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2,338,000 |
Molecular heterogeneity of beta-thalassemia in the United Arab Emirates.
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The beta-thalassemia alleles in 313 national patients of the United Arab Emirates (UAE) have been characterized using PCR-based DNA-diagnostic techniques including DNA sequencing. A total of 212 patients had homozygous beta-thalassemia and the remaining 101 were compound heterozygotes. More than half of the patients were homozygous for the IVS-I-5 (G-->C) mutation followed by the sickle cell gene. The latter accounted for 25% of the chromosomes. In terms of frequency, five beta-thalassemia mutations; IVS-I-5 (G-->C), betaS, -25 bp del, Cd 8/9 (+G) and IVS-II-1 (G-->A) accounted for 83% of the alleles. In addition, 427 expatriate patients were studied: 256 with homozygous beta-thalassemia and 171 were compound heterozygotes. In both the UAE nationals and expatriates, the beta-thalassemia mutations and their frequency followed a similar trend. Our results indicate that the frequency of beta-globin gene defects including beta-thalassemia, sickle cell gene (betaS) and abnormal hemoglobins is significantly increased and poses a major public health problem in the UAE. The number of homozygous patients strongly suggests a high degree of consanguinity among the UAE nationals. With 50 different beta-thalassemia alleles, UAE is arguably the most heterogeneous population in the world. The diversity of these mutations reflects the historical admixture of genes and their migration from different areas in the region. Our data strongly suggest the need for a comprehensive thalassemia control program and provides a basis for population screening, genetic counseling and prenatal diagnosis.
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2,338,001 |
Genetic contribution to high neonatally lethal malformation rate in the United Arab Emirates.
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We examined the contribution of genetic disorders to congenital anomalies (CA) causing neonatal deaths in the Al Ain Medical District (AMD) in the United Arab Emirates (UAE) because of the high consanguineous marriage rate in the community.</AbstractText>Charts of all neonatal deaths in the three perinatal units, which accounted for 99% of all births in AMD (1992-2000), were studied. Data regarding pregnancy, a family history including the level of parental consanguinity, the results of genetic evaluations and neonatal outcomes were recorded as part of an ongoing malformation surveillance system. Causes of death were based on clinical, laboratory and imaging findings.</AbstractText>Of the 508 neonates who died, 212 (42%) had CA, which were the leading cause of death. Forty-four percent of the CA were due to definite genetic disorders and 75% of these were single gene defects. Multisystem malformations were the commonest congenital malformations. Parental consanguinity was associated with a 2-fold increased risk of non-chromosomal multisystem malformations.</AbstractText>Lethal malformations were the leading cause of neonatal deaths, and parental consanguinity was associated with an increased risk of autosomal recessive disorders. The results underscore the importance of genetic screening and counseling in strategies for further significant reductions in the neonatal mortality rate in the UAE.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,338,002 |
Common autosomal recessive diseases in Oman derived from a hospital-based registry.
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The local frequencies of genetic disorders in Oman apart from hemoglobinopathies are largely unknown. The aim of the present study was to evaluate birth prevalence of commonly diagnosed autosomal recessive diseases and to estimate needs and priorities of genetic services.</AbstractText>Analysis of the years 1993-2002 using a hospital-based registry of genetic diseases was attempted. More than 3,000 records were reviewed. Only patients with definite diagnosis were included in the analysis. Genetically determined diseases occurring less frequently than 1 in 50,000 births are not included.</AbstractText>A number of rare autosomal recessive diseases are found to have a prevalence at least 1 in 50,000 livebirths.</AbstractText>The data suggest that genetic diseases are important as major contributors to perinatal and childhood mortality and morbidity. The need for preventive genetic service is essential for the health of the community in Oman. Autosomal recessive diseases were frequently concentrated in specific geographical areas, which can be explained by founder effect and genetic drift. However, the hospital-based registry may present incomplete information. Further prospective studies are needed to provide more detailed data.</AbstractText>
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2,338,003 |
Patients' resistance to risk information in genetic counseling for BRCA1/2.
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Risk information from health care providers is relevant to and used in nearly all medical decisions. Patients often misunderstand their risks, yet little is known about the risk perception that patients derive from risk communications with health care providers. This study examines patients' risk perceptions following communication with health care providers during genetic counseling about the risks of breast cancer and BRCA1/2 mutations.</AbstractText>A prospective, longitudinal study was conducted from October 2002 to February 2004 of women who received genetic counseling. The women completed a survey before their counseling and a telephone interview in the week after the counseling. Main outcome measures included change from precounseling in risk perception and accuracy of postcounseling risk perception (relative to actual risk information communicated).</AbstractText>A total of 108 women agreed to participate in the study. The women's postcounseling risk perceptions were significantly lower than their precounseling risk perceptions (breast cancer: 17%, P<.001; mutation: 13%, P<.001) but were significantly higher than the actual risk information communicated (breast cancer: 19%, P<.001; mutation: 24%, P<.001). Accuracy of breast cancer risk perception but not mutation risk perception was associated with precounseling worry (P = .04), even after adjusting for trait anxiety (P = .01).</AbstractText>This research demonstrates patients' resistance to risk information. Inappropriately high risk perception derived from a risk communication with a health care provider can lead patients to make different, and potentially worse, medical decisions than they would with an accurate risk perception and to be unnecessarily distressed about their risk.</AbstractText>
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2,338,004 |
Genetic screens for genes controlling motor nerve-muscle development and interactions.
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Motor growth cones navigate long and complex trajectories to connect with their muscle targets. Experimental studies have shown that this guidance process critically depends on extrinsic cues. In the zebrafish embryo, a subset of mesodermal cells, the adaxial cells, delineates the prospective path of pioneering motor growth cones. Genetic ablation of adaxial cells causes profound pathfinding defects, suggesting the existence of adaxial cell derived guidance factors. Intriguingly, adaxial cells are themselves migratory, and as growth cones approach they migrate away from the prospective axonal path to the lateral surface of the myotome, where they develop into slow-twitching muscle fibers. Genetic screens in embryos stained with an antibody cocktail identified mutants with specific defects in differentiation and migration of adaxial cells/slow muscle fibers, as well as mutants with specific defects in axonal pathfinding, including exit from the spinal cord and pathway selection. Together, the genes underlying these mutant phenotypes define pathways essential for nerve and muscle development and interactions between these two cell types.
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2,338,005 |
Genotyping single nucleotide polymorphisms by MALDI mass spectrometry in clinical applications.
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Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has become one of the most powerful and widely applied technologies for SNP scoring and determination of allele frequencies in the post-genome sequencing era. Although different strategies for allele discrimination combined with MALDI were devised, in practice only primer extension methods are nowadays routinely used. This combination enables the rapid, quantitative, and direct detection of several genetic markers simultaneously in a broad variety of biological samples. In the field of molecular diagnostics, MALDI has been applied to the discovery of genetic markers, that are associated with a phenotype like a disease susceptibility or drug response, as well as an alternative means for diagnostic testing of a range of diseases for which the responsible mutations are already known. It is one of the first techniques with which whole genome scans based on single nucleotide polymorphisms were carried out. It is equally well suited for pathogen identification and the detection of emerging mutant strains as well as for the characterization of the genetic identity and quantitative trait loci mapping in farm animals. MALDI can also be used as a detection platform for a range of novel applications that are more demanding than standard SNP genotyping such as mutation/polymorphism discovery, molecular haplotyping, analysis of DNA methylation, and expression profiling. This review gives an introduction to the application of mass spectrometry for DNA analysis, and provides an overview of most studies using SNPs as genetic markers and MALDI mass spectrometric detection that are related to clinical applications and molecular diagnostics. Further, it aims to show specialized applications that might lead to diagnostic applications in the future. It does not speculate on whether this methodology will ever reach the diagnostic market.
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2,338,006 |
Speeding disease gene discovery by sequence based candidate prioritization.
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Regions of interest identified through genetic linkage studies regularly exceed 30 centimorgans in size and can contain hundreds of genes. Traditionally this number is reduced by matching functional annotation to knowledge of the disease or phenotype in question. However, here we show that disease genes share patterns of sequence-based features that can provide a good basis for automatic prioritization of candidates by machine learning.</AbstractText>We examined a variety of sequence-based features and found that for many of them there are significant differences between the sets of genes known to be involved in human hereditary disease and those not known to be involved in disease. We have created an automatic classifier called PROSPECTR based on those features using the alternating decision tree algorithm which ranks genes in the order of likelihood of involvement in disease. On average, PROSPECTR enriches lists for disease genes two-fold 77% of the time, five-fold 37% of the time and twenty-fold 11% of the time.</AbstractText>PROSPECTR is a simple and effective way to identify genes involved in Mendelian and oligogenic disorders. It performs markedly better than the single existing sequence-based classifier on novel data. PROSPECTR could save investigators looking at large regions of interest time and effort by prioritizing positional candidate genes for mutation detection and case-control association studies.</AbstractText>
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2,338,007 |
Role of inflammation in mouse lung tumorigenesis: a review.
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Peritumoral and intratumoral macrophages are associated with human and mouse lung cancer The mouse model allows manipulation of the macrophage population to experimentally evaluate its contribution to tumor growth. Genetic and pharmacologic strategies also permit testing the invol vement of specific inflammatory mediators in tumor progression. Among those endogenous mediators thus identified are interleukin (IL)-10, glucocorticoids, prostacyclin, nitric oxide, and surfactant apoprotein D (SP-D); serum SP-D levels are a useful biomarker to monitor tumor growth rate. The importance of understanding the mutually antagonistic roles of individual prostaglandins downstream from cycloxygenase (COX) and how this affects the efficacy of COX-inhibitory drugs is discussed. Promising drug candidates include synthetic glucocorticoids such as budesonide and the sulfone derivative of sulindac, apotosyn.
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2,338,008 |
[Genetic adrenal diseases].
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The development of molecular biological techniques has unveiled much information on the pathogenesis of many disease at the DNA and RNA level, as well as provided a considerable improvement in diagnostic potential and treatment. The advantages achieved in molecular biology and genetic engineering have also found application in endocrinology. This paper reviews current knowledge on the role of genetic factors in the pathogenesis of adrenal diseases. Congenital adrenal hyperplasia, idiopathic hyperaldosteronism, adrenal hypoplasia congenita, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, ACTH resistance syndrome, and adrenal hereditary tumors are described.
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2,338,009 |
Incorporating gene-specific variation when inferring and evaluating optimal evolutionary tree topologies from multilocus sequence data.
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Because of the increase of genomic data, multiple genes are often available for the inference of phylogenetic relationships. The simple approach for combining multiple genes from the same taxon is to concatenate the sequences and then ignore the fact that different positions in the concatenated sequence came from different genes. Here, we discuss two criteria for inferring the optimal tree topology from data sets with multiple genes. These criteria are designed for multigene data sets where gene-specific evolutionary features are too important to ignore. One criterion is conventional and is obtained by taking the sum of log-likelihoods over all genes. The other criterion is obtained by dividing the log-likelihood for a gene by its sequence length and then taking the arithmetic mean over genes of these ratios. A similar strategy could be adopted with parsimony scores. The optimal tree is then declared to be the one for which the sum or the arithmetic mean is maximized. These criteria are justified within a two-stage hierarchical framework. The first level of the hierarchy represents gene-specific evolutionary features, and the second represents site-specific features for given genes. For testing significance of the optimal topology, we suggest a two-stage bootstrap procedure that involves resampling genes and then resampling alignment columns within resampled genes. An advantage of this procedure over concatenation is that it can effectively account for gene-specific evolutionary features. We discuss the applicability of the two-stage bootstrap idea to the Kishino-Hasegawa test and the Shimodaira-Hasegawa test.
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2,338,010 |
Age at diagnosis of isolated unilateral retinoblastoma does not distinguish patients with and without a constitutional RB1 gene mutation but is influenced by a parent-of-origin effect.
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Patients with hereditary cancer are usually diagnosed earlier than patients with non-hereditary tumours. In children with isolated unilateral retinoblastoma, some of whom have a hereditary predisposition, this rule has been subject to debate. We have analysed the clinical manifestation of disease in 188 children with completely resolved mutational status. In 24 (13%) of these patients, testing of blood DNA showed a constitutional RB1 mutation. The distribution of age at diagnosis was not different between patients with and without a constitutional mutation. However, patients with loss of the maternally inherited RB1 allele had an earlier age at diagnosis than patients with loss of the paternally inherited RB1 allele. Our data show that early age at diagnosis does not identify patients with isolated unilateral retinoblastoma that have a higher risk of being carriers of a RB1 gene mutation. Our findings suggest that, at least in some patients, age at diagnosis is modified by a parent-of-origin effect.
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2,338,011 |
Regional variation of airway hyperresponsiveness in children with asthma.
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Families with asthmatic children were recruited to take part in a multi-centre collaborative study into the genetics of asthma. Detailed phenotypic information was collected on all family members including: lung function, anthropomorphic measurements, response to methacholine challenge, skin prick testing, serum IgE measurements and a detailed nurse-administered questionnaire. Families were eligible for entry into the study if they had two children with a doctor-diagnosis of asthma. Bennett/Twin nebulisers were supplied to each centre from a single source and these were calibrated to determine gravimetric nebuliser output prior to use. Asthmatic probands from each centre had similar degrees of asthma severity and atopy. There was no significant difference in the sex ratios or ages of the probands or numbers of parents with a history of smoking in the families recruited at each centre. However, there was a significant difference in the number of children with airway hyperresponsiveness, with 90% of the North Staffordshire group but only 60% of the Sheffield group having a PC20 of <8 mg/ml for methacholine. This difference highlights the difficulty of using families from different centres in genetic and epidemiological studies.
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2,338,012 |
Etiological diagnosis of bilateral, sensorineural hearing impairment in a pediatric Greek population.
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Early diagnosis, evaluation and treatment of childhood deafness are essential for a child's normal growth. Etiological diagnosis of hearing loss makes prevention, family scheduling and more effective therapy feasible goals. Etiological assessment of sensorineural deafness still remains difficult although recently with the progress of genetics it has become more efficient. In this retrospective study, the etiology of bilateral, sensorineural hearing loss with indication for hearing aids has been studied in 153 hearing impaired children. Etiological diagnosis was based on family and patient record, physical, audiological and laboratory examinations. Among the 94 children who completed the diagnostic protocol etiological groups revealed the following distribution: non-hereditary acquired hearing impairment was present in 36 children (38%) and hereditary was present in 44 (47%) children. The etiology remained unknown in 14 (15%) children. Non-syndromic autosomal dominant type accounted for 13 (29% of hereditary hearing loss) children, non-syndromic autosomal recessive type for 21 (48%) children and syndromic deafness for 10 (23%) children. Modern diagnostic methods, such as genetic testing, help diminish the number of cases with hearing impairment of unknown etiology, for the benefit of children who receive early and appropriate medical, audiologic, genetic and educational counseling based on the etiology of their hearing loss.
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2,338,013 |
PEG-appended beta-(1-->3)-D-glucan schizophyllan to deliver antisense-oligonucleotides with avoiding lysosomal degradation.
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Schizophyllan is a natural beta-(1-->3)-d-glucan existing as a triple helix in water and as a single chain in dimethylsulfoxide (DMSO). As we already reported, when a homo-polynucleotide [e.g., poly(dA) or poly(C)] is added to the schizophyllan/DMSO solution and subsequently DMSO is exchanged for water, the single chain of schizophyllan forms a complex with the polynucleotide. One of the potential applications for this novel complex is an antisense-oligonucleotide (AS ODN) carrier. The present paper describes a modification technique that enabled us to introduce PEG only to the side chain of schizophyllan. This technique consisted of periodate oxidation of the glucose side chain and subsequent reaction between methoxypolyethylene glycol amine and the formyl terminate, followed by reduction with NaBH4. Subsequently, we made a complex from PEG-appended schizophyllan and an AS ODN sequence, and carried out an in vitro antisense assay, administrating the AS ODN complex to depress A375 c-myb mRNA of A375 melanoma cell lines. The PEG-SPG/AS ODN complex showed more enhanced antisnese effect than naked AS ODN dose, i.e., the same level as that of RGD-appended SPG. Here, the RGD system has been shown one on the most effective AS ODN carrier (Science 261 (1993) 1004-1012). When we added nigericin to the assay system, the antisense effect was not affected in the PEG-SPG system, on the other hand, it was almost eliminated in the RGD system. Nigericin is well known to interrupt transport from endosome to lysosome. Therefore, the difference between the PEG and RGD complexes indicates that, in the PEG system, AS ODN was able to escape from lysosomal degradation. The present work has thus proposed a new strategy to delivery AS ODN using schizophyllan as a new carrier.
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2,338,014 |
Identification of novel genes affecting mesoderm formation and morphogenesis through an enhanced large scale functional screen in Xenopus.
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The formation of mesoderm is an important developmental process of vertebrate embryos, which can be broken down into several steps; mesoderm induction, patterning, morphogenesis and differentiation. Although mesoderm formation in Xenopus has been intensively studied, much remains to be learned about the molecular events responsible for each of these steps. Furthermore, the interplay between mesoderm induction, patterning and morphogenesis remains obscure. Here, we describe an enhanced functional screen in Xenopus designed for large-scale identification of genes controlling mesoderm formation. In order to improve the efficiency of the screen, we used a Xenopus tropicalis unique set of cDNAs, highly enriched in full-length clones. The screening strategy incorporates two mesodermal markers, Xbra and Xmyf-5, to assay for cell fate specification and patterning, respectively. In addition we looked for phenotypes that would suggest effects in morphogenesis, such as gastrulation defects and shortened anterior-posterior axis. Out of 1728 full-length clones we isolated 82 for their ability to alter the phenotype of tadpoles and/or the expression of Xbra and Xmyf-5. Many of the clones gave rise to similar misexpression phenotypes (synphenotypes) and many of the genes within each synphenotype group appeared to be involved in similar pathways. We determined the expression pattern of the 82 genes and found that most of the genes were regionalized and expressed in mesoderm. We expect that many of the genes identified in this screen will be important in mesoderm formation.
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2,338,015 |
A gynogenetic screen to isolate naturally occurring recessive mutations in Xenopus tropicalis.
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In the rapidly developing, diploid amphibian Xenopus tropicalis, genetics can be married to the already powerful tools of the amphibian system to overcome a disability that has hampered Xenopus laevis as a model organism: the difficulties inherent in conducting genetic analyses in a tetraploid organism with a longer generation time. We describe here a gynogenetic screen to uncover naturally occurring recessive mutations in wild X. tropicalis populations, a procedure that is both faster and easier than conventional genetic screens traditionally employed in model organisms to dissect early developmental pathways. During the first round of our screen, gynogenetic diploids from over 160 females comprising four different wild-caught populations were examined. Forty-two potential mutant phenotypes were isolated during this round of gynogenesis. From this group, we describe 10 lines that have genetically heritable recessive mutations. A wide range of developmental defects were obtained in this screen, encompassing effects limited to individual organs as well phenotypes characterized by more global changes in tadpole body morphology. The frequency of recessive mutations detected in our screen appears lower than that seen in other vertebrate genetic screens, but given constraints on the screening procedure used here, is likely to be consistent with rates seen in other animals, and clearly illustrates how wild-caught animals can be a productive source of developmental mutations for experimental study. The development of genetic strategies for the Xenopus system, together with new genomic resources, existing technologies for transgenesis, and other means for manipulating gene expression, as well as the power of performing embryonic manipulations, will provide an impressive set of tools for resolving complex cell and developmental phenomena in the future.
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2,338,016 |
Medical devices; clinical chemistry and clinical toxicology devices; drug metabolizing enzyme genotyping system. Final rule.
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The Food and Drug Administration (FDA) is classifying drug metabolizing enzyme (DME) genotyping test systems into class II (special controls). The special control that will apply to the device is the guidance document entitled "Class II Special Controls Guidance Document: Drug Metabolizing Enzyme Genotyping System." The agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. Elsewhere in this issue of the Federal Register, FDA is publishing a notice of availability of a guidance document that is the special control for this device.
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2,338,017 |
Prognostic values of tumor endothelial markers in patients with colorectal cancer.
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Tumor endothelial markers (TEMs) are a newly discovered family of endothelial markers associated with tumor specific angiogenesis. This study sought to examine the levels of expression (qualitatively and quantitatively) for TEMs in human colon cancer.</AbstractText>Human colorectal cancer tissues (n = 48) and normal background tissues (n = 31) were obtained after surgery. RNA was extracted from frozen sections for gene amplification. The expression of TEMs (TEM-1 to TEM-8) was assessed using RT-PCR and their transcript levels were determined using real-time-quantitative PCR (Q-RT-PCR).</AbstractText>TEM-1 (P = 0.01), TEM-7 (P = 0.04), TEM-7R (P = 0.03), TEM-8 (P = 0.001) significantly raised in colon cancer tissues compared with the levels detected in normal background tissues. The expressions of TEM-2 and TEM-6 were found to be not significantly different between tumor tissues and normal tissues (P > 0.05). Patients who had cancer penetrating into and through the muscularis propria of the bowel wall and developed nodal involvement (Dukes C) exhibited significantly higher levels of TEM -8 compared to patients who were node negative (P < 0.05). TEM-7 and TEM-7R showed high level of transcripts in Dukes C, but they were not statistically significant.</AbstractText>The level of the expression of TEM-1, TEM-7, TEM-7R and TEM-8 (but not TEM-2 and TEM-6) were associated with both nodal involvement and disease progression, and may therefore, have a prognostic value in colorectal cancer.</AbstractText>
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2,338,018 |
A microarray-based gastric carcinoma prewarning system.
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To develop a microarray-based prewarning system consisting of gastric cancer chip, prewarning data and analysis software for early detection of gastric cancer and pre-cancerous lesions.</AbstractText>Two high-density chips with 8,464 human cDNA sites were used to primarily identify potential genes specific for normal gastric mucosa, pre-cancerous lesion and gastric cancer. The low-density chips, composed of selected genes associated with normal gastric mucosa, precancerous lesion and gastric cancer, were fabricated and used to screen 150 specimens including 60 specimens of gastric cancer, 60 of pre-cancerous tissues and 30 of normal gastric mucosa. CAD software was used to screen out the relevant genes and their critical threshold values of expression levels distinguishing normal mucosa from pre-cancerous lesion and cancer. All data were stored in a computer database to establish a prewarning data library for gastric cancer. Two potential markers brcaa1 and ndr1 were identified by Western blot and immunohistochemistry.</AbstractText>A total of 412 genes associated with three stages of gastric cancer development were identified. There were 216 genes displaying higher expression in gastric cancer, 85 genes displaying higher expression in pre-cancerous lesion and 88 genes displaying higher expression in normal gastric mucosa. Also 15 genes associated with metastasis of gastric cancer and 8 genes associated with risk factors were screened out for target genes of diagnosis chip of early gastric cancer. The threshold values of 412 selected genes to distinguish gastric cancer, pre-cancerous lesion from normal gastric mucosa were defined as 6.01+/-2.40, 4.86+/-1.94 and 5.42+/-2.17, respectively. These selected 412 genes and critical threshold values were compiled into an analysis software, which can automatically provide reports by analyzing the results of 412 genes obtained by examining gastric tissues. All data were compiled into a prewarning database for gastric cancer by CGO software. Northern blot and immunohistochemistry analysis confirmed that gene and protein of brcaa1 displayed lower expression in normal gastric mucosa and higher expression in gastric cancer tissues, conversely, ndr1 displayed lower expression in gastric cancer and higher expression in normal gastric mucosa.</AbstractText>The microarray-based prewarning system for gastric cancer was developed. This system consisted of gastric cancer-associated gene chip, prewarning data and analysis software, which has a high potential for applications in the early detection of gastric cancer. The two potential markers brcaa1 and ndr1 identified may be used to distinguish cancer status fand non-cancer status.</AbstractText>
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2,338,019 |
Reduction of selection bias in genomewide studies by resampling.
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The accuracy of gene localization, the reliability of locus-specific effect estimates, and the ability to replicate initial claims of linkage and/or association have emerged as major methodological concerns in genomewide studies of complex diseases and quantitative traits. To address the issue of multiple comparisons inherent in genomewide studies, the use of stringent criteria for assessing statistical significance has been generally acknowledged as a strategy to control type I error. However, the application of genomewide significance criteria does not take account of the selection bias introduced into parameter estimates, e.g., estimates of locus-specific effect size of disease/trait loci. Some have argued that reliable locus-specific parameter estimates can only be obtained in an independent sample. In this report, we examine statistical resampling techniques, including cross-validation and the bootstrap, applied to the initial sample to improve the estimation of locus-specific effects. We compare them with the naive method in which all data are used for both hypothesis testing and parameter estimation, as well as with the split-sample approach in which part of the data are reserved for estimation. Upward bias of the naive estimator and inadequacy of the split-sample approach are derived analytically under a simple quantitative trait model. Simulation studies of the resampling methods are performed for both the simple model and a more realistic genomewide linkage analysis. Our results suggest that cross-validation and bootstrap methods can substantially reduce the estimation bias, especially when the effect size is small or there is no genetic effect.
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2,338,020 |
Human coxsackie adenovirus receptor (CAR) expression in transgenic mouse prostate tumors enhances adenoviral delivery of genes.
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Transgenic mice that recapitulate the progression of human diseases are potentially useful models for testing the effectiveness of new therapeutic strategies. Their use in pre-clinical testing of adenovirally-delivered gene therapies, however, is limited because of restricted cell surface expression of Coxsackie adenovirus receptor (CAR) in mice.</AbstractText>To develop a more suitable transgenic mouse model for testing adenoviral-based gene therapies for prostate cancer, we generated prostate specific antigen/human CAR (PSA/hCAR) transgenic mice in which a chimeric enhancer/promoter sequence of the human PSA gene drives expression of a functional hCAR coding sequence.</AbstractText>Expression of an adenovirally-delivered luciferase reporter gene in prostate tumor cells in bigenic mice (PSA/hCAR + TRAMP) was enhanced compared to the level in tumor cells lacking the PSA/hCAR transgene.</AbstractText>Breeding PSA/hCAR mice to existing transgenic mouse models for prostate cancer (e.g., TRAMP) results in improved mouse models for testing adenovirally-delivered therapeutic genes.</AbstractText>Copyright 2005 Wiley-Liss, Inc.</CopyrightInformation>
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2,338,021 |
Parallel minisequencing followed by multiplex matrix-assisted laser desorption/ionization mass spectrometry assay for beta-thalassemia mutations.
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Beta-thalassemia is a common monogenic disease caused by mutations in the human beta-globin gene (HBB), many of which are differentially represented in human subpopulations stratified by ethnicity. This study describes an efficient and highly accurate method to screen for the eight most-common disease-causing mutations, covering more than 98% of HBB alleles in the Taiwanese population, using parallel minisequencing and multiplex assay by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The MALDI-TOF MS was optimized for sensitivity and resolution by "mass tuning" the PinPoint assay for eight HBB SNPs. Because of the close proximity and clustering of mutations in HBB, primer extension reactions were conducted in parallel. Efficient sequential desalting using POROS and cationic exchange chromatography allowed for an unambiguous multiplex genotyping by MALDI-TOF MS. The embellishing SNP assay allowed for highly accurate identification of the eight most-common beta-thalassemia mutations in homozygous normal control, carrier, and eight heterozygous carrier mixtures, as well as the diagnosis of a high-risk family. The results demonstrated a flexible strategy for rapid identification of clustering SNPs in HBB with a high degree of accuracy and specificity. It can be adapted easily for high-throughput diagnosis of various hereditary diseases or to establish family heritage databases for clinical applications.
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2,338,022 |
Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness.
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To describe the clinical features and genetic analysis of eight X-linked congenital stationary night blindness (XLCSNB) Dutch patients.</AbstractText>Electroretinogram (ERG) measurements were assessed in Dutch patients. Molecular genetic testing by denaturing high performance liquid chromatography (DHPLC), single stranded conformation polymorphism (SSCP) analysis, and direct sequencing of the CACNA1F and NYX genes were performed in the patients possessing a negative Schubert Bornschein ERG.</AbstractText>Molecular genetic testing of CACNA1F and NYX revealed three novel and two known CACNA1F sequence variants as well as two novel sequence alterations in the NYX gene. While one of the CACNA1F sequence variants (5756G>A, R1919H) has been previously described as a common polymorphism in Japanese families, we did not found this transition in 100 European control alleles.</AbstractText>In a pool of eight diagnosed XLCSNB patients, five showed a sequence variation in the CACNA1F and two in the NYX gene. In only one of the eight patients no sequence alteration could be detected. This might be explained by a mutation in other, as yet unidentified coding or regulatory sequences of NYX or CACNA1F or additional genes.</AbstractText>
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2,338,023 |
Insulin-like growth factors as diagnostic tools in growth hormone deficiency during childhood and adolescence: the KIGS experience.
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Growth hormone (GH) deficiency in children covers a spectrum of disorders involving an impairment in GH secretion and a clinical syndrome characterized by permanent stunting of growth. Ascertaining impairments in GH secretion directly is complex, especially if GH deficiency (GHD) is isolated and not caused by congenital or acquired pituitary defects or genetic abnormalities. It has been established that the concentrations of GH-dependent peptides, such as insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3), are low in patients with GHD. Their levels are, however, also influenced by a multitude of factors, such as age, gender, height, liver function, nutritional status and other hormones. In addition, the type of complex formed, e.g. either binary or ternary, may influence the measurements of IGFs and their binding proteins. Therefore, levels of IGF-I and IGFBP-3 are generally lower in short children compared with age-matched norms. The reported diagnostic value of sub-normal basal levels of IGF-I and IGFBP-3 is, in terms of sensitivity and specificity, approximately 70%. Thus, definite proof of GHD can only be achieved by means of GH measurements. As the diagnosis of GHD is somewhat unlikely if IGF testing shows normal values, it is clearly advantageous to schedule these tests as part of the initial diagnostic work-up in short children, as their implementation is not only practical but also inexpensive. The Pfizer International Growth Database (KIGS) analysis of IGF-I (n = 2,750) and IGFBP-3 (n = 1,300) levels in children with idiopathic GHD shows that these two parameters are now firmly embedded in diagnostic strategies around the world.
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2,338,024 |
Immunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma.
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The t(4;14) translocation detected by fluorescence in situ hybridization (FISH) is an independent prognostic factor for an adverse outcome of multiple myeloma (MM). Because t(4;14) uniquely results in fibroblast growth factor receptor 3 (FGFR3) expression, decalcified, paraffin-embedded bone marrow biopsies were immunostained for FGFR3, and its expression was correlated with the t(4;14) status. FISH detected t(4;14) in 16 (19%) of 85 MM patient specimens, and immunocytochemistry detected aberrant FGFR3 expression in 13 (15%). Twelve (75%) t(4;14)-positive cases expressed FGFR3, and 12 (92%) FGFR3-positive cases harbored a t(4;14). FGFR3 expression and t(4;14) were strongly correlated (P < .001). FGFR3 expression by immunohistochemistry was associated with the immunoglobulin A (IgA) isotype (P < .001), a shorter progression-free survival (median, 11.5 versus 25.8 months; P < .001), and a shorter overall survival (median, 19.2 versus 46.3 months; P < .001).
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2,338,025 |
Dissecting the genetic etiology of major depressive disorder using linkage analysis.
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Major depressive disorder (MDD) is clinically and genetically heterogeneous. Studies suggest that recurrence, early onset and comorbid phenotypes define more genetically homogeneous sub-samples. The concordance of linkage findings in recent studies using such approaches is encouraging. Sex-specific analyses and broader phenotypes have also yielded interesting results. These findings indicate that future research should consider comorbid disorders and sex-specific analyses. However, this direction must be approached with caution, owing to the complex multiple-testing issues that arise when considering numerous related phenotypes. With appropriate interpretation, these findings indicate a new potential for positional cloning efforts to locate genes in consensus regions. Genes found might influence specific subtypes of MDD or broader phenotypes, leading to enhanced clinical characterization and management of MDD.
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2,338,026 |
Retrospective family study of childhood medulloblastoma.
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Medulloblastoma is the most common malignant central nervous system tumor of childhood and can occur sporadically or in association with inherited cancer susceptibility syndromes such as the nevoid basal cell carcinoma syndrome (NBCCS). To determine whether an association existed between the risk of developing medulloblastoma and undiagnosed syndromes, we retrospectively reviewed clinical data on 33 patients with medulloblastoma from a single institution and compared them with their unaffected relatives (n = 46). Six patients had tumors showing desmoplastic histology. Two of the six met diagnostic criteria for NBCCS. One NBCCS patient had a missense mutation of patched-1 (PTCH1); the other had no identifiable PTCH1 mutation. Two patients with isolated desmoplastic medulloblastoma had an insertion and splice site mutation, respectively, in suppressor of fused (SUFU). All patients with nondesmoplastic medulloblastoma histology received molecular testing for SUFU. None of these patients had an identifiable mutation in PTCH1 or SUFU. We performed a clinical evaluation for Greig cephalopolysyndactyly syndrome (GCPS) in four medulloblastoma families, who exhibited macrocephaly as the only finding consistent with the diagnosis of GCPS. Molecular analysis of GLI3 in these four families was negative. There was a paucity of clinical findings among the majority of medulloblastoma patients in this study group to suggest a definable cancer genetic syndrome. We conclude that clinically recognizable syndromes are uncommon among patients with medulloblastoma, however, PTCH1 and SUFU mutations are present at a low but significant frequency.
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2,338,027 |
Genetic screening and diagnosis.
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To review the latest developments in screening and diagnosis of non-chromosomal genetic diseases.</AbstractText>Major recent advances include the completion of the Human Genome Project, the use of microarray and related technologies for mass screening and diagnosis of thousands of genetic abnormalities, and non-invasive prenatal diagnosis using fetal DNA in maternal plasma.</AbstractText>The rapid development in molecular biological technologies makes it possible to screen and to diagnosis thousands of genetic conditions, mutations and also predispositions to chronic diseases or traits, either prenatally or after birth. Clinical application of non-invasive prenatal diagnosis using fetal DNA in maternal plasma has become a reality. The arrival of the molecular genetic era also leads to many new ethical, social and medico-legal problems and dilemmas that obstetricians will have to face in the near future. There is an urgent need for the development of a new model for provision of genetic screening and diagnosis.</AbstractText>
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2,338,028 |
A novel spermatogenesis related factor-2 (SRF-2) gene expression affected by TCDD treatment.
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We have cloned a gene which is specifically expressed at the stage of sexual maturation in the rat testis by means of differential display, and have named it spermatogenesis-related factor-2 (SRF-2). Testicular expression was first detected at 5 weeks of age, and its level of the expression increased up to 7 weeks, and was maintained even at 63 weeks. Its cDNA was 2,789 bp in length and encoded an open reading frame of 718 amino acids. This gene was mainly expressed in the spermatocyte, judging from the result of in situ hybridization. The hypothetical gene product had a motif highly homologous with RabGAP/TBC protein. Taken together, this gene is considered to have some important functions for meiosis. The gene expression was significantly decreased by treatment with TCDD, a candidate endocrine disruptor, when administered to male rats of the nursling period. Body weight and testis weight were decreased by the treatment, but even then the sperm concentration in cauda epididymis was not changed significantly. SRF-2 gene may be a promising biomarker to construct a detection system of uncertain endocrine disruptors.
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2,338,029 |
Overview: animal models of osteopenia and osteoporosis.
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Prior to initiating a clinical trial in a post-menopausal osteoporosis study, it is reasonable to recommence the evaluation of treatment in the 9-month-old ovariectomized female rat. A female rat of this age has reached peak bone mass and can be manipulated to simulate clinical findings of post-menopausal osteoporosis. Ample time exists for experimental protocols that either prevent estrogen depletion osteopenia or restore bone loss after estrogen depletion. More time can be saved by acceleration of the development of the osteopenia by combining ovariectomized (OVX) plus immobilization (IM) models. Methods like serum biochemistry, histomorphometry and densitometry used in humans are applicable in rats. Like most animal models of osteopenia, the rat develops no fragility fractures, but mechanical testing of rat bones substitutes as a predictor of bone fragility. Recent studies have shown that the prevailing activity in cancellous and cortical bone of the sampling sites in rats is remodeling. The problems of dealing with a growing skeleton, the site specificity of the OVX and IM models, the lack of trabecular and Haversian remodeling and the slow developing cortical bone loss have been and can be overcome by adding beginning and pre-treatment controls and muscle mass measurements in all experimental designs, selecting cancellous bone sampling sites that are remodeling, concentrating the analysis of cortical bone loss to the peri-medullary bone and combining OVX and IM in a model to accelerate the development of both cancellous and cortical bone osteopenia. Not to be forgotten is the distal tibia site, an adult bone site with growth plate closure at 3 months and low trabecular bone turnover and architecture similar to human spongiosa. This site would be most challenging to the action of bone anabolic agents. Data about estrogen-deplete mice are encouraging, but the ovariectomized rat model suggests that developing an ovariectomized mouse model as an alternative is not urgent. Nevertheless, the mouse model has a place in drug development and skeletal research. In dealing with drug development, it could be a useful model because it is a much smaller animal requiring fewer drugs for screening. In skeletal research mice are useful in revealing genetic markers for peak bone mass and gene manipulations that affect bone mass, structure and strength. When the exciting mouse glucocorticoid-induced bone loss model of Weinstein and Manolagas is confirmed by others, it could be a significant breakthrough for that area of research. Lastly, we find that the information generated from skeletal studies of nonhuman primates has been most disappointing and recommend that these expensive skeletal studies be curtailed unless it is required by a regulatory agency for safety studies.
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2,338,030 |
Genetic regulation of bone mineral density in mice.
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Peak bone mass is a major determinant of risk of osteoporotic fracture. Family and twin studies have found a strong genetic component to the determination of bone mineral density (BMD). However, BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. The number, locations and effects of the individual genes contributing to natural variation in this trait are all unknown. The extreme difficulty of dissecting out environmental factors from genetic ones in humans has motivated the investigation of animal models. Genetically distinct animal strains raised under strict environmental control are critical tools for defining genetic regulation. The availability of inbred strains, combined with its relative fecundity, has established the mouse as the best model system for the study of mammalian genetics and physiology. Importantly, genes identified in murine analyses can usually be readily mapped to particular human chromosomal regions because of the high degree of synteny that exists between the mouse and human genomes. We employed quantitative trait locus (QTL) analysis to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (BXD RI). The distribution of BMD values among these strains clearly indicated the presence of strong genetic influences, with an estimated narrow sense heritability of 35%. The differences in peak whole body BMD in the BXD strains were integrated with a large database of genetic markers previously defined in the RI BXD strains to generate chromosome map sites for QTL locations. This QTL analysis provisionally identified a number of chromosomal sites linked to BMD. In the second phase of our BMD QTL mapping efforts, we used three independent mouse populations (all derived from B6 and D2 progenitor strains) to confirm and narrow the genetic locations of 4 QTLs (on chromosomes 1, 2, 4, and 11) that strongly influence the acquisition of peak BMD in mice. Using a novel, fine-mapping approach (recombinant inbred segregation testing), we have succeeded in narrowing two of the BMD-related chromosomal regions and in the process eliminated a number of candidate genes. The homologous regions in the human genome for each of these murine QTLs have been identified in recent human genetic studies. In light of this, we believe that findings in mice should aid in the identification of specific candidate genes for study in humans.
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2,338,031 |
Animal models of osteoarthritis in an era of molecular biology.
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Animal models of osteoarthritis (OA) are used to study the pathogenesis of cartilage degeneration and to evaluate potential anti-arthritic drugs for clinical use. In general, these models fall into 2 categories, spontaneous and induced (surgical instability or genetic manipulation). Animal models of naturally occurring OA occur in knee joints of guinea pigs, mice and Syrian hamsters. Commonly utilized surgical instability models include medial meniscal tear in guinea pigs and rats, medial or lateral partial meniscectomy in rabbits, medial partial or total meniscectomy or anterior cruciate transection in dogs. Transgenic models have been developed in mice. These models all have potential use in the study of molecular mechanisms associated with OA development via use of immunohistochemistry, biochemistry and molecular probes to identify altered matrix molecules at different stages in disease progression. Testing of specific types of inhibitors developed through evaluation of matrix changes in the disease process will ultimately help identify key processes which initiate and perpetuate the disease and will lead to discovery of new disease modifying pharmaceutical agents for OA patients. This paper will focus on the discussion of several models which are likely to be useful in the molecular dissection of processes involved in cartilage degeneration.
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2,338,032 |
Genetic testing for Alzheimer's disease and its impact on insurance purchasing behavior.
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New genetic tests for adult-onset diseases raise concerns about possible adverse selection in insurance markets. To test for this behavior, we followed 148 cognitively normal people participating in a randomized clinical trial of genetic testing for Alzheimer's disease for one year after risk assessment and Apolipoprotein E (APOE) genotype disclosure. Although no significant differences were found in health, life, or disability insurance purchases, those who tested positive were 5.76 times more likely to have altered their long-term care insurance than those who did not receive APOE genotype disclosure. If genetic testing for Alzheimer's risk assessment becomes common, it could trigger adverse selection in long-term care insurance.
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2,338,033 |
Overview of molecular, cellular, and genetic neurotoxicology.
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It has become increasingly evident that the field of neurotoxicology is not only rapidly growing but also rapidly evolving, especially over the last 20 years. As the number of drugs and environmental and bacterial/viral agents with potential neurotoxic properties has grown, the need for additional testing has increased. Only recently has the technology advanced to a level that neurotoxicologic studies can be performed without operating in a "black box." Examination of the effects of agents that are suspected of being toxic can occur on the molecular (protein-protein), cellular (biomarkers, neuronal function), and genetic (polymorphisms) level. Together, these areas help to elucidate the potential toxic profiles of unknown (and in some cases, known) agents. The area of proteomics is one of the fastest growing areas in science and particularly applicable to neurotoxicology. Lubec et al, provide a review of the potential and limitations of proteomics. Proteomics focuses on a more comprehensive view of cellular proteins and provides considerably more information about the effects of toxins on the CNS. Proteomics can be classified into three different focuses: post-translational modification, protein-expression profiling, and protein-network mapping. Together, these methods represent a more complete and powerful image of protein modifications following potential toxin exposure. Cellular neurotoxicology involves many cellular processes including alterations in cellular energy homeostasis, ion homeostasis, intracellular signaling function, and neurotransmitter release, uptake, and storage. The greatest hurdle in cellular neurotoxicology has been the discovery of appropriate biomarkers that are reliable, reproducible, and easy to obtain. There are biomarkers of exposure effect, and susceptibility. Finding the appropriate biomarker for a particular toxin is a daunting task. The appropriate biomarker for a particular toxin is a daunting task. The advantage to biomarker/toxin combinations is they can be detected and measured shortly following exposure and before overt neuroanatomic damage or lesions. Intervention at this point, shortly following exposure, may prevent or at least attenuate further damage to the individual. The use of peripheral biomarkers to assess toxin damage in the CNS has numerous advantages: time-course analysis may be performed, ethical concerns with the use of human subjects can partially be avoided, procedures to acquire samples are less invasive, and in general, peripheral studies are easier to perform. Genetic neurotoxicology comprises two focuses--toxin-induced alterations in genetic expression and genetic alterations that affect toxin metabolism, distribution, and clearance. These differences can be beneficial or toxic. Polymorphisms have been shown to result in altered metabolism of certain toxins (paraoxonase and paraoxon). Conversely, it is possible that some polymorphisms may be beneficial and help prevent the formation of a toxic by-product of an exogenous agent (resistance to ozone-induced lung inflammation). It has also become clear that interactions of potential toxins are not straightforward as interactions with DNA, causing mutations. There are numerous agents that cause epigenetic responses (cellular alterations that are not mutagenic or cytotoxic). This finding suggests that many agents that may originally have been thought of as nontoxic should be re-examined for potential "indirect" toxicity. With the advancement of the human genome project and the development of a human genome map, the effects of potential toxins on single or multiple genes can be identified. Although collectively, the field of neurotoxicology has recently come a long way, it still has a long way to go reach its full potential. As technology and methodology advances continue and cooperation with other disciplines such as neuroscience, biochemistry, neurophysiology, and molecular biology is improved, the mechanisms of toxin action will be further elucidated. With this increased understanding will come improved clinical interventions to prevent neuronal damage following exposure to a toxin.
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2,338,034 |
Emerging human papillomavirus vaccines.
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Human papillomavirus (HPV) infections are a leading cause of virus-associated cancers of the anogenital, oropharyneal and cutaneous epithelium. The most prevalent of these is cervical cancer, which is responsible for approximately 500,000 deaths annually worldwide. A group of about 15 serologically unrelated 'high-risk' HPV types are responsible for almost all HPV-associated cancers. Prevention of papillomavirus infection can be achieved by induction of capsid-specific neutralising antibodies in preclinical animal papillomavirus models and in recent human clinical trials. High titres of conformationally-dependent, type-specific HPV-neutralising antibodies are triggered by HPV virus-like particle (VLP) vaccines. Overcoming the problems of type-specificity of the responses to these VLP vaccines is a potentially important area of current HPV vaccine research, with an emphasis on induction of more broadly cross-protective neutralising responses. Viral oncogenes E6 and E7 are continuously present in HPV-associated cancers and are prime targets for HPV therapeutic vaccines. A variety of approaches are being tested in therapeutic vaccine clinical trials and in various preclinical animal papillomavirus models for efficacy. Approaches include genetic vaccines, recombinant virus vaccines, dendritic cell-based strategies, immunomodulatory strategies and various combination strategies to maximise cell-mediated immunity to papillomavirus proteins present in HPV infections and cancers. The success of preventive HPV VLP vaccines in clinical trials is clear. However, current therapeutic vaccine trials are less effective with respect to disease clearance. Nevertheless, a series of combination approaches have shown significant therapeutic enhancement in preclinical papillomavirus models and await testing in patient populations to determine the most effective strategy. There is much encouragement that HPV vaccines will be the most effective approach to prevention and cure of infections caused by this group of viruses, which re-present a significant human pathogen.
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2,338,035 |
Hemoglobinopathies, G6PD deficiency, and hereditary elliptocytosis in Bahrain.
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The native population of Bahrain has a high prevalence of hemoglobinopathies and G6PD deficiency, probably as a result of past malarial endemism. We used the Biorad-Variant hemoglobin testing system for primary screening of hemoglobinopathies in 20,000 individuals. Hemoglobin abnormalities were detected in 7,206 (36.3%) cases.
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2,338,036 |
COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia.
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The skeletal dysplasias are a clinically and genetically heterogeneous group of conditions affecting the development of the osseous skeleton and fall into the category of rare genetic diseases in which the diagnosis can be difficult for the nonexpert. Two such diseases are pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), which result in varying degrees of short stature, joint pain and stiffness and often resulting in early onset osteoarthritis. PSACH and some forms of MED result from mutations in the cartilage oligomeric matrix protein (COMP) gene and to aid the clinical diagnosis and counselling of patients with a suspected diagnosis of PSACH or MED, we developed an efficient and accurate molecular diagnostic service for the COMP gene. In a 36-month period, 100 families were screened for a mutation in COMP and we identified disease-causing mutations in 78% of PSACH families and 36% of MED families. Furthermore, in several of these families, the identification of a disease-causing mutation provided information that was immediately used to direct reproductive decision-making.
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2,338,037 |
ICAM G241A polymorphism and soluble ICAM-1 serum levels: evidence for an active immune process in schizophrenia.
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We have previously reported reduced serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) in schizophrenic patients. A single-nucleotide polymorphism (SNP) of the ICAM-1 gene was described at position 241. The G-->A SNP results in a nonsynonymous amino acid exchange of the ICAM-1 protein, and the A allele was shown to be also associated with several immunological disorders like rheumatoid arthritis.</AbstractText>We investigated 70 schizophrenic patients and 128 unrelated healthy control persons regarding the relationship between the serum levels of sICAM-1 and the ICAM-1 G214A polymorphism.</AbstractText>We were able to replicate our previous finding of reduced sICAM-1 levels in schizophrenia. Healthy control persons carrying the polymorphic A allele showed markedly lower sICAM-1 serum levels than carriers of the homozygous GG wild type (p < 0.004). In contrast, no significant difference in the sICAM-1 serum levels were seen regarding the G241A genotype distribution in schizophrenic patients.</AbstractText>We hypothesize that the biochemical effect of the G241A SNP is masked in schizophrenic patients, indicating a disease-related mechanism leading to reduced levels of sICAM-1 in schizophrenia.</AbstractText>
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2,338,038 |
Cross-species sperm-FISH assays for chemical testing and assessing paternal risk for chromosomally abnormal pregnancies.
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The father, like the mother, can transmit genetic defects to his offspring that are detrimental for normal development and a healthy life. Epidemiological studies have identified associations between several paternal exposures and abnormal reproductive outcomes, but these types of studies are inherently complex and expensive, and the risk factors for the paternal contribution to abnormal reproductive outcomes remain poorly understood. Several sensitive methods have been developed for detecting mutations and chromosomal damage directly in sperm. These assays are potential bioindicators for paternal risk factors for infertility, spontaneous abortions, aneuploidy syndromes, and genetic diseases in children. Among these methods, fluorescence in situ hybridization (FISH) has been adapted for the detection of numerical and structural chromosomal abnormalities in the sperm of an expanding number of species, including humans and rodents. Sperm FISH has identified several potential paternal risk factors such as age, drugs, lifestyles, and various environmental/occupational exposures. Here, we summarize the status of the development and usage of these sperm-FISH assays and suggest strategies for prioritizing chemical agents for epidemiological investigations to assess paternal risk for abnormal reproductive outcome.
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2,338,039 |
Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease.
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One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer.</AbstractText>We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer.</AbstractText>Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p.</AbstractText>Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed.</AbstractText>Copyright 2005 Wiley-Liss, Inc.</CopyrightInformation>
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2,338,040 |
Polymorphisms in SPINK5 are not associated with asthma in a Dutch population.
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Asthma and allergic phenotypes are complex genetic diseases with known linkage to chromosome 5q. This region has many candidate genes, including serine protease inhibitor Kazal type 5 (SPINK5), which has been associated with asthma and atopic dermatitis in family-based studies of children with atopic dermatitis.</AbstractText>We sought to investigate whether single nucleotide polymorphisms in SPINK5 are associated with asthma, atopic phenotypes, and atopic dermatitis.</AbstractText>We investigated whether single nucleotide polymorphisms in SPINK5 (ie, -785 A/G, Asn368Ser, and Lys420Glu) are associated with asthma, atopic phenotypes, and atopic dermatitis in 200 families ascertained by a proband with asthma (nonaffected spouses served as a matched control population) and an independent set of 252 trios with asthma.</AbstractText>We found no association with asthma, atopic phenotypes, and atopic dermatitis after correction for multiple testing.</AbstractText>The negative results in this study suggest that SPINK5 is not associated with asthma or atopic phenotypes in individuals ascertained by a proband with asthma. This is consistent with the finding that SPINK5 is not expressed in the lung. Because our patients were ascertained for asthma, a role of SPINK5 in atopic dermatitis cannot be excluded.</AbstractText>
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2,338,041 |
Inherited medullary thyroid cancer and the duty to warn: revisiting Pate v. Threlkel in light of HIPAA.
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Familial medullary thyroid cancer (FMTC) is one of the few autosomal dominant cancers for which genetic testing provides a clear medical indication for prophylactic and/or curative therapy, and for which prophylactic thyroidectomy, followed by thyroid hormone replacement, presents a relatively low morbidity risk. Medullary thyroid cancer (MTC) is a particularly aggressive type of thyroid cancer, and screening by traditional biochemical markers yields a high proportion of advanced stage diagnoses in individuals from FMTC families. This is particularly hazardous since there are no curative systemic treatments for MTC. Genetic testing for germline mutations of the RET proto-oncogene provides a reliable method of identifying at-risk family members in those FMTC families in which a mutation has been identified in the proband. Prophylactic thyroidectomy in such at-risk family members has significantly reduced the proportion of advanced stage MTC diagnoses in MTC families. Since a clear medical benefit exists for genetic testing in family members, and a clear danger to family members exists in the absence of genetic counseling, establishing genetic diagnosis as standard of care has critical legal and ethical implications for medical providers caring for probands and family members. The "duty to warn," reinforced by the courts in the legal case of Pate v. Threlkel, may override recent confidentiality legislation, known as the HIPAA Privacy Rules, which came into effect April 12, 2003.
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2,338,042 |
Strategies for the study of meiosis in rye.
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We describe how we are furthering our understanding of meiosis in rye (Secale cereale L.) using a combination of cytogenetic and molecular biological approaches. Fluorescent in situ hybridisation, electron microscopy of synaptonemal complexes, sequencing of meiosis-specific genes, and the immunolocalisation of recombinogenic proteins are being combined to build up phenotypic "identikits" of wild type, asynaptic mutants sy1 and sy9, and desynaptic mutant sy10. From this information, we review the status of our current understanding of the genetic control of meiosis in rye, and consider strategies for determining more precisely the interrelationships between meiosis-specific genes and their products.
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2,338,043 |
MTX-induced white matter changes are associated with polymorphisms of methionine metabolism.
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Methotrexate (MTX) is a folate antagonist inhibiting nucleic acid and methionine synthesis. Methionine is necessary for CNS myelination. In 42 patients with primary CNS lymphoma (PCNSL) treated with a systemic and intraventricular high-dose MTX-based polychemotherapy, the presence of a risk haplotype defined by polymorphisms influencing methionine metabolism referred a relative risk for CNS white matter changes of 4.7 (p = 0.001). The authors conclude that methionine metabolism influences MTX neurotoxicity.
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2,338,044 |
High mutation rate in dopa-responsive dystonia: detection with comprehensive GCHI screening.
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Mutations in GTP cyclohydrolase I (GCHI) are found in 50 to 60% of cases with dopa-responsive dystonia (DRD). Heterozygous GCHI exon deletions, undetectable by sequencing, have recently been described in three DRD families. We tested 23 individuals with DRD for the different mutation types by conventional and quantitative PCR analyses and found mutations, including two large exon deletions, in 87%. The authors attribute this high mutation rate to rigorous inclusion criteria and comprehensive mutational analysis.
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2,338,045 |
Testing the usefulness of the molecular coancestry information to assess genetic relationships in livestock using a set of Spanish sheep breeds.
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Recent studies have proposed the use of molecular coancestry coefficients as a measure of genetic variability and as a useful tool for conservation purposes. Using simulated data, molecular coancestry has been shown to become constant very quickly after separation of populations, leading to population diversity remaining constant. However, the use of molecular coancestry information to study the genetic relationships between breeds has not yet been widely explored. Here we analyze the polymorphism of 14 microsatellites in 222 unrelated individuals belonging to seven native Spanish breeds to ascertain the usefulness of molecular coancestry-based methodologies in providing information on their genetic relationships. Average kinship distance (D(k)) and average molecular coancestry coefficients (f(ij)) were compared with well-known genetic distances, such as between-breed Reynolds' distance (D(R)), Nei's standard distance (D(s)), and shared allele distance (D(AS)). Kinship distance and f(ij) have moderate to low correlations with the other genetic distances, showing that they provide different information: both D(k) and f(ij) account for the allele frequencies in the founder population, whereas D(R), D(s), and D(AS) characterize the short-term evolution of the populations. Furthermore, D(k) and f(ij) were only moderately correlated (-0.500). The present study used field data to confirm previous research pointing out the ability of molecular coancestry coefficients to assess genetic differentiation of an ancestral origin. In this respect, molecular coancestry-based parameters may be used with classical genetic parameters to obtain information on population dynamics in livestock breeds. This study additionally presents reliable evidence on the history of these sheep breeds.
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2,338,046 |
Dissemination of transferable CTX-M-type extended-spectrum beta-lactamase-producing Escherichia coli in Korea.<Pagination><StartPage>921</StartPage><EndPage>927</EndPage><MedlinePgn>921-7</MedlinePgn></Pagination><Abstract><AbstractText Label="AIMS" NlmCategory="OBJECTIVE">Among 365 Escherichia coli isolated in 2003, 31 cefotaxime-resistant isolates were obtained from clinical specimens taken from adults hospitalized in Busan, Korea. Six extended-spectrum beta-lactamase (ESBL)-producing isolates were investigated further to determine the mechanism of resistance.</AbstractText><AbstractText Label="METHODS AND RESULTS" NlmCategory="RESULTS">These isolates were analysed by antibiotic susceptibility testing, pI determination, plasmid profiles, transconjugation test, PCR-restriction fragment length polymorphism (RFLP), enterobacterial repetitive consensus (ERIC)-PCR and DNA sequencing. All six of these isolates were found to contain the CTX-M-type ESBL genes. Five clinical isolates and their transconjugants produced CTX-M-3. One clinical isolate (K17391) and its transconjugant (trcK17391) produced CTX-M-15. Five clinical isolates also produced another TEM-1. One clinical isolate (K12776) also contained another TEM-52. CTX-M-3 ESBL gene was responsible for the resistance to piperacillin, cephalothin, cefotaxime, cefepime and aztreonam. CTX-M-15 or TEM-52 was especially responsible for the resistance to ceftazidime.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">These results appear to represent the in vivo evolution of CTX-M-type beta-lactamase genes (bla(CTX-M-3) --> bla(CTX-M-15)) under the selective pressure of antimicrobial therapy (especially ceftazidime). PCR-RFLP is a reliable method to discriminate CTX-M-15 gene from CTX-M-3 gene. ERIC-PCR analysis revealed that dissemination of CTX-M-3 was not due to a clonal outbreak of a resistant strain but to the intra-species spread of resistance to piperacillin, cephalothin, cefotaxime, cefepime and aztreonam in Korea.</AbstractText><AbstractText Label="SIGNIFICANCE AND IMPACT OF THE STUDY" NlmCategory="CONCLUSIONS">This is the first report of the occurrence of CTX-M-1 cluster ESBLs in Korea. A more comprehensive survey of these ESBL types from Korea is urgently needed because of the in vivo evolution of CTX-M-15 from CTX-M-3. The emergence of these CTX-M-type ESBLs suggests that diagnostic laboratories should screen for ESBLs with ceftazidime as well as cefotaxime; they should still perform clavulanate synergy tests on resistant isolates.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Jeong</LastName><ForeName>S H</ForeName><Initials>SH</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine and Graduate School of Public Health, Kosin University College of Medicine, Busan, Republic of Korea.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bae</LastName><ForeName>I K</ForeName><Initials>IK</Initials></Author><Author ValidYN="Y"><LastName>Kwon</LastName><ForeName>S B</ForeName><Initials>SB</Initials></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>J H</ForeName><Initials>JH</Initials></Author><Author ValidYN="Y"><LastName>Song</LastName><ForeName>J S</ForeName><Initials>JS</Initials></Author><Author ValidYN="Y"><LastName>Jung</LastName><ForeName>H I</ForeName><Initials>HI</Initials></Author><Author ValidYN="Y"><LastName>Sung</LastName><ForeName>K H</ForeName><Initials>KH</Initials></Author><Author ValidYN="Y"><LastName>Jang</LastName><ForeName>S J</ForeName><Initials>SJ</Initials></Author><Author ValidYN="Y"><LastName>Lee</LastName><ForeName>S H</ForeName><Initials>SH</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>J Appl Microbiol</MedlineTA><NlmUniqueID>9706280</NlmUniqueID><ISSNLinking>1364-5072</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000900">Anti-Bacterial Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004269">DNA, Bacterial</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.5.2.-</RegistryNumber><NameOfSubstance UI="C055184">beta-lactamase TEM-3</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.5.2.6</RegistryNumber><NameOfSubstance UI="D001618">beta-Lactamases</NameOfSubstance></Chemical><Chemical><RegistryNumber>N2GI8B1GK7</RegistryNumber><NameOfSubstance UI="D002439">Cefotaxime</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000900" MajorTopicYN="N">Anti-Bacterial Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001483" MajorTopicYN="N">Base Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002439" MajorTopicYN="N">Cefotaxime</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018550" MajorTopicYN="N">Cephalosporin Resistance</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003227" MajorTopicYN="N">Conjugation, Genetic</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004269" MajorTopicYN="N">DNA, Bacterial</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004926" MajorTopicYN="N">Escherichia coli</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000302" MajorTopicYN="N">isolation & purification</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005798" MajorTopicYN="N">Genes, Bacterial</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007525" MajorTopicYN="N">Isoelectric Focusing</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007723" MajorTopicYN="N" Type="Geographic">Korea</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008826" MajorTopicYN="N">Microbial Sensitivity Tests</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010957" MajorTopicYN="N">Plasmids</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016133" MajorTopicYN="N">Polymerase Chain Reaction</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012150" MajorTopicYN="N">Polymorphism, Restriction Fragment Length</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001618" MajorTopicYN="N">beta-Lactamases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>10</Month><Day>19</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15752339</ArticleId><ArticleId IdType="doi">10.1111/j.1365-2672.2004.02526.x</ArticleId><ArticleId IdType="pii">JAM2526</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15752239</PMID><DateCompleted><Year>2005</Year><Month>05</Month><Day>18</Day></DateCompleted><DateRevised><Year>2019</Year><Month>01</Month><Day>31</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0098-6577</ISSN><JournalIssue CitedMedium="Print"><Issue>94</Issue><PubDate><Year>2005</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Kidney international. Supplement</Title><ISOAbbreviation>Kidney Int Suppl</ISOAbbreviation></Journal>Genetic factors in end-stage renal disease.<Pagination><StartPage>S46</StartPage><EndPage>S49</EndPage><MedlinePgn>S46-9</MedlinePgn></Pagination><Abstract><AbstractText>Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Satko</LastName><ForeName>Scott G</ForeName><Initials>SG</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine/Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Freedman</LastName><ForeName>Barry I</ForeName><Initials>BI</Initials></Author><Author ValidYN="Y"><LastName>Moossavi</LastName><ForeName>Shahriar</ForeName><Initials>S</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01-HL56266</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Kidney Int Suppl</MedlineTA><NlmUniqueID>7508622</NlmUniqueID><ISSNLinking>0098-6577</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007676" MajorTopicYN="N">Kidney Failure, Chronic</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>34</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>5</Month><Day>19</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15752239</ArticleId><ArticleId IdType="doi">10.1111/j.1523-1755.2005.09411.x</ArticleId><ArticleId IdType="pii">S0085-2538(15)50791-6</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15752238</PMID><DateCompleted><Year>2005</Year><Month>05</Month><Day>18</Day></DateCompleted><DateRevised><Year>2019</Year><Month>01</Month><Day>31</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0098-6577</ISSN><JournalIssue CitedMedium="Print"><Issue>94</Issue><PubDate><Year>2005</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Kidney international. Supplement</Title><ISOAbbreviation>Kidney Int Suppl</ISOAbbreviation></Journal>Genetics of common progressive renal disease.
|
Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Satko</LastName><ForeName>Scott G</ForeName><Initials>SG</Initials><AffiliationInfo><Affiliation>Department of Internal Medicine/Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Freedman</LastName><ForeName>Barry I</ForeName><Initials>BI</Initials></Author><Author ValidYN="Y"><LastName>Moossavi</LastName><ForeName>Shahriar</ForeName><Initials>S</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01-HL56266</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Kidney Int Suppl</MedlineTA><NlmUniqueID>7508622</NlmUniqueID><ISSNLinking>0098-6577</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007676" MajorTopicYN="N">Kidney Failure, Chronic</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>34</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>5</Month><Day>19</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>9</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15752239</ArticleId><ArticleId IdType="doi">10.1111/j.1523-1755.2005.09411.x</ArticleId><ArticleId IdType="pii">S0085-2538(15)50791-6</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15752238</PMID><DateCompleted><Year>2005</Year><Month>05</Month><Day>18</Day></DateCompleted><DateRevised><Year>2019</Year><Month>01</Month><Day>31</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0098-6577</ISSN><JournalIssue CitedMedium="Print"><Issue>94</Issue><PubDate><Year>2005</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Kidney international. Supplement</Title><ISOAbbreviation>Kidney Int Suppl</ISOAbbreviation></Journal><ArticleTitle>Genetics of common progressive renal disease.</ArticleTitle><Pagination><StartPage>S41</StartPage><EndPage>S45</EndPage><MedlinePgn>S41-5</MedlinePgn></Pagination><Abstract>Familial aggregation of common chronic kidney diseases provides a unique opportunity to investigate the susceptibility genetic and environmental factors. In the past decade, a wealth of new data has become available concerning the genetic susceptibility leading to numerous nephropathies. Knowledge of the genetic components allows better understanding of initiation and progression of these chronic kidney diseases. In addition, one can envision that identification of genetically susceptible individuals might lead to earlier diagnosis and potential reversal of the current epidemic of end-stage renal disease. The goal of the current discussion is to review various issues pertaining to the role of genetic factors in common chronic kidney diseases, as exemplified by two leading causes of end-stage renal diseases worldwide, nephropathy of type 2 diabetes and IgA nephropathy. The genetic and environmental interplay leading to the nephropathies is highlighted.
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2,338,047 |
Student screening for inherited blood disorders in Bahrain.
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In Bahrain and neighbouring countries inherited disorders of haemoglobin, i.e. sickle-cell disease, thalassaemias and glucose-6-phosphate dehydrogenase (G6PD) deficiency, are common. As part of the National Student Screening Project to determine the prevalence of genetic blood disorders and raise awareness among young Bahrainis, we screened 11th-grade students from 38 schools (5685 students), organized lectures and distributed information about these disorders. Haemoglobin electrophoresis, high performance liquid chromatography, blood grouping and G6PD deficiency testing were performed. Prevalences were: 1.2% sickle-cell disease; 13.8% sickle-cell trait; 0.09% beta-thalassaemia; 2.9% beta-thalassaemia trait; 23.2% G6PD deficiency; 1.9% G6PD deficiency carrier. Health education, carrier screening and premarital counselling remain the best ways to reduce disease incidence with potentially significant financial savings and social and health benefits.
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2,338,048 |
Three new 46,XX male patients: a clinical, cytogenetic and molecular analysis.
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XX males range phenotypically from completely masculinised individuals to true hermaphrodites and include a subset of SRY negative patients. The correlation between genotype (SRY+/-) and phenotype is still unclear.</AbstractText>To report three new patients with this rare condition, one of whom was diagnosed prenatally and another was SRY negative, and to verify in our patients whether the presence of SRY results in a more masculinised phenotype.</AbstractText>We present two phenotypically normal XX male patients (10 and 13.5 years) and one 3.1 years old XX male with ambiguous external male genitalia Prader IV. The patients were diagnosed by clinical, hormonal, sonographic, genetic and histological criteria.</AbstractText>Basal hormonal status was normal for phenotype but an excessive response to GnRH testing was noticed in the second patient together with insufficient hCG stimulation in all three patients. Pelvic ultrasound displayed male structures without Müllerian ducts; testicular biopsy, performed only in the intersex patient, showed Sertoli and Leydig cell hypoplasia. Chromosome analysis confirmed 46,XX karyotype. FISH analysis and molecular analysis by PCR were positive for Yp fragments/SRY gene on Xp in two patients and negative in the patient with ambiguous external genitalia.</AbstractText>In our observation Y chromosome-specific material containing the SRY gene translocated to the X chromosome results in a completely masculinised phenotype. In the intersex patient, incomplete masculinisation without SRY suggests a mutation of one or more downstream non-Y testis-determining genes.</AbstractText>
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2,338,049 |
Update on the prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency.
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11beta-Hydroxylase deficiency is a common form of congenital adrenal hyperplasia causing virilization of the female fetus and hypertension. DNA analysis of the gene (CYP11B1) encoding 11beta-hydroxylase has been reported previously to be effective in the prenatal diagnosis of one affected female fetus. In that case, prenatal treatment with dexamethasone resulted in normal female genitalia. We now report five new pregnancies that underwent prenatal diagnosis for 11beta-hydroxylase deficiency. In the first family, the proband is homozygous for a T318M mutation and all fetuses from four subsequent pregnancies are carriers. In a second family, the mother is homozygous for a A331V mutation and was started on dexamethasone, but identification of a homozygous normal fetus led to the discontinuation of treatment. In another family, the fetus was a male homozygous for R384Q and treatment was discontinued. Lastly, a novel G444D mutation in exon 8 was identified and proven to reduce 11beta-hydroxylase activity.
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2,338,050 |
Outpatient genetic risk assessment in women with breast cancer: one center's experience.
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A chart audit at one cancer center, of 193 women with breast cancer, was completed to assess whether a complete family history that may indicate genetic predisposition was obtained and if that information led a provider to suggest risk reduction strategies. A risk management tool, which included a pedigree template, was used. Of the 193 charts reviewed, 88.6% had family history information recorded; 41.5% reported three generations of family history. Risk management was undocumented in 21.8% of the charts reviewed and, for those that were reported (78.2%), 7.25% were referred for genetic counseling. These results suggest that a more detailed assessment of hereditary breast cancer risk incorporating three generations of family history and additional types of cancer need to be integrated into medical oncology practice. An algorithm was developed as a guide to improve the process of evaluation and referral for genetic risk assessment.
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2,338,051 |
Nurses' views of longitudinal genetic screening of and research on children.
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There is a lack of empirical data exploring ethical issues of genetic screening and longitudinal research involving children. Therefore, this pilot interview study explored the perceptions of nurses and midwives in relation to their involvement in an ongoing genetic preventive screening process involving children - the All Babies in South-east Sweden (ABIS) study (n=17,005). Data were collected through semistructured interviews with 10 nurses involved in all information and sampling procedures. While providing the preliminary nature of this study, it supports the idea of the importance of further research, both from a nursing professional perspective and from other parties involved in clinical research. The findings made in this study suggest that for such studies it is vital that nurses and midwives are fully informed about aims, methods, and potential intervention/prevention since in many cases they have a central role in several areas of screening and clinical longitudinal research involving children, e.g. information to potential research participants, obtaining informed consent, and data collection. With a thorough understanding of the research, including both basic aims and methods as well as potential future prevention aims, the nursing staff involved will be better placed to help participants make an informed choice and to provide additional information to the participants. Further research may be needed that aims to develop effective methods in preparing data collectors. It is also suggested that the design of the information process, and especially in longitudinal research involving young children, is of utmost importance before such studies are commenced.
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2,338,052 |
HIV-1 resistance genotyping on dried serum spots.
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To assess the feasibility of HIV-1 group M resistance genotyping on dried serum spots, by testing samples from previously untreated patients, patients on treatment, and patients having stopped treatment, representing a wide genetic diversity panel.</AbstractText>Serum samples from 62 HIV-1-infected Caucasian and African patients, with viral load values from 715 copies/ml to more than 750,000 copies/ml, were deposited on filter paper. After elution and RNA extraction, nested RT-PCR was used to amplify the protease and RT regions of the pol gene. Resistance sequencing was performed on all the protease and RT amplicons. The sequences obtained for resistance genotyping were used for subtyping by phylogenetic analysis.</AbstractText>Amplification was successful in the protease region in 53/62 cases (85.5%) and in the RT region in 51/62 cases (82.3%). All samples with viral loads of at least 5 Log (17 of 62) were successfully amplified in both the RT and protease regions. Of the 29 samples with viral loads between 4 Log and 5 Log, 28 (97%) were amplified in the RT region and 25 (86%) in the protease region. The detected mutations were in keeping with the treatment status. Marked natural polymorphism was observed in the protease region, but no major consequences were deduced in terms of resistance. The results showed a broad diversity of the panel, including subtype B (n = 36) and non B or recombinant forms (n = 20).</AbstractText>Our results show the feasibility of this dried serum spot method for monitoring resistance to antiretroviral drugs and the molecular epidemiology of HIV diversity. The simplicity of sample preparation, storage and transport potentially makes this an importance tool for individual and epidemiological monitoring throughout the world.</AbstractText>
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2,338,053 |
Vi antigen expression in Salmonella enterica serovar Typhi clinical isolates from Pakistan.
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The accurate identification of Salmonella enterica subsp. enterica serovar Typhi variants that fail to express the capsular polysaccharide, Vi, is an important and much discussed issue for medical microbiology. We have tested a multiplex PCR method which shows the presence or absence of the genetic locus required for Vi expression. Of 2,222 Salmonella serovar Typhi clinical isolates collected from patients' blood over a 4-year period in a region of Pakistan where typhoid is endemic, 12 tested negative for Vi expression by serological agglutination. However, only 1 of these 12 was Vi negative by the multiplex PCR method. This result was confirmed by immunofluorescence, the most sensitive method for Vi characterization in Salmonella serovar Typhi. The multiplex PCR described therefore represents a simple and accurate method for surveillance for Vi-negative variants of Salmonella serovar Typhi in Pakistan. Testing of clinical isolates of Salmonella serovar Typhi, before subculture, from other regions where Vi-negative Salmonella serovar Typhi has been described should be carried out so that the impact of vaccination with purified Vi antigen on the levels of Vi-negative Salmonella serovar Typhi in bacterial populations can be assessed.
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2,338,054 |
Polar body diagnosis for hemophilia a using multiplex PCR for linked polymorphic markers.
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Preimplantation genetic diagnosis (PGD) is usually performed on blastomeres. In Germany, the only possibility to perform PGD is by analysis of polar bodies. We performed PGD using polar bodies in a woman who is a carrier of hemophilia A. Multiplex PCR followed by nested fluorescent PCR for five linked polymorphic markers was established. From 11 analyzed polar bodies, only 1 showed alleles linked to the mutation. The corresponding oocyte was transferred and no pregnancy was established. As seen in other investigations, the rate of heterozygous first polar bodies is surprisingly high.
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2,338,055 |
Preimplantation genetic diagnosis--an overview.
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Since the early 1990s, preimplantation genetic diagnosis (PGD) has been expanding in scope and applications. Selection of female embryos to avoid X-linked disease was carried out first by polymerase chain reaction, then by fluorescence in situ hybridization (FISH), and an ever-increasing number of tests for monogenic diseases have been developed. Couples with chromosome rearrangements such as Robertsonian and reciprocal translocations form a large referral group for most PGD centers and present a special challenge, due to the large number of genetically unbalanced embryos generated by meiotic segregation. Early protocols used blastomeres biopsied from cleavage-stage embryos; testing of first and second polar bodies is now a routine alternative, and blastocyst biopsy can also be used. More recently, the technology has been harnessed to provide PGD-AS, or aneuploidy screening. FISH probes specific for chromosomes commonly found to be aneuploid in early pregnancy loss are used to test blastomeres for aneuploidy, with the aim of replacing euploid embryos and increasing pregnancy rates in groups of women who have poor IVF success rates. More recent application of PGD to areas such as HLA typing and social sex selection have stoked public controversy and concern, while provoking interesting ethical debates and keeping PGD firmly in the public eye.
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2,338,056 |
Allele frequencies for 70 autosomal SNP loci with U.S. Caucasian, African-American, and Hispanic samples.
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189 samples from 3 different U.S. sample groups Caucasian (74), African American (71) and Hispanic (44) were typed for 70 autosomal genetic markers. These 70 markers are bi-allelic (C/T) short nucleotide polymorphisms (SNPs). For each sample, the 70 SNP markers were typed in 11 unique 6-plexes and a single 4-plex PCR. A total of 10 of the 210 tests (70 loci x 3 populations) for Hardy-Weinberg equilibrium indicated a statistically significant result. In order to evaluate the minimum number of SNP loci needed to distinguish all 189 samples from one another, we ranked the loci according to their levels of observed heterozygosity and p-values obtained upon testing for Hardy-Weinberg equilibrium. The top 12 loci according to these ranking criteria were tabulated along with the number of unique genotypes observed when combining subsequent SNP markers. The 12 selected SNPs possessed an observed heterozygosity of >0.45 in all three populations examined and thus would be expected to exhibit more differences between samples. All of the 189 samples in this study were individualized with a subset of 12 SNP loci. However, it is likely that the addition of more than 12 SNP loci will be required to resolve larger sets of unrelated individuals from one another. By way of comparison, in these same 189 individuals all but one pair is resolved from one another with three of the traditional short tandem repeat (STR) loci possessing the highest heterozygosity values (D2S1338, D18S51, and FGA) run with the Identifiler kit. The final pair of unrelated samples could be resolved with the combination of 4 STR loci: D2S1338, D18S51, FGA, and VWA.
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2,338,057 |
Making and breaking serotonin neurons and autism.
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Dysfunction of brain serotonin system development is hypothesized to contribute to autistic behaviors. The testing of this hypothesis will likely depend on a better understanding of the genes and mechanisms involved in serotonin neuron cell fate specification. In this review we summarize the main features of vertebrate serotonin neuroanatomical development and recent studies that have revealed critical steps in the molecular genetic program that controls serotonin neuron phenotype. We then discuss the potential relevance of these findings to advances in autism research and to new molecular genetic tools under development that will impact future testing of the hypothesis.
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2,338,058 |
Dissecting the genetics of human high myopia: a molecular biologic approach.
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Despite the plethora of experimental myopia animal studies that demonstrate biochemical factor changes in various eye tissues, and limited human studies utilizing pharmacologic agents to thwart axial elongation, we have little knowledge of the basic physiology that drives myopic development. Identifying the implicated genes for myopia susceptibility will provide a fundamental molecular understanding of how myopia occurs and may lead to directed physiologic (ie, pharmacologic, gene therapy) interventions. The purpose of this proposal is to describe the results of positional candidate gene screening of selected genes within the autosomal dominant high-grade myopia-2 locus (MYP2) on chromosome 18p11.31.</AbstractText>A physical map of a contracted MYP2 interval was compiled, and gene expression studies in ocular tissues using complementary DNA library screens, microarray matches, and reverse-transcription techniques aided in prioritizing gene selection for screening. The TGIF, EMLIN-2, MLCB, and CLUL1 genes were screened in DNA samples from unrelated controls and in high-myopia affected and unaffected family members from the original seven MYP2 pedigrees. All candidate genes were screened by direct base pair sequence analysis.</AbstractText>Consistent segregation of a gene sequence alteration (polymorphism) with myopia was not demonstrated in any of the seven families. Novel single nucleotide polymorphisms were found.</AbstractText>The positional candidate genes TGIF, EMLIN-2, MLCB, and CLUL1 are not associated with MYP2-linked high-grade myopia. Base change polymorphisms discovered with base sequence screening of these genes were submitted to an Internet database. Other genes that also map within the interval are currently undergoing mutation screening.</AbstractText>
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2,338,059 |
Host susceptibility and clinical outcomes in toll-like receptor 5-deficient patients with typhoid fever in Vietnam.
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Toll-like receptor 5 (TLR5) mediates innate immune responses to bacterial pathogens by binding to flagellin. A polymorphism in the TLR5 gene introduces a premature stop codon (TLR5(392STOP)) that is associated with susceptibility to legionnaires disease. Here we investigated whether TLR5(392STOP) was associated with typhoid fever. The frequency of TLR5(392STOP) was not significantly different in 565 patients with typhoid fever and 281 ethnically matched control subjects. Furthermore, TLR5 deficiency had no measurable effect on a number of clinical parameters associated with typhoid fever, including fever clearance time, pathogen burden, disease severity, or age at acquisition of disease. TLR5 may not play an important role in TLR-stimulated innate immune responses to human infection with Salmonella enterica serovar Typhi. Initiation of these responses may rely on other TLRs that recognize different bacterial ligands.
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2,338,060 |
Recent advances in hereditary hemochromatosis.
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Hereditary hemochromatosis, a very common genetic defect in the Caucasian population, is characterized by progressive tissue iron overload which leads to irreversible organ damage if it is not treated in a timely manner. Recent developments in the field of molecular medicine have radically improved the understanding of the physiopathology and diagnosis of this disease. However, transferrin saturation and serum ferritin are still the most reliable tests for identifying subjects with hereditary hemochromatosis. Therapeutic phlebotomy is the mainstay of the treatment of this disease and the life expectancy of these patients is similar to that of the normal population if phlebotomy is started before the onset of irreversible organ damage. In this review we discuss the genetics, pathophysiology, diagnosis, clinical features, and management of hereditary hemochromatosis.
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2,338,061 |
Genetic analysis of selected strains of eastern oyster (Crassostrea virginica Gmelin) using AFLP and microsatellite markers.
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Amplified fragment length polymorphisms (AFLPs) and microsatellite markers were used to examine genetic variation and divergence in 4 selected strains (DBH, NEH, FMF, and CTS) and 1 wild population (DBW) of the eastern oyster Crassostrea virginica Gmelin. Eighty-six AFLP markers (from 3 primer pairs) and 5 microsatellite loci were used for the analysis of 30 oysters from each of the 5 populations. Microsatellite loci were considerably more variable than AFLPs. The observed heterozygosity ranged from 0.560 to 0.640 across populations for microsatellites, and from 0.186 to 0.207 for AFLPs. Both Fst and phiPT of microsatellite data and phiPT statistics of AFLP data revealed significant divergence between all pairs of populations. There was no significant reduction in heterozygosity in all 4 selected strains; however, the number of alleles per locus was considerably lower in the selected strains than in the wild population. Two strains subjected to long-term selection for disease resistance shared frequency shifts at a few loci, which deserve further analysis to determine if they are linked to disease-resistance genes.
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2,338,062 |
Nonreplication in genetic studies of complex diseases--lessons learned from studies of osteoporosis and tentative remedies.
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Inconsistent results have accumulated in genetic studies of complex diseases/traits over the past decade. Using osteoporosis as an example, we address major potential factors for the nonreplication results and propose some potential remedies. Over the past decade, numerous linkage and association studies have been performed to search for genes predisposing to complex human diseases. However, relatively little success has been achieved, and inconsistent results have accumulated. We argue that those nonreplication results are not unexpected, given the complicated nature of complex diseases and a number of confounding factors. In this article, based on our experience in genetic studies of osteoporosis, we discuss major potential factors for the inconsistent results and propose some potential remedies. We believe that one of the main reasons for this lack of reproducibility is overinterpretation of nominally significant results from studies with insufficient statistical power. We indicate that the power of a study is not only influenced by the sample size, but also by genetic heterogeneity, the extent and degree of linkage disequilibrium (LD) between the markers tested and the causal variants, and the allele frequency differences between them. We also discuss the effects of other confounding factors, including population stratification, phenotype difference, genotype and phenotype quality control, multiple testing, and genuine biological differences. In addition, we note that with low statistical power, even a "replicated" finding is still likely to be a false positive. We believe that with rigorous control of study design and interpretation of different outcomes, inconsistency will be largely reduced, and the chances of successfully revealing genetic components of complex diseases will be greatly improved.
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2,338,063 |
Partition-distance via the assignment problem.
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Accuracy testing of various pedigree reconstruction methods requires an efficient algorithm for the calculation of distance between a known partition and its reconstruction. The currently used algorithm of Almudevar and Field takes a prohibitively long time for certain partitions and population sizes.</AbstractText>We present an algorithm that very efficiently reduces the partition-distance calculation to the classic assignment problem of weighted bipartite graphs that has known polynomial-time solutions. The performance of the algorithm is tested against the Almudevar and Field partition-distance algorithm to verify the significant improvement in speed.</AbstractText>Computer code written in java is available upon request from the first author.</AbstractText>
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2,338,064 |
Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism.
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Defects in the human thyroid peroxidase (TPO) gene are reported to be one of the causes of congenital hypothyroidism (CH) due to a total iodide organification defect. The aim of the present study was to determine the nature and frequency of TPO gene mutations in patients with CH, characterised by elevated TSH levels and orthotopic thyroid gland, identified in the Portuguese National Neonatal Screening Programme.</AbstractText>The sample comprised 55 patients, from 53 unrelated families, with follow-up in the endocrinology clinics of the treatment centres of Porto and Lisbon. Mutation screening in the TPO gene (exons 1-17) was performed by single-strand conformational analysis followed by sequencing of fragments with abnormal migration patterns.</AbstractText>Eight different mutations were detected in 13 patients (seven homozygotes and six compound heterozygotes). Novel mutations included three missense mutations, namely 391T > C (S131P), 1274A > G (N425S) and 2512T > A (C838S), as well as the predictable splice mutation 2748G > A (Q916Q/spl?). The undocumented polymorphism 180-47A > C was also detected.</AbstractText>The results are in accordance with previous observations confirming the genetic heterogeneity of TPO defects. The proportion of patients in which the aetiology was determined justifies the implementation of this molecular testing in our CH patients with dyshormonogenesis.</AbstractText>
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2,338,065 |
Personality stability in late adulthood: a behavioral genetic analysis.
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A sample of 833 twins from the Minnesota Twin Study of Adult Development and Aging completed the Multidimensional Personality Questionnaire (MPQ; Tellegen, 1982) twice, averaging 59.4 (sd=9.7) years of age at first and 64.4 (sd=10.2) years of age at second testing (average retest interval 5.0 years, sd=2.36, range 1.0-10.4 years). Both means and standard deviations of scale scores were extremely stable from first to second testing. In addition, sample participants tended to retain their rank order on the scales (average r=.76 across scales). Bivariate biometric analyses showed that the genetic influences on most of the scale scores were almost perfectly correlated across the two waves (range .95 to 1.00). The nonshared environmental influences were also highly correlated across the two waves (range .53 to .73). Models specifying identical variance components at the two time points and fixing the genetic correlation to 1.00 provided improved fit. The results suggest that the high stability of personality in later adulthood has a strong genetic foundation, supplemented by stability of environmental effects.
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2,338,066 |
Hereditary nonpolyposis colorectal cancer (Lynch syndrome): criteria for identification and management.
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Hereditary nonpolyposis colorectal carcinoma (HNPCC), or Lynch syndrome, is an autosomal dominant syndrome accounting for 5 to 10% of the total colorectal cancer population. Patients with this syndrome develop colorectal carcinoma at an early age, but disease onset can happen in all age groups. Usually the carcinomas are synchronous or metachronous, and most of them arise proximal to the splenic flexure. The prognosis is better than for the sporadic form of cancer, and there is increased risk for cancer development in certain extracolonic sites, such as the endometrium, ovary, stomach, small bowel, hepatobiliary tract, ureter, and renal pelvis. Most patients with HNPCC have a mutation in one of two DNA mismatch repair genes, hMSH2 or hMLH 1. More than 90% of colorectal carcinoma patients with hMSH2 or hMLH1 demonstrate high-frequency microsatellite instability (MSI-H). If a patient is suspected to belong to an HNPCC family, the first screening test should be immunohistochemistry for the detection of hMLH1 and hMSH2 proteins, and if it is indicative, it should be followed by genomic sequencing for the identification of mutations in the mismatch repair genes. Genetic counseling and surveillance for high risk HNPCC family members should begin at age 25. Surveillance includes annual colonoscopy of the entire large bowel, with fecal occult blood testing performed twice a year. Systematic surveillance and individually designed treatment of affected patients may help to detect cancers at an earlier stage and subsequently improve the prognosis of the disease further.
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2,338,067 |
Separating predictive genetic testing from snake oil: regulation, liabilities, and lost opportunities.
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This article explores the extent to which completion of maps of the human genome, coupled with the introduction of technology that will accelerate the identification of gene and protein function, have introduced immeasurable potential to advance life science and health care through genetic profiling. In light of definitional uncertainty, the regulatory and legal environment surrounding predictive genetic testing threatens to impede clinical utilization of genetic profiling technologies that could significantly improve human health. Especially given that genetic testing technologies have been stigmatized in the public and medical community, they must enter the marketplace with a regulatory framework that assures safety, efficacy, and market responsibility.
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2,338,068 |
Hereditary melanoma and predictive genetic testing: why not?
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Since p16-Leiden presymptomatic testing for hereditary melanoma has become available in the Netherlands, the benefits and risks of offering such testing are evaluated. The current paper investigated why the non-participants were reluctant to participate in genetic testing.</AbstractText>Sixty six eligible individuals, who were knowledgeable about the test but had not participated in genetic testing by January 2003, completed a self-report questionnaire assessing motivation, anxiety, family dynamics, risk knowledge and causal attributions.</AbstractText>Non-participants reported anxiety levels below clinical significance. A principal components analysis on reasons for non-participation distinguished two underlying motives: emotional and rational motivation. Rational motivation for non-participation was associated with more accurate risk knowledge, the inclination to preselect mutation carriers within the family and lower scores on anxiety. Emotional motivation for non-participation was associated with disease misperceptions, hesitation to communicate unfavourable test results within the family and higher scores on anxiety.</AbstractText>Rational and emotional motivation for non-participation in the genetic test for hereditary melanoma was found. Emotionally motivated individuals may be reluctant to disseminate genetic risk information. Rationally motivated individuals were better informed than emotionally motivated individuals. It is suggested that a leaflet is added to the invitation letter to enhance informed decision-making about genetic testing.</AbstractText>
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2,338,069 |
Testing the possibility to protect bovine PrPC transgenic Swiss mice against bovine PrPSc infection by DNA vaccination using recombinant plasmid vectors harboring and expressing the complete or partial cDNA sequences of bovine PrPC.
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The objective of this study was to investigate the molecular mechanisms of neurobiological processes involved in the degeneration of the central nervous system. The bovine spongiform encephalopathy (BSE) was used as experimental model system for investigation of transmissible spongiform encephalopathy (TSE). The experimental strategy was to evaluate the possibility for protection of bovine PrP(C) transgenic mice against a bovine PrP(Sc) infection by DNA vaccination using the complete or partial cDNA sequences of the bovine prion protein. Three recombinant plasmids pCR3.1-EX-PrP-BSE-C20 (C20), pCR3.1-EX-PrP-BSE-90-235-C4 (C4), and pCR3.1-EX-PrP-BSE-106-131-C14 (C14) were constructed. These mammalian expression vectors harbor complete (C20) or partial (C4 and C14) cDNA sequences of the Bos taurus PrP(C) (BTPrP(C)) encoding for amino acid residues 1-264 (C20), 90-235 (C4), and 106-131 (C14) of the BTPrP(C). Transgenic mice harboring and expressing BTPrP(C) were generated using the donor strain C57/CBA, receptor strain Swiss mouse, and recombinant plasmid MoPrPXho-boPrP. Crossing of positive transgenic mice to bovine PrP and negative to murine PrP with 129/OLA (murine PrP-/-) and C57BL6x129/OLA (murine PrP+/-) mice was carried out to amplify the colony of transgenic mice termed bovine PrP(C) transgenic Swiss mice (BTPrP-TgM). The capabilities of C20, C4, and C14 to express the corresponding cDNA sequence of BTPrP(C) in vitro and in vivo were confirmed prior to DNA vaccination of the BTPrP-TgM using NIH 3T3 cells and BALB/c mice, respectively. In order to prove the capability of the constructed expression vectors to protect BTPrP-TgM in vivo against a BSE infection 80 female BTPrP-TgM were vaccinated intramuscularly and subcutaneously with DNA of the plasmids C20, C4, C14, and parental vector pCR3.1 (100 microg DNA corresponding to about 26-30 pmol DNA/animal and application) in four groups (each consists of 20 animals). DNA vaccination was followed by three additional boosters. The vaccinated animals (15 animals of each group) were challenged twice per oral with homogenates of brain material obtained from BSE cattle containing the infectious PrP(Sc) (100 microl/animal which corresponds to 15 mg of a 15% brain homogenate). The first and second challenge experiments were performed 76-83 and 181 days post DNA vaccination, respectively. A part of the vaccinated animals (3-5 animals of each group) that served as internal negative control were mock infected using the brain homogenate of healthy cattle or Phosphate saline buffer (PBS). A variety of symptoms and clinical pictures were observed during the monitoring of DNA vaccinated animals. However, the observed diseases seem to be similar in all experimental animal groups. After an observation period of 14 months post the second challenge experiment the remaining animals (some animals died or were sacrificed when moribund during the study) were sacrificed after expiration of the experimental schedule. The right hemisphere of the brain and a half of the spleen tissue of the individual animals were used for detection of PrP(Sc) by Western blot analysis. The misfolded bovine PrP(Sc) was not detected in the brain or spleen tissues of those animals that were vaccinated with DNA of C20, which was able to express the complete bovine PrP(C) protein in vitro and in vivo. In contrast, the bovine PrP(Sc) was detected in the brain or spleen tissues of animals that were DNA vaccinated with DNA of the parental vector pCR3.1, with DNA of C4, or with DNA of C14. The results of these studies underline that the constructed expression vector C20 possesses the protective capacity to inhibit the formation of misfolded bovine PrP(Sc) in BTPrP-TgM under the conditions used. A delay of occurrence of TSE-specific symptoms in the majority of the vaccinated animals seems to be due to the prolonged incubation time of BSE infection.
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2,338,070 |
Effects of race on survival after stem cell transplantation.
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Effects of race or ethnicity on survival after high-dose chemoradiation followed by stem cell transplantation (SCT) have not been thoroughly evaluated. We analyzed survival according to racial/ethnic categories for 3587 consecutive patients who had SCT at a single US institution between July 1992 and December 2000. Among 1366 patients who received autologous SCT, race or ethnicity was not significantly associated with survival. In contrast, among 2221 patients who received allogeneic SCT from HLA-matched unrelated or sibling donors, blacks had a significantly greater mortality than whites (unadjusted hazard ratio, 1.65; 95% confidence interval, 1.21-2.25). Mortality among other racial or ethnic groups was not significantly different from that among whites. The greater mortality hazard among blacks persisted after controlling for donor type, pretransplantation risk category, patient age, donor/patient sex, and cytomegalovirus exposure (hazard ratio, 1.71; 95% confidence interval, 1.25-2.34). SCT from both HLA-matched unrelated and HLA-identical sibling donors was associated with more severe acute graft-versus-host disease and higher nonrelapse mortality among blacks compared with whites. Furthermore, blacks who received SCT for chronic myeloid leukemia had longer diagnosis-to-transplantation intervals than whites. A matched-cohort analysis showed that the higher mortality among blacks could not be explained by obvious socioeconomic differences. The higher incidence of severe graft-versus-host disease among blacks compared with whites, both with HLA-identical sibling donors, might be related to yet-unidentified "immune-enhancing" genetic polymorphisms. We cannot exclude the possibility that the increased mortality risk among blacks after discharge from the transplant center might in part be related to unidentified sociocultural differences that influence medical care.
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2,338,071 |
Viral vector mediated overexpression of human alpha-synuclein in the nigrostriatal dopaminergic neurons: a new model for Parkinson's disease.
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Parkinson's disease is predominantly a dopamine deficiency syndrome, which is produced in the brain by the loss of cells located in a small area in the ventral midbrain called the substantia nigra. Complete unilateral dopamine lesions, based on the administration of toxic substances (ie, 6-hydroxy-dopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates) have been extremely useful in testing strategies of replacement. For example, the functional and biochemical impact of the transplanted ventral mesencephalic dopaminergic progenitors has been characterized to a large extent, using the complete lesion model in rats. Over the last decade, however, studies addressing the ability of neurotrophic factors to protect injured dopamine cells prompted researchers to make available partial and progressive lesion models to allow a window of opportunity to interfere the disease progression. Recent findings relating alpha-synuclein with Parkinson's disease pathology have opened new possibilities to develop alternative models based on the overexpression of this protein using recombinant adeno-associated viral vectors, which is valuable not only for helping to better understand its involvement in the disease process, but also to more closely resemble the neurodegeneration found in Parkinson's disease.
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2,338,072 |
APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder.
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Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.
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2,338,073 |
Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.
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The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk.</AbstractText>To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women.</AbstractText>There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values.</AbstractText>The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.</AbstractText>
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2,338,074 |
Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs.
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The FOXC2 gene on 16q24 is mutated in lymphoedema distichiasis (LD), in which varicose veins (VV) are a common feature. We hypothesised that this gene might be implicated in the development of VV in the normal population, therefore, after performing a classical twin study, we tested for linkage and association in white women. We also tested for linkage with haemorrhoids (H), as a separate venous anomaly at the same locus.</AbstractText>A total of 2060 complete female twin pairs aged 18-80 years from the St Thomas' Adult UK Twin registry replied to questions on VV and H as part of a broader postal survey of 6600 twins (62% response rate). Dizygotic female twin pairs were tested for linkage and association to the candidate marker D16S520 (1903 individuals genotyped), which is located about 80 kb from FOXC2.</AbstractText>Casewise concordance rates were significantly higher for monozygotic than dizygotic twins for both phenotypes (VV 67% v 45%; p = 2.2x10(-6); H 68% v 59%; p = 0.01; H including during pregnancy 73% v 64%; p = 2.1x10(-4)), corresponding to additive genetic heritabilities in liability of 86% (95% confidence interval (CI) 73% to 99%) for VV and 56-61% for H (95% CI 43% to 73%). The presence of VV and H were significantly correlated. We found significant evidence of linkage to the marker for VV (MLS(ASP) = 1.37, p = 0.01; GLM(ASP/DSP) Z = 3.17 p = 0.002), but no association. Both linkage and association tests were negative for H. The combined phenotype of having VV and H did not show any evidence of linkage or association.</AbstractText>These results demonstrate VV and H to be heritable, related conditions, and the data strongly suggest FOXC2 to be implicated in the development of VV in the general population.</AbstractText>
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2,338,075 |
A survey of haplotype variants at several disease candidate genes: the importance of rare variants for complex diseases.
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The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies.</AbstractText>To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence.</AbstractText>Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 x 10(-6) and p = 1.6 x 10(-4), respectively). Large phenotypic differences (4.0 approximately 5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution.</AbstractText>These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.</AbstractText>
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2,338,076 |
Association of partial AZFc region deletions with spermatogenic impairment and male infertility.
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Complete deletions of the AZFc region in distal Yq are the most frequent molecular genetic cause of severe male infertility. They are caused by intrachromosomal homologous recombination between amplicons--large, nearly identical repeats--and are found in 5-10% of cases of azoospermia and severe oligozoospermia. Homologous recombination may also generate different partial deletions of AZFc, but their contribution to spermatogenic impairment has not been confirmed.</AbstractText>In this study we analysed the prevalence and characteristics of different partial AZFc deletions and their association with spermatogenic failure. We studied 337 infertile men with different spermatogenic impairment and 263 normozoospermic fertile men using AZFc specific sequence tagged site markers and DAZ specific single nucleotide variants.</AbstractText>We identified 18 cases of partial AZFc deletions in the infertile group (5.3%) and one case in the control group (0.4%). Seventeen deletions had the "gr/gr" pattern, one the "b2/b3" pattern, and one represented a novel deletion with breakpoints in b3 and b4 amplicons. Partial AZFc deletions were associated with different spermatogenic phenotypes ranging from complete azoospermia to only moderate oligozoospermia.</AbstractText>Together with published data, our analysis of DAZ gene copy suggested that the contribution of the different deletions to male infertility varies: only partial AZFc deletions removing DAZ1/DAZ2 seem to be associated with spermatogenic impairment, whereas those removing DAZ3/DAZ4 may have no or little effect on fertility. These data show that, beside complete AZFc deletions, specific partial deletions represent a risk factor for male infertility, even if with different effect on spermatogenesis.</AbstractText>
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2,338,077 |
Genetic screening for prey in the gut contents from a giant squid (Architeuthis sp.).
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Giant squids (Architeuthis sp.) remain mysterious; they have evaded observation and are rarely taken from their deep sea habitat. Information on the diet of Architeuthis is scarce due to the limited number of specimens with morphologically recognizable remains in their digestive tracts. We explored the use of polymerase chain reaction (PCR)-based methods for detection of DNA in the prey remains and amorphous slurry from an Architeuthis gut sample. The DNA region amplified varied in size, allowing separation of fish and squid components. Sequence comparisons identified fish prey as Macruronus novaezelandiae. Isolation of Architeuthis DNA from an ingested tentacle and the presence of chitin fragments indicate cannibalism occurs in giant squid. Denaturing gradient gel electrophoresis was used to screen for less common DNA types, revealing a high frequency of PCR-generated false alleles, but no additional prey species.
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2,338,078 |
On evolutionary origin of cancer.
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BACKGROUND: The necessary and sufficient capabilities of cancer cell have been identified. Strikingly, this list does not include one that would seem to be a key property, namely the ability of cancer cells to kill their "host". This is believed to be a self-evident consequence of the other capabilities (e.g., metastasis), although the available evidence suggests a distinct killer function. Taking into account this unlisted property can significantly affect the current paradigm of carcinogenesis. PRESENTATION OF THE HYPOTHESIS: On the assumption that killer function is a key capability of the cancer cell, it is suggested that cancer has evolved as a mechanism of negative selection of mutant alleles of vitally important genes present in population. Similarly to apoptosis, which is an altruistic suicidal act of a damaged cell, cancer is an altruistic suicidal act of an individual who carries dangerous alleles and presents a hazard for genetic stability of the population. From this point of view, apoptosis is not a protection means against cancer as generally believed, but rather they are the first and second lines of defense against genome instability, respectively. TESTING THE HYPOTHESIS: The modern DNA array technology is capable of revealing gene expression profiles responsible for killer function of cancer cell as well as those specific targets in the body that are most strongly affected by the tumor growth. IMPLICATIONS OF THE HYPOTHESIS: This hypothesis suggests new avenues of cancer research as well as principally new therapeutic strategies.
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2,338,079 |
Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study.
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Juvenile rheumatoid arthritis (JRA) comprises a group of chronic systemic inflammatory disorders that primarily affect joints and can cause long-term disability. JRA is likely to be a complex genetic trait, or a series of such traits, with both genetic and environmental factors contributing to the risk for developing the disease and to its progression. The HLA region on the short arm of chromosome 6 has been intensively evaluated for genetic contributors to JRA, and multiple associations, and more recently linkage, has been detected. Other genes involved in innate and acquired immunity also map to near the HLA cluster on 6p, and it is possible that variation within these genes also confers risk for developing JRA. We examined the TPSN gene, which encodes tapasin, an endoplasmic reticulum chaperone that is involved in antigen processing, to elucidate its involvement, if any, in JRA. We employed both a case-control approach and the transmission disequilibrium test, and found linkage and association between the TPSN allele (Arg260) and the systemic onset subtype of JRA. Two independent JRA cohorts were used, one recruited from the Rheumatology Clinic at Cincinnati Children's Hospital Medical Center (82 simplex families) and one collected by the British Paediatric Rheumatology Group in London, England (74 simplex families). The transmission disequilibrium test for these cohorts combined was statistically significant (chi2 = 4.2, one degree of freedom; P = 0.04). Linkage disequilibrium testing between the HLA alleles that are known to be associated with systemic onset JRA did not reveal linkage disequilibrium with the Arg260 allele, either in the Cincinnati systemic onset JRA cohort or in 113 Caucasian healthy individuals. These results suggest that there is a weak association between systemic onset JRA and the TPSN polymorphism, possibly due to linkage disequilibrium with an as yet unknown susceptibility allele in the centromeric part of chromosome 6.
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2,338,080 |
A1166C angiotensin II type 1 receptor gene polymorphism may predict hemodynamic response to losartan in patients with cirrhosis and portal hypertension.<Pagination><StartPage>636</StartPage><EndPage>642</EndPage><MedlinePgn>636-42</MedlinePgn></Pagination><Abstract><AbstractText Label="OBJECTIVE" NlmCategory="OBJECTIVE">Losartan, a dose of 25 mg/day, has been found to be effective in 50% of patients with portal hypertension without adverse effects. We evaluated the relationship between genetic polymorphisms of the renin-angiotensin system (A1166C angiotensin II type 1 receptor (AT1R), angiotensinogen T174M and M235T, and angiotensin-converting enzyme I/D) and the effects of losartan on portal and systemic hemodynamic in patients with cirrhosis and portal hypertension.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">We performed a longitudinal study that included 23 consecutive patients with cirrhosis and esophageal varices who received 25 mg/day of losartan during 12 wk. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured at baseline and after treatment. Genomic DNA was extracted from peripheral blood leukocytes; genetic polymorphisms of the renin-angiotensin system were investigated by polymerase chain reaction and restriction fragment length polymorphisms.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">The homozygous patients for AT1R A allele showed higher pulmonary-wedged and free hepatic venous pressure on baseline. After treatment, they showed a higher decrease of HVPG (32.5%+/- 19.2) in comparison with patients with AC/CC genotype (2.4%+/-18.9), p < 0.01. Ten of 15 patients with AA genotype were responders, while only one of eight with AC/CC genotype (p < 0.002); genotype AA showed a positive predictive value of 66.6% and negative predictive value of 87.5%.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">These results suggest that there is a relationship between the AT1R A1166C polymorphisms and the therapeutic response to losartan. The genetic testing may be used as a predictive factor of this response.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sookoian</LastName><ForeName>Silvia</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Cardiología Molecular, Instituto de Investigaciones Médicas A Lanari, Universidad de Buenos Aires, Buenos Aires, Argentina.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Castaño</LastName><ForeName>Gustavo</ForeName><Initials>G</Initials></Author><Author ValidYN="Y"><LastName>García</LastName><ForeName>Silvia I</ForeName><Initials>SI</Initials></Author><Author ValidYN="Y"><LastName>Viudez</LastName><ForeName>Pedro</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>González</LastName><ForeName>Claudio</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Pirola</LastName><ForeName>Carlos J</ForeName><Initials>CJ</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Am J Gastroenterol</MedlineTA><NlmUniqueID>0421030</NlmUniqueID><ISSNLinking>0002-9270</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047228">Angiotensin II Type 1 Receptor Blockers</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D044140">Receptor, Angiotensin, Type 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>JMS50MPO89</RegistryNumber><NameOfSubstance UI="D019808">Losartan</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Am J Gastroenterol. 2005 Nov;100(11):2601-2</RefSource><PMID Version="1">16279926</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D000293" MajorTopicYN="N">Adolescent</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D047228" MajorTopicYN="N">Angiotensin II Type 1 Receptor Blockers</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001794" MajorTopicYN="N">Blood Pressure</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002851" MajorTopicYN="N">Chromatography, High Pressure Liquid</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004932" MajorTopicYN="N">Esophageal and Gastric Varices</DescriptorName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006439" MajorTopicYN="N">Hemodynamics</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006975" MajorTopicYN="N">Hypertension, Portal</DescriptorName><QualifierName UI="Q000503" MajorTopicYN="Y">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008102" MajorTopicYN="N">Liver Circulation</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008103" MajorTopicYN="N">Liver Cirrhosis</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000503" MajorTopicYN="Y">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008137" MajorTopicYN="N">Longitudinal Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019808" MajorTopicYN="N">Losartan</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011110" MajorTopicYN="N">Polymorphism, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D044140" MajorTopicYN="N">Receptor, Angiotensin, Type 1</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>4</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>23</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>4</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15743363</ArticleId><ArticleId IdType="doi">10.1111/j.1572-0241.2005.41168.x</ArticleId><ArticleId IdType="pii">AJG41168</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="KIE"><PMID Version="1">15742511</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>15</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>01</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0362-4331</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2005</Year><Month>Feb</Month><Day>21</Day></PubDate></JournalIssue><Title>The New York times on the Web</Title><ISOAbbreviation>N Y Times Web</ISOAbbreviation></Journal>Panel to advise tests on babies for 29 diseases.
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Losartan, a dose of 25 mg/day, has been found to be effective in 50% of patients with portal hypertension without adverse effects. We evaluated the relationship between genetic polymorphisms of the renin-angiotensin system (A1166C angiotensin II type 1 receptor (AT1R), angiotensinogen T174M and M235T, and angiotensin-converting enzyme I/D) and the effects of losartan on portal and systemic hemodynamic in patients with cirrhosis and portal hypertension.</AbstractText>We performed a longitudinal study that included 23 consecutive patients with cirrhosis and esophageal varices who received 25 mg/day of losartan during 12 wk. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured at baseline and after treatment. Genomic DNA was extracted from peripheral blood leukocytes; genetic polymorphisms of the renin-angiotensin system were investigated by polymerase chain reaction and restriction fragment length polymorphisms.</AbstractText>The homozygous patients for AT1R A allele showed higher pulmonary-wedged and free hepatic venous pressure on baseline. After treatment, they showed a higher decrease of HVPG (32.5%+/- 19.2) in comparison with patients with AC/CC genotype (2.4%+/-18.9), p < 0.01. Ten of 15 patients with AA genotype were responders, while only one of eight with AC/CC genotype (p < 0.002); genotype AA showed a positive predictive value of 66.6% and negative predictive value of 87.5%.</AbstractText>These results suggest that there is a relationship between the AT1R A1166C polymorphisms and the therapeutic response to losartan. The genetic testing may be used as a predictive factor of this response.</AbstractText>
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2,338,081 |
Recombination aneusomy of subtelomeric regions of chromosome 5, resulting from a large familial pericentric inversion inv(5)(p15.33q35.3).
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We present a family with three cases of recombination aneusomy rec(5)dup(5q) originating from a large parental pericentric inversion of chromosome 5. The proband--a 6-year-old girl with mental retardation, speech delay, microcephaly, and slight facial dysmorphism--was referred for subtelomere testing. FISH with a Multiprobe Chromoprobe T System (CytoCell) and with several BAC clones mapping to both subtelomere regions of chromosome 5, revealed a recombinant chromosome rec(5)dup(5q) originating from a paternal pericentric inversion inv(5)(p15.33q35.3). The same inversion was present in the proband's father's twin-brother and rec(5)dup(5q) was also identified in his two mentally retarded daughters. The distance of breakpoints from the telomere was: 0.234-1.4 Mb for 5p and 4.1-4.8 Mb for 5q. HR-CGH analysis confirmed the duplication of the 5q subtelomeric region but did not identify any concomitant deletion in the 5p subtelomere. Precise mapping of the aneusomic regions in the proband enabled mapping the cat cry and speech delay to 5p15.33, making the earlier localizations of these features more precise. Our family shows that the large pericentric inversion with both breakpoints at subtelomeric regions of chromosome 5 is associated with a high risk of rec(5)dup(5q) in the progeny.
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2,338,082 |
Age and manifestation related symptoms in familial adenomatous polyposis.
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To identify early symptoms of familial adenomatous polyposis with a view to improve early diagnosis and treatment. Diagnosis on the basis of genetic testing is usually limited to where there is a known family history, so FAP is more usually diagnosed on clinical grounds. Except for those identified via FAP registers, the majority of patients are symptomatic at the time of diagnosis.</AbstractText>We undertook a retrospective study of 143 FAP patients treated at the Department of Surgery, University of Erlangen between 1971 and 2000. We identified patterns of symptoms, endoscopic findings and extracolonic manifestations in three age groups.</AbstractText>FAP was diagnosed clinically on the basis of symptoms in 84% (120/143) of these patients. Most presented with intestinal symptoms such as colonic bleeding (68%) and diarrhea (42%). All but one of the patients between 20 and 40 years old had rectal polyps (98.7%, 75/76), whereas in those over 40 years old the prevalence was 76% (35/46). Non-specific symptoms such as abdominal pain, fatigue and bloating were less frequent and were mainly reported by patients older than 40.</AbstractText>The commonest presenting features of FAP are alteration of bowel habit and rectal bleeding, but both are found in many other conditions. Patients with these findings need immediate endoscopy to allow prompt diagnosis and prophylactic surgery.</AbstractText>
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2,338,083 |
Asymmetry in host and parasitoid diffuse coevolution: when the red queen has to keep a finger in more than one pie.
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BACKGROUND: Coevolution between pairs of antagonistic species is generally considered an endless "arms race" between attack and defense traits to counteract the adaptive responses of the other species. PRESENTATION OF THE HYPOTHESIS: When more than two species are involved, diffuse coevolution of hosts and parasitoids could be asymmetric because consumers can choose their prey whereas preys do not choose their predator. This asymmetry may lead to differences in the rate of evolution of the antagonistic species in response to selection. The more long-standing the coevolution of a given pair of antagonistic populations, the higher should be the fitness advantage for the consumer. Therefore, the main prediction of the hypothesis is that the consumer trophic level is more likely to win the coevolution race. TESTING THE HYPOTHESIS: We propose testing the asymmetry hypothesis by focusing on the tritrophic system plant/aphid/aphid parasitoid. The analysis of the genetic variability in the virulence of several parasitoid populations and in the defenses of several aphid species or several clones of the same aphid species could be compared. Moreover, the analysis of the neutral population genetic structure of the parasitoid as a function of the aphid host, the plant host and geographic isolation may complement the detection of differences between host and parasitoid trophic specialization. IMPLICATIONS OF THE HYPOTHESIS: Genetic structures induced by the arms race between antagonistic species may be disturbed by asymmetry in coevolution, producing neither rare genotype advantages nor coevolutionary hotspots. Thus this hypothesis profoundly changes our understanding of coevolution and may have important implications in terms of pest management.
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2,338,084 |
Characterization of genetically defined types of Charcot-Marie-Tooth neuropathies by using magnetic resonance neurography.
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Charcot-Marie-Tooth (CMT) disease is a collection of related genetic disorders affecting peripheral nerves with an incidence of one in every 2500 individuals. A diagnosis of CMT disease has classically relied on a medical history, examination, and measurement of nerve conduction velocities. Advancements in genetic testing and magnetic resonance (MR) imaging techniques may provide clinicians with a more precise diagnostic armamentarium. The authors investigated MR neurography as a possible method to characterize CMT subtypes.</AbstractText>The authors performed MR neurography to evaluate sciatic nerves in the mid-thigh area of seven patients with genetically defined subtypes of CMT, one patient with chronic inflammatory demylinating polyneuropathy, and one patient without neuropathy. The authors correlate their findings with normal nerve conduction velocities (NCVs) and present their results as a descriptive case series. Although MR neurography could not be used to distinguish subtypes of CMT disease on nerve area or fascicle number, it appears to characterize phenotypic features and disease progression noninvasively in patients with some subtypes.</AbstractText>In conjunction with NCV measurements, MR neurography may be useful in the diagnosis of CMT neuropathies and in monitoring disease progression.</AbstractText>
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2,338,085 |
[Hereditary multiple exostoses. Molecular genetic analysis of the EXT1 gene in an unusual family].
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Hereditary multiple exostosis (HME), a disorder inherited in an autosomal dominant manner, is characterized by multiple projections of bone, mainly at the extremities. The risk of malignant transformation of the exostoses is estimated to be up to 2%. The most common underlying cause of the disease involves mutations in either the EXT1 or the EXT2 gene. We report on the clinical and molecular findings in a family affected with HME.A mother and her three children from different partnerships, all clinically diagnosed with HME, were referred for genetic counseling. Subsequently, molecular analysis of the EXT1 gene was performed according to standard procedures. We identified a mutation in the EXT1 gene in all four affected family members (delA in codon 133). This mutation has not been previously described and is suggested to cause the disease in this family. Identification of disease causing mutations in patients with HME and their relatives can help to improve the clinical management of tumor prevention, early tumor detection, and orthopedic therapy.
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2,338,086 |
The promise of genetically engineered mice for cancer prevention studies.
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Sophisticated genetic technologies have led to the development of mouse models of human cancers that recapitulate important features of human oncogenesis. Many of these genetically engineered mouse models promise to be very relevant and relatively rapid systems for determining the efficacy of chemopreventive agents and their mechanisms of action. The validation of such models for chemoprevention will help the selection of appropriate agents for large-scale clinical trials and allow the testing of combination therapies.
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2,338,087 |
Selection indices in Holstein cattle of various countries.
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Fifteen countries, based on geographical representation, Interbull membership, and size of progeny testing programs, provided a brief description of national selection index and top bull listings from August 2003. Individual traits included in each selection index were grouped into 3 components as they related to production, durability, and health and reproduction. The relative emphasis for each component within the selection index, as well as the number of common bulls among top listings were compared across countries. Average relative emphasis for production, durability, and health and reproduction, across all countries, was 59.5, 28, and 12.5%, respectively. The main difference between selection indices in various countries was the relative emphasis on production. Overall, the Danish S-Index had the most balanced emphasis across the 3 components, with 34% on production, 29% on durability, and 37% on health and reproduction. Broadening of breeding goals through recent changes to selection indices decreased the similarities of top bull listings across the various countries, with a slightly greater commonality among sires of top bulls.
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2,338,088 |
Data subsetting strategies for estimation of across-country genetic correlations.
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International genetic evaluation of dairy cattle requires estimation of genetic correlations among populations to account for genotype-environment interaction. Simultaneous estimation of across-country genetic correlations among all populations of a widespread breed, such as the Holstein breed is, however, hampered by connectedness problems and computational challenges. The purpose of this study was to examine the effects of using bulls with across-country, balanced distribution of daughters on estimates of genetic correlations. For this purpose, dairy cattle populations undergoing selection in 6 countries were simulated. Two population-size settings were used. In the small population-size setting (S-populations), the 6 simulated countries had 2000 cows and 20 young progeny testing bulls per generation. In the larger population-size setting (L-populations), the 6 simulated countries had between 2000 and 64,000 cows and 20 to 640 young progeny testing bulls per generation. The simulated (true) across-country genetic correlations, depending on the country combination, varied between 0.5 and 0.9. Simulations comprised a base population and 10 generations and were replicated 16 times. Results for the S-populations were not conclusive. For the L-populations, results indicated that by use of data from a relatively small subset of bulls with distribution of daughters balanced across countries, genetic correlations could be estimated with very small bias (overall average of absolute value of bias across replicates was 0.03 for the L-populations). The suggested bull subsetting strategy would allow simultaneous estimation of across-country genetic correlations to be computed for a larger number of countries and in a shorter window of time than was possible previously.
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2,338,089 |
Role of early case detection by screening relatives of patients with HFE-associated hereditary haemochromatosis.
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Hereditary haemochromatosis is a primary inherited disorder of iron metabolism leading to progressive iron loading of parenchymal cells of the liver and other organs with diverse clinical manifestations, including cirrhosis, diabetes and skin pigmentation. This chapter will focus on HFE-associated hereditary haemochromatosis, which accounts for approximately 90% of cases in Caucasian populations. Penetrance is incomplete, with variable clinical expression. The majority of cases demonstrate biochemical expression, but a much lower proportion develop advanced disease. Clinical disease--especially hepatic fibrosis--is related to the level of body iron stores, which is reflected primarily in the liver. The available evidence indicates that adequate screening and diagnostic strategies ensure that early case detection and treatment occur prior to the development of irreversible end-organ damage. The most cost-effective methods of early case detection are family (cascade) screening and evaluation of potential cases by primary care physicians with a high index of clinical suspicion.
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2,338,090 |
The South African bone marrow registry (SABMR) in 2004.
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Because of the presence of rare HLA antigens, particularly in patients of African ancestry, the SABMR was established in 1991. Currently approximately 20% of unique HLA types in the international database is from the SABMR. The SABMR donors now total approximately 45,000. Sixty-five South African patients have received matched unrelated donor transplants, 20 (30%) with a local donor. Most donors are from Caucasian background. To increase the genetic diversity of the SABMR donor pool, the policy is now to enrol more black and mixed ancestry donors.
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2,338,091 |
Preparation of recombinant African horse sickness virus VP7 antigen via a simple method and validation of a VP7-based indirect ELISA for the detection of group-specific IgG antibodies in horse sera.
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This paper describes the production and purification of a group-specific recombinant protein VP7 of African horse sickness virus serotype 3 (AHSV-3) and validation of an I-ELISA for the detection of IgG-antibodies to VP7 in horse sera. Baculovirus-expressed VP7 crystals were purified from infected insect cells. Analytical accuracy of the I-ELISA was examined using sera (n = 38) from an experimentally infected horse, from foals born to vaccinated mares, from guinea-pigs immunized with nine serotypes of AHSV, and from sera of animals infected with other orbiviruses. Compared to traditional serological assays, the I-ELISA was more sensitive in detection of the earliest immunological response in an infected horse and declining levels of maternal immunity in foals. Antibodies to all nine serotypes of AHSV could be detected. Cross-reactivity to related orbiviruses was not observed. Diagnostic accuracy of the I-ELISA was assessed by testing sera from vaccinated horses (n = 358) residing in AHS-enzootic areas and from unvaccinated horses (n = 481) residing in an AHS-free area. Sera were categorised as positive or negative for antibodies to AHSV using virus neutralisation tests. The TG-ROC analysis was used for the selection of the cut-off value. At a cut-off of 11.9 of the high positive control serum (percentage positivity), the I-ELISA specificity was 100%, sensitivity 99.4%, and the Jouden index was 0.99.
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2,338,092 |
Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age?
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BACKGROUND: Biochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age. METHODS: An age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma. RESULTS: The sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test). CONCLUSION: An adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.
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2,338,093 |
Quantification of melanoma micrometastases in sentinel lymph nodes using real-time RT-PCR.
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Detection of micrometastases in the regional tumor-draining lymph nodes is critical for staging and prognosis in melanoma patients. We applied a quantitative multiple-marker RT-PCR assay to improve the detection of occult melanoma cells in the sentinel lymph node (SLN). From 139 patients with primary cutaneous melanoma who underwent sentinel lymphadenectomy, a total of 235 SLN were assessed for Melan-A and tyrosinase expression by real-time quantitative RT-PCR. Twenty-three patients (17%) were positive by histopathology and expressed messenger RNA of one or two markers. Of the patients with histopathologically negative SLN 39 (28%) were reclassified by positive RT-PCR. Patients were examined for tumor recurrences during a median follow-up period of 29 mo. Tumor recurrences were demonstrated in eight patients (35%) with histopathologically positive SLN, in four patients (10%) with submicroscopic tumor cells detected exclusively by real-time RT-PCR, and in none of the patients negative by both methods. The differences in recurrence rates were statistically significant (p=0.01). These data indicate that real-time quantitative RT-PCR for the detection of minimal residual melanoma in SLN improves the prediction of disease-free survival.
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2,338,094 |
Comparison of maximum statistics for hypothesis testing when a nuisance parameter is present only under the alternative.
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In many practical problems, a hypothesis testing involves a nuisance parameter which appears only under the alternative hypothesis. Davies (1977, Biometrika 64, 247-254) proposed the maximum of the score statistics over the whole range of the nuisance parameter as a test statistic for this type of hypothesis testing. Freidlin, Podgor, and Gastwirth (1999, Biometrics 55, 883-886) studied two other simpler maximum test statistics, the maximum of the score statistics at two extreme points of the nuisance parameter, and the maximum of the score statistics at three points of the nuisance parameter including the two extreme points. In this article, we compare the powers of these three maximum-type statistics in the context of three genetic problems.
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2,338,095 |
Detection of t(14;18)(q32;q21) in B-cell chronic lymphocytic leukemia.
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Cytomorphologic testing and multiparameter flow cytometry are the mainstays in diagnosing B-cell chronic lymphocytic leukemia, whereas fluorescence in situ hybridization that targets the translocation t(14;18)(q32;q21) often is used to identify follicular lymphoma. Therapy is highly diverse between both diseases. We describe a case with cytomorphologically and immunologically proven B-cell chronic lymphocytic leukemia in which t(14;18)(q32;q21) was found.
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2,338,096 |
Cholestasis Familiaris Groenlandica: an epidemiological, clinical and genetic study.
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Accumulation of Cholestasis Familiaris Groenlandica (CFG) or progressive familial intrahepatic cholestasis type 1 (PFIC1) occurs in indigenous Inuit families in Greenland. It is an autosomal recessive inherited liver disease. From early childhood the children suffer from failure to thrive, jaundice, pruritus and enlarged liver. Affected persons generally die very young.</AbstractText>Patients' information has been collected from the Greenlandic death register and hospital records.</AbstractText>Detailed genealogy including clinical description and examination if possible. Interviews of parents and relatives, linkage and DNA analysis of the probands and the closest relatives have been studied.</AbstractText>46 affected cases from a highly inbred population have been diagnosed since 1943. The disease is caused by a missense mutation in the FIC1 gene ATP8B1, chromosome 18q21. Six affected children are alive aged 1-21 years. Among the tested relatives 220 are heterozygote. One prenatal diagnosis has been performed.</AbstractText>The mutation causing Cholestasis Familiaris Groenlandica is widespread in Greenland, but accumulation is seen in certain areas. The disease is burdensome for the child, the parents and the Greenlandic society. Genetic counselling and carrier screening are strongly recommended.</AbstractText>
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2,338,097 |
Molecular diagnostic techniques.
|
Molecular diagnostic techniques will continue to transform clinical microbiology. They provide more rapid and sensitive testing that impacts directly on clinical management of infected patients. Molecular diagnostic tests arose from the need to detect micro-organisms that are slow or difficult to grow, or that are present in only small numbers. Nucleic acid amplification techniques (e.g. polymerase chain reaction, PCR) can detect DNA or RNA specific to certain micro-organisms and do not rely on either the recovery of the pathogen or an immune response in the infected patient. Alternative nucleic acid amplification methods have emerged recently because of increasing commercial interest in infectious disease diagnostics and the comprehensive patient protection of PCR technology. Such techniques are gaining widespread acceptance, and have displaced more conventional gold-standard testing in some areas of infectious disease (e.g. viral load testing in HIV-1 infected patients, diagnosis of Chlamydia trachomatis infection). Genetic characterization techniques are increasingly used to determine the relatedness of micro-organisms in the clinical setting. These methods are useful in establishing routes or sources of infection in outbreaks of disease, and are powerful epidemiological tools in large-scale clinical investigations. Recently, there has been a move towards pathogen characterization techniques based on direct nucleotide sequencing (e.g. single nucleotide polymorphism analysis, multi-locus sequence typing). These techniques offer unambiguous, portable data that can be exchanged via the Internet, strengthening collaborative efforts in the field of infectious disease research.
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2,338,098 |
personalized medicine and pharmacogenomics: ethical and social challenges.
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Recent developments in human genetic variation research have fueled predictions of an imminent era of personalized medicine. Defined as a shift toward greater integrated and heuristic innovation in healthcare, personalized medicine seeks to create differentiated strategies for the prevention of disease defined at the molecular level [1] . Recent developments in gene sequencing technologies have focused efforts toward improving efficacy and efficiency in the drug development process. Emerging from the discipline of pharmacogenetics, pharmacogenomics - the study of gene-to-gene interactions through the use of high-throughput technologies - has gained attention as the field most able to deliver on the promises of genomic medicine [2] . The distinction between pharmacogenetics and pharmacogenomics is not clear; while some have argued that differences of scale and focus distinguish the fields, this article uses the term, 'pharmacogenomics', to mean the broad scope of research on inherited variation in drug response. Through differential diagnosis, drug response is being linked to molecular subgroups that may allow for the development of 'tailored' medications [3] . However, several challenges confront these potential benefits. Critical to the success of pharmacogenomics and personalized drug therapies are the creation of large databases containing human genotypic and phenotypic information, the adoption of pharmacogenomic testing as a standard of medical care, and greater regulatory guidance on balancing commercial and public health priorities. In anticipation of these healthcare trajectories, serious engagement with the ethical and social implications of pharmacogenomics is needed. This article reviews several of these issues and highlights concerns that must be addressed in anticipation of personalized drug development.
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2,338,099 |
Pharmacogenetics and individualized medicine - bridging the gap between pharmacogenetic research and the patient.
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A considerable component of the variability seen in drug response or drug disposition has been explained by pharmacogenetic factors. Thus, diagnosing inherited variability in molecules involved in drug response may help to optimize drug therapy and provide more individualized treatment. However, despite the availability of a large amount of pharmacogenetic research data, there are still only a few examples of genotyping being incorporated into clinical drug therapy. In order to bridge the gap between pharmacogenetic research and clinical application, the unequivocal proof of the benefit of pharmacogenetic diagnostics in a certain drug therapy is warranted. But this is not all; there is a clear need for research results to be translated into clinically adoptable guidelines or, when this is not possible, more appropriately designed studies should be conducted with the aim of applying the data in the clinic. Furthermore, more education on pharmacogenetics and the genetic mechanisms underlying interindividual variability in disease susceptibility, treatment course and treatment response should be provided. As a third point, an infrastructure for genetic testing has to be established and this should not only include valid methods for genetic analyses, but especially the logistics of sample shipping, clear indications and instructions for blood sampling from patients, and valid interpretation and communication of the results. Thus, in order to routinely apply pharmacogenetic testing in drug therapy, several concrete steps have to be undertaken, in addition to the optimization of research studies.
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