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2,338,800 |
Neurosurgical delivery of chemotherapeutics, targeted toxins, genetic and viral therapies in neuro-oncology.
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Local delivery of biologic agents, such as gene and viruses, has been tested preclinically with encouraging success, and in some instances clinical trials have also been performed. In addition, the positive pressure infusion of various therapeutic agents is undergoing human testing and approval has already been granted for routine clinical use of biodegradable implants that diffuse a chemotherapeutic agent into peritumoral regions. Safety in glioma patients has been shown, but anticancer efficacy needs additional refinements in the technologies employed. In this review, we will describe these modalities and provide a perspective on needed improvements that should render them more successful.
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2,338,801 |
[Thrombophilia].
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A survey on definitions, epidemiology, clinical manifestations of congenital thrombophilias and clinical relevant acquired thrombophilias is given. Diagnostic and therapeutical strategies are presented.
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2,338,802 |
Comprehensive identification and characterization of diallelic insertion-deletion polymorphisms in 330 human candidate genes.
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Despite being the second most frequent type of polymorphism in the genome, diallelic insertion-deletion polymorphisms (indels) have received far less attention in the study of sequence variation. In this report, we describe an approach that can detect indels in the heterozygous state and can comprehensively identify indels in the target sequence. Using this approach, we identified 2393 indels in a set of 330 candidate genes, i.e. an average of seven indels per gene with about two indels per gene being common (minor allele frequency >or=0.1). We compared the population genetic characteristics of indels with substitutions in this data. Our data supported the findings that deletions occur more frequently in the human genome. 5'-UTR and coding regions of the genes showed a significantly lower diversity for indels compared with other regions, suggesting differences in effects of selection on indels and substitutions. Sequence diversity and pairwise linkage disequilibrium (LD) findings of the different populations were similar to earlier results and included a greater skew towards low-frequency variants and a faster rate of LD decay in the African-descent population compared with the non-African populations. Within populations, the allele frequency spectra and LD-decay profiles for indels were similar to substitutions. Overall, the findings suggest that, although the mechanisms giving rise to indels may be different from those causing substitutions, the evolutionary histories of indels and substitutions are similar, and that indels can play a valuable role in association studies and marker selection strategies.
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2,338,803 |
Testing the status-dependent ESS model: population variation in fighter expression in the mite Sancassania berlesei.
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The conditional evolutionarily stable strategy (ESS) with status-dependent tactics is the most commonly invoked ESS for alternative reproductive tactics within the sexes. Support for this model has recently been criticized as apparent rather than real. We address key predictions of the status-dependent ESS in three populations of the male dimorphic mite Sancassania berlesei. In S. berlesei'fighter' males are characterized by a thickened pair of legs used for killing rivals; 'scramblers' are benign. Most males in each population could be manipulated to become fighters by decreasing density, fulfilling the prediction that males make a 'decision'. There was evidence of genetic covariance between sire status and offspring morph, but also a strong effect of sire morph on offspring morph ratio. This was consistent with considerable genetic variation for the status-dependent switch point as a breeding experiment found no support for single-locus inheritance. We also found evidence that switch points evolve independently of distributions of status. This study supports the current status-dependent ESS model.
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2,338,804 |
[Analysis of the IT15 gene in Huntington's disease families].
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Direct molecular genetic testing carried out in 59 Huntington's disease patients belonging to 46 families from Bashkortostan revealed the (CAG)n repeat expansion in exon 1 of the IT15 gene in 57 of them. By use of this analysis the disease status was not confirmed in two patients with atypical form of the disease and negative family history. The (CAG)n repeat expansion was identified in 27 out of 127 asymptomatic at-risk individuals. Analysis of the mutant (CAG)n allele inheritance demonstrated extremely high instability and high mutation rate predominantly leading to the appearance of the alleles with increasing number of (CAG)n repeats in subsequent generations. The instability was mostly observed in cases of paternal transmission. Almost complete linkage disequilibrium between the (CCG)7 mutant alleles and the del2642 deletion was demonstrated. Three major haplotypes revealed, (CCG)7/del-, (CCG)7/del+, and (CCG)10/del-, implied the existence of at least three sources of the origin of Huntington's disease in Bashkortostan. The identified haplotype frequency distribution patterns displayed similarities with those in European populations. The contribution of a number of genetic factors to the age of onset of Huntington's disease was analyzed.
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2,338,805 |
DHPLC is superior to SSCP in screening p53 mutations in esophageal cancer tissues.
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Mutations of the p53 tumor-suppressor gene universally occur on exons 5-8 in human cancer. We analyzed these mutations in esophageal cancer tissue from 207 patients in China using 2 methods, single-strand conformation polymorphism (SSCP), one of the most frequently used methods, and the recently developed denaturing high-performance liquid chromatography (DHPLC), and compared their sensitivity and efficiency. Exons 5-8 of p53 were amplified from esophageal cancer tissue genomes, screened for fragments of mutations and polymorphisms by SSCP and DHPLC in a blind study and confirmed by direct sequencing to detect the mutations and polymorphisms. The numbers detected by DHPLC were greater than those detected by SSCP, though the rate of mutations and polymorphisms was lower in SSCP than in DHPLC, which appeared to detect smaller mutations (substitutions and 1 bp insertions/deletions). Of the mutations with substitutions detected by DHPLC but not by SSCP, 50% substituted adenosine for other nucleotides, suggesting that these mutations are often missed when SSCP is used. According to these data, the sensitivity of SSCP and DHPLC was 81% and 97%, respectively, and the specificity was 97% and 85%, respectively. Our results suggest that DHPLC may be recommended over SSCP when screening gene mutations. Thus, rates of p53 mutations and polymorphisms in esophageal cancer tissue in Chinese patients were 49% and 41% by DHPLC and SSCP, respectively.
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2,338,806 |
Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population.
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Fanconi anemia (FA) is a rare autosomal recessive disorder of hematopoiesis, with at least 11 complementation groups. FANCA, a gene for group A, accounts for the majority of FA patients. Previous studies of FANCA mutations revealed high allelic heterogeneity, frequent occurrence of large deletions, and interpopulation differences. However, systematic mutational analysis, including gene dosage assay to detect large deletions, has not been documented for Asian populations. A newly developed TaqMan quantitative PCR-based gene dosage assay, combined with sequencing of exons and cDNA fragments, allowed for detection of 48 mutant alleles of FANCA in 27 (77%) of 35 unrelated Japanese FA families with no detectable mutations in FANCC or FANCG. We identified 29 different mutations (21 nucleotide substitutions or small deletions/insertions and eight large deletions), at least 20 of which were novel. The FANCA mutational spectrum of the Japanese was different from that of other ethnic groups so far studied. This is the largest scale of mutation analysis of FANCA in the Japanese population. Characterization of these mutations provided new information regarding the mutagenesis mechanisms and structure-function relationship of FANCA. Specifically, our data suggest that diverse mechanisms including nonhomologous recombination as well as Alu-mediated homologous recombination are involved in the generation of large deletions in FANCA.
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2,338,807 |
Testing for clonal propagation.
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The conceptual basis for testing clonal propagation is reconsidered with the result that two steps need to be distinguished clearly: (1) specification of the characteristics of multilocus genotype frequencies that result from sexual reproduction together with the kinds of deviations from these characteristics that are produced by clonal propagation, and (2) a statistical method for detecting these deviations in random samples. It is pointed out that a meaningful characterization of sexual reproduction reflects the association of genes in (multilocus) genotypes within the bounds set by the underlying gene frequencies. An appropriate measure of relative gene association is developed which is equivalent to a multilocus generalization of the standardized gametic disequilibrium (linkage disequilibrium). Its application to the characterization of sexually produced multilocus genotypes is demonstrated. The resulting hypothesis on the frequency of a sexually produced genotype is tested with the help of the (significance) probability of obtaining at least two copies of the genotype in question in a random sample of a given size. If at least two copies of the genotype are observed in a sample, and if the probability is significant, then the hypothesis of sexual reproduction is rejected in favor of the assumption that all copies of the genotype belong to the same clone. Common testing approaches rest on the hypothesis of completely independent association of genes in genotypes and on the (significance) probability of obtaining at least as many copies of a genotype as observed in a sample. The validity of these approaches is discussed in relation to the above considerations and recommendations are set out for conducting appropriate tests.
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2,338,808 |
Phylogeographic evidence for the existence of an ancient biogeographic barrier: the Isthmus of Kra Seaway.
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Biogeographic boundaries are characterised by distinct faunal and floral assemblages restricted on either side, but patterns among groups of taxa often vary and may not be discrete. Historical biogeography as a consequence, while providing crucial insights into the relationship between biological diversity and earth history, has some limitations. Patterns of intraspecific molecular variation, however, may show unambiguous evidence for such historical divides, and can be used to test competing biogeographic hypotheses (often based on the dispersal-vicariance debate). Here, we utilise this method to test the hypothesis that a major biogeographic transition zone between the Sundaic and Indochinese biotas, located just north of the Isthmus of Kra in SE Asia, is the result of Neogene marine transgressions that breached the Isthmus in two locations for prolonged periods of time (>1 million year duration). Phylogeographic analyses of a freshwater decapod crustacean, the giant freshwater prawn Macrobrachium rosenbergii, strongly supports the historical existence of the more northerly postulated seaway. Results presented here highlight the power of utilising intraspecific molecular variation in testing biogeographical hypotheses.
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2,338,809 |
Genetic testing in hereditary melanoma.
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Advances in our understanding of molecular genetics bring about unique challenges in our ability to practice molecular medicine. With the availability of commercial testing for various genetic cancer syndromes, including hereditary melanoma, specific issues regarding its use and limitations require attention before full translation of this tool into the clinical setting.
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2,338,810 |
Intragenomic variation of the rDNA internal transcribed spacers in sponges (Phylum Porifera): implications for phylogenetic studies.
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The internal transcribed spacer regions (ITS1 and ITS2) of the tandemly repeated nuclear ribosomal DNA clusters are frequently used as markers for fine scale analyses in diverse animals. In certain taxa, ITS is nearly exclusively used for population level or inter-specific studies, despite the frequent presence of divergent paralogs within individual genomes that can be phylogenetically misleading. For the first time we survey diverse marine sponges to determine the extent and phylogenetic implications of intragenomic polymorphisms (IGPs) exhibited at their ITS loci. We discover that the extent of IGP varies greatly between taxa (with most taxa exhibiting very few) and cannot be predicted by taxonomy. Furthermore, we demonstrate that ITS can be phylogenetically informative between species when moderate levels of IGPs are detected, but that ITS paralogy can interfere with population level studies. We caution against the routine use of ITS in phylogenetic studies of sponges without (1) screening for IGPs in specimens from every population sampled; (2) including all divergent paralogs in phylogenetic analyses; (3) testing ITS data using other single-copy, unlinked loci (such as nuclear introns).
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2,338,811 |
Detecting phylogenetic incongruence using BIONJ: an improvement of the ILD test.
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The problem of testing for congruence between phylogenetic data has long been debated among phylogeneticists, but reaches a critical point with the availability of large amount of biological sequences. Notably in prokaryotes, where the amount of lateral transfers is believed to be important, the inference of phylogenies using multiple genes requires testing for incongruence before concatenating the genes. On another scale, incongruence tests can be used to detect recombination points within single gene alignments. The incongruence length difference test (ILD), based on parsimony, has been proved to be useful for finding incongruent data sets, but its application remains limited to small data sets for computational time reasons. Here, we have adapted the principle of ILD to the BIONJ algorithm. This algorithm is based on a tree length minimisation criterion and is suitable to replace parsimony in this test when used with uncorrected distance (model-free approach). We show that this new test, ILD-BIONJ, while being much faster, is often more accurate than the ILD test, especially when the alignments compared are simulated under different evolutionary models.
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2,338,812 |
Delivery of a vector encoding mouse hyaluronan synthase 2 via a crosslinked hyaluronan film.
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We have developed a crosslinked hyaluronic acid (HA) film with DNA incorporated within its structure and have characterized this system for its efficacy in sustained transferring of a vector encoding mouse hyaluronan synthase 2 (Has2). Analysis of the DNA release kinetics indicated that the HA films degraded when treated with hyaluronidase and that they released DNA over a prolonged period of time. Gel electrophoresis revealed that this DNA was intact and immunohistochemical analysis verified the transfection capabilities of DNA release samples. The ability of released DNA encoding Has2 to promote HA synthesis was confirmed by quantifying the amount of HA produced by COS-1 cells that were transfected with release samples. The intended future application of the HA films is in prevention of post-operative peritoneal adhesions. In addition to serving as a physical barrier, the film would function as a vehicle for sustained delivery of DNA encoding Has2, which would promote the synthesis of HA in transfected tissues.
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2,338,813 |
Nipah virus glycoprotein: production in baculovirus and application in diagnosis.
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A method for serological diagnosis of Nipah virus (NiV) is described. DNA encoding truncated G protein of NiV was cloned into the pFastBac HT vector, and the fusion protein to His-tag was expressed in insect cells by recombinant baculovirus. The resulting His-G recombinant fusion protein was purified by affinity chromatography and used as the coating antigen for serological testing by indirect enzyme-linked immunosorbant assay (ELISA). When tested against a panel of swine serum samples, the recombinant G protein-based ELISA successfully discriminated all 40 samples previously determined to be serum neutralizing test (SNT) positive from 11 SNT negatives samples. The data show that the recombinant G protein exhibits the antigenic epitopes and conformation necessary for specific antigen-antibody recognition. The main advantage of the recombinant G protein-based NiV ELISA compared to an ELISA using whole virus antigen is the use of a single antigenic protein instead of inactivated whole virus which is required to be prepared under high risk and cost. This test is suitable for routine diagnosis of NiV and also for epidemiological surveys as it allows highly reliable testing of a large number of sera rapidly.
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2,338,814 |
Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia.
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Hereditary haemorrhagic telangiectasia (HHT) is a rare disorder with one per 6000-10,000 affected individuals in the general Caucasian population. HHT is genetically heterogeneous, involving at least two loci HHT1 mapping to chromosome 9q34.1 and HHT2 mapping to chromosome 12q31. The loci have been identified as endoglin (ENG) and activin receptor-like kinase 1 (ALK1). In order to gain knowledge of the genotype distribution and prevalence in the Danish population and to establish a reproducible and sensitive molecular genetic test method, we developed a denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci. Twenty-five Danish HHT families were tested. A total of eight new as well as seven previously reported mutations were identified. A founder mutation was characterized present in seven families and possibly introduced around 350 years ago. In one individual, a presumed spontaneous mutation was characterized. The method developed proved to be very sensitive for mutation detection in both ENG and ALK1. Genetic screening in HHT families facilitates an early treatment strategy for silent HHT manifestations in first degree relatives.
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2,338,815 |
Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability.
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Usher syndrome type III is an autosomal recessive disorder clinically characterized by the association of retinitis pigmentosa (RP), variable presence of vestibular dysfunction and progressive hearing loss, being the progression of the hearing impairment the critical parameter classically used to distinguish this form from Usher syndrome type I and Usher syndrome type II. Usher syndrome type III clinical subtype is the rarest form of Usher syndrome in Spain, accounting only for 6% of all Usher syndrome Spanish cases. The gene responsible for Usher syndrome type III is named clarin-1 and it is thought to be involved in hair cell and photoreceptor cell synapses. Here, we report a screening for mutations in clarin-1 gene among our series of Usher syndrome Spanish patients. Clarin-1 has been found to be responsible for the disease in only two families: the first one is a previously reported family homozygous for Y63X mutation and the second one, described here, is homozygous for C40G. This accounts for 1.7% of Usher syndrome Spanish families. It is noticeable that, whereas C40G family is clinically compatible with Usher syndrome type III due to the progression of the hearing loss, Y63X family could be diagnosed as Usher syndrome type I because the hearing impairment is profound and stable. Thus, we consider that the progression of hearing loss is not the definitive key parameter to distinguish Usher syndrome type III from Usher syndrome type I and Usher syndrome type II.
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2,338,816 |
Health motivation and emotional vigilance in genetic testing for prostate cancer risk.
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Actual uptake of genetic testing for cancer susceptibility is generally lower than 50%, despite a high initial interest above 80%. As population-based genetic testing for cancer susceptibility becomes more widespread, there will be an increasing need to understand the relationship of patient-affective factors to test intention and actual uptake behavior. Using hypothetical genetic testing for prostate cancer susceptibility as an example, we used surveys of 400 men in the general population of Philadelphia to develop a Structural Equation Modeling diagram to reveal the influence of affective factors implicated in the intention to undergo genetic testing for prostate cancer risk. Results showed that most men want genetic testing for prostate cancer, believe strongly in its benefits, and are not deterred by negative affect. Our data suggest that high positive expectations, plus a high desire to comply with physician and family suggestions, result in an increased test intention. Informed consent assessment, therefore, requires an appreciation not only of patient risk, but awareness of patient motivation and affect as well.
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2,338,817 |
Psychological impact of genetic testing for hereditary non-polyposis colorectal cancer.
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The psychological impact of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC) was assessed in 114 individuals (32 carriers and 82 non-carriers) attending familial cancer clinics, using mailed self-administered questionnaires prior to, 2 weeks, 4 months and 12 months after carrier status disclosure. Compared to baseline, carriers showed a significant increase in mean scores for intrusive and avoidant thoughts about colorectal cancer 2 weeks (t = 2.49; p = 0.014) and a significant decrease in mean depression scores 2 weeks post-notification of result (t = -3.98; p < 0.001) and 4 months post-notification of result (t = -3.22; p = 0.002). For non-carriers, significant decreases in mean scores for intrusive and avoidant thoughts about colorectal cancer were observed at all follow-up assessment time points relative to baseline. Non-carriers also showed significant decreases from baseline in mean depression scores 2 weeks, 4 months and 12 months post-notification. Significant decreases from baseline for mean state anxiety scores were also observed for non-carriers 2 weeks post-notification (t = -3.99; p < 0.001). These data indicate that predictive genetic testing for HNPCC leads to psychological benefits amongst non-carriers, and no adverse psychological outcomes were observed amongst carriers.
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2,338,818 |
Small de novo duplication in the repeat region of the TATA-box-binding protein gene manifest with a phenotype similar to variant Creutzfeldt-Jakob disease.
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A 20-year-old North American patient developed rapidly progressive cognitive decline and pronounced ataxia, a phenotype compatible with prion disease. No structural changes were found in the PRNP gene, which excludes genetic prion disease, but the patient's PRNP codon 129 Met/Met genotype is known to predispose to variant Creutzfeldt-Jakob disease (vCJD). Further studies identified an expanded allele with 55 CAG/CAA repeats in the TBP gene. The increase of trinucleotide repeat number in the coding region of the TBP gene has previously been associated with spinocerebellar ataxia type 17 (SCA17). The patient's unaffected parents and siblings show normal-size TBP alleles with 37-38 repeats. Haplotype and nucleotide sequence analyses clearly indicate that the mutation has occurred de novo on a paternal chromosome by insertion/duplication of a (CAA)(CAG)(CAA)(CAG)(15) sequence. This report presents a second fully investigated sporadic case of SCA17 occurring as a result of a DNA rearrangement within the polymorphic TBP trinucleotide repeat region. Our findings suggest that patients suspected of vCJD should undergo testing for SCA17, Huntington's disease and other neurodegenerative disorders having phenotypic similarities with vCJD.
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2,338,819 |
[Families at risk of colon cancer II. Hereditary nonpolyposis colorectal carcinoma].
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Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant inherited disease characterised by almost inevitable development of colorectal carcinoma and/or endometrium and other defined malignancies in affected individuals. HNPCC is caused by a germline mutation in a mismatch repair genes (MMR). The purpose of this review is to summarize current knowledge regarding HNPCC with the focus on recent data on genetic testing, surveillance guidelines and therapy. Available medical databases were searched from 1998 to May 2003 using the keywords "hereditary nonpolyposis colorectal cancer", followed by further search for particular issues. Additional articles were identified through the reference sections of retrieved articles and from personal archive of authors. Approximately 200 papers on HNPCC are published yearly. The major progress in recent research of HNPCC has been made in the area of genetic testing and clinical surveillance. Current guidelines recommend identification of microsatelite instability in a tumour of affected family member followed by germline testing in this person. Once mutation in particular MMR gene is found, screening of all at risk members is recommended. Alternative approach suggests direct germline testing in unaffected family member provided that the testing in affected member is not possible. Annual colonoscopy examinations starting at 20-25 years and gyneacological examination starting at 30-35 years are recommended in all family members at risk. Recent advances in genetic tests and surveillance strategies result in decreased mortality of HNPCC patient.
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2,338,820 |
Myotonic dystrophy presenting as new-onset hand weakness and recurrent pneumonia in a patient with paraplegia: a case report.
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We describe a previously independent T11 paraplegic patient who had delayed-onset hand weakness and recurrent pneumonia caused by myotonic dystrophy. A man in his late thirties suffered a thoracic spinal cord injury (SCI) from a gunshot wound at the age of 17 years, with resultant T11 American Spinal Injury Association class A paraplegia. He lived independently until the age of 36 years when he was hospitalized multiple times for pneumonia. During a rehabilitation stay after one of the acute hospitalizations, the patient's hand weakness and diffuse muscular atrophy were noted. Electrodiagnostic testing was performed, which showed myotonic discharges. Genetic testing was consistent with myotonic dystrophy. This case shows the importance of considering causes of weakness that affect the population as a whole when evaluating a patient with SCI who presents with delayed-onset weakness.
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2,338,821 |
Genetics of colorectal cancer.
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Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. As such, it assumes a significant role in both health policy decision-making and scientific research. CRC has been a model for investigating the molecular genetics of cancer development and progression; this is in part due to the easily detectable, sequential transition of cells from normal colonic epithelium to adenoma and then to adenocarcinoma. In addition, familial syndromes that predispose to CRC, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), have significantly contributed to our understanding of the genetic mechanisms underlying CRC formation. It is now well recognized that hereditary CRC syndromes are due to germline mutations of genes that function as tumor suppressors or, less frequently, oncogenes. Accumulation of subsequent mutations in other genes with related functions results in the stepwise progression to carcinoma. It is important to note that somatic changes in similar genes are involved in the formation of sporadic CRC. The identification of these important CRC-related genes may help facilitate the early diagnosis, prevention, and treatment of CRC. This article reviews the various familial CRC syndromes along with their genetic etiology, as well as discusses the principle of genetic testing for these conditions.
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2,338,822 |
Multidrug-resistant tuberculosis.
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Multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis resistant to both isoniazid and rifampicin with or without resistance to other drugs is among the most worrisome elements of the pandemic of antibiotic resistance. Globally, about three per cent of all newly diagnosed patients have MDR-TB. The proportion is higher in patients who have previously received antituberculosis treatment reflecting the failure of programmes designed to ensure complete cure of patients with tuberculosis. While host genetic factors may probably contribute, incomplete and inadequate treatment is the most important factor leading to the development of MDR-TB. The definitive diagnosis of MDR-TB is difficult in resource poor low income countries because of non-availability of reliable laboratory facilities. Efficiently run tuberculosis control programmes based on directly observed treatment, short-course (DOTS) policy is essential for preventing the emergence of MDR-TB. Management of MDR-TB is a challenge which should be undertaken by experienced clinicians at centres equipped with reliable laboratory service for mycobacterial culture and in vitro sensitivity testing as it requires prolonged use of expensive second-line drugs with a significant potential for toxicity. Judicious use of drugs, supervised individualised treatment, focussed clinical, radiological and bacteriological follow up, use of surgery at the appropriate juncture are key factors in the successful management of these patients. In certain areas, currently available programme approach may not be adequate and innovative approaches such as DOTS-plus may have to be employed to effectively control MDR-TB.
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2,338,823 |
Clinical genetic counselling for familial cancers requires reliable data on familial cancer risks and general action plans.
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Familial cancer clustering, without obvious heritability, poses a major challenge for current cancer risk assessment and management. Reliable determination of familial risks for cancer is important for clinical genetic counselling, but medically verified data on familial risks for many malignancies have been limited. However, the nationwide Swedish Family-Cancer Database allows a reliable characterisation of familial risk for all major neoplasms. Even though alert genetic counsellors and certainly clinical cancer geneticists will consider familial cancer clustering in their purview, the standard medical referral systems, which have already been shown to be poor in capturing and referring families at high risk for heritable cancers, are unlikely to ascertain familial aggregations of other cancers that are not known to belong to an inherited cancer syndrome. The data will be helpful in implementing evidence based guidelines for helping the general medical system to ascertain and refer even familial cancer clusters to cancer genetics professionals.
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2,338,824 |
A polymer library approach to suicide gene therapy for cancer.
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Optimal gene therapy for cancer must (i) deliver DNA to tumor cells with high efficiency, (ii) induce minimal toxicity, and (iii) avoid gene expression in healthy tissues. To this end, we generated a library of >500 degradable, poly(beta-amino esters) for potential use as nonviral DNA vectors. Using high-throughput methods, we screened this library in vitro for transfection efficiency and cytotoxicity. We tested the best performing polymer, C32, in mice for toxicity and DNA delivery after intratumor and i.m. injection. C32 delivered DNA intratumorally approximately 4-fold better than one of the best commercially available reagents, jetPEI (polyethyleneimine), and 26-fold better than naked DNA. Conversely, the highest transfection levels after i.m. administration were achieved with naked DNA, followed by polyethyleneimine; transfection was rarely observed with C32. Additionally, polyethyleneimine induced significant local toxicity after i.m. injection, whereas C32 demonstrated no toxicity. Finally, we used C32 to deliver a DNA construct encoding the A chain of diphtheria toxin (DT-A) to xenografts derived from LNCaP human prostate cancer cells. This construct regulates toxin expression both at the transcriptional level by the use of a chimeric-modified enhancer/promoter sequence of the human prostate-specific antigen gene and by DNA recombination mediated by Flp recombinase. C32 delivery of the A chain of diphtheria toxin DNA to LNCaP xenografts suppressed tumor growth and even caused 40% of tumors to regress in size. Because C32 transfects tumors locally at high levels, transfects healthy muscle poorly, and displays no toxicity, it may provide a vehicle for the local treatment of cancer.
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2,338,825 |
Inherited cancer in children: practical/ethical problems and challenges.
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Over recent years significant molecular advances have led to a better understanding of the genetics of both syndromic and non-syndromic paediatric cancers. In addition many hereditary cancer predisposition syndromes are now recognised, some of which have implications for children in affected families. Improvements in gene mutation screening will increase the sensitivity, accuracy and therefore the applicability of genetic testing in these conditions. This review will deal with four main areas pertaining to paediatric cancer genetics (i) genetic aspects of some non-syndromic paediatric cancers (ii) paediatric cancer predisposition syndromes, (iii) the management of children in families with predominantly adult- onset cancer predisposition syndromes and (iv) special ethical, legal, social and psychological considerations in the management of children, with actual or possible genetic cancer predisposition. Current concepts and controversies in the rapidly changing field of paediatric cancer genetics will be examined in detail and the application of existing guidelines and their limitations will be discussed.
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2,338,826 |
[Active screening for genetic pathology in newborns. II. Genetic counseling and prenatal diagnosis in high risk families].<Pagination><StartPage>32</StartPage><EndPage>35</EndPage><MedlinePgn>32-5</MedlinePgn></Pagination><Abstract><AbstractText>Active screening for genetic pathology over a period of 12 years (1990-2001) involved examination of 29629 newborns at the Clinic of Obstetrics and Gynaecology. Congenital anomalies were detected in 1244 cases (live-, stillbirths and terminated pregnancies) which gives an average incidence rate of 42.0 per 1000 among the studied population. Chromosomal abnormalities were diagnosed in 70 cases (5.6%), single gene conditions--in 164 cases (13.2%), multifactorially determined conditions--in 449 cases (36.1%). The total genetic contribution of all recognized cases with genetic conditions was 54.9% (683 cases). Genetic counseling was provided to 560 out of 1244 (45%) couples who given births to affected children. During that period prenatal diagnosis was performed on 110 (44%) pregnancies and most of them (90%) ended successfully (healthy child was born). Our strategy for identifying CD by active screening enabled us to provide more accurate genetic counselling and prenatal diagnosis for genetic diseases. Screening of newborn population is likely to be an effective and necessary service.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kovacheva</LastName><ForeName>K</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Angelova</LastName><ForeName>L</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Simeonova</LastName><ForeName>M</ForeName><Initials>M</Initials></Author></AuthorList><Language>bul</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><VernacularTitle>Aktiven skrining za genetichna patologiia sred novorodeni. II. Genetichna konsultatsiia i prenatalna diagnostika pri riskovi semeĭstva.</VernacularTitle></Article><MedlineJournalInfo><Country>Bulgaria</Country><MedlineTA>Akush Ginekol (Sofiia)</MedlineTA><NlmUniqueID>0370455</NlmUniqueID><ISSNLinking>0324-0959</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D002031" MajorTopicYN="N" Type="Geographic">Bulgaria</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D025063" MajorTopicYN="N">Chromosome Disorders</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000013" MajorTopicYN="N">Congenital Abnormalities</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000453" MajorTopicYN="Y">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005817" MajorTopicYN="N">Genetic Counseling</DescriptorName><QualifierName UI="Q000706" MajorTopicYN="Y">statistics & numerical data</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="Y">Genetic Testing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015994" MajorTopicYN="N">Incidence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007231" MajorTopicYN="N">Infant, Newborn</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011247" MajorTopicYN="N">Pregnancy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018566" MajorTopicYN="Y">Pregnancy, High-Risk</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011296" MajorTopicYN="N">Prenatal Diagnosis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012189" MajorTopicYN="N">Retrospective Studies</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>11</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>12</Month><Day>16</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>11</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15518282</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15517793</PMID><DateCompleted><Year>2004</Year><Month>12</Month><Day>02</Day></DateCompleted><DateRevised><Year>2009</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1293-8505</ISSN><JournalIssue CitedMedium="Print"><Issue>103</Issue><PubDate><Year>2004</Year><Month>Sep</Month></PubDate></JournalIssue><Title>Revue de l'infirmiere</Title><ISOAbbreviation>Rev Infirm</ISOAbbreviation></Journal>[Conquering cystic fibrosis: reasons to get angry].
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Active screening for genetic pathology over a period of 12 years (1990-2001) involved examination of 29629 newborns at the Clinic of Obstetrics and Gynaecology. Congenital anomalies were detected in 1244 cases (live-, stillbirths and terminated pregnancies) which gives an average incidence rate of 42.0 per 1000 among the studied population. Chromosomal abnormalities were diagnosed in 70 cases (5.6%), single gene conditions--in 164 cases (13.2%), multifactorially determined conditions--in 449 cases (36.1%). The total genetic contribution of all recognized cases with genetic conditions was 54.9% (683 cases). Genetic counseling was provided to 560 out of 1244 (45%) couples who given births to affected children. During that period prenatal diagnosis was performed on 110 (44%) pregnancies and most of them (90%) ended successfully (healthy child was born). Our strategy for identifying CD by active screening enabled us to provide more accurate genetic counselling and prenatal diagnosis for genetic diseases. Screening of newborn population is likely to be an effective and necessary service.
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2,338,827 |
Nesidioblastosis: an old term and a new understanding.
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Nesidioblastosis is a clinically, pathologically, and genetically heterogeneous disease. Differences between well described forms in neonates with persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and rare forms in adults are described. Histopathologic criteria include hypertrophic islets occasionally showing beta cells with pleomorphic nuclei, ductuloinsular complexes, and neoformation of islets from ducts. These changes can be found as diffuse or focal forms of nesidioblastosis. Although most cases occur sporadically, several genetic defects ( SUR1, Kir6.2, GCK, and GLUD1 genes) have been described in neonates. In adults a higher rate of nesidioblastosis is observed in conjunction with multiple endocrine neoplasia type 1. The disease is diagnosed biochemically by a supervised fasting test in adults and in neonates by determining the glucose requirements to maintain normoglycemia, inappropriately high insulin and c-peptide levels, low free fatty acid and ketone body concentrations, glycemic response to glucagons, and the absence of ketonuria. If all highly selective noninvasive imaging techniques fail to identify a tumor, selective arterial calcium stimulation testing for gradient-guided surgery in adults and percutaneous transhepatic pancreatic venous sampling in neonates should be performed. a 95% pancreatectomy is necessary in neonates with a diffuse form of nesidioblastosis, whereas focal forms can be treated by partial pancreatectomy.
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2,338,828 |
Hereditary breast cancer in Jews.
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A family history of breast cancer poses higher risks for Jewish versus non-Jewish women, particularly for early-onset breast cancer. This appears to be due in large part to the high prevalence (2.5%) of three BRCA1 and BRCA2 founder mutations in Ashkenazi Jews. About 4 to 8% of non-Jewish male breast cancer cases versus 19% of Jewish male breast cancer cases carry germline BRCA mutations. Jewish women are disproportionately impacted by BRCA mutations throughout life, with a 10% carrier rate for breast cancer diagnosed at any age and a 21 to 30% carrier rate for breast cancer diagnosed by age 40. Comparable rates in non-Jewish populations are 6.1% for breast cancer diagnosed before age 50. Lifetime penetrance estimates based on genotyping of probands have ranged widely in Jewish and non-Jewish populations. However, a study of 1008 Jewish women with breast cancer which extended genotyping to relatives found high penetrance rates with considerably smaller standard errors. This study and studies of early-onset incident breast cancer in non-Jews have found that at least half of high-risk cases would be missed by family history screening alone. While the carrier rate in non-Jewish populations is too low to consider genetic screening, the carrier rate in Ashkenazi Jews is high and genetic screening poses fewer technical barriers. The high genetic attributable cancer risks of Ashkenazi BRCA founder mutations, the sobering lethality of ovarian and early onset breast cancers, and the increasing clarity about effectiveness of medical interventions make imperative further dialogue and research to keep guidelines for genetic screening up to date.
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2,338,829 |
Fanconi anemia in Ashkenazi Jews.
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Fanconi anemia (FA) should be included among the genetic diseases that occur at high frequency in the Ashkenazi Jewish population. FA exhibits extensive genetic heterogeneity; there are currently 11 complementation groups reported, and 8 (i.e., FANCA, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, and FANCL) genes have been isolated. While patients may be from widely diverse ethnic groups, a single mutation in complementation group FA-C, c.711 + 4A > T (commonly known as IVS4 + 4A > T prior to current nomenclature rules) is unique to FA patients of Ashkenazi Jewish ancestry, and has a carrier frequency of greater than 1/100 in this population. In addition, a mutation (c.65G > A) in FANCA (FA-A is the most common complementation group in non-Jewish patients) and the mutation c.6174delT in FANCD1/BRCA2 are also unique to the Ashkenazi Jewish population. Therefore, the study of Fanconi anemia can lend insight into the types of cancer-predisposing genetic diseases specific to the Ashkenazi.
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2,338,830 |
Inflammatory bowel disease in Ashkenazi Jews: implications for familial colorectal cancer.
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Inflammatory bowel disease (IBD) has a multifactorial etiology and includes ulcerative colitis (UC) and Crohn's disease (CD). Powerful epidemiologic and genetic studies have provided ample evidence that a subset of both CD and UC are attributable to a likely primary genetic etiology. This is evidenced by the recent identification of the IBD1 gene ( NOD2 ) mutations which show an association with susceptibility to CD. The IBD complex shows a significant increased frequency in Jews when compared to non-Jews. While there is an increased incidence of colorectal cancer (CRC) in patients with IBD, it nevertheless is important to realize that IBD likely accounts for no more than 1-3% of all cases of CRC in Ashkenazi Jews. Importantly, however, awareness of the increased CRC risk in IBD may aid immeasurably in preventive interventions. The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat, dysplastic tissue or dysplasia-associated lesions or masses (DALMs). An important model, but by no means an absolute one, for colon carcinogenesis in IBD follows progression from an absence of dysplasia, to indefinite dysplasia, to low-grade dysplasia, on to high-grade dysplasia, and ultimately to invasive CRC. This carcinogenic process relates to the disease duration with respect to the extent of colonic involvement and may also involve primary sclerosing cholangitis. Given this knowledge of an increased risk for CRC in UC and CD, surveillance colonoscopy should initially be performed 8-10 years after onset of symptoms as opposed to diagnosis, and it should be performed 1-2 years after 8 years of disease in patients with pancolitis or after 15 years in those with left-sided colitis. A search for dysplasia of colonic mucosa with biopsies performed in all four quadrants every 10 cm throughout the colon is exceedingly important. Additional biopsies should be taken of any flat lesions, masses, or strictures. Prophylactic colectomy may then be indicated when severe dysplasia is confirmed by knowledgeable pathologists.
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2,338,831 |
A636P testing in Ashkenazi Jews.
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Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited colorectal cancer syndrome attributable to mutations in one of several DNA mismatch repair genes, most commonly MLH1 and MSH2 . In certain populations, founder mutations account for a substantial portion of HNPCC. In this report we summarize the literature and our personal experience testing for a specific founder mutation in the Ashkenazi Jewish population, MSH2*1906G > C , also known as A636P. Although rare in the general population, the A636P mutation is detected in up to 7% of Ashkenazi Jewish patients with early age-of-onset colorectal cancer, and may account for up to one third of HNPCC in the Ashkenazi Jewish population. In addition, we summarize our initial experience with a prospective A636P testing protocol aimed at Ashkenazi Jewish patients at high or intermediate risk for harboring the A636P mutation.
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2,338,832 |
Trends in colorectal cancer incidence and mortality in the Israeli Jewish ethnic populations.
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Ashkenazi Jews, as compared to non-European Jews and non-Jews, are at increased risk for colorectal cancer (CRC), this is attributed to genetic susceptibility and/or lifestyle.</AbstractText>To follow Israeli long-term trends in CRC incidence and mortality and their associations with ethnicity.</AbstractText>All Israeli CRC data accumulated 1970-2001 was used, age standardized rates (adjusted to world standard population) was computed by cancer site, US Surveillance, Epidemiology and End Results Program (SEER) Stage and ethnic group (continent of birth: Europe-America, Asia, Africa, Israel).</AbstractText>From 1970, CRC incidence increased 190% in males and 140% in females; mainly colon cancer (270% and 185% respectively) (P < 0.01), while rectal cancer incidence decreased and is now stable. Stage 3 CRC increased while stage 4 decreased significantly (P < 0.01 for both). In 2001, CRC incidence per 100,000 in European-American-born males was 48.3, Asian and African born 35.5 and Israeli born 32.7 (relative risk (RR) 1.36, P = 0.03), while European-American female rates were 35 and all the others 26 (RR 1.35, P < 0.01). Overall survival increased 9% over 30 years (P < 0.01), 5 years survival since 1988-1996 for European-American born was 43.1%, Asian 46.7%, African 47.5% and Israeli 55.8%. Stage-2 CRC 5 years survivals for 1970-1996 (most had no post surgical treatment) for European-American born were 41.7%, Asian and African 44.8% and Israeli 53.4% (P < 0.05). Stage-3 CRC survivals (most received adjuvant therapy in addition to surgery) for European-American born was 38.8%, Asian and African 43.3% and Israeli 45.1% (P < 0.01).</AbstractText>Colon cancer has increased in Israel, mainly in males and European-American born. Israeli-born Jews (of 20 to 60% mixed ethnicity and lifestyle habits) have the lowest incidence and best survival data for stages-2 and -3 CRC. There is evidence of ethnic survival advantage and possibly in response to adjuvant oncological therapy.</AbstractText>
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2,338,833 |
Ashkenazi Jewish genetic disorders.
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The frequency of several genes responsible for 'single-gene' disorders and disease predispositions is higher among Ashkenazi Jews than among Sephardi Jews and non-Jews. The disparity is most likely the result of founder effect and genetic drift, rather than heterozygote advantage. The more common Mendelian Ashkenazi Jewish genetic disorders are summarized, and examples of variable expressivity and penetrance, inconsistent genotype-phenotype correlation, and potential modifiers are presented. The importance of genetic counseling in both the pre- and post-test phases of population screening is emphasized.
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2,338,834 |
Medullary thyroid carcinoma: nationwide Japanese survey of 634 cases in 1996 and 271 cases in 2002.
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Medullary thyroid carcinoma (MTC) occurs sporadically or as an inherited disease, with the latter occurring in the form of multiple endocrine neoplasia (MEN) type 2A, MEN type 2B, or familial non-MEN medullary carcinoma (FMTC). MTC is inherited as an autosomal dominant trait and is associated with germline mutations of the RET proto-oncogene. Genetic testing identifies carriers of the mutant gene and enables preventive thyroidectomy. A nationwide questionnaire-based survey was conducted in 1996 and again in 2002, and we report here the results of the two surveys that characterize the clinical course of the inherited form of MTC. The data show a higher rate of inherited MTC than previously described, although MEN2A was found to be the most common inherited form of MTC, the same as in earlier studies. The most important finding was the difference in method of detection of MTC between the two surveys. Since the discovery of the genetic association with the disease, genetic testing has become the diagnostic method of choice, replacing indicators such as neck mass and elevated non-stimulated serum calcitonin level. Genetic testing enables early detection of the disease, which provides patients with the possibility of better outcome.
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2,338,835 |
Population structure in Pseudoroegneria spicata (Poaceae: Triticeae) modeled by Bayesian clustering of AFLP genotypes.
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Pseudoroegneria spicata (Poaceae: Triticeae) is an abundant, allogamous species widely adapted to the temperate, semiarid steppe and open woodland regions of western North America. Amplified fragment length polymorphism (AFLP), model-based Bayesian clustering, and other methods of hypothesis testing were used to investigate genetic diversity and population structure among 565 P. spicata plants from 82 localities representing much of the species distribution. Comparisons with four Asiatic Pseudoroegneria species and two North American Elymus wawawaiensis accessions demonstrate cohesiveness in P. spicata. However, P. spicata genotypes group by locality and geographic region based on genetic distance analysis. Average DNA polymorphism among P. spicata localities was significantly correlated (r = 0.58) with geographical distance. The optimum Bayesian cluster model included 21 P. spicata groups, indicating that dispersal among sampling locations was not sufficient to group genotypes into one unstructured population. Approximately 18.3% of the DNA polymorphism was partitioned among the 21 regional groups, 14.9% among localities within groups, and 66.8% within accessions. Average DNA polymorphism among Bayesian groups was correlated (r = 0.53) with the average geographic distance among Bayesian groups, which partly reflects isolation by distance. However, conspicuous regional boundaries were discernable among several divergent genetic groups.
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2,338,836 |
Systematic screening and identification of antigens recognized by monoclonal antibodies raised against the developing lateral olfactory tract.
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During development, olfactory bulb axons navigate a complex microenvironment composed of myriad molecules to construct a bundle called the lateral olfactory tract. The axons themselves also express thousands of different molecules. In the present study, we produced and characterized six monoclonal antibodies that label the lateral olfactory tract and its surroundings in a unique pattern. The labeling profiles suggested that the antigen molecules recognized by each antibody are heterogeneously distributed around the developing lateral olfactory tract. We developed an efficient screening method to identify the antigen molecules by combining expression of a cDNA library in COS-7 cells and the subsequent immunohistochemical staining of the cells. The systematic screening successfully identified specific cDNA clones for all of the monoclonal antibodies, which highly probably coded for the antigen molecules, and therefore unveiled the molecular nature of local components that embrace the developing lateral olfactory tract in mice.
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2,338,837 |
Chronic and recurrent otitis media: a genome scan for susceptibility loci.
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Otitis media (OM) is the most common childhood disease. Almost all children experience at least one episode, but morbidity is greatest in children who experience chronic/recurrent OM (COME/ROM). There is mounting evidence that COME/ROM clusters in families and exhibits substantial heritability. Subjects who had tympanostomy tube surgery for COME/ROM (probands) and their families were recruited for the present study, and an ear examination was performed, without knowledge of the subject's history, to determine presence of OM sequelae. In addition, tympanometric testing was performed at three frequencies (226, 630 or 710, and 1,400 Hz) to detect abnormal middle-ear mechanics, and hearing was screened at 20 dB for the speech frequencies. Of these families, 121 had at least two individuals who had received the diagnosis of COME/ROM (364 affected and genotyped individuals), of whom 238 affected and informative relative pairs were used for analyses. Single-point nonparametric linkage analysis provided evidence of linkage of COME/ROM to chromosome 10q at marker D10S212 (LOD 3.78; P=3.0 x 10(-5)) and to chromosome 19q at marker D19S254 (LOD 2.61; P=5.3 x 10(-4)). Analyses conditional on support for linkage at chromosomes 10q and 19q resulted in a significant increase in LOD score support on chromosome 3p (between markers D3S4545 and D3S1259). These results suggest that risk of COME/ROM is determined by interactions between genes that reside in several candidate regions of the genome and are probably modulated by other environmental risk factors.
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2,338,838 |
Comparison of microsatellites versus single-nucleotide polymorphisms in a genome linkage screen for prostate cancer-susceptibility Loci.
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Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a 2-3-fold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Although the suggestion of linkage has been reported for many chromosomes, the most promising regions have been difficult to replicate. In this study, we compare genome linkage scans using microsatellites with those using single-nucleotide polymorphisms (SNPs), performed in 467 men with prostate cancer from 167 families. For the microsatellites, the ABI Prism Linkage Mapping Set version 2, with 402 microsatellite markers, was used, and, for the SNPs, the Early Access Affymetrix Mapping 10K array was used. Our results show that the presence of linkage disequilibrium (LD) among SNPs can lead to inflated LOD scores, and this seems to be an artifact due to the assumption of linkage equilibrium that is required by the current genetic-linkage software. After excluding SNPs with high LD, we found a number of new LOD-score peaks with values of at least 2.0 that were not found by the microsatellite markers: chromosome 8, with a maximum model-free LOD score of 2.2; chromosome 2, with a LOD score of 2.1; chromosome 6, with a LOD score of 4.2; and chromosome 12, with a LOD score of 3.9. The LOD scores for chromosomes 6 and 12 are difficult to interpret, because they occurred only at the extreme ends of the chromosomes. The greatest gain provided by the SNP markers was a large increase in the linkage information content, with an average information content of 61% for the SNPs, versus an average of 41% for the microsatellite markers. The strengths and weaknesses of microsatellite versus SNP markers are illustrated by the results of our genome linkage scans.
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2,338,839 |
Cholesterol metabolism and suicidality in Smith-Lemli-Opitz syndrome carriers.
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The authors examined the relationship between cholesterol metabolism and suicidality in carriers of Smith-Lemli-Opitz syndrome and their families. This population has a partial deficiency in 7-dehydrocholesterol reductase (DHCR7), the enzyme that catalyzes the last step in cholesterol biosynthesis.</AbstractText>Suicidal behavior, depression, misuse of alcohol and drugs, and family history of psychopathology, including attempted or completed suicide, were assessed by structured interview in 51 carriers of Smith-Lemli-Opitz syndrome and 54 matched comparison subjects.</AbstractText>There were significantly more suicide attempters and completers among the biological relatives of Smith-Lemli-Opitz syndrome carriers than comparison subjects, but family history of psychopathology did not significantly differ between the groups. More suicide attempts were reported among Smith-Lemli-Opitz syndrome carriers than among the comparison subjects.</AbstractText>These results, based on a unique study design, provide additional evidence supporting the relationship between cholesterol metabolism and suicidal behavior.</AbstractText>
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2,338,840 |
Effect of two- and three-locus linkage disequilibrium on the power to detect marker/phenotype associations.
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There has been much recent interest in describing the patterns of linkage disequilibrium (LD) along a chromosome. Most empirical studies that have examined this issue have concentrated on LD between collections of pairs of markers and have not considered the joint effect of a group of markers beyond these pairwise connections. Here, we examine many different patterns of LD defined by both pairwise and joint multilocus LD terms. The LD patterns we considered were chosen in part by examining those seen in real data. We examine how changes in these patterns affect the power to detect association when performing single-marker and haplotype-based case-control tests, including a novel haplotype test based on contrasting LD between affected and unaffected individuals. Through our studies we find that differences in power between single-marker tests and haplotype-based tests in general do not appear to be large. Where moderate to high levels of multilocus LD exist, haplotype tests tend to be more powerful. Single-marker tests tend to prevail when pairwise LD is high. For moderate pairwise values and weak multilocus LD, either testing strategy may come out ahead, although it is also quite likely that neither has much power.
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2,338,841 |
Mutation rate and predicted phenotypic target sizes in ethylnitrosourea-treated mice.
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Chemical mutagenesis of the mouse is ongoing in several centers around the world, with varying estimates of mutation rate and number of sites mutable to phenotype. To address these questions, we sequenced approximately 9.6 Mb of DNA from G1 progeny of ethylnitrosourea-treated mice in a large, broad-spectrum screen. We identified 10 mutations at eight unique sites, including six nonsynonymous coding substitutions. This calibrates the nucleotide mutation rate for two mutagenesis centers, implies significance criteria for positional cloning efforts, and provides working estimates of effective genetic target sizes for selected phenotypes.
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2,338,842 |
Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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Congenital adrenal hyperplasias (CAH) are inherited defects of cortisol biosynthesis. More than 90% of CAH are caused by 21-hydroxylase deficiency (21-OHD), found in 1:10 000 to 1:15 000 live births. Females with 'classical' 21-OHD, being exposed to excess androgens prenatally, are born with virilized external genitalia. Potentially lethal adrenal insufficiency is characteristic of two-thirds to three-quarters of patients with the classical salt wasting (SW) form of 21-OHD. Non-SW 21-OHD may be diagnosed on genital ambiguity in affected females, and/or later on the occurrence of androgen excess in both sexes. Non-classical 21-OHD, detected in > or =1:100 of certain populations, may present as precocious pubarche in children or polycystic ovarian syndrome in young women. 21-OHD is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombination between CYP21 and the closely linked CYP21P pseudogene. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disorder. This close association between genotype and phenotype makes it possible to predict clinical outcome in affected subjects. The risk of SW and prenatal virilization can be estimated, and overtreatment can be avoided in mildly affected cases. Glucocorticoid and mineralocorticoid replacement therapies are the mainstays of treatment, but additional therapies are being developed. A first trimester prenatal diagnosis should be proposed in families in whom molecular studies have been performed previously. The state of heterozygotism can be predicted by hormonal testing and confirmed by molecular studies. Prenatal diagnosis by direct mutation detection in previously genotyped families permits prenatal treatment of affected females in order to avoid or minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before SW crises develop, reducing mortality in this disorder.
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2,338,843 |
Lateralised brain function in anurans: comparison to lateralisation in other vertebrates.
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In recent years researchers have begun to investigate lateralisation of behaviour in amphibians. Given the mounting evidence of lateralisation in birds and mammals, and even reptiles, over the past two or more decades, it is not surprising that amphibians have attracted attention in this context. In particular, the evidence for lateralisation in fish has provided a strong basis for this research. This paper summarises the currently available information on lateralisation in anuran amphibians and discusses it in comparison to lateralisation in other vertebrate species, beginning with examples of motor lateralisation and then discussing functional asymmetries that occur between the left and right sides of the brain. The latter are manifested as side biases in responding to different stimuli or, in a number of non-amphibian species, revealed by monocular testing. Most of the examples discussed refer to lateralisation present at the level of the forebrain hemispheres, and so represent hemispheric specialisation. Lateralisation usually refers to examples in which there is a population bias for the majority of individuals in a population to be lateralised in the same direction. In other words, there is a significant skew in the frequency distribution. Such population biases in lateralisation are now known to be widespread among the vertebrates and, as shown, there are some surprisingly similar patterns of lateralisation in those species of fish, amphibians, reptiles, birds, and mammals that have been studied so far. It is also noted that, despite their ubiquity in vertebrates, far from all forms of lateralisation develop solely, or even largely, according to genetic determinants. In fact, the clear and powerful influences of environmental stimulation on development of some kinds of lateralisation in birds provide a basis for similar investigations in anurans.
|
2,338,844 |
Molecular targets for neuroprotection.
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Amyotrophic lateral sclerosis (ALS) is a fatal paralytic neurodegenerative disorder. Experimental models of ALS such as the transgenic rodents expressing mutant superoxide dimutase-1 are playing a pivotal role in our understanding of ALS pathogenesis, and in our testing of new therapeutic interventions aimed at protecting against neurodegeneration. Apoptosis has emerged as a significant pathogenic factor in several neurodegenerative diseases, including ALS. Constructed of multiple interacting molecules, the apoptosis machinery offers a host of attractive targets for pharmacological and genetic interventions to be tested in experimental models of ALS. Information generated by these pre-clinical studies holds the promise to provide sound scientific basis for the development of effective neuroprotective therapies for ALS.
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2,338,845 |
Positionally cloned susceptibility genes in allergy and asthma.
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After several years of research to find asthma-susceptibility genes using genome-wide linkage scans and refined genetic mapping methods, four highly interesting candidate genes have recently been reported. Each of these genes represents a different functional class, and might point to a new pathway in the pathogenesis of asthma. Current research is focusing on confirming the genetic associations in diverse populations and understanding the biochemical functions of the proteins. These second-generation candidate genes for asthma susceptibility will stimulate much research, and might also enable the testing of multigenic models with sufficiently large sample sets.
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2,338,846 |
Recent advances in the management of the child who has hemophilia.
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This article discusses recent advances in the management of the child who has hemophilia.
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2,338,847 |
Glucocorticoid receptor polymorphisms and post-traumatic stress disorder.
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Post-traumatic stress disorder (PTSD) is reported in some studies to be associated with increased glucocorticoid (GC) sensitivity. Two common glucocorticoid receptor (GR) polymorphisms (N363S and BclI) appear to contribute to the population variance in GC sensitivity. There is some evidence that there may be a genetic predisposition to PTSD. Hence we studied 118 Vietnam war veterans with PTSD for (i) GR polymorphisms, particularly the N363S and the BclI polymorphisms which are thought to be GC sensitising, and (ii) two measures of GC sensitivity, the low-dose 0.25 mg dexamethasone suppression test (LD-DST) and the dermal vasoconstrictor assay (DVVA). The DST and GR polymorphisms were also performed in 42 combat exposed Vietnam war veterans without PTSD. Basal plasma cortisol levels were not significantly different in PTSD (399.5+/-19.2 nmol/L, N=75) and controls (348.6+/-23.0 nmol/L, N=33) and the LD-DST resulted in similar cortisol suppression in both groups (45.6+/-3.2 vs. 40.8+/-4.1%). The cortisol suppression in PTSD patients does not correlate with Clinician Administered PTSD Scores (CAPS), however there was a significant association between the BclI GG genotype and low basal cortisol levels in PTSD (P=0.048). The response to the DVVA was similar to controls (945+/-122, N=106 vs. 730+/-236, N=28, P=0.42). PTSD patients with the GG genotype, however, tended to be more responsive to DVVA and in this group the DVVA correlated with higher CAPS scores. The only exon 2 GR polymorphisms detected were the R23K and N363S. Heterozygosity for the N363S variant in PTSD, at 5.1% was not more prevalent than in other population studies of the N363S polymorphism in Caucasians (6.0-14.8%). The GG genotype of the BclI polymorphism found to be associated with increased GC sensitivity in many studies showed a tendency towards increased response with DVVA and correlated with higher CAPS scores. In conclusion, the N363S and BclI GR polymorphisms were not more frequent in PTSD patients than controls and reported population frequencies. Our PTSD group did not display GC hypersensitivity, as measured by the LD-DST and DVVA. In a subset of PTSD patients with the BclI GG genotype, CAPS scores and basal cortisol levels were negatively correlated.
|
2,338,848 |
Development of a D-FISH method to detect DEK/CAN fusion resulting from t(6;9)(p23;q34) in patients with acute myelogenous leukemia.
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The t(6;9)(p23;q34)-DEK/CAN fusion occurs with an incidence of 1-5% in adult patients with acute myelogenous leukemia (AML) and tends to have an unfavorable prognosis at diagnosis. Due to the subtle appearance of this chromosome rearrangement, both initial detection and minimal residual disease (MRD) tracking by conventional karyotyping can be difficult. Unfortunately, no commercial or previously published fluorescence in situ hybridization (FISH) strategies exist for this recurrent anomaly. We have developed a highly sensitive assay using dual-color, double-fusion FISH (D-FISH), which can be used both for initial detection and MRD monitoring. We analyzed archived bone marrow samples from 15 patients with a previously identified t(6;9)(p23;q34) and 10 corresponding post-treatment samples. The results demonstrate that our D-FISH method effectively identified all abnormal samples, including a low-level MRD sample that was considered to be normal by conventional cytogenetic analysis. Normal value ranges were established from 30 negative controls to be < 0.6% when 500 interphase nuclei were analyzed. The development of this sensitive D-FISH strategy for the detection of the t(6;9)(p23;q34) adds to the AML FISH testing repertoire, and is effective in the detection of low-level disease in post-treatment samples in these patients.
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2,338,849 |
Update on newborn screening for cystic fibrosis.
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Cystic fibrosis (CF) is the most common lethal genetic disorder in the United States to be identified in childhood. In November 2003 the US Cystic Fibrosis Foundation and the Centers for Disease Control and Prevention convened an expert panel to review the indications for CF newborn screening. In this review we discuss the information during the year leading up to this meeting as well as publications since the meeting.</AbstractText>During the past several years an increasing number of CF patients have been diagnosed with newborn screening. These patients have demonstrated several benefits to screening while also uncovering new challenges. Health benefits have included improved nutrition persisting for many years and the avoidance of nutritional complications. Early identification has also meant that these often clinically healthy infants are being followed in CF centers for care. This has added to the need for avoiding infection risks to which these patients might not have otherwise been exposed. Psychosocial benefits include the avoidance of stress due to delayed diagnosis as well as assistance with family planning. Psychosocial challenges include carrier identification and detection of patients with mild disease or without a clear diagnosis.</AbstractText>Although no study has definitively shown reduced lung disease or prolonged survival in CF patients detected by newborn screening, the general consensus is that improved nutrition and cognitive potential, in addition to the reduced costs for hospitalization and intensive therapies, support the benefits of screening.</AbstractText>
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2,338,850 |
Enhancement of Ad-p53 therapy with docetaxel in head and neck cancer.
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The objective of this project was to determine the mechanisms in which docetaxel enhances Ad-p53 tumor suppressive effects in head and neck cancer.</AbstractText>In advanced head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate is less than 40%. Because patients with advanced HNSCC have a high rate of local-regional failure (40-60%) with existing treatment modalities, aggressive local therapy approaches need to be developed. Previous data show that docetaxel or Ad-p53 alone have significant anti-tumor activity in HNSCC. Before testing whether a combination approach (Ad-p53 and docetaxel) could be developed in clinical trials, preclinical experiments were performed.</AbstractText>The p53 gene was overexpressed in 2 head and neck squamous carcinoma (HNSCC) cell lines, HN30 and HN12, and a murine Balb/c mucoepidermoid carcinoma (BMEC) cell line. Docetaxel's enhancement of adenoviral transduction (bGAL expression), coxsakie-adenovirus receptor (CAR) expression, and Ad-p53 induction of apoptosis (Annexin V expression) were measured. The modulation of regulators in the cell cycle, apoptosis and signal transduction pathways were measured using Western blot.</AbstractText>Docetaxel increased adenoviral transduction, which was dependent on the dose of docetaxel and levels of Ad-bGAL. The enhanced viral transduction was due in part to the upregulation of the CAR protein. Pretreatment with docetaxel enhanced Ad-p53-induced apoptosis through increased expression of exogenous p53. Together, the combination of docetaxel and Ad-p53 altered expression of key regulators in the cell cycle, apoptosis and signal transduction pathways with an increase in the expression of p53, bax, cleaved PARP, cleaved caspase-3 and phosphorylation of c-Jun at position at Ser. Cyclin A and B1 expression were down regulated by docetaxel and Ad-p53. When comparing the docetaxel-resistant to sensitive cell lines, the altered expression of p27 and skp1 by docetaxel and Ad-p53 were dissimilar between these cell lines.</AbstractText>Docetaxel enhanced Ad-p53 transduction and increased expression of exogenous p53 gene transfer, apoptosis, and antitumor mechanisms. These results support a clinical combination of docetaxel with p53 gene therapy in patients with head and neck cancer.</AbstractText>
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2,338,851 |
HyPhy: hypothesis testing using phylogenies.
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The HyPhypackage is designed to provide a flexible and unified platform for carrying out likelihood-based analyses on multiple alignments of molecular sequence data, with the emphasis on studies of rates and patterns of sequence evolution.</AbstractText>http://www.hyphy.org</AbstractText>[email protected]</AbstractText>HyPhydocumentation and tutorials are available at http://www.hyphy.org.</AbstractText>
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2,338,852 |
Colonic crypt changes during adenoma development in familial adenomatous polyposis: immunohistochemical evidence for expansion of the crypt base cell population.
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Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27(kip1)) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas.
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2,338,853 |
A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting.
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ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.
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2,338,854 |
Gene therapy of the hemophilias.
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Development of hemophilia gene therapy depends on testing gene transfer vectors in hemophilic and nonhemophilic animals. Available animal models include factor VIII or factor IX knockout mice as well as dogs with spontaneous hemophilia A or B. Large animals (particularly dogs) more closely replicate the requirements for correction of human hemophilia than do mice. Small animals are more convenient to maintain and require significantly less vector for testing than do large animals. Nonhemophilic animals (mice or nonhuman primates), whose endogenous factor VIII and factor IX complicate analysis of the human proteins, have utility for safety testing of vectors; some assays can discriminate between human coagulation factors and the endogenous coagulation factors. Most animal models suffer the limitations imposed by the immune response to human factor VIII or IX protein. Clinical trials have failed to achieve significant factor VIII expression in hemophilia A patients, while one clinical trial in hemophilia B patients showed only transient therapeutic increments of factor IX expression. Gene therapy remains an investigational method with many obstacles to overcome before it can be widely used as treatment for hemophilia.
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2,338,855 |
Immunotherapeutic strategies for hepatocellular carcinoma.
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There is a continuing need for innovative, alternative therapies for hepatocellular carcinoma (HCC). Immunotherapy for cancer is attractive because of the exquisite specificity of the immune response. Activation of an HCC-specific response can be accomplished by strategies targeting tumor-associated self-antigens (for example, alpha-fetoprotein [AFP]). Gene array studies have added to the list of HCC-specific gene products that can be targeted. Alternatively, the immune response can be targeted against viral antigens in those patients infected with hepatitis B or C virus. Uncharacterized and mutated antigens can also be targeted with whole tumor cell or tumor lysate-based immunization strategies or with vectors coding for genes that make the tumor immunogenic, allowing the immune system to naturally evolve specificity against immunogenic target antigens. Strategies being investigated in animal models include increasing tumor immunogenicity by targeting cytokines or costimulatory molecules to tumor; immunization with tumor cells fused with antigen-presenting cells; adoptive transfer of viral antigen-specific T cells; and targeting AFP-expressing HCC cells by DNA, adenovirus, peptide, and dendritic cell (DC) strategies. Strategies that have been tested in human clinical trials include adoptive transfer of lymphocytes and autologous tumor-pulsed DC as well as 2 AFP-based strategies: AFP-derived peptides in Montanide and AFP peptides pulsed onto autologous DC. These trials, testing novel immune-based interventions in HCC subjects, have resulted in immunologic responses and have impacted recurrence and survival in HCC subjects.
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2,338,856 |
Characterization of a closed femur fracture model in mice.
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The goal of this study was to develop and characterize a closed femur fracture model for mice that can be used for the molecular and genetic analysis of fracture healing.</AbstractText>Longitudinal time study of species-specific fracture healing.</AbstractText>A protocol was developed for creating reproducible, closed femur fractures in mice. Impending fractures were stabilized by retrograde insertion of a 0.01-inch-diameter, stainless steel wire into the intramedullary canal. The intramedullary wire was held in place with a wedge made from the first 2 mm of a 30-gauge needle. Fractures were produced by 3-point bending. Fracture healing was assessed by radiography, histology, and torsional mechanical testing.</AbstractText>The mouse femur fracture technique produced good results with minimal loss of animals. Of the 246 mice used in the study, 22 mice were excluded due to poor fracture quality (8), loss of fracture stabilization (6), or to anesthesia death (8). Radiography showed a consistent pattern of fracture healing between mice with peak fracture callus volume evident at 10 (15 mice) to 14 days (18 mice) after fracture. Fracture bridging was apparent in all 3-week postfracture radiographs (35 mice). Histologic examination of 117 specimens at 9 time points showed chondrocyte differentiation within the fracture callus by 7 days after fracture, endochondral ossification occurring by 10 days after fracture, and bone remodeling evident as early as 3 weeks after fracture. Despite radiologic and histologic evidence of fracture bridging after 3 weeks, torsional mechanical testing of 68 mice at 3, 4, 6, and 12 weeks after fracture (group size of 15 to 18 mice at each time point) indicated that significant increases in structural or material strength did not occur until 6 to 12 weeks after fracture.</AbstractText>Femur fracture healing in mice follows a typical endochondral ossification pathway with fracture bridging occurring approximately 1 week faster in mice than rats. This fracture model is amenable to the molecular and genetic analysis of fracture healing using different inbred, transgenic, and knockout strains of mice.</AbstractText>
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2,338,857 |
Quantitative PCR detection of t(14;18) bcl-2/JH fusion sequences in follicular lymphoma patients: comparison of peripheral blood and bone marrow aspirate samples.
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In patients with follicular lymphoma (FL), it is unresolved whether peripheral blood (PB) can replace bone marrow (BM) aspirate samples for detection of bcl-2/JH fusion sequences that result from the t(14;18)(q32;q21). We compare here the results of quantitative polymerase chain reaction (q-PCR) analysis for bcl-2/JH involving the major breakpoint cluster region (mbr) on paired PB and BM aspirate samples from 60 consecutive FL patients. There was a significant correlation between the level of bcl-2/JH fusion sequence obtained from PB and BM aspirate samples (r = 0.886), with 82% of samples showing less than one log of difference. Patients who had histological evidence of FL involving concurrent BM biopsy specimens had moderate to high levels of bcl-2/JH in both PB and BM aspirate samples, allowing unequivocal determination of translocation status (median bcl-2/JH to cyclophilin level was 8.014%). In contrast, patients with no detectable FL in their BM biopsy specimens often showed low levels of bcl-2/JH in both PB and BM aspirate samples (bcl-2/JH to cyclophilin median level = 0.006%), in a range similar to background levels that could be detected in patients without FL (n = 15, median bcl-2 mbr/JH to cyclophilin level = 0.002%). We conclude that PB can be used in place of BM aspirate samples to test for the presence of bcl-2 mbr/JH fusion sequence in FL patients and that either PB or BM aspirate testing yields a rough approximation of the degree of BM involvement by FL. However, in patients with minimal levels of bcl-2/JH in PB or BM aspirate samples, confirmation of this result by testing the primary tumor is recommended to confirm the presence of an identical bcl-2/JH fusion sequence and exclude false-positive results.
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2,338,858 |
Microsphere bead arrays and sequence validation of 5/7/9T genotypes for multiplex screening of cystic fibrosis polymorphisms.
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The development of simple and rapid methods for the detection of the common genetic mutations associated with cystic fibrosis (CF) requires access to positive-control samples including the 5/7/9T variants of intron 8. We used PCR and a simple multiplex bead-array assay to identify 5/7/9T control samples from 29 commercially available DNA samples. Unpurified PCR products were directly hybridized to color-coded beads containing allele-specific capture probes for 5/7/9T detection. The performance of the assay was investigated using reverse-complement oligonucleotides, individual PCR products, and multiplex PCR products for 5/7/9T detection within a complex CFTR screening assay. Samples were genotyped by grouping the relative signal intensities from each capture probe. Of 29 commercially available DNA samples analyzed, 2 5T/7T, 2 5T/9T, 9 7T/9T, 11 7T/7T, and 5 9T/9T genotypes were identified. The genotype within each sample group was confirmed by DNA sequencing. The assay was compatible with the analysis of 10 to 1000 ng of genomic DNA isolated from whole blood and allowed for the separate identification of primary CFTR mutations from reflex variants. The correct identification of positive controls demonstrated the utility of a simple bead-array assay and provided accessible samples for assay optimization and for routine quality control in the clinical laboratory.
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2,338,859 |
Hereditary non-syndromic sensorineural hearing loss: transforming silence to sound.
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Tremendous progress has been made in our understanding of the molecular basis of hearing and hearing loss. Through recent advances, we have begun to understand the fascinating biology of the auditory system and unveiled new molecular mechanisms of hearing impairment. Changes in the diagnostic impact of genetic testing have occurred, as well as exciting developments in therapeutic options. Molecular diagnosis, which is already a reality for several hearing-associated genes, will doubtlessly continue to increase in the near future, both in terms of the number of mutations tested and the spectrum of genes. Genetic analysis for hearing loss is mostly used for diagnosis and treatment, and relatively rarely for reproductive decisions, in contrast to other inherited disorders. Inherited hearing loss, however, is characterized by impressive genetic heterogeneity. An abundance of genes carry a large number of mutations, but specific mutations in a single gene may lead to syndromic or non-syndromic hearing loss. Some mutations predominate in individual ethnic groups. For clinical and laboratory diagnosticians, it is challenging to keep abreast of the unfolding discoveries. This review aims to provide the framework pertinent to diagnosticians and a practical approach to mutation analysis in the hearing impaired.
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2,338,860 |
Breast cancer surveillance in women with hereditary risk due to BRCA1 or BRCA2 mutations.
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Women with germline mutations in BRCA1 or BRCA2 are known to be at substantially elevated risk for breast cancer. With increasing acceptance of genetic testing, significant numbers of mutation carriers are being identified, but evidence-based guidelines for the management of women at hereditary risk are lacking. This article reviews the most commonly recommended modalities employed in breast cancer surveillance for women at increased risk. It is apparent that the standard techniques of breast self-examination, clinical breast examination, and mammography are suboptimal for the identification of hereditary breast cancer. At least half of the cancers in this population appear to be detected by physical examination in the intervals between routine radiographic surveillance. Host factors (eg, breast density) and tumor features (rapid proliferative rates) likely contribute to the relative insensitivity of mammography. These factors may be mitigated by the deployment of screening techniques for breast cancer such as ultrasound and magnetic resonance imaging. However, the effect of incremental screening on either stage at diagnosis or breast cancer mortality has not been defined. In addition, the impact of the relatively limited specificity of these techniques on the quality of life (QOL) of women at risk has not been studied. Further research is needed to evaluate the effect of incremental radiographic screening on outcomes, to delineate the best way to integrate the different modalities in terms of sequencing and frequency, and to identify interventions that will minimize the impact of intensive surveillance programs on the QOL of the women engaged in them.
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2,338,861 |
Multivariate search for differentially expressed gene combinations.
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To identify differentially expressed genes, it is standard practice to test a two-sample hypothesis for each gene with a proper adjustment for multiple testing. Such tests are essentially univariate and disregard the multidimensional structure of microarray data. A more general two-sample hypothesis is formulated in terms of the joint distribution of any sub-vector of expression signals.</AbstractText>By building on an earlier proposed multivariate test statistic, we propose a new algorithm for identifying differentially expressed gene combinations. The algorithm includes an improved random search procedure designed to generate candidate gene combinations of a given size. Cross-validation is used to provide replication stability of the search procedure. A permutation two-sample test is used for significance testing. We design a multiple testing procedure to control the family-wise error rate (FWER) when selecting significant combinations of genes that result from a successive selection procedure. A target set of genes is composed of all significant combinations selected via random search.</AbstractText>A new algorithm has been developed to identify differentially expressed gene combinations. The performance of the proposed search-and-testing procedure has been evaluated by computer simulations and analysis of replicated Affymetrix gene array data on age-related changes in gene expression in the inner ear of CBA mice.</AbstractText>
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2,338,862 |
[Should we support large-scale screening for genetic haemochromatosis in France?].
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Genetic hemochromatosis meets the principal World Health Organization criteria for diseases warranting systematic population screening. Indeed, it is a frequent, late-onset, severe disease that is easy to diagnose and cure. However, its penetrance is much lower than thought prior to the discovery of the HFE1 gene, whose C282 Y mutation is responsible for more than 95% of cases with phenotypic expression. Moreover, several questions remain to be answered, notably concerning practical modalities [genotypic or phenotypic screening? at what age?, etc.], the risk of genetic discrimination, and cost-effectiveness. Current recommendations should include [i] broad information of the general population and GPs on early symptoms, [ii] transferrin saturation assay in all patients with symptoms compatible with hemochromatosis and, when elevated, genetic testing, the cost of which should be covered by public health insurance, [iii] both phenotypic and genotypic screening of all proband families, and [iv] implementation of regional and national pilot studies aimed at assessing disease penetrance and the acceptability and cost-effectiveness of large-scale screening.
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2,338,863 |
Lack of association of birth size with polymorphisms of two imprinted genes, IGF2R and GRB10.
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Little is known about the determinants of birth size variability among individuals. Maternal and nutritional factors have been studied, but familial clustering suggests genetic factors as well. As a first step in testing this hypothesis, we examined common sequence variants in IGF2R and GRB10, two genes involved in the regulation of growth and subject to parental imprinting. The IGF2R gene was scanned with five polymorphisms spanning the coding and 3'-UTR for possible association with birth size in a set of 97 normal newborns in Greece. In addition, a silent SNP in GRB10 exon 2 was similarly tested as an exploratory first step. Birth weight and length were compared between groups of newborns divided according to which allele they had received from heterozygous parents. No significant differences were found between alleles in either gene, examined either by parental origin or in aggregate. Thus, we found no evidence that IGF2R variants modulate intrauterine growth within the normal range. If such variants exist in GRB10, they are not in linkage disequilibrium with the marker studied.
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2,338,864 |
The prevalence of celiac disease among family members of celiac disease patients.
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Celiac disease (CD) is more common in certain risk groups. Family members of known celiac patients represent the most important group. Serological screening enables us to detect patients before they develop serious complications. HLA typing has also proven to be a valuable diagnostic tool, especially in excluding the disease.</AbstractText>To assess the prevalence of CD among family members, we screened 106 first-degree relatives (73 parents, 33 siblings; mean age 27.9 years) of 45 celiac patients in NE Slovenia. We analysed antigliadin (AGA) and antiendomysium (EMA) antibodies. Levels of IgG and IgAAGA were determined using the ELISA method, and EMA using indirect immunofluorescence. Serologically positive patients were recalled for intestinal biopsy and were HLA typed. Intestinal biopsy was performed by peroral aspiration capsule or during upper GI endoscopy. Biopsy specimens were examined histologically.</AbstractText>Six family members (5.67%) were both AGA IgG and EMA positive, and one (0.94%) was only EMA positive. All were either HLA DQ2 or DQ8 positive. Nine family members (8.49%) were only AGA IgG positive, two of them lacked the HLA DQ susceptibility alleles. Intestinal biopsy was performed in six family members, and the diagnosis of CD confirmed in five. All were both AGA IgG and EMA positive. They were either symptom-free or had only mild gastrointestinal symptoms, and carried the known HLA DQ risk alleles. The minimum prevalence of CD among family members in NE Slovenia can therefore be estimated at 4.72%.</AbstractText>The prevalence of CD among first-degree relatives is much higher than the prevalence of the disease in the general population. Most of these patients have an atypical form of the disease and would therefore be overlooked without an active search. Serological testing is recommended for all first-degree relatives of CD patients; they should also undergo HLA typing to detect those whose HLA phenotype is consistent with CD. This approach can also help in excluding individuals who do not need further diagnostic procedures for CD.</AbstractText>
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2,338,865 |
Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia.
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Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.
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2,338,866 |
Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort.
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This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 91 gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P<0.001). However, younger female carriers (<50 years) showed a rise in cancer-related worry 1 month post-testing (P<0.05). This returned to pre-testing baseline levels 12 months later, but worry remained significantly higher than noncarriers throughout (P<0.01). There were no significant differences in GHQ scores between males and females (both carriers and noncarriers) at any time point. Female carriers engaged in significantly more risk management strategies than noncarriers in the year following testing (e.g. mammograms; 92% carriers vs 30% noncarriers). In the 12 months post-testing, 28% carriers had bilateral risk-reducing mastectomy and 31% oophorectomy. Oophorectomy was confined to older (mean 41 yrs) women who already had children. However, worry about cancer was not assuaged by surgery following genetic testing, and this requires further investigation. In all, 20% of female carriers reported insurance problems. The data show persistent worry in younger female gene carriers and confirm changes in risk management consistent with carrier status. Men were not adversely affected by genetic testing in terms of their general mental health.
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2,338,867 |
Coincidence of two genetic forms of Charcot-Marie-Tooth disease in a single family.
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The authors report a family in which two affected first cousins had a severe demyelinating Charcot-Marie-Tooth disease (CMT) phenotype. One had related parents, and there were no other affected relatives, suggesting an autosomal recessive mode of inheritance. Molecular studies showed that a de novo duplication in 17p11.2 and a second mutation in MTMR2 were present.
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2,338,868 |
Clinical phenotype of Brazilian families with spinocerebellar ataxia 10.
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Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant ataxia caused by an ATTCT repeat expansion in an intron of the SCA10 gene. SCA10 has been reported only in Mexican families, in which the disease showed a combination of cerebellar ataxia and epilepsy. The authors report 28 SCA10 patients from five new Brazilian families. All 28 patients showed cerebellar ataxia without epilepsy, suggesting that the phenotypic expression of the SCA10 mutation differs between Brazilian and Mexican families.
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2,338,869 |
The -1021C->T DBH gene variant is not associated with epilepsy or antiepileptic drug response.
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Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE). Animal studies show that genes in the NE pathway are candidates for susceptibility to epilepsy and antiepileptic drug (AED) response. The authors genotyped the -1021C-->T major functional polymorphism in the DBH gene in 675 patients with epilepsy and 1,087 controls. The authors found no association with epilepsy, several epilepsy subtypes, or AED response. The results suggest that the -1021C-->T variant does not contribute to epilepsy.
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2,338,870 |
PINK1 (PARK6) associated Parkinson disease in Ireland.
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Mutations in the PINK1 gene have recently been shown to cause autosomal recessive Parkinson disease (PD). The authors assessed the prevalence of PINK1 gene mutations in 290 well-characterized early- and late-onset PD patients from Ireland. In a 51-year-old PD patient with a family history of PD, the authors identified a novel heterozygous mutation (R147H) in exon 2 of the PINK1 gene. Overall, these data indicate that PINK1 mutations are a rare cause of PD in Ireland.
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2,338,871 |
PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations.
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The authors performed linkage analysis in 39 families with autosomal recessive early-onset PD (AR-EOPD) negative for parkin and DJ-1 mutations. Eight families including three Japanese, two Taiwanese, one Turkish, one Israeli, and one Philippine showed evidence of linkage with PARK6 with multipoint log of the odds (lod) score of 9.88 at D1S2732. The results indicate worldwide distribution of PARK6-linked parkinsonism.
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2,338,872 |
APOE epsilon4 and cognitive decline in older stroke patients with early cognitive impairment.
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Dementia is common post stroke, but the potential role of early cognitive impairment and APOE epsilon4 as risk factors is unclear.</AbstractText>Stroke survivors older than 75 years without dementia at 3 months post stroke received a detailed neuropsychological evaluation at 3 and 15 months post stroke, which included the Cambridge Assessment of Mental Disorders in the Elderly (CAMCOG). Early cognitive impairment was diagnosed using the criteria for cognitive impairment/no dementia (vascular CIND). APOE genotype was determined using a standardized method.</AbstractText>One hundred thirty-seven older stroke patients without dementia (mean age 80.6 +/- 4.3, mean CAMCOG score 83.5 +/- 10.4, 68 women) participated in the study, of whom 40 met the criteria for CIND. Stroke patients with one or more APOE epsilon4 alleles were significantly more likely to have CIND (14/40 vs 17/97, odds ratio = 2.5, 95% CI 1.1 to 5.8). Over the 1 year of follow-up, CIND patients with one or more APOE epsilon4 alleles had a mean decline on the total CAMCOG of 2.7 points compared with an improvement of >4 points among patients without APOE epsilon4 (T = 2.9 p = 0.006). CIND patients with an APOE epsilon4 allele also experienced greater decline in memory (T = 2.5, p = 0.015).</AbstractText>In older stroke patients with early cognitive impairment, the presence of an APOE epsilon4 allele is associated with greater progression of cognitive decline. This has implications for interventions aimed at the secondary prevention of dementia in stroke patients.</AbstractText>
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2,338,873 |
Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population.
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Hepatocyte nuclear factor (HNF)-4alpha is part of a transcription factor network that is key for the development and function of the beta-cell. Rare mutations in the HNF4alpha gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4alpha gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.
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2,338,874 |
Emergence of multidrug-resistant Salmonella enterica serovar typhi in Korea.
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A chloramphenicol-resistant strain of Salmonella enterica serovar Typhi was first noted in Korea in 1992, when a resistant isolate was detected in a returned traveler. Continued isolation of multidrug-resistant (MDR) strains thereafter in other settings prompted a retrospective analysis of laboratory records and phenotypic and genotypic analyses of 12 chloramphenicol-resistant isolates. Among these, one isolate was resistant only to chloramphenicol, and the other isolates were also resistant to ampicillin and co-trimoxazole. MDR was transferred by conjugation from 9 of the 11 isolates. PCR showed that all isolates had an incompatible group HI1 plasmid, and oriT was detected in 10 isolates, which included strains with an unsuccessful transfer of resistance. All of the ampicillin-resistant isolates had a beta-lactamase band of pI 5.4 and bla(TEM) alleles. A PCR amplicon from an isolate showed that the sequences were identical to those of bla(TEM-1), suggesting that all isolates had a TEM-1 beta-lactamase. All isolates had class 1 integrons: 10 isolates had integrons of ca. 1.2 kb with dhfr7 gene cassettes, and 1 isolate had an integron of ca. 2.3 kb with aacA4 and bla(OXA-1)-like gene cassettes. The pulsed-field gel electrophoresis patterns of 7 of 11 MDR isolates were identical and indistinguishable from those reported for isolates in India and Indonesia. In conclusion, some of the MDR strains in Korea are related to those in other Asian countries. Susceptibility testing became necessary for selection of antimicrobial agents for the optimal treatment of patients with the emergence of MDR Salmonella serovar Typhi in Korea.
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2,338,875 |
The effect of mutation on Rhodococcus equi virulence plasmid gene expression and mouse virulence.
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An 81 kb virulence plasmid containing a pathogenicity island (PI) plays a crucial role in the pathogenesis of Rhodococcus equi pneumonia in foals but its specific function in virulence and regulation of plasmid-encoded virulence genes is unclear. Using a LacZ selection marker developed for R. equi in this study, in combination with an apramycin resistance gene, an efficient two-stage homologous recombination targeted gene mutation procedure was used to mutate three virulence plasmid genes, a LysR regulatory gene homologue (ORF4), a ResD-like two-component response regulator homologue (ORF8), and a gene (ORF10) of unknown function that is highly expressed by R. equi inside macrophages, as well as the chromosomal gene operon, phoPR. Virulence testing by liver clearance after intravenous injection in mice showed that the ORF4 and ORF8 mutants were fully attenuated, that the phoPR mutant was hypervirulent, and that virulence of the ORF10 mutant remained unchanged. A virulence plasmid DNA microarray was used to compare the plasmid gene expression profile of each of the four gene-targeted mutants against the parental R. equi strain. Changes were limited to PI genes and gene induction was observed for all mutants, suggesting that expression of virulence plasmid genes is dominated by a negative regulatory network. The finding of attenuation of ORF4 and ORF8 mutants despite enhanced transcription of vapA suggests that factors other than VapA are important for full expression of virulence. ORF1, a putative Lsr antigen gene, was strongly and similarly induced in all mutants, implying a common regulatory pathway affecting this gene for all four mutated genes. ORF8 is apparently the centre of this common pathway. Two distinct highly correlated gene induction patterns were observed, that of the ORF4 and ORF8 mutants, and that of the ORF10 and phoPR mutants. The gene induction pattern distinguishing these two groups paralleled their virulence in mice.
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2,338,876 |
The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease.
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Dispositions for genes encoding opioid receptors may explain some variability in morphine efficacy. Experimental studies show that morphine and morphine-6-glucuronide are less effective in individuals carrying variant alleles caused by the 118 A > G polymorphism in the mu-opioid receptor gene (OPRM1). The purpose of the study was to investigate whether this and other genetic polymorphisms in OPRM1 influence the efficacy of morphine in cancer pain patients.</AbstractText>We screened 207 cancer pain patients on oral morphine treatment for four frequent OPRM1 gene polymorphisms. The polymorphisms were the -172 G > T polymorphism in the 5'untranslated region of exon 1, the 118 A > G polymorphism in exon 1, and the IVS2 + 31 G > A and IVS2 + 691 G > C polymorphisms, both in intron 2. Ninety-nine patients with adequately controlled pain were included in an analysis comparing morphine doses and serum concentrations of morphine and morphine metabolites in the different genotypes for the OPRM1 polymorphisms.</AbstractText>No differences related to the -172 G > T, the IVS2 + 31 G > A and the IVS2 + 691 G > C polymorphisms were observed. Patients homozygous for the variant G allele of the 118 A > G polymorphism (n = 4) needed more morphine to achieve pain control, compared to heterozygous (n = 17) and homozygous wild-type (n = 78) individuals. This difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, time until death, or adverse symptoms.</AbstractText>Patients homozygous for the 118 G allele of the mu-opioid receptor need higher morphine doses to achieve pain control. Thus, genetic variation at the gene encoding the mu-opioid receptor contributes to variability in patients' responses to morphine.</AbstractText>
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2,338,877 |
Clinical management where medicine meets management. Array of hope.
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Routine use of genetic profiling for managing some cancers could soon be a reality. Its wider application in cancer care will require substantial public investment in research and development, IT and setting up a service infrastructure. The first commercial test kits for breast cancer prognosis have already been launched in Europe and the US.
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2,338,878 |
Data partitions and complex models in Bayesian analysis: the phylogeny of Gymnophthalmid lizards.
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Phylogenetic studies incorporating multiple loci, and multiple genomes, are becoming increasingly common. Coincident with this trend in genetic sampling, model-based likelihood techniques including Bayesian phylogenetic methods continue to gain popularity. Few studies, however, have examined model fit and sensitivity to such potentially heterogeneous data partitions within combined data analyses using empirical data. Here we investigate the relative model fit and sensitivity of Bayesian phylogenetic methods when alternative site-specific partitions of among-site rate variation (with and without autocorrelated rates) are considered. Our primary goal in choosing a best-fit model was to employ the simplest model that was a good fit to the data while optimizing topology and/or Bayesian posterior probabilities. Thus, we were not interested in complex models that did not practically affect our interpretation of the topology under study. We applied these alternative models to a four-gene data set including one protein-coding nuclear gene (c-mos), one protein-coding mitochondrial gene (ND4), and two mitochondrial rRNA genes (12S and 16S) for the diverse yet poorly known lizard family Gymnophthalmidae. Our results suggest that the best-fit model partitioned among-site rate variation separately among the c-mos, ND4, and 12S + 16S gene regions. We found this model yielded identical topologies to those from analyses based on the GTR+I+G model, but significantly changed posterior probability estimates of clade support. This partitioned model also produced more precise (less variable) estimates of posterior probabilities across generations of long Bayesian runs, compared to runs employing a GTR+I+G model estimated for the combined data. We use this three-way gamma partitioning in Bayesian analyses to reconstruct a robust phylogenetic hypothesis for the relationships of genera within the lizard family Gymnophthalmidae. We then reevaluate the higher-level taxonomic arrangement of the Gymnophthalmidae. Based on our findings, we discuss the utility of nontraditional parameters for modeling among-site rate variation and the implications and future directions for complex model building and testing.
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2,338,879 |
Testing the phylogenetic position of a parasitic plant (Cuscuta, Convolvulaceae, asteridae): Bayesian inference and the parametric bootstrap on data drawn from three genomes.
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Previous findings on structural rearrangements in the chloroplast genome of Cuscuta (dodder), the only parasitic genus in the morning-glory family, Convolvulaceae, were attributed to its parasitic life style, but without proper comparison to related nonparasitic members of the family. Before molecular evolutionary questions regarding genome evolution can be answered, the phylogenetic problems within the family need to be resolved. However, the phylogenetic position of parasitic angiosperms and their precise relationship to nonparasitic relatives are difficult to infer. Problems are encountered with both morphological and molecular evidence. Molecular data have been used in numerous studies to elucidate relationships of parasitic taxa, despite accelerated rates of sequence evolution. To address the question of the position of the genus Cuscuta within Convolvulaceae, we generated a new molecular data set consisting of mitochondrial (atpA) and nuclear (RPB2) genes, and analyzed these data together with an existing chloroplast data matrix (rbcL, atpB, trnL-F, and psbE-J), to which an additional chloroplast gene (rpl2) was added. This data set was analyzed with an array of phylogenetic methods, including Bayesian analysis, maximum likelihood, and maximum parsimony. Further exploration of data was done by using methods of phylogeny hypothesis testing. At least two nonparasitic lineages are shown to diverge within the Convolvulaceae before Cuscuta. However, the exact sister group of Cuscuta could not be ascertained, even though many alternatives were rejected with confidence. Caution is therefore warranted when interpreting the causes of molecular evolution in Cuscuta. Detailed comparisons with nonparasitic Convolvulaceae are necessary before firm conclusions can be reached regarding the effects of the parasitic mode of life on patterns of molecular evolution in Cuscuta.
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2,338,880 |
Toxicogenomic approach to endocrine disrupters: identification of a transcript profile characteristic of chemicals with estrogenic activity.
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Public concerns have been raised in recent years over the possible adverse effects that may result from exposure to chemicals in the environment that have the potential to interfere with the normal function of the endocrine system in wildlife and humans ("endocrine disrupters"). Regulations have been established that require the testing of pesticides used in food crops and drinking water contaminants, for estrogenicity and other hormonal activities. In the United States, the U.S. EPA proposed the Endocrine Disrupter Screening Program, which consists of a Tier 1 screening battery of tests that is designed to identify chemicals capable of interacting with various hormonal systems, and different Tier 2 testing assays that are designed to verify and broaden the Tier 1 results. We identify 2 main problems with this approach: (1) the fact that the developmental stages that are the most susceptible to endocrine disruption are not represented in the screening tier, mainly because developmental effects tend to be latent, and there is no way to economically screen in developing models; and (2) the expense to screen each chemical to be included in this program. Thus, the need arises for an accurate, rapid, and cost effective method for assessing the potential endocrine activity of multiple chemicals during development. We hypothesize that the largely latent developmental effects of some endocrine disruptors are preceded by immediate changes in gene expression in the embryo and fetus. Therefore, an approach to assess the potential estrogenic (and other steroid hormonal) activity of different compounds is to identify those patterns of gene expression elicited in a tissue/organ exposed to these particular classes of chemicals. In this paper, the potential utility of such an approach for screening and better understanding of mechanism of action for specific chemicals with endocrine disrupter activities is presented, using as an example chemicals with estrogenic activity.
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2,338,881 |
Gene delivery: intelligent but just at the beginning.
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Gene therapy is used to treat genetic disorders, which may be achieved both ex vivo and in vivo. Gene-delivery systems usually include a carrier system which both protects the gene expression plasmid and allows its extracellular and intracellular trafficking. Viruses are used in most of the clinical trials today; however, they do have important drawbacks. Non-viral vectors based on lipids, water-soluble polycations, other non-condensing polymers and nano- or microparticles/capsules have been proposed. Cationic polymers, especially carrying novel targeting ligands. are receiving increasing attention. Intelligent polymers with temperature, pH, and light sensitivities for a controllable and effective non-viral transfection have recently been introduced but are just at the beginning. Our preliminary studies showed that block copolymers of N-isopropylacrylamide-acrylic acid with poly(ethylene imine) could be one example of these novel non-viral vectors.
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2,338,882 |
His tag effect on solubility of human proteins produced in Escherichia coli: a comparison between four expression vectors.
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We have compared four different vectors for expression of proteins with N- or C-terminal hexahistidine (His6) tags in Escherichia coli by testing these on 20 human proteins. We looked at a total recombinant protein production levels per gram dry cell weight, solubility of the target proteins, and yield of soluble and total protein when purified by immobilized metal ion affinity purification. It was found that, in general, both N- and C-terminal His6 tags have a noticeable negative affect on protein solubility, but the effect is target protein specific. A solubilizing fusion tag was able to partly counteract this negative effect. Most target proteins could be purified under denaturing conditions and about half of the proteins could be purified under physiological conditions. The highest protein production levels and yield of purified protein were obtained from a construct with C-terminal His tag. We also observe a large variation in cell growth rate, which we determined to be partly caused by the expression vectors and partly by the targets. This variation was found to be independent of the production level, solubility and tertiary structure content of the target proteins.
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2,338,883 |
A rapid and efficient transformation protocol for the grass Brachypodium distachyon.
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A fast and efficient microprojectile bombardment-mediated transformation protocol is reported for the grass species Brachypodium distachyon, a proposed alternative model plant to Oryza sativa for functional genomics in grasses. Embryogenic calli derived from immature embryos were transformed by a construct containing the uidA (coding for beta-glucuronidase) and bar (coding for phosphinothricin acetyl transferase) genes, and bialaphos, a non-selective herbicide, was used as the selection agent throughout all phases of the tissue culture. Average transformation efficiencies of 5.3% were achieved, and for single bombardments transformation efficiencies of up to 14% were observed. The time frame from the bombardment of embryogenic callus to the harvesting of transgenic T1 seeds was 29 weeks and 25 weeks for the diploid and two tetraploid accessions used, respectively. Since the seed-to-seed life cycle is 19 weeks for the diploid and 15 weeks for the tetraploid accessions, our B. distachyon transformation system allows testing of both the T0 and the T1 generation as well as production of T2 seeds within 1 year.
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2,338,884 |
MED, COMP, multilayered and NEIN: an overview of multiple epiphyseal dysplasia.
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This overview covers the group of disorders that presents radiographically as multiple epiphyseal dysplasia (MED). The disorders include "classic MED" (Ribbing and Fairbank types): MED that is caused by mutations in the cartilage oligomeric matrix protein (COMP), type IX collagen, and matrilin 3 genes (MATN3); and MED with multilayered patella, brachydactyly, and clubbed feet resultant from mutations in gene defect diastrophic dysplasia (DTDST). The recently identified gene/molecular abnormalities in these disorders have made more exact identification possible in many cases, although clinical testing is not always available. However, there are specific radiographic findings that allow the accurate diagnosis to be made, thus potentially guiding which molecular defect(s) should be investigated. The modes of inheritance of these distinct MED conditions are not identical. When a specific diagnosis is made, proper genetic counseling as well as prognostication, management issues and complications can be delineated to the patient and family. This review will include the mechanics of diagnostic and molecular triage for these disorders.
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2,338,885 |
[Congenital hearing loss. Molecular genetic diagnosis of connexin genes and genetic counselling].
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About 50% of congenital non-syndromic hearing impairment is caused by genetic factors. Research on the genetics of deafness has revealed a vast number of relevant genes. Mutations in the GJB2 gene have been shown to be the most common in several populations.</AbstractText>Mutation analysis of the genes for connexin 26, 30 and 31 (GJB2, GJB6 and GJB3) was performed in 67 patients with profound hearing loss.</AbstractText>Of the participants, 9% had two pathogenic mutations in the GJB2 gene. Pedigree information indicates that in these families further offspring have a 25% to a 100% chance of having hearing impairment.</AbstractText>Patients with non-syndromic hearing impairment should be offered molecular diagnostics of the GJB2 gene. Genetic counseling is mandatory for mutation carriers in order to advise them on the individual consequences of the gene test results.</AbstractText>
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2,338,886 |
Osteogenesis imperfecta presenting as simultaneous bilateral tibial tubercle avulsion fractures in a child: a case report.
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This is a case report of a unique presentation of a mild form of osteogenesis imperfecta (OI) (type IA) in a 9-year-old African-American boy who presented with simultaneous bilateral tibial tubercle avulsion fractures. The boy presented to the authors' emergency room complaining of acute bilateral knee pain. He could not perform a straight leg raise. Other than his orthopaedic examination, significant findings included blue sclera and irregular teeth. Radiographs and magnetic resonance imaging (MRI) confirmed bilateral tibia tubercle avulsion fractures. The patient underwent open reduction and internal fixation of his fractures, and postoperative genetic testing confirmed that the patient was heterozygous for OI. The authors present the fourth reported case of simultaneous bilateral tibial tubercle fractures. To their knowledge this is the first case of OI presenting with these fractures, the youngest reported case, and the first case with MRI documentation.
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2,338,887 |
Genotyping technologies: application to biotransformation enzyme genetic polymorphism screening.
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Pharmacogenomics encompasses several major areas: the study of polymorphic variations in drug response and disease susceptibility, identification of the effects of drugs/xenobiotics at the genomic level, and genotype/phenotype associations. The most common type of human genetic variations is single-nucleotide polymorphisms (SNPs). Several novel approaches to detection of SNPs are currently available. The range of new methods includes modifications of several conventional techniques, such as PCR, mass spectrometry (ms), and sequencing, as well as more innovative technologies such as fluorescence resonance energy transfer (FRET) and microarrays. The application of each of these techniques is largely dependent on the number of SNPs to be screened and sample size. The current chapter presents an overview of the general concepts of a variety of genotyping technologies, with an emphasis on the recently developed methodologies, including a comparison of the advantages, applicability, cost efficiency, and limitations of these methods.
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2,338,888 |
Haplotypic association of DDAH1 with susceptibility to pre-eclampsia.
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Association between pre-eclampsia (PEE1) and the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes, which play a role in the regulation of nitric oxide synthesis and release, was studied. In a case-control study design single nucleotide polymorphisms (SNPs) were determined at eight sites in the DDAH1 gene and at one site (Pro231Pro) in the DDAH2 gene from 132 women with pre-eclampsia and 112 healthy controls. Three SNPs in the DDAH1 gene were associated with pre-eclampsia, showing complete linkage disequilibrium with each other, but none of the associations in the allele or genotype data reached statistical significance in either of the genes after the correction for multiple testing. Haplotype frequencies were estimated using a population based on a maximum likelihood method (EM algorithm). Four common DDAH1 haplotypes were present and a significant association of haplotypes H2 and H3 with pre-eclampsia (P=0.03) was found. The risk of pre-eclampsia was greatest in individuals (odds ratio: 3.93; 95% confidence interval: 1.54-9.99) who had two copies of the high-risk haplotypes (H2 or H3). The observed haplotypic association provides the first evidence of the importance of DDAH1 polymorphisms in pre-eclampsia susceptibility.
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2,338,889 |
Mutational spectrum of p53 mutations in primary breast and ovarian tumors.
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Breast and ovarian cancers, like other cancers, occur due to genetic damage. Research aimed to determine the specific genes involved in the development of breast and ovarian cancers will help to understand how normal breast and ovarian epithelial cells escape regulation of proliferation, apoptosis and senescence. It was determined that approximately 10% of ovarian cancers and 20-30% of breast cancers arise in women who have inherited mutations in cancer susceptibility genes such as BRCA1, BRCA2 and other DNA repair genes. The ability to perform genetic testing permits the identification of women at increased risk who can then be offered preventive strategies. The vast majority of ovarian and breast cancers are sporadic, presumably resulting from the accumulation of genetic damage over lifetime. Several genes involved in breast and ovarian carcinogenesis have been identified, most notably the p53 tumor suppressor. The recent availability of expression microarrays has facilitated the simultaneous screening of thousands of genes and this will extend further the understanding of molecular events involved in the dynamic development of ovarian and breast cancers. Then, all this knowledge could be translated into effective screening, surveillance, prevention, and treatment strategies in the future.
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2,338,890 |
[Socio-psychological and ecological aspects within the system of nuclear radiation risk mitigation].
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The authors bring into light several aspects of nuclear radiation risks, i.e. physical safety of nuclear technologies and ecology, place of operator within the nuclear radiation safety system (proficiency, protective culture, safety guides) and consider approaches to the human factor quantification within the system of mitigation of risks from nuclear technologies, and IAEA recommendations on probable risk estimation. Future investigations should be aimed at extension of the radiation sensitivity threshold, personnel selection as by psychological so genetic testing for immunity to ionizing radiation, development of pharmachemical and physical protectors and methods of enhancing nonspecific resistance to extreme, including radiation, environments, and building of radiation event simulators for training.
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2,338,891 |
[Clinical and molecular genetic findings in isolated sporadic Duane syndrome].
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Duane retraction syndrome (DURS) accounts for 1 - 4 % of all cases of strabismus. Approximately 90 % of the cases are sporadic with a preponderance for females and the left eye. Many associated ocular and systemic findings have been described. Recently, mutations of SALL4 have been found in patients with autosomal-dominantly inherited Okihiro syndrome (DURS associated with forearm malformations). The aim of this study was the clinical examination of patients with isolated sporadic DURS and the molecular genetic analysis of SALL4 in these patients.</AbstractText>Twenty-five patients with non-familial DURS (aged 1 - 75 years, 16 female, 9male) were examined clinically and were interviewed concerning associated pathologies. DNA was prepared from peripheral lymphocytes, and the complete coding region of SALL4 was sequenced.</AbstractText>In 18 patients DURS affected the left eye, in four the right eye, and was bilateral in three patients. One patient had fused vertebrae, one had a cone-rod-dystrophy. No hearing impairments or malformation of the upper limbs were observed. No mutation in the coding region of SALL4 could be detected.</AbstractText>Associated conditions in DURS patients most commonly involve the ear, the spinal column, the kidneys and the heart and the upper limbs. No mutations in SALL4 could be detected in patients with isolated sporadic DURS as opposed to findings in familial Okihiro syndrome. However, Okihiro syndrome shows marked intra- and interfamilial variability, suggesting that in rare cases of isolated DURS a causative SALL4 mutation may be found.</AbstractText>
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2,338,892 |
[Accuracy of videokeratographic quantitative criteria for detection of keratoconus suspects in families with keratoconus].
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We statistically assessed the videokeratographic data obtained from families with keratoconus in order to determine reliable criteria for detecting keratoconus suspects.</AbstractText>Fourteen keratoconus patients from 12 families were enlisted. We investigated 55 relatives (110 eyes). Standard videokeratographic data were obtained by screening 30 individuals (60 eyes) with clinically normal eyes, with no history of ocular disorders, contact lens wear, or keratoconus individuals in their family. Videokeratographic qualitative and quantitative analyses were performed on every subject. The videokeratographic threshold values obtained from the control group were used as a reference.</AbstractText>Two criteria based on the Klyce/Maeda indices proved their statistical significance in detecting keratoconus suspects. When considering the significant criteria ascertained by the statistical analysis, building pedigrees favored the autosomal dominant mode of inheritance. Two of the pedigrees corresponded to either a recessive mode of transmission or the potential occurrence of a de novo mutation.</AbstractText>We have determined videokeratographic criteria of statistical significance for detecting keratoconus suspects. The knowledge of the status of each member of families with keratoconus is a prerequisite to performing genetic linkage analyses, which may allow a precise locus linked with this disorder to be refined.</AbstractText>
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2,338,893 |
A novel single nucleotide polymorphism (SNP) of the CYP2C19 gene in a Japanese subject with lowered capacity of mephobarbital 4'-hydroxylation.
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We sequenced all nine exons and exon-intron junctions of the cytochrome P450 2C19 (CYP2C19) gene from a Japanese subject with a lowered capacity of CYP2C19-mediated 4'-hydroxylation after an oral administration of mephobarbital. We found a novel single nucleotide polymorphism (SNP) of CYP2C19 gene as follows: SNP, 040110MoritaJ001; GENENAME: CYP2C19; ACCESSION NUMBER: NT_030059.8; LENGTH; 25 bases; 5'-GAGGGCCTGGCCC/TGCATGGAGCTGT-3'. The SNP (168946C>T) induced an amino acid alteration (Arg442Cys) located in exon 9 close to the heme-binding region of CYP2C19, which may result in the decrease in the catalytic properties of CYP2C19. A new allele having this SNP was designated as CYP2C19*16.
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2,338,894 |
Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons.
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Approximately 14% of genetic mutations in patients with ataxia-telangiectsia (A-T) are single-nucleotide changes that result in primary premature termination codons (PTCs), either UAA, UAG, or UGA. The purpose of this study was to explore a potential therapeutic approach for this subset of patients by using aminoglycosides to induce PTC read-through, thereby restoring levels of full-length ATM (A-T mutated) protein. In experiments using a modified in vitro cDNA coupled transcription/translation protein truncation test, 13 A-T cell lines carrying PTC mutations in different contexts exhibited read-through expression of ATM fragments, with three of four aminoglycosides tested. In ex vivo experiments with lymphoblastoid cell lines, we used radiosensitivity, radioresistant DNA synthesis, and irradiation-induced autophosphorylation of ATM Ser-1981 to show that the aminoglycoside-induced full-length ATM protein was functional and corrected, to various extents, the phenotype of A-T cells. These results encourage further testing of other compounds in this class, as well as follow up animal studies. Because some A-T patients with 5-20% of normal levels of ATM protein show slower neurological progression, A-T may prove to be a good model for aminoglycoside-induced read-through therapy.
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2,338,895 |
DEMSIM: a discrete event based mechanistic simulation platform for gene expression and regulation dynamics.
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In this paper, a discrete event based mechanistic simulation platform DEMSIM is developed for testing and validating putative regulatory interactions. The proposed framework models the main processes in gene expression, which are transcription, translation and decay processes, as stand-alone modules while superimposing the regulatory circuitry to obtain an accurate time evolution of the system. The stochasticity inherent to gene expression and regulation processes is captured using Monte Carlo based sampling. The proposed framework is applied to the extensively studied lac operon system, the SOS response system and the araBAD operon system of Escherichia coli. The results for the lac gene system demonstrate the simulation framework's ability to capture the dynamics of gene regulation, whereas the results for the SOS response system indicate that the framework is able to make accurate predictions about system behavior in response to perturbations. Finally, simulation studies for the araBAD system suggest that the developed framework is able to distinguish between different plausible regulatory mechanisms postulated to explain observed gene expression profiles. Overall, the obtained results highlight the effectiveness of DEMSIM at describing the underlying biological processes involved in gene regulation for querying alternative regulatory hypotheses.
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2,338,896 |
Altered molecular pathways in gliomas: an overview of clinically relevant issues.
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Primary central nervous system (CNS) tumors constitute a small fraction of the overall incidence of human cancer, but they represent a major source of cancer-related morbidity and mortality. The most common CNS tumor subtype in adults, high-grade astrocytoma, confers a dismal prognosis with a median survival of only 1 to 2 years. Other common adult CNS tumors, ie, low-grade astrocytomas and oligodendrogliomas, carry a less ominous, yet still poor prognosis. Unfortunately, there has been little progress in extending the survival or quality of life for glioma patients, despite nearly four decades of extensive research. This research has, however, greatly increased our understanding of the underlying molecular biology of these tumors, examples of which include the determination of elevated epidermal growth factor receptor (EGFR) as well as platelet-derived growth factor receptor (PDGF) signaling, and the inactivation of p53 , p16 , and PTEN tumor-suppressor genes (TSGs) that negatively regulate specific enzymatic activities in normal glial cells. Such observations have greatly improved our understanding of the pathogenesis of these tumors and have potential diagnostic as well as therapeutic relevance. With respect to the latter of these two issues, the identification of aberrant enzymatic activities in gliomas has promoted the development of novel therapeutic agents that target specific signaling effectors, and whose inhibition should, in theory, prove to be cytostatic, if not cytotoxic, to tumor cells. Several clinical trials are currently underway for testing these therapeutic agents in patients with primary brain tumors, and it is hoped that the targeting of pro-tumorigenic enzymatic activities will lead to better patient outcomes. In this review, we will describe the most pertinent genetic and signaling pathway alterations that are clinically relevant to the management of glial tumors.
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2,338,897 |
Molecular evolution and phylogenetic utility of the petD group II intron: a case study in basal angiosperms.
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Sequences of spacers and group I introns in plant chloroplast genomes have recently been shown to be very effective in phylogenetic reconstruction at higher taxonomic levels and not only for inferring relationships among species. Group II introns, being more frequent in those genomes than group I introns, may be further promising markers. Because group II introns are structurally constrained, we assumed that sequences of a group II intron should be alignable across seed plants. We designed universal amplification primers for the petD intron and sequenced this intron in a representative selection of 47 angiosperms and three gymnosperms. Our sampling of taxa is the most representative of major seed plant lineages to date for group II introns. Through differential analysis of structural partitions, we studied patterns of molecular evolution and their contribution to phylogenetic signal. Nonpairing stretches (loops, bulges, and interhelical nucleotides) were considerably more variable in both substitutions and indels than in helical elements. Differences among the domains are basically a function of their structural composition. After the exclusion of four mutational hotspots accounting for less than 18% of sequence length, which are located in loops of domains I and IV, all sequences could be aligned unambiguously across seed plants. Microstructural changes predominantly occurred in loop regions and are mostly simple sequence repeats. An indel matrix comprising 241 characters revealed microstructural changes to be of lower homoplasy than are substitutions. In showing Amborella first branching and providing support for a magnoliid clade through a synapomorphic indel, the petD data set proved effective in testing between alternative hypotheses on the basal nodes of the angiosperm tree. Within angiosperms, group II introns offer phylogenetic signal that is intermediate in information content between that of spacers and group I introns on the one hand and coding sequences on the other.
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2,338,898 |
[Mono- and dizygotic twins in forensic paternity testing in practice at the Department of Forensic Medicine (Silesian Academy of Medicine, Katowice) in the years 1996-2003].
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Giving an opinion on disputable paternity, concerning monozygotic twins in practice at the Department of Forensic Medicine (Silesian Academy of Medicine, Katowice) demonstrated their ideal agreement according to examined genetic markers possible. Even the mutation, which was revealed using the RFLP-VNTR method was the same for both twin sisters. In the case of dizygotic twins a firm differentiation of paternity index and probability of paternity was proved. This was the consequence of independent features segregation in first, reductive meiotic division. While the rare, out-ladder allele 16 at the CSF1PO locus was transmitted to both twins: a daughter and a son by the putative father.
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2,338,899 |
[Rare, out-ladder alleles at the STR loci in the population of Upper Silesia].<Pagination><StartPage>101</StartPage><EndPage>106</EndPage><MedlinePgn>101-6</MedlinePgn></Pagination><Abstract><AbstractText>Among individuals (participants of paternity testing) from the Upper Silesia region rare, out-ladder alleles in four STRs (routinely used in paternity testing) were found. There are alleles: VWA*12 and 21, CSF1PO*16, D13S317*6 and TPOX*5 with the following frequency: 0.0006 and 0.0006, 0.0005, 0.0006 and 0.0005.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Raczek</LastName><ForeName>Ewa</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Z Katedry Medycyny Sadowej Slaskiej AM w Katowicach. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>pol</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><VernacularTitle>Rzadkie, pozadrabinowe allele w STRowych loci w populacji Górnego Slaska.</VernacularTitle></Article><MedlineJournalInfo><Country>Poland</Country><MedlineTA>Arch Med Sadowej Kryminol</MedlineTA><NlmUniqueID>1260766</NlmUniqueID><ISSNLinking>0324-8267</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005819">Genetic Markers</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D016172" MajorTopicYN="N">DNA Fingerprinting</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005554" MajorTopicYN="N">Forensic Medicine</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005787" MajorTopicYN="Y">Gene Frequency</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005819" MajorTopicYN="N">Genetic Markers</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014644" MajorTopicYN="Y">Genetic Variation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010334" MajorTopicYN="Y">Paternity</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011044" MajorTopicYN="N" Type="Geographic">Poland</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012016" MajorTopicYN="N">Reference Values</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013048" MajorTopicYN="N">Specimen Handling</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020080" MajorTopicYN="N">Tandem Repeat Sequences</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>10</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>12</Month><Day>16</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>10</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15495554</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15495068</PMID><DateCompleted><Year>2005</Year><Month>03</Month><Day>23</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>21</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>4</Issue><PubDate><Year>2004</Year><Month>Oct</Month><Day>18</Day></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal>Disclosing to parents newborn carrier status identified by routine blood spot screening.
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Among individuals (participants of paternity testing) from the Upper Silesia region rare, out-ladder alleles in four STRs (routinely used in paternity testing) were found. There are alleles: VWA*12 and 21, CSF1PO*16, D13S317*6 and TPOX*5 with the following frequency: 0.0006 and 0.0006, 0.0005, 0.0006 and 0.0005.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Raczek</LastName><ForeName>Ewa</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Z Katedry Medycyny Sadowej Slaskiej AM w Katowicach. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>pol</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><VernacularTitle>Rzadkie, pozadrabinowe allele w STRowych loci w populacji Górnego Slaska.</VernacularTitle></Article><MedlineJournalInfo><Country>Poland</Country><MedlineTA>Arch Med Sadowej Kryminol</MedlineTA><NlmUniqueID>1260766</NlmUniqueID><ISSNLinking>0324-8267</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005819">Genetic Markers</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D016172" MajorTopicYN="N">DNA Fingerprinting</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005554" MajorTopicYN="N">Forensic Medicine</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005787" MajorTopicYN="Y">Gene Frequency</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005819" MajorTopicYN="N">Genetic Markers</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014644" MajorTopicYN="Y">Genetic Variation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010334" MajorTopicYN="Y">Paternity</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011044" MajorTopicYN="N" Type="Geographic">Poland</DescriptorName><QualifierName UI="Q000453" MajorTopicYN="N">epidemiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012016" MajorTopicYN="N">Reference Values</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013048" MajorTopicYN="N">Specimen Handling</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020080" MajorTopicYN="N">Tandem Repeat Sequences</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>10</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>12</Month><Day>16</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>10</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15495554</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15495068</PMID><DateCompleted><Year>2005</Year><Month>03</Month><Day>23</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>21</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>4</Issue><PubDate><Year>2004</Year><Month>Oct</Month><Day>18</Day></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal><ArticleTitle>Disclosing to parents newborn carrier status identified by routine blood spot screening.</ArticleTitle><Pagination><StartPage>CD003859</StartPage><MedlinePgn>CD003859</MedlinePgn></Pagination><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Newborn blood spot screening programmes are designed to detect serious conditions affecting individuals, where early treatment can improve health. It is suggested that screening can improve the experience of diagnosis for parents. For example, without newborn screening, when a child with cystic fibrosis becomes symptomatic a period of uncertainty can arise prior to diagnosis. These potential advantages of screening need to be weighed against potential disadvantages of screening at individual and population levels. Some newborn screening programmes inadvertently identify newborn infants who, although not affected by the condition, carry a gene for it and can pass on that gene to their children; these are 'genetic carriers'. Knowledge of newborn carrier status can lead to: testing of parents and family members, and concern about possible affected future siblings should both parents be identified as carriers; the possibility of such testing revealing the putative father is not the biological father; concern about the child's future reproductive choices; and unjustified anxiety about the health of the carrier newborn. There is an urgent need to develop clear guidance as to how to respond, with advances in technology fuelling the expansion of newborn blood spot screening and raised expectations of informed consent and disclosing test results. Depending on the condition for which screening is offered, options include: employing tests that do not identify carrier status, if available; identifying acceptable ways of disclosing carrier status; or identifying acceptable ways of not disclosing carrier status. These options are illustrated by screening programmes for sickle cell disorders and cystic fibrosis. Currently, there are no screening tests available for sickle cell disorders that do not identify carrier status. For cystic fibrosis, the policy choice is between an extended period of testing, and a screening result that is available sooner for most newborns, but inadvertently identifies carrier babies.<AbstractText Label="OBJECTIVES" NlmCategory="OBJECTIVE">The aim of this review was to assess the impact of disclosing to parents newborn carrier status inadvertently identified by routine newborn blood spot screening.<AbstractText Label="SEARCH STRATEGY" NlmCategory="METHODS">We searched for reports addressing disclosing newborn carrier status to parents following newborn screening for sickle cell disorders and cystic fibrosis in: commercially available electronic databases (October 2002), specialist registers, online journals, online abstracts and conference abstracts. We also scanned the reference lists of included papers.<AbstractText Label="SELECTION CRITERIA" NlmCategory="METHODS">Studies addressing the impact of disclosing carrier status using a soundly controlled trial or randomised controlled trial.<AbstractText Label="DATA COLLECTION AND ANALYSIS" NlmCategory="METHODS">Two researchers independently scanned titles and abstracts for relevance using the pre-specified inclusion criteria. Full reports of selected citations were then located and screened again for relevance by two researchers independently. At each stage, results were compared and discrepancies resolved by discussion.<AbstractText Label="MAIN RESULTS" NlmCategory="RESULTS">We found no controlled trials about disclosing carrier status.<AbstractText Label="REVIEWERS' CONCLUSIONS" NlmCategory="CONCLUSIONS">There is a need to develop and evaluate the effects of interventions to support the disclosure of carrier status to parents following newborn screening.
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