence-Oriented families. Reported distress appears to vary for different family emphases based on family and personal cancer history. A moral-religious family emphasis consistently appeared to be associated with decreased psychological distress. Preliminary analyses comparing these community women (who were not part of a hereditary registry but were self- or physician-referred) seeking genetic testing with normal and distressed family means found that increased cohesion and expressiveness may be related to decreased conflict, indicative of potentially supportive family environments for these women. When compared with normative data, a subset consisting of the Ashkenazi Jewish women showed a trend of less cohesion than normal families, but similar cohesion levels as distressed families.
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2,338,556 |
Initiation of reflective frames in counseling for Huntingtons Disease predictive testing.
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Genetic professionals and clients are likely to assign different meanings to the extended format of the counseling protocols for predictive testing. In order to facilitate informed, client-centered decisions about the possibility of predictive testing, counselors routinely use the question format to initiate what we call "reflective frames" that invite clients to discuss their feelings and encourage them to adopt introspective and self-reflective stances toward their own experience--spanning the past, the present, and the hypothetical future. We suggest that such initiations of reflective frames constitute a key element of counselors' nondirective stance, although the exact nature of their formulations can be complex and varied. Examining 24 Huntington's Disease (HD) clinic sessions involving 12 families in South Wales with the tools of discourse analysis, our focus in this paper is twofold: (i) to propose a classification of six types of reflective questions (e.g. nonspecific invites, awareness and anxiety, decision about testing, impact of result, dissemination, and other) and to examine their distribution across the various clinic appointments, and (ii) to investigate the scope of these questions in terms of temporal and social axes. We link our analysis to the current debate within the genetic counseling profession about the merits of reflection- versus information-focused counseling styles and the need to abide by professionally warranted and institutionally embedded counseling protocols.
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2,338,557 |
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
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These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.
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2,338,558 |
Using overall allele-sharing to detect the presence of large-scale data errors and parameter misspecification in sib-pair linkage studies.
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Data errors and marker allele frequency misspecification can lead to incorrect inference in linkage analysis. Here we demonstrate the effect of each on an allele-sharing statistic in a sample of sib pairs. In the context of relationship testing, we propose a new test that compares the sample genome-wide sib-pair allele sharing to its expectation and show that this test can detect the presence of large-scale data and model errors.
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2,338,559 |
The size of the chi-square test for the Hardy-Weinberg law.
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Many scientific problems can be formulated in terms of a statistical model indexed by parameters, only some of which are of scientific interest and the other parameters, called nuisance parameters, are not of interest in themselves. For testing the Hardy-Weinberg law, a relation among genotype and allele probabilities is of interest and allele probabilities are of no interest and now nuisance parameters. In this paper we investigate how the size (the maximum of the type I error rate over the nuisance parameter space) of the chi-square test for the Hardy-Weinberg law is affected by the nuisance parameters. Whether the size is well controlled or not under the nominal level has been frequently investigated as basic components of statistical tests. The size represents the type I error rate at the worst case. We prove that the size is always greater than the nominal level as the sample size increases. Extensive computations show that the size of the chi-squared test (worst type I error rate over the nuisance parameter space) deviates more upwardly from the nominal level as the sample size gets larger. The value at which the maximum of the type I error rate was found moves closer to the edges of the the nuisance parameter space with increasing sample size. An exact test is recommended as an alternative when the type I error is inflated.
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2,338,560 |
Inherited iron loading: genetic testing in diagnosis and management.
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Elucidation of the molecular pathways of iron transport through cells and its control is leading to an understanding of genetic iron loading conditions. The general phenotype of haemochromatosis is iron accumulation in liver parenchymal cells, a raised serum transferrin saturation and ferritin concentration. Four types have been identified: type 1 is the common form and is an autosomal recessive disorder of low penetrance strongly associated with mutations in the HFE gene on chromosome 6(p21.3); type 2 (juvenile haemochromatosis) is autosomal recessive, of high penetrance with causative mutations identified in the HFE2 gene on chromosome 1 (q21) and the HAMP gene on chromosome 19 (q13); type 3 is also autosomal recessive with mutations in the TfR2 gene on chromosome 3 (7q22); type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene. In type 4, iron accumulates in both parenchymal and reticuloendothelial cells and the transferrin saturation may be normal. There are also inherited neurodegenerative conditions associated with iron accumulation. The current research challenges include understanding the central role of the HAMP gene (hepcidin) in controlling iron absorption and the reasons for the variable penetrance in HFE type 1.
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2,338,561 |
The use of subtelomeric probes to study mental retardation.
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In this chapter, we focus on the genetic basis of mental retardation (MR), specifically the use of subtelomeric probes to provide new diagnoses in idiopathic MR. We discuss both the background to the clinical demand for diagnoses and the technological advances that culminated in the development of subtelomeric testing strategies. We explain the theory behind these strategies and briefly outline the protocols involved, giving the advantages, limitations, and pitfalls of the analyses. Finally, we give an overview of the MR subtelomeric studies to date and how subtelomeric testing has become a widely used tool in clinical diagnostic laboratories, particularly in the diagnosis of unexplained MR, but also in other fields of clinical medicine. The conclusion addresses the overall impact that subtelomeric testing has had on the diagnosis of MR, the implications for patients and their families, and future research avenues for exploring the genetic causes of MR and improving our overall understanding of neurocognitive development.
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2,338,562 |
[Hereditary neuropathy with liability to pressure palsy presenting with an acute inflammatory demyelinating polyneuropathy].
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Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant peripheral neuropathy characterized by compressive focal neuropathies and an underlying sensorimotor demyelinative polyneuropathy. It is usually caused by a 1.5 Mb deletion of the PMP22 gene (17p11.2).</AbstractText>We describe the case of a 31 year-old woman who presented with acute demyelinative peripheral polyneuropathy affecting the four limbs and elevated cerebrospinal fluid protein content a few days after a viral illness. Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barré syndrome) was suspected. However, electrophysiologic examination suggested HNPP and subsequent genetic testing was confirmatory.</AbstractText>This case demonstrates that HNPP can present in an acute manner, mimicking AIDP.</AbstractText>
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2,338,563 |
Power of microsatellite markers for fingerprinting and parentage analysis in Eucalyptus grandis breeding populations.
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We report the genetic analysis of 192 unrelated individuals of an elite breeding population of Eucalyptus grandis (Hill ex Maiden) with a selected set of six highly polymorphic microsatellite markers developed for species of the genus Eucalyptus. A full characterization of this set of six loci was carried out generating allele frequency distributions that were used to estimate parameters of genetic information content of these loci, including expected heterozygosity, polymorphism information content (PIC), power of exclusion, and probability of identity. The number of detected alleles per locus ranged from 6 to 33, with an average of 19.8 +/- 9.2. The average expected heterozygosity was 0.86 +/- 0.11 and the average PIC was 0.83 +/- 0.16. Using only three loci, it was possible to discriminate all 192 individuals. The overall probability of identity considering all six EMBRA microsatellite markers combined was lower than 1 in 2 billion. An analysis of the sample size necessary to estimate expected heterozygosity with minimum variance indicated that at least 64 individuals have to be genotyped to characterize this parameter with adequate accuracy for most microsatellites in Eucalyptus. The high degree of multiallelism and the clear and simple codominant Mendelian inheritance of the set of microsatellites used provide an extremely powerful system for the unique identification of Eucalyptus individuals for fingerprinting purposes and parentage testing.
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2,338,564 |
Major genes affecting ovulation rate in sheep.
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Research conducted since 1980 in relation to inheritance patterns and DNA testing of major genes for prolificacy has shown that major genes have the potential to significantly increase the reproductive performance of sheep flocks throughout the world. Mutations that increase ovulation rate have been discovered in the BMPR-1B, BMP15 and GDF9 genes, and others are known to exist from the expressed inheritance patterns although the mutations have not yet been located. In the case of BMP15, four different mutations have been discovered but each produces the same phenotype. The modes of inheritance of the different prolificacy genes include autosomal dominant genes with additive effects on ovulation rate (BMPR-1B; Lacaune), autosomal over-dominant genes with infertility in homozygous females (GDF9), X-linked over-dominant genes with infertility in homozygous females (BMP15), and X-linked maternally imprinted genes (FecX2). The size of the effect of one copy of a mutation on ovulation rate ranges from an extra 0.4 ovulations per oestrus for the FecX2 mutation to an extra 1.5 ovulations per oestrus for the BMPR-1B mutation. A commercial DNA testing service enables some of these mutations to be used in genetic improvement programmes based on marker assisted selection.
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2,338,565 |
Integration of association statistics over genomic regions using Bayesian adaptive regression splines.
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In the search for genetic determinants of complex disease, two approaches to association analysis are most often employed, testing single loci or testing a small group of loci jointly via haplotypes for their relationship to disease status. It is still debatable which of these approaches is more favourable, and under what conditions. The former has the advantage of simplicity but suffers severely when alleles at the tested loci are not in linkage disequilibrium (LD) with liability alleles; the latter should capture more of the signal encoded in LD, but is far from simple. The complexity of haplotype analysis could be especially troublesome for association scans over large genomic regions, which, in fact, is becoming the standard design. For these reasons, the authors have been evaluating statistical methods that bridge the gap between single-locus and haplotype-based tests. In this article, they present one such method, which uses non-parametric regression techniques embodied by Bayesian adaptive regression splines (BARS). For a set of markers falling within a common genomic region and a corresponding set of single-locus association statistics, the BARS procedure integrates these results into a single test by examining the class of smooth curves consistent with the data. The non-parametric BARS procedure generally finds no signal when no liability allele exists in the tested region (ie it achieves the specified size of the test) and it is sensitive enough to pick up signals when a liability allele is present. The BARS procedure provides a robust and potentially powerful alternative to classical tests of association, diminishes the multiple testing problem inherent in those tests and can be applied to a wide range of data types, including genotype frequencies estimated from pooled samples.
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2,338,566 |
Parent responses to participation in genetic screening for diabetes risk.
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Screening for type 1 diabetes (T1DM) risk in newborns has little negative emotional impact on mothers. In this study, the impact on the mother and the father was evaluated both in the general population and in families with diabetes. All parents with a newborn in Skane, Sweden, were invited to a screening for T1DM risk in their children (the Diabetes Prediction in Skane (DiPiS)). Blood was obtained at delivery from the mother and the child. When the child was 2 months old, parents gave written consent and filled out questionnaires, but were not informed about the genetic risk. Of the 10 538 invited families, 6831 (64.8%) consented and 806 (7.7%) declined participation. Five questions addressing both parents were filled out by 6676 (63.4%) mothers and 6099 (57.8%) fathers. In 146/6676 (2.2%) families, one family member had diabetes (D-families). Participation in DiPiS did not affect most parents and the majority was satisfied with the information. The majority of parents (28.9%) were reassured and only 1.1% (140/12,670) reported increased worries because of participation, compared to 2.8% of the mothers in D-families. Parents in D-families more often ascribed diabetes risk to their child as well as the risk being higher. Mothers and fathers differed in their answers on four of the five study questions, with mothers being more satisfied with the information, reporting more knowledge of diabetes, estimating lower risk of their child to get diabetes, but reporting more worries of possible future chronic disease in the child. Parents with lower education, being born abroad, or being younger who reported worries of chronic disease in the child were also reassured by participation in the study. These results confirm that screening for T1DM risk in newborns does not create worries in most parents, but stress that fathers differ from mothers in opinions and reactions, that parents' reactions are affected by diabetes in the family, and that demographic factors might be important for the parents' reports.
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2,338,567 |
[Analysis of polymorphism of ACTBP2 locus in Han population in Chengdu and triplexing of three STR loci].
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To obtain the polymorphism of ACTBP2 locus in Han Chinese in Chengdu and establish the triplexing of three STR loci (DHFRP2,FIBRA and ACTBP2).</AbstractText>Amp-FLP, PAGE and silver stain were used to analyze 147 individuals.</AbstractText>Twenty alleles and 86 genotypes were observed in ACTBP2. The discriminating power (DP), observed heterozygosity(h), polymorphism information content (PIC) and chance of paternity exclusion power (EP) were 0.9861, 0.9728, 0.9310 and 0.8203, respectively. The distributions of the genotypes were in good agreement with Hardy-Weinberg equilibrium. Studies of the families revealed that the locus was in accord with the Mendelian law.</AbstractText>These data indicate that ACTBP2 is of good polymorphism and can be applied to human genetic study, forensic parentage testing and identification.</AbstractText>
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2,338,568 |
[Diagnostic value of mitochondrial DNA analysis in chronic progressive external ophthalmoplegia (CPEO)].
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Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial cytopathy presenting with ptosis and external ophthalmoparesis. Mitochondrial disorders are characterized by a broad clinical spectrum and genetic background with marked genotype/phenotype variability. The routine diagnostic work-up usually includes clinical and laboratory examinations as well as histological and histochemical analysis of skeletal muscle biopsy. In our case only an additional molecular biological examination allowed the diagnosis of CPEO.</AbstractText>We report a 35-year-old woman with a 7-years history of slowly progressive diplopia due to impaired ocular motility and bilateral ptosis. We performed ophthalmological and neurological examinations, laboratory testing, lower limb skeletal muscle biopsy including histological and histochemical investigations, biochemical analysis of respiratory chain enzymes in skeletal muscle homogenate and molecular genetic testing of skeletal muscle DNA.</AbstractText>Although clinical, laboratory, histological and biochemical analyses did not give any hints suggesting a mitochondrial cytopathy, molecular genetic testing of total DNA from skeletal muscle tissue by Southern blot analysis finally revealed a 3.8 kb mitochondrial DNA deletion with a degree of heteroplasmy of 45 %.</AbstractText>In patients with unexplained binocular diplopia , oculomotor deficits and/or acquired ptosis, an underlying mitochondrial cytopathy should be considered. Even in the case of inconspicuous skeletal muscle histology and biochemistry, molecular genetic testing of skeletal muscle DNA is advisable in order to establish the diagnosis.</AbstractText>
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2,338,569 |
Genomewide two-generation screens for recessive mutations by ES cell mutagenesis.
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Forward genetic mutation screens in mice are typically begun by mutagenizing the germline of male mice with N-ethyl-N-nitrosourea (ENU). Genomewide recessive mutations transmitted by these males can be rendered homozygous after three generations of breeding, at which time phenotype screens can be performed. An alternative strategy for randomly mutagenizing the mouse genome is by chemical treatment of embryonic stem (ES) cells. Here we demonstrate the feasibility of performing genome-wide mutation screens with only two generations of breeding. Mice potentially homozygous for mutations were obtained by crossing chimeras derived from ethylmethane sulfonate (EMS)-mutagenized ES cells to their daughters, or by intercrossing offspring of chimeras. This strategy was possible because chimeras transmit variations of the same mutagenized diploid genome, whereas ENU-treated males transmit numerous unrelated genomes. This also results in a doubling of screenable mutations in a pedigree compared to germline ENU mutagenesis. Coupled with the flexibility to treat ES cells with a variety of potent mutagens and the ease of producing distributable, quality-controlled, long-term supplies of cells in a single experiment, this strategy offers a number of advantages for conducting forward genetic screens in mice.
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2,338,570 |
Complete mitochondrial genome sequences of the South american and the Australian lungfish: testing of the phylogenetic performance of mitochondrial data sets for phylogenetic problems in tetrapod relationships.
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We determined the complete nucleotide sequences (16403 and 16572 base pairs, respectively) of the mitochondrial genomes of the South American lungfish, Lepidosiren paradoxa, and the Australian lungfish, Neoceratodus forsteri (Sarcopterygii, Dipnoi). The mitochondrial DNA sequences were established in an effort to resolve the debated evolutionary positions of the lungfish and the coelacanth relative to land vertebrates. Previous molecular phylogenetic studies based on complete mtDNA sequences, including only the African lungfish, Protopterus dolloi, sequence were able to strongly reject the traditional textbook hypothesis that coelacanths are the closest relatives of land vertebrates. However, these studies were unable to statistically significantly distinguish between the two remaining scenarios: lungfish as the closest relatives to land vertebrates and lungfish and coelacanths jointly as their sister group (Cao et al. 1998; Zardoya et al. 1998; Zardoya and Meyer 1997a). Lungfish, coelacanths, and the fish ancestors of the tetrapod lineage all originated within a short time window of about 20 million years, back in the early Devonian (about 380 to 400 million years ago). This short divergence time makes the determination of the phylogenetic relationships among these three lineages difficult. In this study, we attempted to break the long evolutionary branch of lungfish, in an effort to better resolve the phylogenetic relationships among the three extant sarcopterygian lineages. The gene order of the mitochondrial genomes of the South American and Australian lungfish conforms to the consensus gene order among gnathostome vertebrates. The phylogenetic analyses of the complete set of mitochondrial proteins (without ND6) suggest that the lungfish are the closest relatives of the tetrapods, although the support in favor of this scenario is not statistically significant. The two other smaller data sets (tRNA and rRNA genes) give inconsistent results depending on the different reconstruction methods applied and cannot significantly rule out any of the three alternative hypotheses. Nuclear protein-coding genes, which might be better phylogenetic markers for this question, support the lungfish-tetrapod sister-group relationship (Brinkmann et al. 2004).
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2,338,571 |
Uptake of offer to receive genetic information about BRCA1 and BRCA2 mutations in an Australian population-based study.
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Research on the utilization of genetic testing services for mutations in BRCA1 and BRCA2 has focused on women with a strong family history of breast and ovarian cancer. We conducted a population-based case-control-family study of Australian women diagnosed with invasive breast cancer before age 40 years, unselected for family history, and tested for germ line mutations in BRCA1 and BRCA2. Case subjects found to carry a deleterious mutation and their relatives who had given a research blood sample were informed by mail that the study had identified "genetic information" and were offered the opportunity to learn more. Those interested were referred to a government-funded family cancer clinic. Of 94 subjects who received the letter, 3 (3%) did not respond and 38 (40%) declined to learn their result (16 declined the referral, 10 accepted but did not attend a clinic, and 12 attended a clinic but declined testing), and 12 (13%) remain "on hold." The remaining 41 (44%) chose to learn their result (3 of whom already knew their mutation status). There was no evidence that the decision to learn of mutation status depended on age, gender, family history, or having been diagnosed with breast cancer. Of 19 families with more than one participant, in 11 (58%) there was discordance between relatives in receiving genetic results. Although in Australia genetic testing is offered free of charge and insurance issues are not a major consideration, we found considerable reluctance, indecision, and unexplained variability both between and within case families in the desire to know their mutation status.
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2,338,572 |
Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites.
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Data from several countries indicate that 1% to 2% of Ashkenazi Jews carry a pathogenic ancestral mutation of the tumor suppressor gene BRCA1. However, the prevalence of BRCA1 mutations among non-Ashkenazi Whites is uncertain. We estimated mutation carrier prevalence in U.S. non-Hispanic Whites, specific for Ashkenazi status, using data from two population-based series of San Francisco Bay Area patients with invasive cancers of the breast or ovary, and data on breast and ovarian cancer risks in Ashkenazi and non-Ashkenazi carriers. Assuming that 90% of the BRCA1 mutations were detected, we estimate a carrier prevalence of 0.24% (95% confidence interval, 0.15-0.39%) in non-Ashkenazi Whites, and 1.2% (95% confidence interval, 0.5-2.6%) in Ashkenazim. When combined with U.S. White census counts, these prevalence estimates suggest that approximately 550,513 U.S. Whites (506,206 non-Ashkenazim and 44,307 Ashkenazim) carry germ line BRCA1 mutations. These estimates may be useful in guiding resource allocation for genetic testing and genetic counseling and in planning preventive interventions.
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2,338,573 |
Utilization of screening and preventive surgery among unaffected carriers of a BRCA1 or BRCA2 gene mutation.
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Women who are carriers of BRCA gene mutations have an elevated lifetime risk of developing breast or ovarian cancer. Although a number of risk-reducing options are currently available to mutation carriers, uncertainty exists in terms of their efficacy. A systematic review of the literature was conducted to describe the utilization of screening and preventive surgery among unaffected mutation carriers in the face of uncertainty.</AbstractText>MEDLINE, PubMed, and CANCERLIT, English-only computerized literature searches were done to identify articles pertaining to decisions made by unaffected BRCA mutation carriers to reduce risk of breast and ovarian cancer. Studies were required to include information on choices taken by at-risk women following disclosure of a positive BRCA test.</AbstractText>Only seven studies (5 American and 2 Dutch studies) were identified. The proportion of mutation carriers who chose preventive surgery over screening varied widely across the studies, ranging from 0% to 54% for prophylactic mastectomy and from 13% to 53% for prophylactic oophorectomy. Furthermore, a significant minority of women who chose surveillance failed to comply with the recommended schedule.</AbstractText>There is considerable variability within and between countries in risk reduction strategies utilized by healthy mutation carriers. This variability may relate to differences in (1) population characteristics; (2) recommendations for follow-up care of unaffected carriers; (3) prevailing values towards body integrity, femininity, and preventive surgery; and (4) health care funding systems. Future research needs to provide further insight into factors influencing women's decisions to adopt various risk reduction strategies.</AbstractText>
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2,338,574 |
Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism.
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It has recently been shown that loss-of-function mutations of the G protein-coupled receptor (GPR)54 lead to isolated hypogonadotropic hypogonadism (IHH) in mice and humans. Such mutations are thought to be rare, even within the clinical IHH population, and only a handful of alleles have been described, making further screening of IHH populations imperative. We examined the genes encoding GPR54 and its putative endogenous ligand, kisspeptin-1, for mutations in a cohort of 30 patients with normosmic HH or delayed puberty. One subject with HH, of mixed Turkish-Cypriot and Afro-Caribbean ancestry, was found to be a compound heterozygote for two previously undescribed missense mutations in GPR54: cysteine 223 to arginine (C223R) in the fifth transmembrane helix and arginine 297 to leucine (R297L) in the third extracellular loop. Assessed in vitro using a previously described sensitive signaling assay in cells stably expressing GPR54, the C223R variant was found to exhibit profoundly impaired signaling, whereas the R297L variant showed a mild reduction in ligand-stimulated activity across the ligand dose range. These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54.
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2,338,575 |
Population consequences of fipronil and degradates to copepods at field concentrations: an integration of life cycle testing with leslie matrix population modeling.
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The predominant data used in ecological risk assessment today are individual-based rather than population-based; yet environmental policies are usually designed to protect populations of threatened species or communities. Most current methods in ecotoxicology are limited by largely logistic/ technology-driven requirements that yield data for a relatively small number of test species and end points that focus on acute lethality or sublethal nonproduction-based parameters (e.g., biomarkers, mutagenesis, genetic change, physiological condition). A contrasting example is presented here showing the predictive ability of meiobenthos-based full life cycle toxicity testing to extrapolate multi-generational effects of chemicals on variables of import to population growth and maintenance. Less than 24-h-old larvae of a meiobenthic copepod were reared individually in 96-well microplate exposures to parent and degradates of the phenylpyrazole insecticide fipronil. Survival, development rates, sex ratio change, fertility, fecundity, and hatching success were tracked daily for 32 d through mating and production of three broods in spiked seawater. These data were then inserted in a Leslie (Lefkovitch) matrix stage-based population growth model to predict relative rates of population increase (lambda) and changes in net population growth with time and toxicant concentration. Field-reported test concentrations produced strong reproductive (52-88%) and net production (40-80%) depressions for parent (at 0.25 and 0.5 microg/L), desthionyl (0.25 and 0.5 microg/L), and sulfide (0.15 microg/L) moieties as compared to controls. Spiked sediment exposures of 65-300 ng of fipronil/g of dry sediment yielded significantly reduced production rates per female that were 67-50% of control production. The consistent reproductively linked impacts of fipronil and its degradation products at the population maintenance levels suggest risks to sediment-dwelling crustaceans at concentrations well below noneffects for most aquatic test species based on risk assessment data from primarily acute and sub-life cycle toxicity tests.
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2,338,576 |
Microarray genotyping resource to determine population stratification in genetic association studies of complex disease.
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We have developed a robust microarray genotyping chip that will help advance studies in genetic epidemiology. In population-based genetic association studies of complex disease, there could be hidden genetic substructure in the study populations, resulting in false-positive associations. Such population stratification may confound efforts to identify true associations between genotype/haplotype and phenotype. Methods relying on genotyping additional null single nucleotide polymorphism (SNP) markers have been proposed, such as genomic control (GC) and structured association (SA), to correct association tests for population stratification. If there is an association of a disease with null SNPs, this suggests that there is a population subset with different genetic background plus different disease susceptibility. Genotyping over 100 null SNPs in the large numbers of patient and control DNA samples that are required in genetic association studies can be prohibitively expensive. We have therefore developed and tested a resequencing chip based on arrayed primer extension (APEX) from over 2000 DNA probe features that facilitate multiple interrogations of each SNP, providing a powerful, accurate, and economical means to simultaneously determine the genotypes at 110 null SNP loci in any individual. Based on 1141 known genotypes from other research groups, our GC SNP chip has an accuracy of 98.5%, including non-calls.
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2,338,577 |
Guthrie test samples: is the problem solved?
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Most babies born in New Zealand have a blood sample taken shortly after birth for the purposes of certain screening tests. The samples are retained indefinitely. This paper considers whether such samples are the property of the child and whether the present changes in the Health (National Cervical Screening Programme) Amendment Bill and the Code of Health and Disability Services Consumers' Rights of 1996 are sufficient to resolve the issues. The paper expresses concern about the delegation of decision-making in this area to ethics committees.
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2,338,578 |
Cytogeneticists' stories around the ethics and social consequences of their work: a New Zealand case study.
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This paper is based on anthropological research in three New Zealand cytogenetics laboratories involving participant observation carried out over three months and interviews with sixteen cytogeneticists in order to elucidate the distinctive characteristics of their views on the social consequences of their work in prenatal genetic testing. The discourses employed by cytogeneticists to describe their work are placed against other discourses in the contemporary debate surrounding prenatal genetic testing, i.e. clinical, ethical, feminist, social science and disability rights. In general, cytogeneticists frame their moral responsibilities in terms of the need to carry out what we have termed 'distanced care' of both the mothers being tested and the foetal cells which they cultivate in the laboratories. Certain paradoxes arise in these accounts of their work however, such as the idea of distanced care versus their demonstrated personalisation of the foetal cells with which they work and also between their burdensome awareness of the consequences for individual women of their karyotyping and their repeated references to the ethical and social consequences of their work as being determined by society not by their own actions.
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2,338,579 |
APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study.
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Both family aggregation and apolipoprotein E (APOE) epsilon4 allele are well-known risk factors for dementia, but the relation between these two factors remains unclear.</AbstractText>To explore whether the risk of dementia and Alzheimer disease (AD) due to a positive family history is explained by APOE genotypes.</AbstractText>Community-based cohort study.</AbstractText>The Kungsholmen district of Stockholm, Sweden.</AbstractText>A total of 907 nondemented people 75 years or older, followed up for 6 years to detect incident dementia and AD cases according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.</AbstractText>Risk of dementia and AD by Cox proportional hazards models after controlling for several potential confounders.</AbstractText>Subjects who had at least 2 siblings with dementia were at an increased risk of AD. Individuals with both APOE epsilon4 allele and at least 2 affected first-degree relatives had a higher risk of dementia and AD compared with those without these 2 factors. Similar results were obtained for history of dementia separately in parents or siblings. Among the epsilon4 allele carriers, subjects with 2 or more first-degree demented relatives had increased risk of dementia and AD, whereas no increased risk was detected among non-epsilon4 carriers.</AbstractText>Family history of dementia was associated with an increased risk of dementia and AD in this very old population, but only among APOE epsilon4 carriers. This suggests the existence of other genetic or environmental risk factors that may be active in the presence of the APOE epsilon4 allele.</AbstractText>
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2,338,580 |
A Leishmania major response locus identified by interval-specific congenic mapping of a T helper type 2 cell bias-controlling quantitative trait locus.
|
The propensity of naive CD4 T cells to become T helper (Th) type 2 cells correlates with susceptibility to infection by the protozoal parasite Leishmania major. Using genetic linkage analysis, we earlier identified Dice1 as a Th2 cell bias-controlling quantitative trait locus on chromosome 16. Using interval-specific congenic mapping, we now resolve Dice1 into two independent genetic loci, Dice1.1 and Dice1.2, which control Il4 expression from naive Th cells and thereby indirectly control Th2 cell bias. Interestingly, only one of the two congenic intervals containing Dice1.1 and Dice1.2, respectively, also contained an L. major response locus, indicating that L. major responsiveness can be insensitive to determinants that influence Th2 cell bias by controlling naive T cell Il4 expression. These results lay the groundwork for identifying the Dice1.1 and Dice1.2 genes controlling naive T cell Il4 expression and L. major responses, and for testing whether these control other Th2 cell-dependent processes such as worm expulsion, allergic asthma, and dermatitis.
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2,338,581 |
Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex.
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To find the mutation and polymorphism spectrum of TSC1 and TSC2 genes in patients affected with tuberous sclerosis complex from the Indian population.</AbstractText>All coding exons and promoter regions of both TSC genes were screened for mutations and polymorphisms in 24 TSC families using polymerase chain reaction-single strand conformation polymorphism and DNA sequencing techniques.</AbstractText>A single previously known mutation, c.2111_2112delAT was identified in the TSC1 gene. A total of 11 mutations were identified in the TSC2 gene. Of these, seven mutations, c.137_138delGA, c.2070delC, c.2087_2088insAA, c.3080T>C (p.L1027P), c.648+1G>A, c.3131+1G>A and c.5034C>G were novel. The remaining four mutations, c.4544_4547delACAA, c.1941_1942insT, c.1831C>T (p.R611W) and c.1832G>A (p.R611Q) had been reported previously in other populations. The novel mutation, c.137_138delGA was predicted to result in the production of a very small tuberin protein of 64 amino acids lacking all seven functional domains. In addition, we also detected three and 10 polymorphisms in the TSC1 and TSC2 genes respectively. DNA sequence analysis of promoter regions of both TSC genes in 24 families did not show any variation.</AbstractText>This is the first molecular genetic study of TSC in an Indian population. A total of 12 mutations were detected in 24 Indian TSC families in TSC genes. All except one mutation were detected in the TSC2 gene. No variation was found in the promoter regions of either gene. As observed in the western and Japanese populations, the mutations were scattered across the TSC2 gene.</AbstractText>Blackwell Munksgaard 2004</CopyrightInformation>
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2,338,582 |
Heterogeneity testing in meta-analysis of genome searches.
|
Genome searches for identifying susceptibility loci for the same complex disease often give inconclusive or inconsistent results. Genome Search Meta-analysis (GSMA) is an established non-parametric method to identify genetic regions that rank high on average in terms of linkage statistics (e.g., lod scores) across studies. Meta-analysis typically aims not only to obtain average estimates, but also to quantify heterogeneity. However, heterogeneity testing between studies included in GSMA has not been developed yet. Heterogeneity may be produced by differences in study designs, study populations, and chance, and the extent of heterogeneity might influence the conclusions of a meta-analysis. Here, we propose and explore metrics that indicate the extent of heterogeneity for specific loci in GSMA based on Monte Carlo permutation tests. We have also developed software that performs both the GSMA and the heterogeneity testing. To illustrate the concept, the proposed methodology was applied to published data from meta-analyses of rheumatoid arthritis (4 scans) and schizophrenia (20 scans). In the first meta-analysis, we identified 11 bins with statistically low heterogeneity and 8 with statistically high heterogeneity. The respective numbers were 9 and 6 for the schizophrenia meta-analysis. For rheumatoid arthritis, bins 6.2 (the HLA region that is a well-documented susceptibility locus for the disease) and 16.3 (16q12.2-q23.1) had both high average ranks and low between-study heterogeneity. For schizophrenia, this was seen for bin 3.2 (3p25.3-p22.1) and heterogeneity was still significantly low after adjusting for its high average rank. Concordance was high between the proposed metrics and between weighted and unweighted analyses. Data from genome searches should be synthesized and interpreted considering both average ranks and heterogeneity between studies.
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2,338,583 |
Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees.
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Several genetic predisposition loci for prostate cancer have been identified through linkage analysis, and it is now generally recognized that no single gene is responsible for more than a small proportion of prostate cancers. However, published confirmations of these loci have been few, and failures to confirm have been frequent. The genetic etiology of prostate cancer is clearly complex and includes significant genetic heterogeneity, phenocopies, and reduced penetrance. Powerful analyses that involve robust statistics and methods to reduce genetic heterogeneity are therefore necessary. We have performed linkage analysis on 143 Utah pedigrees for the previously published Xq27-28 (HPCX) prostate cancer susceptibility locus. We employed a robust multipoint statistic (TLOD) and a novel splitting algorithm to reduce intra-familial heterogeneity by iteratively removing the top generation from the large Utah pedigrees. In a dataset containing pedigrees having no more than five generations, we observed a multipoint TLOD of 2.74 (P=0.0002), which is statistically significant after correction for multiple testing. For both the full-structure pedigrees (up to seven generations) and the smaller sub-pedigrees, the linkage evidence was much reduced. This study thus represents the first significant confirmation of HPCX (Xq27-28) and argues for the continued utility of large pedigrees in linkage analyses for complex diseases.
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2,338,584 |
Familial polyposis coli: clinical manifestations, evaluation, management and treatment.
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Familial adenomatous polyposis (FAP) is an autosomal dominant, hereditary colon cancer syndrome that is characterized by the presence of innumerable adenomatous polyps in the colon and rectum. Gardner's syndrome is a variant of FAP, which in addition to the colonic polyps, also presents extracolonic manifestations, including desmoid tumors, osteomas, epidermoid cysts, various soft tissue tumors, and a predisposition to thyroid and periampullary cancers. Mutations of the APC gene are thought to be responsible for the development of FAP, and the location of the mutation on the gene is thought to influence the nature of the extracolonic manifestations that a given patient might develop. Though patients are often asymptomatic, bleeding, diarrhea, abdominal pain and mucous discharge frequently occur. Diagnostic tools include genetic testing, endoscopy, and monitoring for extra-intestinal manifestations. Currently, surgery is the only effective means of preventing progression to colorectal carcinoma. Restorative proctocolectomy with ileal pouch anal anastomosis (RPC/IPAA) with mucosectomy is the preferred surgical procedure, since it attempts to eliminate all colorectal mucosa without the need for an ostomy. Periampullary carcinoma and intra-abdominal desmoid tumors are a significant cause of morbidity and mortality in these patients after colectomy. Frequent endoscopy is needed to prevent the former, while there is no definitive treatment available yet for the latter. The following article presents a case and reviews the evaluation, management and treatment of Gardner's syndrome.
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2,338,585 |
A model for GFR alpha 4 function and a potential modifying role in multiple endocrine neoplasia 2.
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Mutations of the RET proto-oncogene are found in the majority of patients with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). A minority of cases, however, have no detectable RET mutation and there is considerable phenotypic variation within and among MEN 2 families with the same RET mutation, suggesting a role for other loci in this disease. A candidate for such a gene is glial cell line-derived neurotrophic factor receptor alpha 4 (GFRA4), which encodes a cell surface-bound co-receptor (GFR alpha 4) required for interaction of RET with its ligand persephin. The GFRA4 gene has multiple alternative splices leading to three distinct protein isoforms that are prominently expressed in thyroid. We postulated that mutations of GFRA4 contribute to MEN 2 in the absence of RET mutations or modify the RET mutation phenotype. We screened patients with MEN 2 or MEN 2-like phenotypes, with and without RET mutations, for variants of GFRA4. We identified 10 variants, one of which was over represented in, and two of which were found exclusively in, our patient populations. One of these was a single-base substitution upstream of the GFR alpha 4 coding region, where it may alter gene expression. The second was a 7 bp insertion, which results in a change in reading frame for all three GFR alpha 4 isoforms. This would cause a relative shift in membrane bound and soluble forms of GFR alpha 4, which would significantly alter the formation of RET signalling complexes. Our data suggest a model of wild-type GFR alpha 4 isoform expression that includes both activating and inhibiting co-receptors for RET.
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2,338,586 |
Asymptomatic microhematuria: an indication of hereditary hemorrhagic telangiectasia?
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Hereditary hemorrhagic telangiectasia (HHT) is a genetic angiodysplasia affecting multiple organs. Clinical manifestations include spontaneous and recurrent epistaxis, mucocutaneous telangiectases that bleed easily and arteriovenous malformations in many organs. Despite the anecdotal recommendations of some groups, to our knowledge information regarding the prevalence of microscopic hematuria (MH) in patients with HHT has not been reported to date. We evaluated the prevalence of MH in patients with HHT.</AbstractText>Between January 2002 and June 2003, 116 consecutive patients with HHT were studied, of whom 20 were excluded because of a possible false-positive MH bias. Therefore, 53 males and 43 females with a mean age +/- SD of 45.8 +/- 15.8 years who had HHT underwent urine dipstick testing for heme and microscopic urinary examination. A control group of 192 males and 148 females with a mean age of 46.5 +/- 14.2 years and no statistical age or sex differences without HHT who were hospitalized in the same period at the same medical unit for gastrointestinal disorders was compared to the HHT cohort.</AbstractText>MH was detected in 45 of 96 patients with HHT (47%) compared to 41 of 340 controls (12%) (p <0.0005). None of the patients with HHT showed abnormal renal function, proteinuria, hypercalciuria or hyperuricosuria. MH was due to glomerular hematuria in 29 of 45 patients (65%), postglomerular hematuria in 13 (29%) and mixed hematuria in 3 (6%). No gross hematuria was detected.</AbstractText>Our results show that MH is common in patients with HHT. This might indicate the possibility of weak urinary tract bleeding due to telangiectases and/or small arteriovenous fistulas, which are typical HHT lesions. Therefore, HHT should be considered among the causes of MH. Urinalysis should always be performed when there is severe anemia in HHT patients with HHT, particularly those without other apparent bleeding sites.</AbstractText>
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2,338,587 |
Cost effectiveness of a new strategy to identify HNPCC patients.
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Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives.</AbstractText>To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years.</AbstractText>The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals.</AbstractText>Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of 3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became 2184 per life year gained. Sensitivity analysis showed these findings to be robust.</AbstractText>MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.</AbstractText>
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2,338,588 |
In silico fine-mapping: narrowing disease-associated loci by intergenomics.
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Genetic linkage and association studies define quantitative trait loci (QTLs) and susceptibility loci (SLs) that influence the phenotype of polygenic traits. A web-accessible application was created to identify intergenomic consensuses to fine map QTLs and SLs in silico and select particularly promising candidate genes for such traits. Furthermore, this approach offers an empirical evaluation of animal models for their applicability to the study of human traits.</AbstractText>http://qtl.pzr.uni-rostock.de/qtlmix.php</AbstractText>[email protected].</AbstractText>
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2,338,589 |
Detection of aneuploidies by paralogous sequence quantification.
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Chromosomal aneuploidies are a common cause of congenital disorders associated with cognitive impairment and multiple dysmorphic features. Pre-natal diagnosis of aneuploidies is most commonly performed by the karyotyping of fetal cells obtained by amniocentesis or chorionic villus sampling, but this method is labour intensive and requires about 14 days to complete.</AbstractText>We have developed a PCR based method for the detection of targeted chromosome number abnormalities termed paralogous sequence quantification (PSQ), based on the use of paralogous genes. Paralogous sequences have a high degree of sequence identity, but accumulate nucleotide substitutions in a locus specific manner. These sequence differences, which we term paralogous sequence mismatches (PSMs), can be quantified using pyrosequencing technology, to estimate the relative dosage between different chromosomes. We designed 10 assays for the detection of trisomies of chromosomes 13, 18, and 21 and sex chromosome aneuploidies.</AbstractText>We evaluated the performance of this method on 175 DNAs, highly enriched for abnormal samples. A correct and unambiguous diagnosis was given for 119 out of 120 aneuploid samples as well as for all the controls. One sample which gave an intermediate value for the chromosome 13 assays could not be diagnosed.</AbstractText>Our data suggests that PSQ is a robust, easy to interpret, and easy to set up method for the diagnosis of common aneuploidies, and can be performed in less than 48 h, representing a competitive alternative for widespread use in diagnostic laboratories.</AbstractText>
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2,338,590 |
Genome-wide scan linkage analysis for Parkinson's disease: the European genetic study of Parkinson's disease.
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To undertake a full genome-wide screen for Parkinson's disease susceptibility loci.</AbstractText>A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson's disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at approximately 10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test.</AbstractText>There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11-q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11-q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (approximately 17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance.</AbstractText>These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11-q12 and 5q23 regions, with these two regions contributing independently to Parkinson's disease susceptibility.</AbstractText>
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2,338,591 |
Screening for subtelomeric rearrangements in 210 patients with unexplained mental retardation using multiplex ligation dependent probe amplification (MLPA).
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Subtelomeric rearrangements contribute to idiopathic mental retardation and human malformations, sometimes as distinct mental retardation syndromes. However, for most subtelomeric defects a characteristic clinical phenotype remains to be elucidated.</AbstractText>To screen for submicroscopic subtelomeric aberrations using multiplex ligation dependent probe amplification (MLPA).</AbstractText>210 individuals with unexplained mental retardation were studied. A new set of subtelomeric probes, the SALSA P036 human telomere test kit, was used.</AbstractText>A subtelomeric aberration was identified in 14 patients (6.7%) (10 deletions and four duplications). Five deletions were de novo; four were inherited from phenotypically normal parents, suggesting that these were polymorphisms. For one deletion, DNA samples of the parents were not available. Two de novo submicroscopic duplications were detected (dup 5qter, dup 12pter), while the other duplications (dup 18qter and dup 22qter) were inherited from phenotypically similarly affected parents. All clinically relevant aberrations (de novo or inherited from similarly affected parents) occurred in patients with a clinical score of >or=3 using an established checklist for subtelomeric rearrangements. Testing of patients with a clinical score of >or=3 increased the diagnostic yield twofold to 12.4%. Abnormalities with clinical relevance occurred in 6.3%, 5.1%, and 1.7% of mildly, moderately, and severely retarded patients, respectively, indicating that testing for subtelomeric aberrations among mildly retarded individuals is necessary.</AbstractText>The value of MLPA is confirmed. Subtelomeric screening can be offered to all mentally retarded patients, although clinical preselection increases the percentage of chromosomal aberrations detected. Duplications may be a more common cause of mental retardation than has been appreciated.</AbstractText>
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2,338,592 |
Construction of a eukaryotic expression system of HSP65 gene from Mycobacterium tuberculosis, and anti-HSP65 IgG produced in mice.
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The purpose of this study was to express the HSP65 gene of Mycobacterium tuberculosis in eukaryotic cells and study its primary immune effect in animals. The HSP65 gene was amplified from the H37Rv strain of M. tuberculosis by PCR and then inserted into the expression plasmid pcDNA3.1(-). The recombinant plasmid pcHSP65 was transfected into HeLa cells by using the liposome transfection method and also injected into BALB/C mice to accomplish DNA immunization. The inserted gene was demonstrated to be identical to the reported HSP65 gene sequence. The transfected HeLa cells expressed HSP65 protein; Western blot showed the presence of a 65 kDa band of the inclusion body protein and immunofluorescence testing identified the protein expressed in cytoplasm. Specific IgG for the HSP65 protein could be identified in immunized mice. This study shows that recombinant eukaryotic expression plasmid pcHSP65 was constructed successfully, which lays a foundation for further study of gene therapy.
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2,338,593 |
Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum.
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Some clinical isolates of Mycobacterium fortuitum are naturally resistant to macrolides, e.g. clarithromycin. Thus, the aim of this study was to identify the gene(s) conferring this resistance.</AbstractText>M. fortuitum ATCC 6841T DNA libraries were screened for plasmids that complemented the macrolide-susceptible phenotype of Mycobacterium smegmatis variant ermKO4 [erm(38)-negative]. Macrolide-resistant M. smegmatis transformants were selected on agar containing 128 mg/L erythromycin.</AbstractText>Genetic complementation identified an M. fortuitum rRNA methylase gene, termed erm(39), 69% identical to erm(38) of M. smegmatis. In addition, erm(39) was found to be in the same chromosomal location as erm(38) in their respective hosts. Like erm(38), erm(39) conferred resistance (MIC >128 mg/L) to macrolide-lincosamide (ML) agents, but not to streptogramin B. Analysis of erm gene expression in M. fortuitum showed that ML agents increased erm(39) RNA levels, reaching a steady state level approximately 20-fold higher than baseline. Screening of 32 M. fortuitum clinical isolates by PCR showed that all were positive for erm(39), irrespective of clarithromycin susceptibility. A majority of clarithromycin-susceptible (MIC < or = 2 mg/L) isolates were postulated to carry a disabled erm(39) gene as they had a GTG-->CTG mutation in the putative initiation codon of the erm(39) gene.</AbstractText>The similarity of the erm genes of M. smegmatis and M. fortuitum suggests that they were inherited from a common ancestor. Although the clinical impact of erm(39) on the therapeutic utility of clarithromycin is unclear, induction of this gene is consistent with the trailing end-points commonly seen during susceptibility testing of M. fortuitum isolates against macrolides.</AbstractText>
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2,338,594 |
Endoscopic closure of fetal membrane defects: comparing iatrogenic versus spontaneous rupture cases.
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Currently, physicians manage preterm premature rupture of membranes (PPROM) by expectant management or termination of the gestation. A therapy aimed at sealing membranes would be optimal to maintain the pregnancy and achieve a normal neonate. Our objective was to compare an endoscopic technique for intrauterine closure of fetal membrane defects after both iatrogenic and spontaneous rupture of membranes.</AbstractText>Our technique was performed on four patients experiencing PPROM spontaneously and four patients after genetic amniocentesis. Intrauterine endoscopy allowed direct visualization of membrane defects. Rapid sequential injections of platelets, fibrin glue and powdered collagen slurry were administered at the site of the defect and of trocar placement. Sonography for amniotic fluid index, nitrazine and fern testing and pad count were performed after each procedure at three intervals: immediately post-procedure, and after 24 and 48 h.</AbstractText>Eight patients underwent endoscopic intrauterine sealing of ruptured membranes between 16 and 24 weeks of gestation: four were spontaneous ruptures and four were ruptures post-amniocentesis. In the post-amniocentesis group, three patients delivered viable infants at 26, 32 and 34 weeks. In one patient, the membranes ruptured again 12 h after the sealing procedure and she decided to undergo termination of pregnancy. Of the four spontaneous rupture patients, two experienced preterm labor and delivery within 2 days of the procedure. One patient was diagnosed with fetal demise 12 h post-procedure, and one patient delivered a neonate at 31 weeks of gestation with severe respiratory distress syndrome.</AbstractText>This technique for sealing ruptured membranes is effective after amniocentesis, but may not be of benefit with spontaneous rupture.</AbstractText>
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2,338,595 |
Screening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class I HDAC profiles between epithelial and stromal cells.
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Histone deacetylases (HDACs) represent a large family of enzymes identified as key regulators of nucleosomal histone acetylation, a major epigenetic event that controls eukaryotic gene transcription. Inappropriate deacetylation mediated by HDACs has been associated with profound alterations in cellular biology. We have thus hypothesized that an altered HDAC expression may favor cancer development/progression. To test this possibility, we have sought to screen the expression profiles of several class I and class II HDACs (HDAC1-8) in DU-145, PC-3 and LNCaP human prostate cancer cell lines as well as in matched malignant and non-malignant prostate tissues by use of real time RT-PCR, immunoblot and immunohistochemistry. All HDAC transcripts tested were detected at various levels in all prostate cancer cell lines and tissue samples analyzed. In prostate tissues, the abundance of HDAC1 protein, which was exclusively expressed in the cell nucleus, was similar in normal and malignant epithelial cells, but was usually lower in stromal cells. Unexpectedly, HDAC8, another class I HDAC, was not detected in epithelial cells but was uniquely expressed in the cytoplasm of stromal cells. HDAC5, a class II HDAC involved in myogenesis, was not detected in the tissues. Altogether, our findings indicate that epithelial and stromal cells exhibit distinct class I HDAC expression profiles, and the abundance of HDAC1 is not altered in human prostate cancer. In addition, our observations are the first to demonstrate the prominently cytosolic distribution of a class I HDAC, HDAC8.
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2,338,596 |
Molecular characterization of hemophilia B in North Indian families: identification of novel and recurrent molecular events in the factor IX gene.
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Hemophilia B is an X-linked recessive, bleeding disorder caused by mutations in the factor IX gene. A wide range of mutations, showing large molecular heterogeneity, has been described in hemophilia B patients. Our study was aimed at characterizing mutations in the factor IX gene in a cohort of North Indian hemophilia B patients.</AbstractText>Polymerase chain reaction (PCR) amplification and direct sequencing of all regions of likely functional significance- the coding regions, promoter, the 5' UTR, the splice junctions and parts of the 3' UTR of the factor IX gene was done in 18 families carrying a severe form of hemophilia B.</AbstractText>We identified 10 point mutations (including 2 novel ones); one novel deletion and one donor splice site mutation. Recurrence of a nonsense and a missense mutation was observed. The mutation in 3 families could not be characterized. None of the 14 polymorphic positions reported in the Haemophilia B Mutation database in the regions sequenced were polymorphic; herein we report four novel synonymous single base mismatches. One mutation reported to be causative in the database was found to be more likely a non-causal polymorphism.</AbstractText>Our data confirm the remarkable heterogeneity of the mutational spectrum in hemophilia B among affected families. This is the first mutation report on the disease in the Indo-Aryan population from the Indian subcontinent. Identification of a causative mutation leads to more precise carrier detection than does conventional polymorphism-based linkage analysis. This can effectively be used to establish genotype/ phenotype relationships.</AbstractText>
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2,338,597 |
Absence of de novo Y-chromosome microdeletions in male children conceived through intracytoplasmic sperm injection.
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Molecular screening for Y-chromosome microdeletions in 96 Spanish male children conceived through intracytoplasmic sperm injection (ICSI) was conducted. No microdeletions were detected; these results support the notion that de novo Y-chromosome alterations are rare and unrelated to the ICSI technique itself.
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2,338,598 |
Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models.
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To evaluate subrenal capsule xenografting of primary ovarian tumor tissues in mice for development of new ovarian cancer models.</AbstractText>Pieces (1 x 3 x 3 mm) of ovarian tumor specimens from patients were meticulously grafted under renal capsules of female NOD/SCID mice within 2 h of surgical removal. Tumor types included papillary serous adenocarcinomas, borderline and benign mucinous cystadenomas, granulosa cell tumors, a serous borderline tumor and a grade 3 mixed surface epithelial tumor of transitional and undifferentiated types. After 1-2 months, grafts were retrieved for comparison with original tissues. Hematoxylin and eosin (H&E) and immunohistochemical staining was carried out using tissue micro-arrays and CEA, B72.3, WT-1, OC125, keratin, inhibin, CK7, CK20, Cam5.2, and MIB-1 as markers.</AbstractText>Tumor tissue engraftment rate was > 95%. Comparison of donor and post-graft tissues showed highly similar histopathological features; 91 +/- 5% concordance in immunostaining indicated major preservation of immunophenotypes in the xenografts for 30-60 days. There was a small, but significant, increase in MIB-1 proliferative index in xenografts compared to original specimens.</AbstractText>Subrenal capsule xenografts of primary human ovarian tumors in SCID mice can retain major histopathological and immunohistochemical characteristics of the original tissues. The achievable, consistently high engraftment rate allows use of such xenografts as tools for studying a wide range of ovarian tumors, including granulosa cell tumors and benign, borderline, and malignant surface epithelial neoplasms. Potential applications include preclinical testing of patients' tumor responses to various chemotherapeutic regimens, evaluation of novel therapeutic agents, analysis of tumor progression at cellular and molecular levels, and identification of new therapeutic targets.</AbstractText>
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2,338,599 |
Genetic osteoarticular diseases under the molecular biology spotlight.
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Major strides have been made recently in unraveling the genetic underpinnings of various bone and joint diseases. In many cases, progress in molecular biology has provided detailed knowledge in this area. An overview is given herein.
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