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2,338,900 |
A second-generation genomic screen for multiple sclerosis.
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Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.
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2,338,901 |
Genome-wide screening using array-CGH does not reveal microdeletions/microduplications in children with Kabuki syndrome.
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Kabuki syndrome (KS) is a rare multiple congenital anomaly/mental retardation syndrome. It is characterized by a distinct facial appearance, mental retardation, postnatal growth retardation, skeletal anomalies, unusual dermatoglyphics and fetal fingertip pads. It has previously been speculated that KS is caused by a microdeletion or duplication. In a recent report, an interstitial microduplication of 8p22-23.1 was presented in several cases with this disorder. We investigated 10 Caucasian patients diagnosed with KS by fluorescence in situ hybridization and microsatellite markers located on 8p22-23.1. Using the same clones that were previously reported to be duplicated on chromosome 8p, we could exclude the duplication in all our patients. In addition, we performed a genome-wide screening on this group of patients using array-based comparative genomic hybridization containing BAC clones spaced at approximately 1 Mb intervals across the genome and could not find any evidence for gene dose alterations. The characteristics of KS are variable, a fact that complicates the diagnosis of this disorder. It is possible that we will find genetic heterogeneity among Kabuki patients, and therefore it is unlikely that all patients have an interstitial 8p duplication. We conclude that the etiology of KS remains to be solved and further genetic studies are necessary to delineate its genetic cause.
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2,338,902 |
A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12.
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Our previous results pointed to a putative gene for susceptibility to bipolar affective disorder located on the chromosomal region 12q23-q24 that segregated in the Saguenay-Lac-St-Jean population of Quebec. We report here results from a second genome-wide scan based on the analysis of 380 polymorphic microsatellite markers. For the purpose of this analysis, an additional 18 families were recruited from the Saguenay-Lac-St-Jean region and pooled to our previous sample to improve its statistical power, giving a total of 394 sampled individuals. This work confirms the presence of a susceptibility locus for affective disorder on chromosome 12q24 with parametric LOD score value of 3.35 at D12S378 when pedigrees were broken into nuclear families and analysed under a recessive segregation model. This result was supported by neighbouring markers and by a LOD score value of 5.05 at D12S378 under model-free analysis. Other regions of lower interest were indicated on chromosomes 2, 5, 7, 9, 10, 17 and 20.
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2,338,903 |
High sensitive approach for point mutation detection based on electrochemiluminescence.
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An electrochemiluminescence-polymerase chain reaction (ECL-PCR) method for point mutation detection has been developed. The target is amplified using a tris (bipyridine) ruthenium (TBR)-labeled forward and a biotinylated reverse primer. The amplification products are digested with specific restriction enzyme, then captured onto streptavidin-coated paramagnetic beads, and detected by measuring the ECL signal of the TBR label. The established technique was further applied to detect a specific point mutation in H-ras oncogene in T24 cell line. The results show that the system has a low detection limit of 100 fmol and a linear range of more than 3 orders of magnitude for H-ras amplicon; the two genotypes can be reliably discriminated. In summary, the mutant specific ECL-PCR method can be used to detect a point mutation that creates or destroys a restriction site in any gene. It is useful in single nucleotide polymorphism (SNP) and mutation detection due to its safety, high sensitivity and simplicity.
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2,338,904 |
[Diagnostics of mucopolysaccharidoses presented through the case of Sanfilippo syndrome].
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Mucopolysaccharidoses (MPS) are recessive inheritable, progressive diseases of disordered degradation and storage of acid glucosaminoglycans. A five-year old child with psychomotor development retardation, which started at his age of two, was presented in our study. Clinical examination showed big head with rough facial features, skeleton deformities and hepatosplenomegaly. The diagnosis Dysostosis epifisealis multiplex was also confirmed by the X-ray examination of skeleton. Karyotype: 46, XY. Mental retardation: IQ--48. Clinically suspected mucopolysaccharidosis called for metabolic screening of first morning urine and the positive toluidine blue test result indicated the increased excretion of mucopolysaccharides. Further enzyme analyses of peripheral blood leucocytes confirmed the heparin sulphate sulphatase deficiency on the basis of which A (MPS III) Sanfilippo syndrome was defined. Our patient was born as a twin sibling. The other sibling is clinically healthy and of normal metabolic screening. It was not possible to define precisely the healthy heterozygote by testing the enzyme activities. A large number of mutations at various loci and big genetic heterogeneity of mucopolysaccharidoses made molecular diagnostics difficult. In the subsequent pregnancy, the mother was recommended prenatal diagnostics by enzyme analysis from the cultured chorionic villus. The prognosis of the presented patient is bad, the course of the disease is progressive and the patient can be expected to die in spastic tetraplegia in the second decade of life. The treatment is symptomatic for the time being.
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2,338,905 |
Inter-patient variation in efficacy of five oncolytic adenovirus candidates for ovarian cancer therapy.
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Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24.</AbstractText>DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer.</AbstractText>An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group.</AbstractText>All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.</AbstractText>Copyright 2004 John Wiley & Sons, Ltd.</CopyrightInformation>
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2,338,906 |
Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation.
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Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.
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2,338,907 |
[Universal hearing screening in newborns. Recommendations for organizing and conducting universal hearing screening for congenital hearing loss in Germany].
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The Interdisciplinary Consensus Conference for Newborn Hearing Screening (IKKNHS) has worked out joint recommendations for universal hearing screening of newborns. In the consensus paper, 11 professional associations and scientific societies in the fields of gynecology and obstetrics, ENT, pediatrics, and phoniatrics and pedaudiology came to an agreement on how to implement newborn hearing screening in Germany. The paper deals with the following topics: goals of universal newborn hearing screening, target group of hearing screening, schedule for screening, personnel involved in the screening program, technologies and framework conditions of hearing screening, documentation, continuous quality control of screening, confirmation diagnostics for conspicuous test subjects, motivation to take part in screening, information on newborn hearing screening, tracking, various infrastructural situations in urban and rural regions, follow-up care, in-patient vs. out-patient screening, cost factors of screening, reporting children with permanent hearing loss to the German Central Registry for hearing loss in children.
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2,338,908 |
Screening for G71R mutation of the UGT1A1 gene in the Javanese-Indonesian and Malay-Malaysian populations.
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There are significant differences in the prevalence and severity of neonatal jaundice among various populations. Recently, it has been reported that a mutation of the UGT1A1 gene, glycine to arginine at codon 71 (G71R), is related to the development of neonatal jaundice in East Asian populations. However, whether the G71R mutation contributes to the high incidence of neonatal jaundice in different Asian populations remains unknown. The authors screened for this mutation in the Javanese-Indonesian and Malay-Malaysian populations.</AbstractText>One hundred and thirty-six subjects were enrolled in this study: 68 Javanese-Indonesian adults and 68 Malay-Malaysian newborns (32 with jaundice and 36 without jaundice). Denaturing high-performance liquid chromatography (DHPLC) was used to screen for the G71R mutation, and the results were confirmed by nucleotide sequencing analysis.</AbstractText>With DHPLC, the authors easily and clearly detected seven subjects carrying the G71R mutation: two Javanese-Indonesian adults and five Malay-Malaysian newborns. In the 68 Javanese-Indonesian adults, the genotype distribution for G71R mutation was 66 G/G, two G/R and no R/R genotypes, and the mutated allele frequency was 0.015. In the 68 Malay-Malaysian newborns, genotype distribution for the mutation was 63 G/G, five G/R and no R/R genotypes, and the mutated allele frequency was 0.037. The genotype distributions did not differ significantly between the newborns with jaundice and those without jaundice.</AbstractText>The G71R mutation is present, but very rare, in Javanese-Indonesians and Malay-Malaysians. Thus, G71R mutation may not contribute to the high incidence of the neonatal jaundice in South-east Asian populations. DHPLC analysis is a very useful method for detecting the G71R mutation.</AbstractText>
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2,338,909 |
Legal and ethical issues in cancer genetics nursing.
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This article will set forth major interests at stake for patients considering predictive genetic testing, some legal bases for protecting patients, and general ethical principles that can guide cancer genetic nurses in their practice.</AbstractText>Review of health, ethical, and legal literature</AbstractText>There are many potential interests at stake for patients considering genetic testing for susceptibility to cancer and a number of legal protections for patients against genetic discrimination. Nurses and physicians who offer genetic testing should be aware of applicable laws in their states, and remain cognizant of evolving ethical principles that can guide the practice</AbstractText>Ethical and legal questions surrounding genetic testing linger--particularly for nurses and physicians whose primary concern is the best interests of the patient.</AbstractText>
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2,338,910 |
Psychosocial aspects of genetic counseling and testing.
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To highlight areas where persons who undergo BRCA1/2 mutation testing may benefit from psychosocial or behavioral support and intervention.</AbstractText>Published scientific literature, cal, and research experiences.</AbstractText>Key psychosocial areas that deserve attention by clinicians and researchers include: indeterminate or inconclusive test results, selection of risk management strategies in unaffected BRCA1/2 mutation carriers, and genetic testing in minority communities.</AbstractText>By addressing the psychosocial issues faced by patients undergoing genetic testing for cancer, nurses have the potential to maximize opportunities for prevention, early detection, and healthy coping.</AbstractText>
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2,338,911 |
Common hereditary cancer syndromes.
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To review cancer risk assessment and counseling, hereditary cancer syndrome risk factors, indicators for cancer predisposition testing, and interpretation of genetic test results.</AbstractText>Research studies, review articles, and authors' experience.</AbstractText>Approximately 10% of those with a diagnosis of cancer may have a hereditary predisposition. In many cases genetic testing for susceptibility genes may be available. Knowledge of the results of genetic testing can be helpful when developing a plan for cancer prevention and early detection, and addressing concerns associated with genetic testing with the individual and family.</AbstractText>Nurses need to know how to access genetic resources and to identify, evaluate, and care for patients and families at risk of or diagnosed with common hereditary cancer syndromes.</AbstractText>
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2,338,912 |
Haplotype studies support slippage as the mechanism of germline mutations in short tandem repeats.
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Germline mutations of human short tandem repeat (STR) loci are expansions or contractions of repeat arrays which are not well understood in terms of the mechanism(s) underlying such mutations. Although polymerase slippage is generally accepted as a mechanism capable to explain most features of such mutations, it is still possible that unequal crossing over plays some role in those events, as most studies in humans could not exclude unequal crossing over (UCO). Crossing over can be studied by analyzing haplotypes using flanking markers. To check for UCO in mutations, we have analyzed 150 paternity cases for which more than the usual trio (mother, child, and father) were available for testing by analyzing 16 STR loci. In a total of 4900 parent-child allele transfers four mutations were observed at different loci (D8S1179, D18S51, D21S11, and SE33/ACTBP2). To identify the mutated allele and to check for UCO, we typed at least four informative loci flanking the mutated locus and used the pedigree data to establish haplotypes. By doing so we were able to exclude UCO in each case. Moreover, we were able to identify the mutations as one-repeat contractions/expansions. Our data thus support slippage as the mechanism of germline mutations in STRs.
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2,338,913 |
Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome.
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We used differential-display PCR of peripheral blood mononuclear cells (PBMCs) to search for candidate biomarkers for chronic fatigue syndrome (CFS). PBMCs were collected from a subject with CFS and an age- and sex-matched control before and 24 h after exercise. RNA expression profiles were generated using 46 primer combinations, and the similarity between the individuals was striking. Differentially expressed bands were excised, reamplified, and sequenced, yielding 95 nonredundant sequences, of which 50 matched to known gene transcripts, 38 matched to genes with unknown functions, and 7 had no similarity to any database entry. Most (86%) of the differences between the two subjects were present at baseline. Differential expression of ten genes was verified by real-time reverse-transcription PCR: five (cystatin F, MHC class II, platelet factor 4, fetal brain expressed sequence tag, and perforin) were downregulated, and the remaining five genes (cathepsin B, DNA polymerase epsilon4, novel EST PBMC191MSt, heparanase precursor, and ORF2/L1 element) were upregulated in the subject with CFS. Many of these genes have known functions in defense and immunity, thus supporting prior suggestions of immune dysregulation in the pathogenesis of CFS. Differential-display PCR is a powerful tool for identification of candidate biomarkers. Investigation of these markers in samples from well-designed epidemiological studies of CFS will be required to determine the validity of these candidate biomarkers. The real-time reverse-transcription PCR assays that we developed for assay of these biomarkers will facilitate high-throughput testing of these additional samples.
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2,338,914 |
Russell-Silver syndrome: molecular diagnosis of maternal uniparental disomy of chromosome 7 using methylation-specific polymerase chain reaction assay and single nucleotide polymorphisms genotyping.
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Russell-Silver syndrome (RSS) should be suspected in patients with prenatal and postnatal growth retardation. Because there is no clinical feature specific for RSS, molecular analysis is necessary to confirm the diagnosis. Recently, maternal uniparental disomy of chromosome 7 (mUPD7) has been reported in approximately 10% of RSS patients. We describe a 10-year-old Taiwanese RSS girl with prenatal and postnatal growth retardation, relative macrocephaly, a triangular face, frontal bossing, and mild fifth finger clinodactyly. Molecular diagnosis of mUPD7 was confirmed by use of methylation-specific polymerase chain reaction and haplotype analysis with single nucleotide polymorphisms (SNPs) genotyping. Analyzing the methylation status of the PEG1/MEST gene is a cost-effective screening method for mUPD7 molecular diagnosis. However, positive cases should be subsequently confirmed by haplotype analysis using SNPs genotyping or short tandem repeat markers.
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2,338,915 |
[Cloning of the Aspergillus fumigatus squalene epoxidase gene].
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To clone Aspergillus fumigatus squalene epoxidase gene and to further investigate its role in terbinafine resistance.</AbstractText>The A.fumigatus genomic DNA library was transformed into pyrG-A. fumigatus strain protoplasts with polyethylene glycol-mediated transformation protocol. TRB-resistant pyrG+ transformants were then isolated by being plated on MM-U with TRB (0.625 mg/L) plates. After confirmation of terbinafine-resistance by using both disk diffusion and NCCLS M38-A microdilution antifungal susceptibility testing, the gene conferring terbinafine-resistance was identified. Finally, the gene was cloned and retransformed into pyrG-A. fumigatus strain.</AbstractText>From a total of 5x10(4) transformants, one TRB-resistant pyrG+ transformant was isolated, which showed the terbinafine-specific resistance without cross-resistance to any other antifungals. A. fumigatus squalene epoxidase gene was further identified to confer this terbinafine-resistance. As a result, the complete A. fumigatus squalene epoxidase gene was firstly cloned. Finally, the transformants with extra copies of A. fumigatus squalene epoxidase gene, again, showed the specific resistance to terbinafine.</AbstractText>Extra copies of A. fumigatus squalene epoxidase gene, which was cloned for the first time in this study, could result in A. fumigatus resistance to terbinafine. This is a novel mechanism of terbinafine-resistance that needs further investigation for its clinical significance.</AbstractText>
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2,338,916 |
Coalescent-based association mapping and fine mapping of complex trait loci.
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We outline a general coalescent framework for using genotype data in linkage disequilibrium-based mapping studies. Our approach unifies two main goals of gene mapping that have generally been treated separately in the past: detecting association (i.e., significance testing) and estimating the location of the causative variation. To tackle the problem, we separate the inference into two stages. First, we use Markov chain Monte Carlo to sample from the posterior distribution of coalescent genealogies of all the sampled chromosomes without regard to phenotype. Then, averaging across genealogies, we estimate the likelihood of the phenotype data under various models for mutation and penetrance at an unobserved disease locus. The essential signal that these models look for is that in the presence of disease susceptibility variants in a region, there is nonrandom clustering of the chromosomes on the tree according to phenotype. The extent of nonrandom clustering is captured by the likelihood and can be used to construct significance tests or Bayesian posterior distributions for location. A novelty of our framework is that it can naturally accommodate quantitative data. We describe applications of the method to simulated data and to data from a Mendelian locus (CFTR, responsible for cystic fibrosis) and from a proposed complex trait locus (calpain-10, implicated in type 2 diabetes).
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2,338,917 |
Classification and strength measurement of stationary-phase promoters by use of a newly developed promoter cloning vector.
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When an Escherichia coli culture changes from exponential growth to the stationary phase, expression of growth-related genes levels off, while a number of stationary-phase-specific genes are turned on. To gain insight into the growth phase-dependent global regulation of genome transcription, we analyzed the strength and specificity of promoters associated with the stationary-phase genes. For the in vivo assay of promoter activity, 300- to 500-bp DNA fragments upstream from the translation initiation codon were isolated and inserted into a newly constructed doubly fluorescent protein (DFP) vector. The activity of test promoters was determined by measuring the green fluorescent protein (GFP). To avoid the possible influence of plasmid copy number, the level of transcription of reference promoter lacUV5 on the same plasmid was determined by measuring the red fluorescent protein (RFP). Thus, the activities of test promoters could be easily and accurately determined by determining the GFP/RFP ratio. Analysis of the culture time-dependent variation of 100 test promoters indicated that (i) a major group of the stationary-phase promoters are up-regulated only in the presence of RpoS sigma; (ii) the phase-coupled increase in the activity of some promoters takes place even in the absence of RpoS; and (iii) the activity of some promoters increases in the absence of RpoS. This classification was confirmed by testing in vitro transcription by using reconstituted RpoD and RpoS holoenzymes.
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2,338,918 |
Hereditary neuropathy with liability to pressure palsy: fulminant development with axonal loss during military training.
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Hereditary neuropathy with liability to pressure palsy (HNPP) is characterised by recurrent mononeuropathies following minor trauma. We describe a case of fulminant HNPP beginning on the first day of military physical training. Protracted weakness, muscle atrophy, hand contractures, and multifocal sensory loss developed during a further three weeks of basic training. Nerve conduction changes were typical of HNPP, but without segmental slowing. Electromyographically, there was prominent acute denervation in muscles of the hands and right shoulder. Sural nerve biopsy demonstrated tomaculae and remyelination. Genetic testing revealed PMP-22 gene deletion. This case report demonstrates that HNPP can present with rapidly progressive peripheral nerve dysfunction and electrophysiological evidence of focal axonal loss.
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2,338,919 |
Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases.
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The traditional identification of bacteria on the basis of phenotypic characteristics is generally not as accurate as identification based on genotypic methods. Comparison of the bacterial 16S rRNA gene sequence has emerged as a preferred genetic technique. 16S rRNA gene sequence analysis can better identify poorly described, rarely isolated, or phenotypically aberrant strains, can be routinely used for identification of mycobacteria, and can lead to the recognition of novel pathogens and noncultured bacteria. Problems remain in that the sequences in some databases are not accurate, there is no consensus quantitative definition of genus or species based on 16S rRNA gene sequence data, the proliferation of species names based on minimal genetic and phenotypic differences raises communication difficulties, and microheterogeneity in 16S rRNA gene sequence within a species is common. Despite its accuracy, 16S rRNA gene sequence analysis lacks widespread use beyond the large and reference laboratories because of technical and cost considerations. Thus, a future challenge is to translate information from 16S rRNA gene sequencing into convenient biochemical testing schemes, making the accuracy of the genotypic identification available to the smaller and routine clinical microbiology laboratories.
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2,338,920 |
Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.
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Alveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing.
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2,338,921 |
PINK, PANK, or PARK? A clinicians' guide to familial parkinsonism.
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We provide a pragmatic guide for clinicians, and detail the recent developments in the genetics of Parkinson's disease that have shaped our current understanding and management of this disease and other parkinsonian disorders. These developments have been rapid, and in total over 20 genes have been identified, three of which were discovered in the past year. Although there are undoubtedly more genes to be found, the major challenge for the future is to determine how they function and whether they interact. These genes help us to understand the heterogeneity of parkinsonism, and also inform on the molecular and clinical features of individual parkinsonisms. However, their discovery also requires us to raise issues about genetic testing and genetic counselling.
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2,338,922 |
Two prevalent h alleles in para-Bombay haplotypes among 250,000 Taiwanese.
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Alpha(1,2)-fucosyltransferase catalyzes the transfer of fucose to the C-2 position of galactose on type II precursor substrate Gal beta1-4GlcNAc beta1-R. It plays an important biological role in the formation of H antigen, a precursor oligosaccharide for both A and B antigens on red blood cells. Aberration of alpha(1,2)-fucosyltransferase activity by gene mutations results in decreased synthesis of H antigen, leading to the para-Bombay phenotype. In this study, we collected about 250,000 blood samples in Taiwan during 5 yr and identified the subjects with para-Bombay phenotype. Then we analyzed the sequence of the alpha(1,2)-fucosyltransferase gene by direct sequencing and gene cloning methods, using the blood samples of 30 para-Bombay individuals and 30 control subjects who were randomly selected. The goals of this study were to search for new h alleles, to determine the h allele frequencies, and to test whether the sporadic theory is applicable in Taiwan. Six different h alleles (ha, 547-548 AG-del; hb, 880-881 TT-del; hc, R220C; hd, R220H; he, F174L; and hf, N327T) were observed. Two h alleles, he and hf, were newly discovered in Taiwan. The he allele has a nucleotide 522C>A point mutation, predicting the amino acid 174 substitution of Phe to Leu; the hf allele has missense mutation of nucleotide 980A>C, predicting the amino acid 327 substitution of Asn to Thr. Frequencies of the 6 alleles are ha 46.67%, hb 38.33%, hc 5.00%, hd 1.67%, he 3.33%, and hf 5.00%, respectively. These findings in the Taiwanese population confirm previous observations in other populations that the Bombay and para-Bombay phenotypes are due to diverse, sporadic, nonfunctional alleles, predominantly ha and hb, leading to H deficiency of red blood cells. In contrast to previous reports of non-prevalent associations of h alleles with para-Bombay phenotype, our results suggest a regional allele preference associated with para-Bombay individuals in Taiwan.
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2,338,923 |
Runx2/Cbfa1-genetically engineered skeletal myoblasts mineralize collagen scaffolds in vitro.
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Genetic engineering of progenitor and stem cells is an attractive approach to address cell sourcing limitations associated with tissue engineering applications. Bone tissue engineering represents a promising strategy to repair large bone defects, but has been limited in part by the availability of a sustained, mineralizing cell source. This study examined the in vitro mineralization potential of primary skeletal myoblasts genetically engineered to overexpress Runx2/Cbfa1, an osteoblastic transcriptional regulator essential to bone formation. These cells were viable at the periphery of 3D fibrous collagen scaffolds for 6 weeks of static culture. Exogenous Runx2 expression induced osteogenic differentiation and repressed myogenesis in these constructs relative to controls. Runx2-modified cells deposited significant amounts of mineralized matrix and hydroxyapatite, as determined by microcomputed tomography, histological analysis, and Fourier transform infrared spectroscopy, whereas scaffolds seeded with control cells exhibited no mineralized regions. Although mineralization by Runx2-engineered cells was confined to the periphery of the construct, colocalizing with cell viability, it was sufficient to increase the compressive modulus of constructs 30-fold relative to controls. This work demonstrates that Runx2 overexpression in skeletal myoblasts may address current obstacles of bone tissue engineering by providing a potent cell source for in vitro mineralization and construct maturation. Additionally, the use of genetic engineering methods to express downstream control factors and transcriptional regulators, in contrast to soluble signaling molecules, represents a robust strategy to enhance cellular activities for tissue engineering applications.
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2,338,924 |
Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy.
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EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.
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2,338,925 |
Genetic screening: carriers and affected individuals.
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Genetic screening utilizes analytical approaches adapted for high throughput to identify carrier and affected individuals in a targeted population. Currently, genetic screening focuses on carrier screening, prenatal screening, and newborn screening. Newborn screening should serve as a model for all genetic screening, with more than forty years of experience and numerous lessons learned. As with all genetic screening, there are policy concerns in newborn screening regarding which disorders and technologies should be selected, and how centralized or decentralized the process to set policy should be. The need to share experiences and develop databases transcends all other policy considerations in genetic screening. The future will see population-based screening for adult-onset disorders. However, there needs to be extensive research to define predictive risk for various ethnocultural groups and to determine effective interventions. Ethical concerns regarding the timing of population screening, as well as the scope of use of information, will need to be resolved if genomic medicine will achieve its promise of a predictive, preventive, and personalized medicine.
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2,338,926 |
Genetic testing in primary care.
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Rapid advances in genetic research are leading to an expanding array of genetic tests. Primary care providers will increasingly be challenged to identify patients whose symptoms, physical findings, or family history indicate the need for genetic testing, and to determine how to use genetic information most effectively to improve disease prevention. In addressing these challenges, practitioners will need to consider the range of different uses of genetic testing, including diagnosis in symptomatic and asymptomatic people, risk assessment, reproductive decision-making, and population screening. They will need a set of core skills and knowledge to evaluate family history and to recognize clinical findings that indicate genetic risk. At the same time, the primary care perspective will contribute to the evaluation of appropriate uses of genetic testing. A partnership between medical genetics and primary care will help to ensure the development of effective policies, educational tools, and practice guidelines for the coming era of genomic health care.
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2,338,927 |
Genotype-based screening for hereditary haemochromatosis. I: Technical performance, costs and clinical relevance of a German pilot study.
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In 2001, we initiated a pilot study on DNA-based screening of hereditary haemochromatosis (HH) in Germany. A total of 5882 insurants of the German sickness fund Kaufmannische Krankenkasse-KKH requested information on this project, and 3961 of these individuals provided blood samples for testing of the HFE mutation C282Y. Of these, 3930 samples were successfully tested with two independent test methods, and the results were communicated to the referring doctors. In all, 67 of the tested individuals were homozygous for C282Y. Partially, this high rate (1.7%) can be explained by the fact that 42.6% of the homozygotes already knew their clinical diagnosis HH before sending the blood sample. Iron accumulation with further signs or symptoms of HH was present in eight of 34 newly diagnosed C282Y homozygous individuals. Two major aspects of our study were the analytic validity and the direct laboratory costs of different test methods. Of 7860 tests performed, 7841 (99.6%) gave correct results. The overall error rate was 0.24% (95% CI: 0.15-0.38%). The analytic specificity of the tests methods with respect to the detection of homozygosity for C282Y was 100% (7726 of 7726 nonhomozygous test challenges, 95% CI: 99.95-100%), while the analytic sensitivity was 97% (130 of 134 homozygous test challenges, 95% CI: 92.5-99.2%). The direct costs ranged from 11.20-16.35 \[euro] per test method. We conclude that the test methods for C282Y are robust, highly sensitive and specific, and that a DNA-based HH-screening program can be performed at reasonable laboratory costs.
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2,338,928 |
Complex segregation analysis of nasopharyngeal carcinoma in Guangdong, China: evidence for a multifactorial mode of inheritance (complex segregation analysis of NPC in China).
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The striking geographical and ethnic distribution of nasopharyngeal carcinoma (NPC) suggests the involvement of genetic and environmental factors in NPC development. The purpose of this study is to investigate the fit of single gene, polygenic and multifactorial models to the observed pattern of transmission of NPC in a hospital-based family history study conducted by the Cancer Center of Sun Yat-Sen University (CCSYU) in Guangzhou, China. Complex segregation analysis of a total of 1903 Cantonese pedigrees ascertained at CCSYU was conducted using a unified mixed model after the pedigrees were partitioned into 3737 nuclear families. The mixed model assumes that a phenotype is influenced by the additive and independent effect of a major gene, together with multifactorial components (genetic and environmental) and a random environmental effect. The current results do not provide evidence for a major gene and the observed data are best explained by a multifactorial mode of inheritance for NPC.
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2,338,929 |
Computer-assisted prenatal aneuploidy screening for chromosome 13, 18, 21, X and Y based on multiplex ligation-dependent probe amplification (MLPA).
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In routine prenatal diagnostics we used a commercial multiplex ligation-dependent probe amplification (MLPA) kit for aneuploidy screening for chromosomes 13, 18, 21, X and Y. We present the results of 1593 consecutive prenatal samples analysed and diagnosed prior to knowledge of the G-banding analysis during 8-month routine use of computer-assisted MLPA aneuploidy screening. In total, 27 aneuploidies were detected. There were no false positive results while two false negative results could be explained by a placental mosaicism and a partial monosomy, respectively. In total, 3.2% of the samples were inconclusive. We conclude that automatic computer assisted MLPA is a rapid, simple and reliable method for detection of aneuploidies in prenatal diagnostics.
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2,338,930 |
Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia.
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Recently, Hagerman et al described the occurrence of a late-onset neurological disorder in five male carriers of the fragile-X (FMR-1) premutation. The major characteristics of this disorder, designated the Fragile-X Tremor Ataxia Syndrome (FXTAS), are progressive intention tremor, cerebellar ataxia and cognitive decline. Most cases of FXTAS published thus far were ascertained through families with a known fragile-X proband. Since cerebellar ataxia is one of the main cardinal features, we performed FMR-1 premutation screening in 122 male patients, older than 50 years, who were referred to us for testing of the spinocerebellar ataxia (SCA 1, 2, 3, 6, 7) genes and who were found to be negative. In this group of patients, we found five patients with an FMR-1 premutation. In four of them, a definite diagnosis of FXTAS could be made, based on the proposed diagnostic clinical and radiological criteria for FXTAS. In light of these figures, we recommend that FMR-1 analysis should be included in the molecular diagnostic work-up in the group of male ataxia patients older than 50 years.
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2,338,931 |
Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects.
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Serotonin 5-HT2A receptor (5-HT2A) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT2A binding kinetics (Bmax and KD) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher Bmax in all subjects (F=3.53, df=2,211; p=0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F=7.56, df=2,60, p=0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. Bmax was not related to a diagnosis of mood disorders. The TT genotype appears associated with higher platelet 5-HT2A Bmax in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.
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2,338,932 |
Quantitative detection of methylated SOCS-1 , a tumor suppressor gene, by a modified protocol of quantitative real time methylation-specific PCR using SYBR green and its use in early gastric cancer detection.
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Although methylation-specific PCR (MSP) is a sensitive technique in the detection of DNA hypermethylation, it is not quantitative. Here we described a modified PCR protocol to quantify methylated SOCS-1 gene by real time MSP using SYBR green, which involves an additional PCR step after the 72 degrees C extension step. This modified protocol is also useful in the quantitative detection of methylated SOCS-1 gene in serum samples of gastric cancer patients.
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2,338,933 |
Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays.
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We have established highly sensitive and specific androgen and estrogen reporter cell lines which we have named AR (androgen receptor) and ERalpha (estrogen receptor alpha) CALUX (Chemically Activated LUciferase eXpression), respectively. Both bioassays are member of a panel of CALUX reporter cell lines derived from the human U2-OS osteosarcoma cell line, all using highly selective reporter constructs based with a basal promoter element linked to multimerized response elements, allowing efficient and specific measurement of compounds interfering with androgen, estrogen, progesterone, and glucocorticoid receptors. The AR CALUX bioassay contains the human androgen receptor and a luciferase reporter construct containing three androgen-responsive elements coupled to a minimal TATA promoter. This cell line was characterized by its stable expression of AR protein, its highly selective response to low levels of different natural and synthetic androgens, and its insignificant response to other nuclear hormone receptor ligands such as estrogens, progestins, and glucocorticoids. The EC50 of dihydrotestosterone (DHT) was found to be 0.13 nM, consistent with the high affinity of this ligand to the human AR. Flutamide, cyproterone acetate, and the environmental contaminants vinclozolin, DDT, methoxychlor, its metabolite HPTE, and penta-BFR showed clear antagonistic activity in the AR CALUX bioassay, competitively inhibiting DHT-mediated transactivation. The established AR CALUX bioassay proved to excel in terms of easy cell line maintenance, high fold induction range (typical 30 times over solvent control), low minimal detection limit (3.6 pM), and high androgen selectivity. Potential applications such as testing the androgenic or estrogenic activity of pure chemicals and pharmaceuticals and complex mixtures (environmental, food, feed, and clinical) are discussed.
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2,338,934 |
Infrequent milk progesterone measurements in daughters enable bull selection for cow fertility.
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The interval from calving to first luteal activity (CLA) has been suggested as an unbiased and, therefore, preferable measure for selection on female fertility in dairy cattle. However, measurement of this interval for individual cows is not feasible for reasons of cost and labor associated with the necessary frequent (milk) progesterone measurements. The objective of this study was to test the hypothesis that mean sire progesterone profiles based on individual progesterone measurements of daughters at 3- to 6-wk intervals have prospects as a measure for female fertility when selecting sires in a progeny testing scheme. In this study, progesterone concentrations were measured in milk samples collected at routinely performed milk recordings during the first 100 d of lactation of daughters of 20 test bulls. It is demonstrated that a) mean progesterone profiles can be used to calculate the earliest stage of lactation at which at least 50% of the daughters of a test bull has a milk progesterone level >3 ng/mL (indicating luteal activity) and that b) this stage, at which 50% of the daughters of a bull have an active corpus luteum (CLA50%), varies largely between test bulls. We conclude that selecting sires based on daughter CLA50% may improve female fertility.
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2,338,935 |
Implications of genetic risk information in families with a high density of bipolar disorder: an exploratory study.
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While major susceptibility genes for bipolar disorder are yet to be identified, the opportunity exists to systematically ascertain the important issues and societal implications of genetic risk determination for bipolar disorder prior to these technological advances becoming widely available. This study explores, in a sample of families with a high density of bipolar disorder: (i) attitudes to predictive genetic and prenatal testing, using different risk frames; (ii) attributions for bipolar disorder, in particular the degree to which a genetic model is endorsed; and (iii) the impact of these attributions on the perceived stigma of bipolar disorder. A qualitative methodology was selected as most appropriate as no previous research has examined this issue. Participants were ascertained through a molecular genetics study of bipolar disorder. In-depth interviews were conducted with 21 members of families with a high density of bipolar disorder. Most participants reported being interested in genetic testing if it gave a definitive answer, while expressed interest in testing was lower if it gave a probable answer only. Almost all stressed that a genetic susceptibility and environmental factors interacted. Most participants felt that a genetic explanation was likely to decrease the stigma associated with bipolar disorder as it shifted the locus of control and responsibility away from the individual towards the role of heredity. Findings indicate that expressed interest in genetic testing depends on the certainty imparted by the test. Results suggest that families with bipolar disorder are likely to benefit psychologically from information about the genetic basis of bipolar disorder.
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2,338,936 |
Preimplantation genetic diagnosis for polycystic kidney disease.
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To use preimplantation genetic diagnosis for achieving a polycystic kidney disease (PKD)-free pregnancy for a couple in which the female partner was affected by PKD but whose PKD1 or PKD2 carrier status was not established.</AbstractText>Case report.</AbstractText>The IVF program of Reproductive Genetics Institute, Chicago, Illinois.</AbstractText><AbstractText Label="PATIENT(S)" NlmCategory="METHODS">An at-risk couple with the female partner affected by PKD, whose PKD1 or PKD2 carrier status was not established.</AbstractText><AbstractText Label="INTERVENTION(S)" NlmCategory="METHODS">Removal of PB1 and PB2 and testing for three closely linked markers to PKD1 (Kg8, D16S664, and SM7) and four closely linked markers to PKD2 (D4S2922, D4S2458, D4S423, and D4S1557) after standard IVF.</AbstractText><AbstractText Label="MAIN OUTCOME MEASURE(S)" NlmCategory="METHODS">Deoxyribonucleic acid analysis of PB1 and PB2 indicating whether corresponding oocytes were PKD1 or PKD2 allele free, for the purpose of transferring only embryos resulting from mutation-free oocytes.</AbstractText><AbstractText Label="RESULT(S)" NlmCategory="RESULTS">Of 11 oocytes tested by PB1 and PB2 DNA analysis, 7 were predicted to contain PKD1 or PKD2, with the remaining 4 free of both mutations. Three embryos resulting from these oocytes were transferred, yielding a twin pregnancy and the birth of two unaffected children.</AbstractText><AbstractText Label="CONCLUSION(S)" NlmCategory="CONCLUSIONS">This is the first preimplantation genetic diagnosis for PKD, which resulted in the birth of healthy twins confirmed to be free of PKD1 and PKD2. Preimplantation genetic diagnosis based on linked marker analysis provides an alternative for avoiding the pregnancy and birth of children with PKD, even in at-risk couples without exact PKD1 or PKD2 carrier information.</AbstractText>
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2,338,937 |
Novel missense polymorphism in the regulator of G-protein signaling 10 gene: analysis of association with schizophrenia.
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Dysfunction of neuronal signal transduction via G-protein has previously been speculated to be involved in the pathophysiology of schizophrenia. Regulator of G-protein signaling (RGS) is a protein that acts as a GTPase-activator for Galpha protein. A total of 33 Japanese patients with schizophrenia were screened for mutations in the coding region of the RGS10 gene, and a novel missense polymorphism (Val38Met) in the RGS domain was detected. A case-control study did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the RGS10 gene is involved in biological vulnerability to schizophrenia.
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2,338,938 |
Characterization of nodavirus and viral encephalopathy and retinopathy in farmed turbot, Scophthalmus maximus (L.).
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An outbreak of nodavirus infection in turbot larvae is described with respect to histopathology, immunohistochemistry, cell culture cultivation, RT-PCR amplification and sequence analysis of the capsid protein gene RNA2. Affected turbot developed classical signs of viral encephalopathy and retinopathy (VER) with abnormal swimming behaviour and high mortality levels. In the acute stage of infection, light microscopy revealed vacuolation of the central nervous system (CNS), with positive immunohistochemical staining for nodavirus. Later in the infection, CNS lesions appeared more chronic and contained clusters of cells immunopositive for nodavirus. Bacterial overgrowth in the intestines of the fish may have provoked or influenced the course of the nodavirus infection. We were unable to propagate the virus in cell culture. While RT-PCR using primers designed to detect Atlantic halibut nodavirus gave negative results, further testing with primers complementary to a more conserved region of RNA2 resulted in amplification of a product of the expected size. The entire RNA2 segment was cloned and sequenced. Sequence alignment showed that the turbot nodavirus (TNV) was different from previously described fish nodaviruses. In addition, phylogenetic analysis based on an 823 nt region of the sequence indicated that TNV clustered outside the four established fish nodavirus genotypes, suggesting a fifth genotype within the betanodaviruses.
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2,338,939 |
A novel alpha-thalassemia nonsense mutation in codon 23 of the alpha2-globin gene (GAG-->TAG) in a Tunisian family.
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Herein we describe a novel alpha-thalassemia (thal) point mutation in the alpha2-globin gene, found in a 3-year-old Tunisian girl who had Hb Bart's (gamma4) at birth, later on presenting with moderate anemia, microcytosis and hypochromia. She had a normal Hb A2 level and no abnormal hemoglobin (Hb) fraction. After excluding most of the common Mediterranean mutations, the alpha2-globin gene was sequenced and found to have a point mutation in the heterozygous state that creates a premature stop signal for translation (GAG-->TAG or Glu-->Term) at codon 23. The same mutation was also found in the mother in the heterozygous state, while the father had a normal sequence. The presence of the mutation was also confirmed by nucleotide sequencing of the opposite strand. Since the mutation creates a restriction site for the BfaI enzyme, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based assay was established for screening purposes.
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2,338,940 |
The 'hot-spot' of Hb E [beta26(B8)Glu-->Lys] in Southeast Asia: beta-globin anomalies in the Lao Theung population of southern Laos.
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Hb E [beta26(B8)Glu-->Lys], is the most common abnormal hemoglobin (Hb) in Southeast Asian populations. The hitherto highest frequencies of the Hb E gene (HBB*E) in large population samples, approximately 0.3, were observed in the southern part of northeastern Thailand. The finding of even higher frequencies in a small, isolated Austroasiatic group in Northeast Thailand prompted us to examine samples of three Austroasiatic populations in southern Laos (official designation: Lao Theung), an area inhabited by numerous ethnic groups belonging to the Mon-Khmer branch. Blood samples were collected from a total of 603 adult subjects. The HBB*E frequencies were 0.426 in the So of Khammuan Province, 0.433 in the Alak/Ngeh of Sekong Province and 0.253 in the Oy of Attapeu Province. The HBB*E frequencies in the So and Alak/Ngeh are the highest observed in Southeast Asia in representative population samples. None of the common Southeast Asian beta-thalassemia (thal) mutations were found. The results are discussed with respect to natural selection by malaria, selection time, effects of beta-thal and the ethnic history of the population of Southeast Asia.
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2,338,941 |
Contribution to the description of the beta-thalassemia spectrum in Tunisia and the origin of mutation diversity.
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We determined the spectrum of beta-thalassemia (thal) mutations in 118 affected unrelated patients with different forms of beta-thal. Using a combination of reverse dot-blot analysis, denaturing gradient gel electrophoresis (DGGE), polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) and direct nucleotide sequencing, we identified the largest spectrum of beta-thal mutations so far reported in Tunisia, and to the best of our knowledge, within the Mediterranean Basin. A total of 18 distinct alleles were detected at different frequencies, with two alleles [codon 39 (C-->T) and IVS-I-110 (G-->A)] predominating all others. Seven other alleles [frameshift at codon (FSC) 6 (-A), FSC 8 (-AA), codon 30 (G-->C), IVS-I-1 (G-->A), IVS-I-2 (T-->G), IVS-I-6 (T-->C), FSC 44 (-C)] were rare, and nine alleles [-29 (A-->G), IVS-I-2 (T-->C), IVS-I-5 (G-->C), IVS-I-5 (G-->T), IVS-I-116 (T-->G), codon 37 (G-->A), IVS-II-1 (G-->A), IVS-II-745 (G-->C) and IVS-II-849 (A-->C)], albeit described elsewhere, are reported here in Tunisia for the first time. The codon 39 and IVS-I-110 mutations were the two predominant alleles occurring at frequencies of 43.8% and 10.8%, respectively. They are presumably the earliest mutations introduced into this country. The codon 39 allele could have been introduced in Tunisia during the Roman occupation. Similarly, the IVS-I-110 mutation might have been introduced by the Turkish and Phoenician influence. Both gene flow and private mutations may account for the diversity of alleles observed in Tunisia. These data provide the background for implementing prevention programs based on genetic counseling and prenatal diagnosis.
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2,338,942 |
Molecular basis of beta-thalassemia in the population of Tunisia.
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The present study attempts to delineate the spectrum of beta-thalassemia (thal) mutations in Tunisia by studying a large population from different parts of the country. A total of 285 unrelated subjects, 190 of whom had beta-thal major, 72 with Hb S/beta-thal, one with Hb C/beta-thal, one with Hb O-Arab/beta-thal and 21 beta-thal carriers, were studied. The molecular defects were detected in 97.7% of the beta-thalassemic chromosomes (n=475). Nineteen different beta-thalassemic alleles were identified. Two mutations, namely codon 39 (C-->T) and IVS-I-110 (G-->A) accounted for 70.0% of the studied chromosomes, followed by IVS-I-1 (G-->A) (4.5%). Five other mutations, frameshift codon (FSC) 44 (-C), codon 30 (G-->C), IVS-I-2 (T-->G), IVS-II-745 (C-->G), and FSC 6 (-A), are not uncommon in this population, while the remaining 11 mutations, IVS-I-5 (G-->A), -30 (T-->A), codons 25/26 (+T), IVS-I-6 (T-->C), FSC 5 (-CT), IVS-II-848 (C-->A), FSC 8 (-AA), -87 (C-->G), IVS-I-5 (G-->C), IVS-II-1 (G-->A) and IVS-II-849 (A-->C) are quite rare; four of these have not been previously reported in the Tunisian population. Potential origin and spread of these mutations to Tunisia are also discussed.
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2,338,943 |
Unrelated donor marrow transplantation for congenital immunodeficiency and metabolic disease: an update of the experience of the Japan Marrow Donor Program.
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We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program. The patients were aged between 1 and 38 years (median, 4 years). Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich syndrome (n = 16), hemophagocytic syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM syndrome (n = 4), Chédiak-Higashi syndrome (n = 3), Kostmann syndrome (n = 3), and others (n = 5). Fifty-two donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% - 9.8% in the MD group and 47.3% - 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months). The probabilities of 5-year overall survival and event-free survival were 72.6% - 11.5% and 65.3% - 8.6%, respectively, for MD (n = 35) and 72.5% - 7.3% and 63.6% - 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.
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2,338,944 |
Hemoglobin Pakse: presence on red blood cell membrane and detection by polymerase chain reaction-single-strand conformational polymorphism.
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Nondeletional gene mutations giving rise to alpha-thalassemia can be found at polymorphic frequency in Southeast Asia. Although the most common is hemoglobin Constant Spring (Hb CS), caused by a termination codon mutation (UAA --> CAA, Gln) in the alpha2-globin gene and resulting in reduced synthesis of the elongated alpha-globin variant, Hb Pakse (UAA --> UAU, Tyr) also has been observed at a significant prevalence. Western blot analysis of ghost membrane proteins separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis from an individual with alpha-thal 1/Hb Pakse revealed the existence of a higher molecular weight globin of 18 kd consistent with an alpha(Pakse)-globin chain. The presence of alpha(Pakse)-globin on membranes of Hb Pakse-containing red blood cells affords an explanation for the severity of anemia observed in such patients. However, because the 2 Hb variants cannot be distinguished by current biochemical techniques, we developed a convenient single-tube polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) protocol for the simultaneous diagnosis of Hb CS and Hb Pakse by amplifying a short fragment covering the termination codon of the alpha2-globin gene. This PCR-SSCP method required no internal control coamplification or use of restriction enzymes and has the potential of identifying all the other possible termination codon mutations in a single reaction with only 1 pair of primers.
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2,338,945 |
[Patterns of maternal behavior of rats genetically selected for opposite coping styles].
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Maternal behavior of Koltushi High- and Low-avoidance (KHA and KLA) rats strains was assessed over the prewealing period (days 6-21). Ten litters of each strain were observed during the light phase of the light/dark cycle. In a series of experiments, rat pups were taken from the maternal nest and placed into the opposite corner of the cage. The following parameters of the maternal behavior were recorded: the latency of the first contact with the pups, pup licking, latency of carrying/retrieval of the first pup back to the nest, time of returning to the nest of the whole litter, and mother's spontaneous behavior (grooming and locomotion time) over the course of 10 min of observation. KLA mothers stayed with their pups and took care of them more frequently than KHA mothers during the light phase of the circadian cycle. Time of self-grooming was significantly higher in KHA rats. The highest levels of self-grooming of mothers was registered on the first day of testing. The latency of the first coming to pups after their removal from the nest was lower in KHA rats, but they needed more time to returned all pups to the nest. The experimental evidence suggests that the KHA but not KLA rats with the active coping style and higher stress reactivity display disorders in maternal behavior in a novel situation.
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2,338,946 |
Testing the hypothesis of a recombinant origin of the SARS-associated coronavirus.
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The origin of severe acute respiratory syndrome-associated corona-virus (SARS-CoV) is still a matter of speculation, although more than one year has passed since the onset of the SARS outbreak. In this study, we implemented a 3-step strategy to test the intriguing hypothesis that SARS-CoV might have been derived from a recombinant virus. First, we blasted the whole SARS-CoV genome against a virus database to search viruses of interest. Second, we employed 7 recombination detection techniques well documented in successfully detecting recombination events to explore the presence of recombination in SARS-CoV genome. Finally, we conducted phylogenetic analyses to further explore whether recombination has indeed occurred in the course of coronaviruses history predating the emergence of SARS-CoV. Surprisingly, we found that 7 putative recombination regions, located in Replicase 1ab and Spike protein, exist between SARS-CoV and other 6 coronaviruses: porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), bovine coronavirus (BCoV), human coronavirus 229E (HCoV), murine hepatitis virus (MHV), and avian infectious bronchitis virus (IBV). Thus, our analyses substantiate the presence of recombination events in history that led to the SARS-CoV genome. Like the other coronaviruses used in the analysis, SARS-CoV is also a mosaic structure.
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2,338,947 |
TRbase: a database relating tandem repeats to disease genes for the human genome.
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Tandem repeats are associated with disease genes, play an important role in evolution and are important in genomic organization and function. Although much research has been done on short perfect patterns of repeats, there has been less focus on imperfect repeats. Thus, there is an acute need for a tandem repeats database that provides reliable and up to date information on both perfect and imperfect tandem repeats in the human genome and relates these to disease genes.</AbstractText>This paper presents a web-accessible relational tandem repeats database that relates tandem repeats to gene locations and disease genes of the human genome. In contrast to other available databases, this database identifies both perfect and imperfect repeats of 1-2000 bp unit lengths. The utility of this database has been illustrated by analysing these repeats for their distribution and frequencies across chromosomes and genomic locations and between protein-coding and non-coding regions. The applicability of this database to identify diseases associated with previously uncharacterized tandem repeats is demonstrated.</AbstractText>
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2,338,948 |
An empirical Bayes approach to inferring large-scale gene association networks.
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Genetic networks are often described statistically using graphical models (e.g. Bayesian networks). However, inferring the network structure offers a serious challenge in microarray analysis where the sample size is small compared to the number of considered genes. This renders many standard algorithms for graphical models inapplicable, and inferring genetic networks an 'ill-posed' inverse problem.</AbstractText>We introduce a novel framework for small-sample inference of graphical models from gene expression data. Specifically, we focus on the so-called graphical Gaussian models (GGMs) that are now frequently used to describe gene association networks and to detect conditionally dependent genes. Our new approach is based on (1) improved (regularized) small-sample point estimates of partial correlation, (2) an exact test of edge inclusion with adaptive estimation of the degree of freedom and (3) a heuristic network search based on false discovery rate multiple testing. Steps (2) and (3) correspond to an empirical Bayes estimate of the network topology.</AbstractText>Using computer simulations, we investigate the sensitivity (power) and specificity (true negative rate) of the proposed framework to estimate GGMs from microarray data. This shows that it is possible to recover the true network topology with high accuracy even for small-sample datasets. Subsequently, we analyze gene expression data from a breast cancer tumor study and illustrate our approach by inferring a corresponding large-scale gene association network for 3883 genes.</AbstractText>
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2,338,949 |
Multispecific T cell response and negative HCV RNA tests during acute HCV infection are early prognostic factors of spontaneous clearance.
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<AbstractText Label="BACKGROUND/AIMS" NlmCategory="OBJECTIVE">Hepatitis C virus (HCV) infection results in a high frequency of chronic disease. The aim of this study was to identify early prognostic markers of disease resolution by performing a comprehensive analysis of viral and host factors during the natural course of acute HCV infection.</AbstractText>The clinical course of acute hepatitis C was determined in 34 consecutive patients. Epidemiological and virological parameters, as well as cell mediated immunity (CMI) and distribution of human leukocyte antigens (HLA) alleles were analysed.</AbstractText>Ten out of 34 patients experienced self-limiting infection, with most resolving patients showing fast kinetics of viral clearance: at least one negative HCV RNA test during this phase predicted a favourable outcome. Among other clinical epidemiological parameters measured, the self-limiting course was significantly associated with higher median peak bilirubin levels at the onset of disease, and with the female sex, but only the latter parameter was independently associated after multivariate analysis. No significant differences between self-limiting or chronic course were observed for the distribution of DRB1 and DQB1 alleles. HCV specific T cell response was more frequently detected during acute HCV infection, than in patients with chronic HCV disease. A significantly broader T cell response was found in patients with self-limiting infection than in those with chronic evolving acute hepatitis C.</AbstractText>The results suggest that host related factors, in particular sex and CMI, play a crucial role in the spontaneous clearance of this virus. Most importantly, a negative HCV RNA test and broad CMI within the first month after onset of the symptoms represent very efficacious predictors of viral clearance and could thus be used as criteria in selecting candidates for early antiviral treatment.</AbstractText>
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2,338,950 |
A genetic test which can be used to diagnose adult-type hypolactasia in children.
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<AbstractText Label="BACKGROUND/AIMS" NlmCategory="OBJECTIVE">Adult-type hypolactasia (primary lactose malabsorption) affects most of world's human population and limits the use of fresh milk due to lactose intolerance. The diagnosis of adult-type hypolactasia has been difficult to establish because of unsatisfactory diagnostic methods. C/T(-13910) single nucleotide polymorphism residing 13910 base pairs from the 5' end of the lactase gene has been shown to be associated with lactase persistence. The aim of the study was to assess the applicability of the C/T(-13910) variant as a diagnostic test for adult-type hypolactasia during childhood.</AbstractText>Intestinal biopsies were obtained from 329 children and adolescents of African, Finnish, and other White origins aged 0.1-20 years undergoing upper gastrointestinal endoscopy because of abdominal complaints. The biopsies were assayed for lactase, sucrase, and maltase activity and genotyped for the C/T(-13910) variant using polymerase chain reaction minisequencing.</AbstractText>The frequency of the C/C(-13910) genotype defining lactase non-persistence was well in agreement in this study with published figures for the prevalences of adult-type hypolactasia in Africans and Whites. The C/C(-13910) genotype was associated with very low lactase activity (<10 U/g protein) in the majority of children tested at 8 years of age and in every child older than 12 years of age giving a specificity of 100% and sensitivity of 93% for the genetic test. The decline of lactase activity was somewhat earlier in African compared with Finnish children with C/C(-13910) genotype (p<0.03).</AbstractText>Genetic test of C/T(-13910) polymorphism can be used as a first stage screening test for adult-type hypolactasia.</AbstractText>
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2,338,951 |
Non-invasive method for sampling and extraction of mouse DNA for PCR.
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We adapted a non-invasive, fast, reliable and inexpensive procedure for the sampling and extraction of deoxyribonucleic acid (DNA) for genetic testing of mice. The procedure is based on a simple DNA extraction procedure used in the forensic genetic testing of humans. It involves mouth swabbing of the inner cheek using a cotton stick, followed by alkaline lysis of the harvested buccal epithelial cells. This procedure allows for repeated sampling and genetic testing of the individual mouse, and it is faster, simpler and, in our hands, more reliable than the currently used routine procedures for the sampling and extraction of mouse DNA. Current procedures all involve biopsy of a piece of the tail, ear or toe, followed by lengthy procedures to release and isolate the DNA.
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2,338,952 |
Molecular investigation of hepatitis E virus infection in domestic and miniature pigs used for medical experiments.
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Hepatitis E virus (HEV) infection is highly prevalent among domestic pigs in Japan. It has been reported that pig handlers such as farmers and veterinarians are at increased risk of contracting HEV infection. Pigs are regarded as the most acceptable candidate animals for xenotransplantation and, recently, they are being used as experimental animals.</AbstractText>We investigated the prevalence of IgG class antibodies to swine HEV (anti-HEV) and HEV RNA among 152 2-month-old domestic pigs and 38 miniature pigs of 4 to 10 months of age that had been brought to our center for medical experiments from five swine farms (A-E) in Japan. Serum samples were tested for anti-HEV by in-house enzyme immunoassay, and for HEV RNA by reverse transcription-polymerase chain reaction using primers targeting the open reading frame 2 (ORF2) region.</AbstractText>One percent (one of 84), 6% (one of 16), and 38% (20 of 52) of the domestic pigs from farms A, B and C, respectively, had detectable HEV RNA, and the 22 HEV isolates recovered from the viremic pigs were 89.8 to 100% identical to each other in the 412-nucleotide sequence of ORF2 and segregated into three clusters within genotype 3. Although one pig from farm A had detectable HEV RNA reproducibly, the HEV isolate recovered from this pig was up to 100% similar to those recovered from pigs from farm C, and the sera from all 84 pigs from farm A were negative for anti-HEV. These results suggested that farm A is free from HEV infection. As the viremic pig from farm A had been raised for 1 month in a barn at our center before serum sampling, it is most likely that the pig acquired HEV infection in the barn at our center where HEV-viremic pigs from farm C had been reared for several days approximately 3 months earlier. The 38 miniature pigs from farms D and E were negative for both anti-HEV and HEV RNA. In an attempt to further investigate the prevalence of HEV infection, pigs that were being raised in four swine farms (farms A, C, D, and E) were tested for anti-HEV. Although 96 (86%) of the 112 pigs from farm C were positive for anti-HEV, none of the 48 pigs in farm A and 138 miniature pigs in farms D and E was positive for anti-HEV.</AbstractText>These results suggest that three of the five swine farms tested were free from HEV, and that periodic testing for anti-HEV and HEV RNA of pigs used as experimental animals and pigs raised in swine farms from which pigs are purchased, is useful for providing HEV-free pigs to researchers who are engaged in studies using pigs.</AbstractText>
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2,338,953 |
C283Y gamma-sarcoglycan gene mutation in the Bulgarian Roma (Gypsy) population: prevalence study and carrier screening in a high-risk community.
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Limb-girdle muscular dystrophy type 2C (LGMD2C) is caused by mutations in the gamma-sarcoglycan gene where a founder Gypsy mutation C283Y was detected. The Bulgarian Gypsy LGMD2C patients, as the Gypsy patients from other countries, were found to be homozygous for this mutation. Considering the large number of Gypsies in Bulgaria and the high percent of consanguinity and endogamy a raised carrier frequency of the C283Y mutation was expected especially in North-Eastern Bulgaria where most of the patients originate from. Here, we present the precise geographic distribution of the C283Y mutation in the general Roma population from the whole Bulgarian territory by determining the carrier frequency of the mutation in dry blood newborn samples. Our results show that the geographic distribution of this founder mutation and the disease are not geographically restricted only among Gypsies from North-Eastern Bulgaria. We stress upon the regions with detected high carrier and/or disease frequency and upon the results from the performed carrier screening on volunteers in one of these regions. The ongoing carrier-screening programs in isolated Gypsy groups would be of a great benefit for the genetic prophylaxis of the disease. Such regions should be with priority in the Bulgarian healthcare system for performing a carrier-screening program.
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2,338,954 |
SDHB, SDHC, and SDHD mutation screen in sporadic and familial head and neck paragangliomas.
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Mutations within three genes, SDHB, SDHC, and SDHD, encoding distinct subunits of a hetero-oligomeric protein known as the mitochondrial complex II, a component of the mitochondrial electron transport chain and the Krebs cycle have been implicated in the pathogenesis of hereditary paraganglioma (PGL). This study describes a mutation screen of SDHB, SDHC, and SDHD in blood and tumor samples of 14 sporadic and three familial cases of head and neck PGL (HNP). Germline mutations in SDHB and SDHD were identified in two of the three affected individuals with familial HNP. The SDHB mutation was a novel 3 base pair, in-frame deletion of AGC at nucleotide 583-585 encoding serine (delS195). The SDHD mutation was a C to T transition within codon 81 causing substitution of proline with leucine (P81L). In contrast to familial cases, no germline or somatic mutations were identified in the 14 sporadic cases of HNP. The presence of mutations within SDHB and SDHD in two of the three samples of familial PGLs and absence of mutations in sporadic cases is consistent with the significant contribution of these genes to familial but not sporadic PGL. The etiology of sporadic PGL remains to be elucidated.
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2,338,955 |
Attitudes and beliefs concerning prostate cancer genetic screening.
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This quantitative study determines the values, beliefs, and attitudes influencing the intention of men to undergo or defer genetic testing for prostate cancer risk using a model based on components of the Theory of Reasoned Action and Health Belief Model. Telephone interviews of a community sample of 400 men in a large, East Coast metropolitan area of diverse educational, ethnic, and age backgrounds were conducted to rank key values and beliefs about genetic testing for prostate cancer risk in anticipation of its future availability. Descriptive statistics, univariate analyses, and logistic regression were used in data analysis. The factors of values attached to consequences, motivation from self, beliefs in benefits, and a motivation to comply with others (borderline) were statistically significant for testing intention. Of all demographics, only increased education was associated with diminished interest in testing. Desire to be tested varied widely across groups of men. Based on these identified values, health professionals can better understand men's values and beliefs on the risks and benefits of testing. The relationship of men to others, family and society, require further investigation in this and other aspects of genetic testing.
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2,338,956 |
Anticipated reactions to genetic testing for hereditary non-polyposis colorectal cancer susceptibility.
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Genetic testing for cancer susceptibility (e.g. hereditary non-polyposis colorectal cancer) is available for some families with a history of colon cancer. Our aim was to investigate participants' anticipated emotional and behavioral reactions to genetic testing for colon cancer and whether gender or clinical risk influences these reactions. 437 asymptomatic participants with a colorectal cancer family history completed a questionnaire about anticipated emotions and actions, under different genetic testing scenarios. More women than men anticipated feeling worried, regretful, and angry if tested positive. People at lower-risk anticipated more surprise and disbelief than those at higher-risk. People anticipated feeling more guilt, regret and less relief if they were not tested than if they were. High-risk results were anticipated to increase depression and worry. Most people still wanted screening if at low risk, anticipated leading healthier lifestyles whatever the result, but would make more plans for the future if they were at high risk. Clinical implications are that as anticipated emotional effects of not being tested may be more severe than having a test, people choosing to forgo testing should feel able to reconsider their decision anytime. Most people did not anticipate strong emotional reactions but thought it would change their lifestyle and would like continued clinical surveillance whatever the result.
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2,338,957 |
Research issues in genetic testing of adolescents for obesity.
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Obesity is often established in adolescence, and advances are being made in identifying its genetic underpinnings. We examine issues related to the eventual likelihood of genetic tests for obesity targeted to adolescents: family involvement; comprehension of the test's meaning; how knowledge of genetic status may affect psychological adaptation; minors' ability to control events; parental/child autonomy; ability to make informed medical decisions; self-esteem; unclear distinctions between early/late onset for this condition; and social stigmatization. The public health arena will be important in educating families about possible future genetic tests for obesity.
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2,338,958 |
Haplotype analysis and identification of genes for a complex trait: examples from schizophrenia.
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For more than a decade there has been intensive research into the genetic etiology of schizophrenia, yet it is only recently that the first findings of promising genes associating with the disorder have been reported. Linkage analyses in families collected from different populations have provided relatively well defined genomic loci. These have been typically followed by fine mapping studies using single nucleotide polymorphisms (SNPs). A number of analysis programs have been produced to test SNPs and their haplotypes for association. Typically association has been established to specific haplotypes representing an allelic variant of the corresponding gene. The inherent problem of multiple testing in the analysis of haplotypes needs to be addressed fully, to determine if any of these recent findings can be considered as confirmed susceptibility genes for schizophrenia. However, informative haplotypes have provided a way to define allelic variants of genes associated with schizophrenia in numerous study samples, and are a useful tool in characterizing the extent of allelic diversity of putative schizophrenia susceptibility genes within different populations.
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2,338,959 |
A multicenter study of supportive-expressive group therapy for women with BRCA1/BRCA2 mutations.
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Women with a BRCA1/BRCA2 mutation experience significant challenges. These include decision-making regarding surgical options and notification to offspring and family, along with a sense of isolation, which may lead to psychological and emotional distress. The current study developed, standardized, and conducted preliminary testing of a supportive-expressive group therapy intervention designed to address these challenges.</AbstractText>Seventy women with a BRCA1/BRCA2 mutation recruited from familial cancer risk clinics participated in 12 sessions of supportive-expressive group therapy that lasted 6 months. Before and after measures of psychosocial functioning, knowledge, and surveillance/surgery activities were completed.</AbstractText>Sixty-seven women completed the intervention. Significant improvements were observed in psychosocial functioning: cancer worries (P = 0.005), anxiety (P = 0.033), and depression (P = 0.015). Knowledge level and surveillance levels were high at baseline and there were no significant changes postintervention. A significant number of women made decisions concerning prophylactic surgery (oophorectomy/mastectomy) during and after the intervention.</AbstractText>The feasibility of a supportive-expressive group for BRCA1/BRCA2 mutation carriers was demonstrated. Findings from the study are consistent with an effective intervention. However, further research is required using a randomized controlled study design.</AbstractText>(c) 2004 American Cancer Society</CopyrightInformation>
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2,338,960 |
EILATox-Oregon Workshop: blind study evaluation of Vitotox test with genotoxic and cytotoxic sample library.
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In order to assess the robustness, sensitivity and specificity of a recently developed Vitotox test, 17 blind coded chemicals and three environmental water samples were tested at the EILATox-Oregon Workshop using the Thermo Electron Vitotox kit. The Vitotox test is a rapid geno- and cytotoxicity test using standard 96- or 384-well microtitre plates. The genotoxicity test is based on two genetically modified Salmonella typhimurium strains containing bacterial luciferase operon from Vibrio fisheri under the SOS inducible promoter. The SOS system is an inducible network in Escherichia coli that responds to DNA damage and activates DNA repair. The Vitotox genotoxicity test bacteria strain carries bacterial luciferase genes under the control of SOS inducible promoter and therefore any DNA damage inside the cells induces the production of bacterial luciferase. The luciferase expression is then followed with a microtitre plate luminometer for 3 h after mixing different dilutions of sample with the test bacteria. The genotoxicity index is calculated for each dilution and the genotoxicity of the sample is interpreted based on kinetic time curves and genotoxicity vs concentration/dilution curves. Cytotoxicity of the sample is determined simultaneously with another test strain containing the same luciferase operon controlled by the constitutive promoter. This bacterium produces constant bioluminescence and any decrease of the bioluminescence production is used as a marker for cytotoxicity. As a miniaturized microtitre plate assay the Vitotox test requires a very small quantity of the sample material. The samples used in the workshop were diluted 1 : 10 or 1 : 100 before testing. Genotoxicity and cytotoxicity data were collected at dilutions of 1 : 10-1 : 2000. When the samples of the EILATox-Oregon Workshop were tested using the Vitotox test, four coded chemicals out of 17 were determined to be genotoxic. Seven chemicals and one environmental sample were found to be cytotoxic. Three chemical samples were found to be both geno- and cytotoxic.
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2,338,961 |
Testing species boundaries in an ancient species complex with deep phylogeographic history: genus Xantusia (Squamata: Xantusiidae).
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Identification of species in natural populations has recently received increased attention with a number of investigators proposing rigorous methods for species delimitation. Morphologically conservative species (or species complexes) with deep phylogenetic histories (and limited gene flow) are likely to pose particular problems when attempting to delimit species, yet this is crucial to comparative studies of the geography of speciation. We apply two methods of species delimitation to an ancient group of lizards (genus Xantusia) that occur throughout southwestern North America. Mitochondrial cytochrome b and nicotinamide adenine dinucleotide dehydrogenase subunit 4 gene sequences were generated from samples taken throughout the geographic range of Xantusia. Maximum likelihood, Bayesian, and nested cladogram analyses were used to estimate relationships among haplotypes and to infer evolutionary processes. We found multiple well-supported independent lineages within Xantusia, for which there is considerable discordance with the currently recognized taxonomy. High levels of sequence divergence (21.3%) suggest that the pattern in Xantusia may predate the vicariant events usually hypothesized for the fauna of the Baja California peninsula, and the existence of deeply divergent clades (18.8%-26.9%) elsewhere in the complex indicates the occurrence of ancient sundering events whose genetic signatures were not erased by the late Wisconsin vegetation changes. We present a revised taxonomic arrangement for this genus consistent with the distinct mtDNA lineages and discuss the phylogeographic history of this genus as a model system for studies of speciation in North American deserts.
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2,338,962 |
Acanthamoeba keratitis in non-contact lens wearers in India: DNA typing-based validation and a simple detection assay.
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To establish that the protozoan Acanthamoeba is one of the causative organisms associated with non-contact lens-related keratitis in the Indian population and to develop a simple and sensitive diagnostic assay for clinical testing.</AbstractText>DNA sequencing of nuclear 18S and 26S ribosomal DNA motifs was performed and compared with the reference Acanthamoeba strains, to establish the genetic identity of the putative amoeba isolates obtained from the corneal scrapings of non-contact lens-wearing patients with keratitis. Ribosomal DNA typing of clinical corneal scrapings from the patients with keratitis was performed by means of a simple agarose gel-based multiplex polymerase chain reaction assay, to detect the cases of Acanthamoeba keratitis.</AbstractText>The ribosomal DNA analysis of 15 putative amoeba isolates obtained from the corneal scrapings of 14 patients with keratitis and 1 from the patients' environment established the isolates to be pathogenic formsof Acanthamoeba belonging to type T4 ribosomal DNA genotype. Multiplex polymerase chain reaction assay was specific and sensitive enough to detect as low as 5 pg of Acanthamoeba DNA. Its utility as a reliable diagnostic assay was demonstrated directly with the use of 34 additional corneal scrapings.</AbstractText>Acanthamoeba is one of the causative organisms of keratitis in Indian patients with no history of contact lens usage. Moreover, the Acanthamoeba infection can be easily detected in the clinical samples by means of the simple multiplex polymerase chain reaction assay based on ribosomal DNA typing. Clinical Relevance This study suggests the need and means to determine the incidence and prevalance of Acanthamoeba keratitis in India and elsewhere. Moreover, the polymerase chain reaction assay would help in early and definitive diagnosis, leading to better prognosis of Acanthamoeba keratitis condition.</AbstractText>
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2,338,963 |
Temporal bone histopathology in alport syndrome.
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To determine the histopathologic abnormalities within the cochlea in Alport syndrome.</AbstractText>Alport syndrome, which manifests as hereditary nephritis and sensorineural hearing loss (SNHL), is caused by mutations in genes that code for the proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen. The proportional, variant3, proportional, variant4, and proportional, variant5 chains of type IV collagen are present in the basement membrane of the organ of Corti. Previous temporal bone studies have failed to identify histopathologic correlates for the SNHL.</AbstractText>We examined temporal bones from nine individuals with a clinical diagnosis of Alport syndrome. One of our cases also had genetic testing that showed a mutation in the type IV collagen proportional, variant5 chain gene.</AbstractText>By light microscopy, eight of nine cases demonstrated two unique pathologic changes: 1) a "zone of separation" between the basilar membrane and overlying cells of the organ of Corti and 2) presence of cells filling the tunnel of Corti and extracellular spaces of Nuel. The cytologic losses of hair cells, stria vascularis, and cochlear neuronal cells were insufficient to account for the observed SNHL in our cases. Electron microscopy was performed in four cases; all four demonstrated the following: 1) the zone of separation that was observed at light microscopy occurred between the basement membrane and the basilar membrane, 2) the cells within the tunnel of Corti and spaces of Nuel were morphologically similar to supporting cells, and 3) the basement membrane of strial capillaries and the spiral vessel (under the basilar membrane) were normal.</AbstractText>The histopathologic correlates of cochlear involvement in Alport syndrome are abnormalities of the basement membrane of cells of the organ of Corti and dysmorphogenesis (cellular infilling of the tunnel and extracellular spaces) of the organ of Corti. We hypothesize that these abnormalities result in SNHL by altering cochlear micromechanics.</AbstractText>
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2,338,964 |
Public experiences, knowledge and expectations about medical genetics and the use of genetic information.
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The objectives of this study were (1) to explore public experiences, genetic knowledge, expectations of future medical genetic developments, and the attitudes towards the use of genetic information, and (2) to determine whether there are subject characteristics associated with these variables.</AbstractText>Participants (n = 1,308, age > or = 25 years) of a Dutch consumer panel were sent a questionnaire, specifically designed for this study.</AbstractText>Response was 63% (817/1,308). A minority of respondents reported to know someone with a hereditary disease (34%) or to have used a genetic test (8%). Overall, 57% perceived a lack of genetic knowledge. In multivariate analyses, high self-rated knowledge, younger age, having heard of genetic testing, high educational level, female gender, having children living at home, being a health professional, and familiarity with genetic testing were positively associated with genetic knowledge. Future expectations of the consequences of developments in medical genetics varied between the subjects. The great majority expected great benefits for medical practice such as an increasing use of genetic aspects of disease for diagnosis or prevention. One fifth, mainly older people, anticipated a negative impact of genetic developments on society. The results also show that most people are reserved to share their genetic information with others, especially with regard to the wider public domain (e.g. industry and insurers) and employers. Remarkably, respondents were more willing to share their genetic information with scientific researchers (68%) than with their relatives (54%).</AbstractText>This study suggests that although one fifth anticipates negative consequences of genetic developments, the great majority has high expectations about the increasing use of genetics in prevention, diagnosis and treatment of diseases. In developing educational programmes about genetic innovations in medicine, policymakers will have to take into account pre-existing lay knowledge, views and expectations of different groups of citizens towards these developments.</AbstractText>2004 S. Karger AG, Basel.</CopyrightInformation>
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2,338,965 |
Effects of individual and family functioning on interest in genetic testing.
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The present study reports on the important issue of how family communication and support regarding breast cancer risk affects interest in genetic testing and mental health.</AbstractText>Participants (n = 221) were women aged 18-74 who had at least one relative of Ashkenazi Jewish descent, no personal history of breast or ovarian cancer, and lived within 60 miles of Seattle, Wash.</AbstractText>Communication about breast cancer risk was reported with very low frequency across all types of relatives. Women talked with their mothers and sisters more often than their fathers, brothers, or children. The only significant predictor of interest in genetic testing was the individual level variable of seeking social support.</AbstractText>Social support needs might be a part of the genetic testing process.</AbstractText>2004 S. Karger AG, Basel.</CopyrightInformation>
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2,338,966 |
Family communication about genetic risk: the little that is known.
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Although family communication is important in clinical genetics only a small number of studies have specifically explored the passing on of genetic knowledge to family members. In addition, many of these present exploratory or tentative findings based upon small sample sizes, or data collected only a short time after testing. Nevertheless, if health professionals are to develop effective strategies to help patients' deal with communication issues, we need to know more about what actually happens in families. The aim of this commentary is to identify factors which appear to influence whether patients share information about genetic risk with relatives who are unaware of that risk, with whom they share it and how they go about it. The paper draws upon evidence and thinking from the disciplines of psychology (including family therapy), sociology, medicine and genetic counselling. It is presented under the following headings: disease factors, individual factors, family factors and sociocultural factors. It concludes by highlighting a number of key issues which are relevant for health professionals.
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2,338,967 |
Identifying multiple changepoints in heterogeneous binary data with an application to molecular genetics.
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Identifying changepoints is an important problem in molecular genetics. Our motivating example is from cancer genetics where interest focuses on identifying areas of a chromosome with an increased likelihood of a tumor suppressor gene. Loss of heterozygosity (LOH) is a binary measure of allelic loss in which abrupt changes in LOH frequency along the chromosome may identify boundaries indicative of a region containing a tumor suppressor gene. Our interest was on testing for the presence of multiple changepoints in order to identify regions of increased LOH frequency. A complicating factor is the substantial heterogeneity in LOH frequency across patients, where some patients have a very high LOH frequency while others have a low frequency. We develop a procedure for identifying multiple changepoints in heterogeneous binary data. We propose both approximate and full maximum-likelihood approaches and compare these two approaches with a naive approach in which we ignore the heterogeneity in the binary data. The methodology is used to estimate the pattern in LOH frequency on chromosome 13 in esophageal cancer patients and to isolate an area of inflated LOH frequency on chromosome 13 which may contain a tumor suppressor gene. Using simulations, we show that our approach works well and that it is robust to departures from some key modeling assumptions.
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2,338,968 |
Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain.
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Germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1 are responsible for the majority of hereditary non-polyposis colorectal cancer (HNPCC), an autosomal-dominant early-onset cancer syndrome. Genetic testing of both MSH2 and MLH1 from individuals suspected of HNPCC has revealed a considerable number of missense codons, which are difficult to classify as either pathogenic mutations or silent polymorphisms. To identify novel MLH1 missense codons that impair MMR activity, a prospective genetic screen in the yeast Saccharomyces cerevisiae was developed. The screen utilized hybrid human-yeast MLH1 genes that encode proteins having regions of the yeast ATPase domain replaced by homologous regions from the human protein. These hybrid MLH1 proteins are functional in MMR in vivo in yeast. Mutagenized MLH1 fragments of the human coding region were synthesized by error-prone PCR and cloned directly in yeast by in vivo gap repair. The resulting yeast colonies, which constitute a library of hybrid MLH1 gene variants, were initially screened by semi-quantitative in vivo MMR assays. The hybrid MLH1 genes were recovered from yeast clones that exhibited a MMR defect and sequenced to identify alterations in the mutagenized region. This investigation identified 117 missense codons that conferred a 2-fold or greater decreased efficiency of MMR in subsequent quantitative MMR assays. Notably, 10 of the identified missense codons were equivalent to codon changes previously observed in the human population and implicated in HNPCC. To investigate the effect of all possible codon alterations at single residues, a comprehensive mutational analysis of human MLH1 codons 43 (lysine-43) and 44 (serine-44) was performed. Several amino acid replacements at each residue were silent, but the majority of substitutions at lysine-43 (14/19) and serine-44 (18/19) reduced the efficiency of MMR. The assembled data identifies amino acid substitutions that disrupt MLH1 structure and/or function, and should assist the interpretation of MLH1 genetic tests.
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2,338,969 |
Association of CYP3A4 genotype with detection of Vgamma/Jbeta trans-rearrangements in the peripheral blood leukocytes of pediatric cancer patients undergoing chemotherapy for ALL.
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Cancer patients receiving chemotherapy are exposed to high doses of cytotoxic and genotoxic drugs which, in some cases, can lead to treatment related leukemia. Since this only occurs in a minority of patients, however, it is possible some individuals are predisposed due to genetic polymorphisms in genes for enzymes that mediate drug metabolism. To address this possibility we measured the genotoxicity of chemotherapeutic agents in patients receiving treatment for ALL by the frequency of the Vgamma/Jbeta trans-rearrangement in their peripheral blood leukocytes and compared this with CYP3A4 genotype. CYP3A4 is the most abundant of the cytochrome P450 (CYP) enzyme in the liver and intestine which contains a common -392A>G substitution in the promoter region (CYP3A4*1B allele). We found a significant increase in the frequency of rearrangements during chemotherapy only in patients homozygous for the wild type CYP3A4*1A allele. This provides a direct link between CYP3A4 genotype and susceptibility to drug genotoxicity thus strengthening the possibility that predisposition to treatment related leukemia may be measurable by simple genetic testing.
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2,338,970 |
The use of hydrophobins to functionalize surfaces.
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The physiochemical nature of surfaces can be changed by small proteins which are secreted by filamentous fungi. These proteins, called hydrophobins, are characterized by the presence of eight conserved cysteine residues and a typical hydropathy pattern. Upon contact with a hydrophilic-hydrophobic interface they self-assemble into highly insoluble amphipathic membranes. As a result, hydrophobic surfaces become hydrophilic and vice versa. Genetic engineering of hydrophobins was used to study structure-function relationships. In addition, engineered hydrophobins were constructed to increase the biocompatibility of surfaces. The glycosylated N-terminal region of the mature SC3 hydrophobin was deleted and the cell-binding domain of human fibronectin was introduced at the N-terminus. The gross properties of the hydrophobins were not affected. However, the physiochemical properties of the hydrophilic side of the assembled protein did change. Growth of fibroblasts on Teflon could be improved by coating the solid with the engineered hydrophobins. Thus, by changing the N-terminal part of hydrophobins, the physiochemical nature of the hydrophilic side of the assembled form can be altered and a variety of new functionalities introduced. The fact that hydrophobins self-assemble at any hydrophilic-hydrophobic interface, irrespective of the chemical nature of the surface, therefore provides a generic approach to modify surfaces and make them interesting candidates for the use in various technical and medical applications.
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2,338,971 |
Accuracy of phenotypic and genotypic testing for identification of Streptococcus pneumoniae and description of Streptococcus pseudopneumoniae sp. nov.
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We have identified an unusual group of viridans group streptococci that resemble Streptococcus pneumoniae. DNA-DNA homology studies suggested that a subset of these isolates represent a novel species that may be included in the S. oralis-S. mitis group of viridans group streptococci. We suggest that this novel species be termed Streptococcus pseudopneumoniae. A combination of phenotypic and genetic reactions allows its identification. S. pseudopneumoniae strains do not have pneumococcal capsules, are resistant to optochin (inhibition zones, less than 14 mm) when they are incubated under an atmosphere of increased CO2 but are susceptible to optochin (inhibition zones, >14 mm) when they are incubated in ambient atmospheres, are not soluble in bile, and are positive by the GenProbe AccuProbe Pneumococcus test. The bile solubility test is more specific than the optochin test for identification of S. pneumoniae. Genetic tests for pneumolysin (ply) and manganese-dependent superoxide dismutase (sodA) and identification tests with a commercial probe, AccuProbe Pneumococcus, do not discriminate between the new species and S. pneumoniae.
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2,338,972 |
PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis.
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Mutations in the PROP1 gene are the most frequent genetic defects in patients with combined pituitary hormone insufficiency. However, controversy exists about the timing and extent of pituitary insufficiency, and it remains unclear whether adrenal failure is a typical feature of this condition. We performed a retrospective longitudinal analysis of nine patients with PROP1 mutations who were under medical supervision at our clinic for 15.7 +/- 3.4 yr. All patients initially presented with growth failure (height sd score, -3.7 +/- 0.3) at a mean age of 4.9 +/- 0.8 yr. They were first diagnosed with GH and TSH deficiency, and replacement therapy was instituted at 6.1 +/- 1.1 and 6.8 +/- 1.2 yr, respectively. All seven patients who reached pubertal age required sex hormone substitution at 15.0 +/- 0.7 yr. Repeated functional testing of the anterior pituitary axes revealed a progressive decline with age in peak levels of GH, TSH, prolactin, and LH/FSH. All patients developed at least partial adrenal insufficiency, with a gradual decline of the function of the pituitary adrenal axis and eventually required substitution with hydrocortisone at a mean age of 18.4 +/- 3.5 yr. It is concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence.
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2,338,973 |
The catalase -262C/T promoter polymorphism and aging phenotypes.
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A low level of the central antioxidant enzyme catalase has been suggested to be a risk factor for diseases influenced by oxidative stress. In this study, we investigated the possible association of the catalase -262C/T polymorphism with survival, physical and cognitive functioning, and a number of oxidative stress-mediated disorders. The study population was 2223 Danish individuals, aged 45-93 years, drawn from three population-based surveys. The results suggest that the catalase -262C/T polymorphism is not associated with either survival, or the majority of the age-related phenotypes investigated. However, our data indicate a statistical significant association of TT homozygosity with improved physical functioning as well as a trend of the T allele conferring an improved general cognitive functioning, although these results did not remain significant after correcting for multiple testing. The results raise the hypothesis that the catalase -262T allele serves as protection against neurodegenerative and physical decline, although replication in other studies is warranted for confirmation of these findings.
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2,338,974 |
Quantitative genomics: exploring the genetic architecture of complex trait predisposition.
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Most phenotypes with agricultural or biomedical relevance are multifactorial traits controlled by complex contributions of genetics and environment. Genetic predisposition results from combinations of relatively small effects due to variations within a large number of genes, known as QTL. Well over 200 QTL have been reported for growth and body composition traits in the mouse, which likely represent at least 50 to 100 distinct genes. Molecular biology has yielded significant advances in understanding these traits at the metabolic and physiological levels; however, little has been learned regarding the identity and nature of the underlying polygenes. In addition to the significantly poor precision inherent to QTL localization, it is very difficult to differentiate between co-localization and coincidence when comparing QTL with other QTL and with potential candidate genes. The wide gap between our knowledge of physiological mechanisms underlying complex traits and the nature of genetic predisposition significantly impairs discovery of genes underlying QTL. Identification and genetic mapping of key transcriptional, proteomic, metabolomic, and endocrine events will uncover large lists of significant positional candidate genes for growth and body composition. However, integration of experimental approaches to jointly evaluate predisposition and physiology will increase success of QTL identification by merging the power of recombination with functional analysis. Measuring physiologically relevant subphenotypes within a structured QTL mapping population will not only facilitate pathway-specific prioritization among candidate genes, but may also directly identify genes underlying QTL. This would advance our understanding of the genetic architecture of complex traits by testing the central hypothesis that genes controlling predisposition to a quantitative trait are primarily involved in trans-regulation of the primary physiological pathways that regulate the trait.
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2,338,975 |
Highly refractory acute myeloid leukemia.
|
In this study we evaluated 103 patients suffering from acute myeloid leukemia (AML) who did not respond to induction chemotherapy and defined a sub-group of patients with highly refractory disease characterized by a persistence of more than 1 G/L blast cells in the peripheral blood between days 12 and 16 of the first induction cycle. Only seven patients (one female, six males) met these criteria. Their median age was 65 years (range 41-82 years). Four had de novo AML and three secondary AML. Cytogenetic analysis was performed in six patients: complex aberrations were detected in four patients and, unexpectedly, normal karyotypes were found in the other two. Analysis of multidrug-resistance factors revealed high co-expression of P-glycoprotein (P-gp) and lung resistance protein (LRP) in all four patients with highly refractory disease tested a finding in only 6% of patients with refractory disease and 3% of patients who achieved complete remission (CR) of disease. Furthermore, patients with highly refractory AML had substantially higher leukocyte counts than patients with refractory AML or CR, although this was not significant statistically. Overall, patients with highly refractory AML are characterized by a high incidence of complex cytogenetic aberrations and marked expression of drug transporters.
|
2,338,976 |
Development of a universal gap repair vector for yeast-based screening of knockout rodents.
|
Recently, we reported the production of the first knockout rats by combining N-ethyl-N-nitrosourea (ENU)-induced mutagenesis with a yeast-based truncation screening method. To make this new knockout technology more applicable for other laboratories and for high-throughput applications, we have developed a universal gap repair vector that is ready for use in screening for gene knockouts without additional engineering. The universal gap repair vector was validated for its application in both cDNA- and genomic DNA-based yeast truncation mutation assays. Breast cancer genes Brca1, Brca2, and Adenomatosis polyposis coli (Apc) genes from N2 rats of Brca1 and Brca2 knockouts and (Atm x ApcMin/+)F1 mice were examined, respectively. The results indicate that the universal gap repair vector we developed, using randomly selected codons as a universal cassette, is equally efficient at identifying truncation mutations as are those gap repair vectors designed specifically for Brca1 and Brca2. The availability of a universal gap repair vector should facilitate the broader screening of knockouts of most genes of many species using the combined approach of ENU-induced mutagenesis and yeast truncation assay.
|
2,338,977 |
"They want to know where they came from": population genetics, identity, and family genealogy.
|
This paper discusses the changing relationship between population genetics, family genealogy and identity. It reports on empirical research with participants in a genetic study who anticipated that personal feedback on the analysis of their donated samples would elucidate aspects of their own family genealogies. The paper also documents how geneticists, building on the practices of offering personal feedback to research participants, have developed genetic tests marketed directly to people wishing to trace their ancestry. Some of the social and ethical issues raised by this development in the use of genetic testing are considered.
|
2,338,978 |
Ethical issues in the diagnostic genetic testing process.
|
The diagnostic genetic testing process has certain unique ethical features and deserves special consideration. The purpose of this study was to determine through empirical research, using focussed interview, what ethical issues are involved in the diagnostic genetic testing process. This article describes views and perceptions of adult patients, parents of child patients and various personnel groups (n=30). The ethical issues were analysed classified into three main categories: a) personnel characteristics, including personality, professional skills, morals and values; b) realization of ethical principles in the examination process, with subcategories of knowledge, autonomy, data protection and equity; and c) consequences of genetic testing, including patients' control over their own lives, manifestation of heterogeneity and outlook on the world. Problematic ethical issues in all three main categories were described in a more many-sided way by parents and personnel than by adult patients. In the future, attention should be paid to the content areas highlighted by the study, in both clinical practice and further studies.
|
2,338,979 |
Small cell astrocytoma: an aggressive variant that is clinicopathologically and genetically distinct from anaplastic oligodendroglioma.
|
Small cell glioblastoma (GBM) is a variant with monomorphous, deceptively bland nuclei that often is misdiagnosed as anaplastic oligodendroglioma.</AbstractText>To elucidate its clinicopathologic and genetic features, the authors studied 71 adult patients (median age, 57 years), including 22 patients who were identified from a set of 229 GBMs (10%) that had been characterized previously by epidermal growth factor receptor (EGFR)/EGFR-vIII variant immunohistochemistry. Tumors also were analyzed by fluorescence in situ hybridization for 1p, 19q, 10q, and EGFR copy numbers.</AbstractText>Radiologically, 37% of tumors that were not selected for grade showed minimal to no enhancement. Similarly, 33% of tumors had no endothelial hyperplasia or necrosis histologically, qualifying only as anaplastic astrocytoma (Grade III) using World Health Organization criteria. Nevertheless, such tumors progressed rapidly, with mortality rates that were indistinguishable from their Grade IV counterparts. The median survival for 37 patients who were followed until death was 11 months. Oligodendroglioma-like histology included chicken-wire vasculature (86%), haloes (73%), perineuronal satellitosis (58%), and microcalcifications (45%), although mucin-filled microcystic spaces were lacking. No small cell astrocytomas had 1p/19q codeletions, whereas EGFR amplification and 10q deletions were present in 69% and 97% of small cell astrocytomas, respectively. The tumors expressed EGFR and EGFR-vIII more commonly than nonsmall cell GBMs (83% vs. 35% [P < 0.001]; 50% vs. 21% [P < 0.001] respectively).</AbstractText>Small cell astrocytoma is an aggressive histologic variant that behaved like primary GBM, even in the absence of endothelial hyperplasia and necrosis. Despite considerable morphologic overlap with anaplastic oligodendroglioma, clinicopathologic and genetic features were distinct. Fifty percent of small cell astrocytomas expressed the constitutively activated vIII mutant form of EGFR, and molecular testing for 10q deletion improved the diagnostic sensitivity over EGFR alone.</AbstractText>(c) 2004 American Cancer Society</CopyrightInformation>
|
2,338,980 |
New tools for preimplantation genetic diagnosis of Huntington's disease and their clinical applications.
|
Huntington's disease (HD) is a late-onset neurodegenerative disorder transmitted as an autosomal dominant trait. The causative mutation was characterised in 1993. For HD carriers willing to create a family, prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD) based on the mutation identification can be offered. For at-risk persons who do not want to undergo presymptomatic testing (PT), an exclusion test can be proposed. With such a test, only foetuses or embryos that inherit an allele from the unaffected grandparent are considered as unaffected. In cases of PND, if the foetus has one allele of the affected grandparent, termination of pregnancy is proposed. In cases of PGD, only not at-risk embryos are transferred. Since the beginning of our PGD activity, we have had 43 PGD referrals for HD, of which 24 were from patients who know their genetic status and 19 from patients who do not wish to perform PT. We have developed 12 multiplex fluorescent PCR protocols applied at the single-cell level for PGD, some of which target the CAG repeat while others use two different polymorphic microsatellites. We present here these different protocols and their clinical applications, as well as the characterisation and use of a new highly polymorphic intragenic marker. Between May 2001 and December 2003, 39 PGD cycles have been performed for 17 couples, 11 of whom had a known genetic status and six who did not wish to perform PT, resulting in four pregnancies.
|
2,338,981 |
Predictive genetic testing in young people: when is it appropriate?
|
Predictive genetic testing is currently offered to adults for a range of conditions, even when there is no possibility of prophylaxis or treatment. However, similar testing in children and adolescents is advised against in international guidelines. Despite this, several authors have argued against the existing guidelines. Given the lack of empirical evidence, it is important that clinicians are aware not only of the guidelines, but also of the arguments in favour of such testing.
|
2,338,982 |
Methods for testing familial aggregation of diseases in population-based samples: application to Hodgkin lymphoma in Swedish registry data.
|
We use data on lymphoma in families of Hodgkin lymphoma (HL) cases from the Swedish Family Cancer Database (Hemminki et al. 2001) to illustrate survival methods for detecting familial aggregation in first degree relatives of case probands compared to first degree relatives of control probands, from registries that permit sampling of all cases. Because more than one case may occur in a given family, the first degree relatives of case probands are not necessarily independent, and we present procedures that allow for such dependence. A bootstrap procedure also accommodates matching of case and control probands by resampling the matching clusters, defined as the combined set of all first degree relatives of the matched case and control probands. Regarding families as independent sampling units leads to inferences based on "sandwich variance estimators" and accounts for dependencies from having more than one proband in a family, but not for matching. We compare these methods in analysis of familial aggregation of HL and also present simulations to compare survival analyses with analyses of binary outcome data.
|
2,338,983 |
Some statistical and regulatory issues in the evaluation of genetic and genomic tests.
|
The genomics revolution is reverberating throughout the worlds of pharmaceutical drugs, genetic testing and statistical science. This revolution, which uses single nucleotide polymorphisms (SNPs) and gene expression technology, including cDNA and oligonucleotide microarrays, for a range of tests from home-brews to high-complexity lab kits, can allow the selection or exclusion of patients for therapy (responders or poor metabolizers). The wide variety of US regulatory mechanisms for these tests is discussed. Clinical studies to evaluate the performance of such tests need to follow statistical principles for sound diagnostic test design. Statistical methodology to evaluate such studies can be wide ranging, including receiver operating characteristic (ROC) methodology, logistic regression, discriminant analysis, multiple comparison procedures resampling, Bayesian hierarchical modeling, recursive partitioning, as well as exploratory techniques such as data mining. Recent examples of approved genetic tests are discussed.
|
2,338,984 |
Progress in epidermolysis bullosa: genetic classification and clinical implications.
|
Epidermolysis bullosa (EB), a heterogenous group of genodermatoses, is characterized by fragility and blistering of the skin associated with extracutaneous manifestations. Based on clinical severity, constellation of the phenotypic manifestations, and the level of tissue separation within the cutaneous basement membrane zone (BMZ), EB has been divided into distinct subcategories. Traditionally, these include the simplex, junctional, and dystrophic forms of EB, and recently attention has been drawn to hemidesmosomal variants demonstrating tissue separation at the level of the hemidesmosomes. Specific mutations in ten distinct genes expressed within the cutaneous BMZ have been delineated in >500 families with different variants of EB. The types of mutations, their positions along the affected genes, and their consequences at the mRNA and protein levels provide explanation for the phenotypic variability and genetic heterogeneity of this group of genodermatoses. Elucidation of mutations in different forms of EB has direct translational applications for improved diagnosis and molecularly based classification with prognostic implications as well as for genetic counseling and DNA-based prenatal testing in families with EB.
|
2,338,985 |
Huntington's Disease-like 2 (HDL2) in North America and Japan.
|
Huntington's Disease-like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntington's disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin-3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD-like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD-like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of r2=0.29, p=0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD-like phenotype.
|
2,338,986 |
Genetics of human arterial hypertension.
|
Arterial hypertension is one of the major cardiovascular risk factors in Western countries. Besides some well established, but rather rare forms of secondary hypertension, essential hypertension is the most common diagnosis. The hereditary nature of this disease has been well established in many familial studies. The quantitative contribution of genetic factors to blood pressure variance is estimated to be about 30%, however, the genetic background of essential hypertension is complex and currently not fully understood. Besides few monogenetic forms of Mendelian transmitted hypertension, current efforts are usually directed at the identification of single contributing genetic factors. This review is thought to highlight current strategies towards a better understanding of the genetic background of essential hypertension with particular respect to genetic variants of the renin-angiotensin system, of signaling pathways such as heterotrimeric G-proteins and alpha-adducin. Moreover, genetic association studies often fail to replicate findings from previous studies. This may be in part due to the polygenetic nature of the disease. Another potential reason may be the diversity of the investigated populations. The current results of genetic analyses of essential hypertension highlight, thus, the need for a more differentiated approach to the understanding of complex, polygenetic traits implementing gene-gene-, and gene-environment interactions or distinguished functional testing of thoroughly phenotyped cohorts under standardised environmental conditions.
|
2,338,987 |
BagBoosting for tumor classification with gene expression data.
|
Microarray experiments are expected to contribute significantly to the progress in cancer treatment by enabling a precise and early diagnosis. They create a need for class prediction tools, which can deal with a large number of highly correlated input variables, perform feature selection and provide class probability estimates that serve as a quantification of the predictive uncertainty. A very promising solution is to combine the two ensemble schemes bagging and boosting to a novel algorithm called BagBoosting.</AbstractText>When bagging is used as a module in boosting, the resulting classifier consistently improves the predictive performance and the probability estimates of both bagging and boosting on real and simulated gene expression data. This quasi-guaranteed improvement can be obtained by simply making a bigger computing effort. The advantageous predictive potential is also confirmed by comparing BagBoosting to several established class prediction tools for microarray data.</AbstractText>Software for the modified boosting algorithms, for benchmark studies and for the simulation of microarray data are available as an R package under GNU public license at http://stat.ethz.ch/~dettling/bagboost.html.</AbstractText>
|
2,338,988 |
The novel germline mutation of the hMLH1 gene in a case of suspected hereditary non-polyposis colorectal cancer (HNPCC) in a patient with no family history of cancer.
|
Hereditary non-polyposis colorectal cancer (HNPCC) is a very important clinical entity in oncology. In order to identify HNPCC, the international diagnostic criteria, named 'Amsterdam criteria', has been used. In this report, we present a patient with HNPCC who completely lacks a family history of cancer, thus does not meet the revised Amsterdam criteria and was finally confirmed as HNPCC by genetic testing which revealed a novel germline mutation of the hMLH1 gene. The proband was a 52-year-old Japanese female with a diagnosis of advanced ascending colon cancer. She had a past history of Miles' operation for rectal cancer at the age of 40. A subtotal colectomy was performed and the subsequent microsatellite instability (MSI) analysis revealed high MSI in the resected tumor tissue. PCR/direct sequencing analysis of the genomic DNA revealed the base deletion 2006delAAAAG at codon 669 in exon 18 of the hMLH1 gene, which was considered to be a pathogenic mutation. According to the Human Mutation Database and International Collaborative Group on HNPCC (ICG-HNPCC) Database, this is the first report of this type of deletion mutation in the hMLH1 gene.
|
2,338,989 |
Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency.
|
Urea cycle defects (UCDs) typically present with hyperammonemia, the duration and peak levels of which are directly related to the neurologic outcome. Liver transplantation can cure the underlying defect for some conditions, but the preexisting neurologic status is a major factor in the final outcome. Multicenter data indicate that most of the children who receive transplants remain significantly neurologically impaired. We wanted to determine whether aggressive metabolic management of ammonia levels after early referral/transfer to a metabolism center and early liver transplantation would result in better neurologic outcomes. We report on 5 children with UCDs, ie, 2 male patients with X-linked ornithine transcarbamylase deficiency and 2 male patients with carbamoyl phosphate synthase deficiency, all of whom had neonatal presentations and underwent orthotopic liver transplantation before 1 year of age, and 1 female patient with partial X-linked ornithine transcarbamylase deficiency that was intractable to medical therapy, who underwent transplantation at 35 months of age. Developmental testing with the Griffiths scale was performed on 3 occasions each, 12 months apart, up to 45 months after transplantation. Full-scale indices for 3 children who underwent early transplantation showed average developmental quotients of 67. All 5 children had metabolic cures. There were no deaths (30-month survival rate: 100%). One child is currently listed for repeat transplantation because of bile duct stenosis and cirrhosis. We conclude that early liver transplantation and aggressive metabolic management improve early neurologic outcomes for children with UCDs, but longer follow-up monitoring is needed.
|
2,338,990 |
Disruption of a new X linked gene highly expressed in brain in a family with two mentally retarded males.
|
Mental retardation (MR) affects 2-3% of the human population and some of these cases are genetically determined. Although several genes responsible for MR have been identified, many cases have still not been explained.</AbstractText>We have identified a pericentric inversion of the X chromosome inv(X)(p22.3;q13.2) segregating in a family where two male carriers have severe MR while female carriers are not affected.</AbstractText>The molecular characterisation of this inversion led us to identify two new genes which are disrupted by the breakpoints: KIAA2022 in Xq13.2 and P2RY8 in Xp22.3. These genes were not previously fully characterised in humans. KIAA2022 encodes a protein which lacks significant homology to any other known protein and is highly expressed in the brain. P2RY8 is a member of the purine nucleotide G-protein coupled receptor gene family. It is located in the pseudo-autosomal region of the X chromosome and is not expressed in brain.</AbstractText>Because the haploinsufficiency of P2RY8 in carrier mothers does not have a phenotypic consequence, we propose that the severe MR of the affected males in this family is due to the absence of the KIAA2022 gene product. However, screening 20 probands from X linked MR families did not reveal mutations in KIAA2022. Nonetheless, the high expression of this gene in fetal brain and in the adult cerebral cortex could be consistent with a role in brain development and/or cognitive function.</AbstractText>
|
2,338,991 |
Recent advances in understanding haemochromatosis: a transition state.
|
Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.
|
2,338,992 |
High concordance of bipolar I disorder in a nationwide sample of twins.
|
The few studies of bipolar I disorder in twins have consistently emphasized the genetic contribution to disease liability. The authors report what appears to be the first twin study of bipolar I disorder involving a population-based twin sample, in which the diagnoses were made by using structured, personal interviews.</AbstractText>All Finnish same-sex twins (N=19,124) born from 1940 to 1957 were screened for a diagnosis of bipolar I disorder as recorded in the National Hospital Discharge Register between 1969 and 1991 or self-reported in surveys of the Finnish Twin Cohort in 1975, 1981, and 1990. Thirty-eight pairs were thereby identified and invited to participate in the study; the participation rate was 68%. Lifetime diagnoses were made by using the Structured Clinical Interview for DSM-IV. The authors calculated probandwise and pairwise concordances and correlations in liability and applied biometrical model fitting.</AbstractText>The probandwise concordance rates were 0.43 (95% CI=0.10 to 0.82) for monozygotic twins and 0.06 (95% CI=0.00 to 0.27) for dizygotic twins. The correlations in liability were 0.85 and 0.41, respectively. The model with no familial transmission was rejected. The best-fitting model was the one in which genetic and specific environmental factors explained the variance in liability, with a heritability estimate of 0.93 (95% CI=0.69 to 1.00).</AbstractText>The high heritability of bipolar disorder was demonstrated in a nationwide population-based twin sample assessed with structured personal interviews.</AbstractText>
|
2,338,993 |
Induction of comprehensible models for gene expression datasets by subgroup discovery methodology.
|
Finding disease markers (classifiers) from gene expression data by machine learning algorithms is characterized by a high risk of overfitting the data due the abundance of attributes (simultaneously measured gene expression values) and shortage of available examples (observations). To avoid this pitfall and achieve predictor robustness, state-of-the-art approaches construct complex classifiers that combine relatively weak contributions of up to thousands of genes (attributes) to classify a disease. The complexity of such classifiers limits their transparency and consequently the biological insights they can provide. The goal of this study is to apply to this domain the methodology of constructing simple yet robust logic-based classifiers amenable to direct expert interpretation. On two well-known, publicly available gene expression classification problems, the paper shows the feasibility of this approach, employing a recently developed subgroup discovery methodology. Some of the discovered classifiers allow for novel biological interpretations.
|
2,338,994 |
Discovering significant and interpretable patterns from multifactorial DNA microarray data with poor replication.
|
Multivariate analyses are advantageous for the simultaneous testing of the separate and combined effects of many variables and of their interactions. In factorial designs with many factors and/or levels, however, sufficient replication is often prohibitively costly. Furthermore, complicated statements are often required for the biological interpretation of the higher-order interactions determined by standard statistical techniques like analysis of variance.</AbstractText>Because we are usually interested in finding factor-specific effects or their interactions, we assumed that the observed expression profile of a gene is a manifestation of an underlying factor-specific generative pattern (FSGP) combined with noise. Thus, a genetic algorithm was created to find the nearest FSGP for each expression profile. We then measured the distance between each profile and the corresponding nearest FSGP. Permutation testing for the distance measures successfully identified those genes with statistically significant profiles, thus yielding straightforward biological interpretations. Association networks of genes, drugs, and cell lines were created as tripartite graphs, representing significant and interpretable relations, by using a microarray experiment of gastric-cancer cell lines with a factorial design and no replication. The proposed method may benefit the combined analysis of heterogeneous expression data from the growing public repositories.</AbstractText>
|
2,338,995 |
Cancer classification and prediction using logistic regression with Bayesian gene selection.
|
In microarray-based cancer classification and prediction, gene selection is an important research problem owing to the large number of genes and the small number of experimental conditions. In this paper, we propose a Bayesian approach to gene selection and classification using the logistic regression model. The basic idea of our approach is in conjunction with a logistic regression model to relate the gene expression with the class labels. We use Gibbs sampling and Markov chain Monte Carlo (MCMC) methods to discover important genes. To implement Gibbs Sampler and MCMC search, we derive a posterior distribution of selected genes given the observed data. After the important genes are identified, the same logistic regression model is then used for cancer classification and prediction. Issues for efficient implementation for the proposed method are discussed. The proposed method is evaluated against several large microarray data sets, including hereditary breast cancer, small round blue-cell tumors, and acute leukemia. The results show that the method can effectively identify important genes consistent with the known biological findings while the accuracy of the classification is also high. Finally, the robustness and sensitivity properties of the proposed method are also investigated.
|
2,338,996 |
Comprehensive vertical sample-based KNN/LSVM classification for gene expression analysis.
|
Classification analysis of microarray gene expression data has been widely used to uncover biological features and to distinguish closely related cell types that often appear in the diagnosis of cancer. However, the number of dimensions of gene expression data is often very high, e.g., in the hundreds or thousands. Accurate and efficient classification of such high-dimensional data remains a contemporary challenge. In this paper, we propose a comprehensive vertical sample-based KNN/LSVM classification approach with weights optimized by genetic algorithms for high-dimensional data. Experiments on common gene expression datasets demonstrated that our approach can achieve high accuracy and efficiency at the same time. The improvement of speed is mainly related to the vertical data representation, P-tree,Patents are pending on the P-tree technology. This work is partially supported by GSA Grant ACT#:K96130308. and its optimized logical algebra. The high accuracy is due to the combination of a KNN majority voting approach and a local support vector machine approach that makes optimal decisions at the local level. As a result, our approach could be a powerful tool for high-dimensional gene expression data analysis.
|
2,338,997 |
Harnessing the potential of cancer genetics in healthcare.
|
The advancement of knowledge in genetics will have a profound effect on prediction, prevention, and treatment of cancer. It has the potential to offer more personalised healthcare that accords with an individual's genetic profile. However, the complex medical, ethical, legal, and psychosocial issues brought by our ability to test healthy individuals for cancer predisposition and the fast pace of advances in genetics pose great challenges to the medical community. Individuals and families are unlikely to benefit from an effective and ethical application of new genetic knowledge unless high quality cancer-genetics services are developed and integrated into mainstream healthcare, more research is undertaken into the prevention, causes, and treatment of cancer, and further efforts are made to improve public understanding and acceptance of cancer genetics.
|
2,338,998 |
Colorectal cancer and inherited mutations in base-excision repair.
|
Polyposis associated with mutations in the gene MUTYH is an autosomal recessive syndrome characterised by the development of multiple colorectal adenomas and cancer. It is the first cancer-predisposition disorder to be associated with defects in the pathway of base-excision repair. We review our knowledge to date of the disease, discuss base-excision repair in relation to cellular defence against oxidative damage, and give an overview of the molecular genetics and clinicopathological features of tumours associated with MUTYH mutations. No longer a research finding, genetic testing for MUTYH is now a necessary part of molecular diagnosis in familial cancer clinics throughout Australia and the UK. Current recommendations for the screening and management of the disease are also discussed.
|
2,338,999 |
Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study.
|
We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.
|
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