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2,336,900 |
Probing the sweet determinants of brazzein: wild-type brazzein and a tasteless variant, brazzein-ins(R18a-I18b), exhibit different pH-dependent NMR chemical shifts.
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Brazzein is a small, intensely sweet protein. As a probe of the functional properties of its solvent-exposed loop, two residues (Arg-Ile) were inserted between Leu18 and Ala19 of brazzein. Psychophysical testing demonstrated that this mutant is totally tasteless. NMR chemical shift mapping of differences between this mutant and brazzein indicated that residues affected by the insertion are localized to the mutated loop, the region of the single alpha-helix, and around the Cys16-Cys37 disulfide bond. Residues unaffected by this mutation included those near the C-terminus and in the loop connecting the alpha-helix and the second beta-strand. In particular, several residues of brazzein previously shown to be essential for its sweetness (His31, Arg33, Glu41, Arg43, Asp50, and Tyr54) exhibited negligible chemical shift changes. Moreover, the pH dependence of the chemical shifts of His31, Glu41, Asp50, and Tyr54 were unaltered by the insertion. The insertion led to large chemical shift and pKa perturbation of Glu36, a residue shown previously to be important for brazzein's sweetness. These results serve to refine the known sweetness determinants of brazzein and lend further support to the idea that the protein interacts with a sweet-taste receptor through a multi-site interaction mechanism, as has been postulated for brazzein and other sweet proteins (monellin and thaumatin).
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2,336,901 |
Hemoglobin H hydrops fetalis syndrome resulting from the association of the - -SEA deletion and the alphaQuong Szealpha mutation in a Chinese woman.
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A case with Hb H hydrops fetalis syndrome resulting from the association of the - -(SEA) deletion and the alpha(Quong Sze)alpha mutation is reported. This is the first description of Hb H hydrops associated with the Hb Quong Sze mutation.
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2,336,902 |
A novel polymorphism in the 5' untranslated region of the porcine cytochrome b5 (CYB5) gene is associated with decreased fat androstenone level.
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Raising intact male pigs would have a significant economic impact on the pork industry; however, the presence of 16-androstene (a major cause of boar taint) in meat from male pigs would be highly objectionable to consumers. In pigs, a positive correlation has been found between cytochrome b5 (CYB5) and production of 16-androstene. The search for polymorphism of CYB5 and functional analysis of polymorphism found should have an important impact on the efforts to develop genetic markers to select for low androstenone levels in fat from pigs. The aim of this study was to search the porcine CYB5 gene for mutations, examine its expression, identify genetic polymorphisms, and study how a genetic variation in this enzyme translates into interindividual variation in androstenone levels in fat from pig testis. We have identified a single nucleotide polymorphism (SNP) (G --> T) at base 8 up-stream of ATG in the CYB5 5' untranslated region which is associated with a lower fat androstenone level. Of the 229 testis samples tested, 84.8% were homozygous for the variant G, 12.4% were heterozygous, and 2.8% were homozygous for the variant T. Functional analysis of this mutation revealed that an individual homozygous for the T allele showed significantly lower CYB5 activity than an individual homozygous for the G allele. Thus, this may be at least partially responsible for a lower level of androstenone in pigs. Our findings provide an important genetic basis toward the goal of predicting the androstenone status in pigs and developing genetic markers for low androstenone.
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2,336,903 |
Instability of chimaeric antibody secretion by anti-carcinoembryonic antigen producing hybridoma cells after gene targeting.
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To produce a chimaeric version of the 11-285-14 anti-carcinoembryonic antigen (CEA) monoclonal antibody using a gene targeting approach.</AbstractText>A replacement vector was constructed to insert the human constant gamma1 gene within the mouse heavy chain locus of 11-285-14 hybridoma cells. The mouse constant gamma1 gene (1.5 kb) and the mouse mu intron fragment (2.2 kb) were amplified by PCR and cloned into a pKO Scrambler vector. The human constant gamma1 gene fragment (2.2 kb) was cloned next to the intron fragment. Resistant colonies were screened by ELISA for the presence of the human isotype in their supernatants.</AbstractText>Of the 4,370 resistant colonies obtained, 87 colonies showed secretion of the human isotype at levels between 4 and 32 ng/ml. PCR and Southern blot results confirmed the correct integration of the human gene by homologous recombination within the heavy chain locus. Most of the producers ceased to express the human isotype within a few weeks after the initial positive ELISA results. Instability of secretion could not be explained by genetic instability in all the clones, which suggests the presence of other undefined epigenetic or physiologic mechanisms.</AbstractText>Gene targeting resulted in transformants with unstable and low production rates of chimaeric anti-CEA antibody.</AbstractText>Copyright 2005 S. Karger AG, Basel</CopyrightInformation>
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2,336,904 |
Alpha-2-globin gene polyadenylation (AATAAA-->AATAAG) mutation in hemoglobin H disease among Kuwaitis.
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In the Arabian Gulf region, hemoglobin (Hb) H disease usually results from homozygosity or compound heterozygosity involving the alpha2-globin gene polyadenylation (poly A) signal (AATAAA-->AATAAG) mutation (alpha(T)alpha). Here we document the clinical and hemato logical characteristics of children with Hb H disease being followed in Kuwait.</AbstractText>Twenty-four patients (0.5-12 years old, mean 4.7 +/- 3.5 years) with persistent microcytic, hypochromic anemia (and normal iron status as well as normal Hb A2 levels) were referred to the pediatric hematology clinic for further investigations. They were all screened for the alpha+-thalassemia (alpha+-thal; -3.7 kb) deletion using a standard PCR method. They were also screened for the alpha2-globin gene alpha(T)alpha allele and the 5nt deletion (-alpha5nt) in the first intervening sequence, which are common alpha-thal alleles in this population. They were followed up for periods ranging from 2 to 8 years.</AbstractText>Of the 24 patients, 4 (16.7%) also had sickle cell trait (Hb-AS), while 7 (29.2%) were glucose-6-phosphate dehydrogenase deficient. Only 1 patient had significant hepatosplenomegaly and 1 developed gallstones. While none was on chronic transfusion therapy, 8 (33.3%) had been transfused at least once and, in 3 instances, this was secondary to parvovirus B19 +ve aplastic crisis. The alpha-globin genotype was successfully determined in almost all patients. The results showed that 17 (70.8%) patients were homozygous for the poly A mutation (alpha(T)alpha/alpha(T)alpha), 6 (25.0%) were compound heterozygotes for this and the alpha+-thal (-3.7 kb) deletion (-alpha/alpha(T)alpha) and 1 (4.2%) was undetermined. There were no significant differences in the phenotypes of the 2 genotypes and their hematological features were identical.</AbstractText>Hb H disease involving the poly A mutation is a mild thal intermedia phenotype among Kuwaitis. There are no serious complications and there is no need for regular blood transfusion.</AbstractText>Copyright 2005 S. Karger AG, Basel</CopyrightInformation>
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2,336,905 |
Mutations associated with beta-thalassemia intermedia in Kuwait.
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To identify the beta-globin gene mutations associated with beta-thalassemia (beta-thal) intermedia in Kuwait.</AbstractText>Eighteen patients from 13 unrelated families, mean age 12.7 +/- 8.1 years, range 4-31 years, were involved in the study. They did not require regular blood transfusion. Complete blood count and cation exchange high-performance liquid chromatography hemoglobin quantitation were carried out using standard techniques. Beta-thal mutations were identified with a combination of PCR amplification, allele- specific oligonucleotide hybridization or direct DNA sequencing. The patients were also screened for the alpha2-globin gene (-3.7 kb) deletion.</AbstractText>Of the 13 families, 4 were homozygous for the IVS-I-II (G-->A) and 4 for the IVS-I-6 (T-->C) mutations, while 1 each was a compound heterozygote for the following mutation combinations: CD 8 (-AA) and -101 (C-->T); IVS-I-6 (T-->C) and CD 19 (A-->G); IVS-II-1 (G-->A) and -28 (A-->C); IVS-I-110 (G-->A) and deltabeta0 deletion. Therefore, homozygosity for two typically mild mutations (IVS-II-1 and IVS-I-6) accounted for 61% of the genotypes in our patients.</AbstractText>Our results indicate that screening should commence with these two common alleles in Kuwaiti patients presenting with beta-thal syndrome. Early identification of intermedia patients will avoid the complications following an unnecessary hypertransfusion program.</AbstractText>Copyright 2005 S. Karger AG, Basel</CopyrightInformation>
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2,336,906 |
Variability of the 3'APOB minisatellite locus in Eastern Slavonic populations.
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To describe and compare the 3' apolipoprotein (Apo) B minisatellite allele frequency distributions of Eastern Slavonic populations and their Uralic, Altaic, and Caucasian speaking neighbors.</AbstractText>Healthy individuals of 10 populations among Russians, Byelorussians, Komis and Bashkirs were studied for variable number tandem repeats (VNTRs) in the 3'ApoB minisatellite region. Data were analyzed with other results reported for this polymorphism in eastern Europeans and Siberians.</AbstractText>Allele frequency spectra in Eastern Slavonic, Northern Caucasian and Finno-Ugric speaking populations are bimodal with the main peak in alleles 34-36 and a secondary mode around allele 48, whereas Altaic speaking populations have a unimodal allele frequency distribution with a peak of around 34-36 VNTRs. Population relationships were revealed using both multidimensional scaling analysis (based on Nei's genetic distance estimate) and testing for genetic heterogeneity. Eastern Slavonic populations (Russians, Ukrainians, Byelorussians) were most closely related to each other and formed a separate tight clusterwhen plotted. Testing for genetic heterogeneity among the Eastern Slavonic ethnic groups revealed maximum diversity among Byelorussians, followed by Russians, then Ukrainians. The 3'ApoB minisatellite variability reveals little heterogeneityamong the Eastern Slavonic ethnic groups, whereas there wassignificant heterogeneity for Northern Caucasian and Altaic speakers.</AbstractText>For this 3'ApoB polymorphism the Eastern Slavonic populations, despite their wide geographical distribution, appear to be much more homogenous than other ethnic groups of the region. Multidimensional scaling analysis of these data allowed for differentiation between individual populations from an ethnic group even if there is little heterogeneity.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,336,907 |
Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes.
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Malignant salivary gland tumors can arise from a t(11;19) translocation that fuses 42 residues from Mect1/Torc1, a cyclic AMP (cAMP)/cAMP-responsive element binding protein (CREB)-dependent transcriptional coactivator, with 982 residues from Maml2, a NOTCH receptor coactivator. To determine if the Mect1-Maml2 fusion oncogene mediates tumorigenicity by disrupting cAMP/CREB signaling, we have generated in-frame deletions within the CREB-binding domain of Mect1/Torc1 for testing transformation activity and have also developed a doxycycline-regulated Mect1-Maml2 mammalian expression vector for global gene expression profiling. We observed that small deletions within the CREB-binding domain completely abolished transforming activity in RK3E epithelial cells. Further, we have shown that the ectopic induction of Mect1-Maml2 in HeLa cells strongly activated the expression of a group of known cAMP/CREB-regulated genes. In addition, we detected candidate cAMP-responsive element sites within 100 nucleotides of the transcriptional start sites of other genes activated by Mect1-Maml2 expression. In contrast, we did not observe alterations of known Notch-regulated target genes in these expression array profile experiments. We validated the results by reverse transcription-PCR in transfected HeLa, RK3E, and H2009 lung tumor cells and in mucoepidermoid cancer cells that endogenously express the fusion oncopeptide. Whereas overexpression of components of the cAMP pathway has been associated with a subset of human carcinomas, these data provide a direct genetic link between deregulation of cAMP/CREB pathways and epithelial tumorigenesis and suggest future therapeutic strategies for this group of salivary gland tumors.
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2,336,908 |
A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction.
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Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial malformation caused by null mutations in the TCOF1 gene. High inter and intra familial clinical variability, ranging from mild malar hypoplasia to perinatal death due to airway collapse is observed, but, to date, no genotype-phenotype correlation has been reported. Considering haploinsufficiency as the molecular mechanism underlying the disease, we have hypothesized that mutations in the promoter region of the gene, which has never been previously characterized, in trans with a pathogenic mutation, could modulate the phenotype. Therefore, the aims of the present study were to determine the TCOF1 gene's core promoter and to identify mutations in this region that could contribute to the phenotypic variation observed in this syndrome. We have delimitated the minimal promoter to a region of less than 150 bp, with 63% of identity among 5 different species. We screened 1.2 kbp of the TCOF1 5' flanking sequence in the DNA obtained from 21 patients and 51 controls and identified four new single nucleotide polymorphisms (SNPs), one of which (-346C>T), was proved to be functional, as it decreased the promoter activity by 38%. Electrophoretic mobility shift assay (EMSA) analysis demonstrated that the -346T allele impairs DNA-binding to the YY1 transcription factor. This promoter variant represents a candidate allele to explain the clinical variability in patients bearing TCS.
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2,336,909 |
Construction and enzymatic degradation of multilayered poly-l-lysine/DNA films.
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The layer-by-layer (LbL) self-assembly of poly-l-lysine (PLL) and deoxyribonucleic acid (DNA) was used to construct the enzymatic biodegradable multilayered films. The LbL build up of DNA multilayers was monitored by UV-vis spectrometry, and atomic force microscopy (AFM). AFM, UV-vis spectrometry and fluorescence spectrometry measurements indicated that 90% of DNA within the films was released almost linearly under 5 U mL(-1)alpha-chymotrypsin in PBS at 37 degrees C in 35 h. TEM and zeta potential experiments revealed that the released DNA molecules were condensed into the slight positive complexes with size from 20 to several hundred nanometers. The well-structured, easy processed enzymatic biodegradable multilayered film may have great potential for gene applications in tissue engineering, medical implants, etc.
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2,336,910 |
Neuromuscular synaptogenesis in wild-type and mutant zebrafish.
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Genetic screens for synaptogenesis mutants have been performed in many organisms, but few if any have simultaneously screened for defects in pre- and postsynaptic specializations. Here, we report the results of a small-scale genetic screen, the first in vertebrates, for defects in synaptogenesis. Using zebrafish as a model system, we identified seven mutants that affect different aspects of neuromuscular synapse formation. Many of these mutant phenotypes have not been previously reported in zebrafish and are distinct from those described in other organisms. Characterization of mutant and wild-type zebrafish, from the time that motor axons first arrive at target muscles through adulthood, has provided the new information about the cellular events that occur during neuromuscular synaptogenesis. These include insights into the formation and dispersal of prepatterned AChR clusters, the relationship between motor axon elongation and synapse size, and the development of precise appositions between presynaptic clusters of synaptic vesicles in nerve terminals and postsynaptic receptor clusters. In addition, we show that the mechanisms underlying synapse formation within the myotomal muscle itself are largely independent of those that underlie synapse formation at myotendinous junctions and that the outgrowth of secondary motor axons requires at least one cue not necessary for the outgrowth of primary motor axons, while other cues are required for both. One-third of the mutants identified in this screen did not have impaired motility, suggesting that many genes involved in neuromuscular synaptogenesis were missed in large scale motility-based screens. Identification of the underlying genetic defects in these mutants will extend our understanding of the cellular and molecular mechanisms that underlie the formation and function of neuromuscular and other synapses.
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2,336,911 |
Clinical genotyping: the need for interrogation of single nucleotide polymorphisms and mutations in the clinical laboratory.
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Detection of single nucleotide polymorphisms (SNPs) and gene mutations is becoming more routine to the clinical laboratory.</AbstractText>Completion of the Human Genome Project has led to new scientific knowledge of human disease processes that has revealed the most fundamental of abnormalities in nucleic acids while at the same time bringing some of the most sophisticated diagnostic tools to the clinical laboratory. In addition, public awareness (both lay persons and healthcare providers) and sensitivity to human genetics has increased tremendously. Together, this rapidly evolving science and increased public education has led to an increasing demand for genotypic testing.</AbstractText>There are several clinical applications of human genotyping that are available using these newer technologies.</AbstractText>
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2,336,912 |
Applications of Luminex xMAP technology for rapid, high-throughput multiplexed nucleic acid detection.
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As we enter the post-genome sequencing era and begin to sift through the enormous amount of genetic information now available, the need for technologies that allow rapid, cost-effective, high-throughput detection of specific nucleic acid sequences becomes apparent. Multiplexing technologies, which allow for simultaneous detection of multiple nucleic acid sequences in a single reaction, can greatly reduce the time, cost and labor associated with single reaction detection technologies.</AbstractText>The Luminex xMAP system is a multiplexed microsphere-based suspension array platform capable of analyzing and reporting up to 100 different reactions in a single reaction vessel. This technology provides a new platform for high-throughput nucleic acid detection and is being utilized with increasing frequency. Here we review specific applications of xMAP technology for nucleic acid detection in the areas of single nucleotide polymorphism (SNP) genotyping, genetic disease screening, gene expression profiling, HLA DNA typing and microbial detection.</AbstractText>These studies demonstrate the speed, efficiency and utility of xMAP technology for simultaneous, rapid, sensitive and specific nucleic acid detection, and its capability to meet the current and future requirements of the molecular laboratory for high-throughput nucleic acid detection.</AbstractText>
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2,336,913 |
Present and future of rapid and/or high-throughput methods for nucleic acid testing.
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Behind the success of 'completing' the human genome project was a more than 30-year history of technical innovations for nucleic acid testing.</AbstractText>Discovery of specific restriction endonucleases and reverse transcriptase was followed shortly by the development of the first diagnostic nucleic acid tests in the early 1970s. Introduction of Southern, Northern and dot blotting and DNA sequencing later in the 1970s considerably advanced the diagnostic capabilities. Nevertheless, it was the discovery of the polymerase chain reaction (PCR) in 1985 that led to an exponential growth in molecular biology and the introduction of practicable nucleic acid tests in the routine laboratory. The past two decades witnessed a continuing explosion of technological innovations in molecular diagnostics. In addition to classic PCR and reverse transcriptase PCR, numerous variations of PCR and alternative amplification techniques along with an ever-increasing variety of detection chemistries, closed tube (homogeneous) assays, and automated systems were developed. Discovery of real-time quantitative PCR and the development of oligonucleotide microarrays, the 'DNA chip', in the 1990s heralded the beginning of another revolution in molecular biology and diagnostics that is still in progress.</AbstractText>
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2,336,914 |
DRD2 genotypes and substance use in adolescent children of alcoholics.
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Research has identified children of alcoholics (COAs) as a population at increased risk for developing substance use problems. Genetic studies support the Al allele of the D2 dopamine receptor gene (DRD2) as a risk marker for alcoholism and substance use disorders. In this study, substance use was assessed in 48 adolescent boys of alcoholics with the DRDR A1(+) allele (A1A1/A1A2 genotypes) or the A1(-) allele (A2A2 genotype). The results revealed that boys with the A1(+) allele tried (p=0.0001) and got intoxicated on alcohol more often (p=0.009) than boys with the A1(-) allele. Boys with the A1(+) allele tried more (p=0.004) and used more substances overall (p=0.008) than boys with the A1(-) allele. Boys with the A1(+) allele developed a tobacco habit more often (p=0.03) and experienced marijuana high at an earlier age (p=0.001) than boys with the A1(-) allele. The best predictors of substance use severity in boys with the A1(+) allele were Psychoticism (p=0.01) and Negative Affect (p=0.04). The results provide support for the DRD2 A1 allele as a marker identifying a subgroup of COAs at high risk for developing substance use problems.
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2,336,915 |
Gene transfer for hemophilia: can therapeutic efficacy in large animals be safely translated to patients?
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Gene transfer is a novel area of therapeutics in which the active agent is a nucleic acid rather than a protein or small molecule. As early as 1997, investigators reported long-term expression of therapeutic levels of factor IX using gene transfer techniques in hemophilia B mice, and similar data were thereafter reported in mice with hemophilia A. Efforts to translate these results to hemophilic dog models at first yielded only marginally therapeutic levels (1%-2% normal circulating levels), but within the past few years have achieved levels in the range of 10%-20% through multiple different gene transfer strategies. Early phase clinical testing has revealed that many aspects of gene transfer in humans were accurately predicted by studies in hemophilic dogs, but that other aspects were not, and were only appreciated as a result of clinical testing. Studies in the next few years will determine whether the problems identified in preclinical and early phase clinical testing can be solved to develop a therapeutic gene transfer approach to hemophilia.
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2,336,916 |
The alpha-toxin of Clostridium septicum is essential for virulence.
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Clostridium septicum is the causative agent of spontaneous gas gangrene or atraumatic myonecrosis, a sudden and frequently fatal infection that is increasingly associated with malignancy of the colon. Little is known about the disease process although the focus of virulence studies has been the alpha-toxin, a pore-forming cytolysin that is encoded by the csa gene and secreted as an inactive protoxin. Until now a lack of techniques for the genetic manipulation of C. septicum has hindered the use of molecular approaches to understand pathogenesis. By introducing plasmids by conjugation from Escherichia coli, we have developed methods for the genetic manipulation of C. septicum and constructed a chromosomal csa mutant by allelic exchange. Virulence testing of an isogenic series of strains consisting of the wild type, the csa mutant, and a csa mutant complemented with the wild-type csa gene revealed that the development of fulminant myonecrosis in mice was dependent on the ability to produce a functional haemolytic alpha-toxin. Furthermore, the inhibition of leukocyte influx into the lesion, which is very typical of clostridial myonecrosis, was also dependent on the ability to produce alpha-toxin. This study represents the first definitive identification of a virulence factor in this organism and opens the way for further studies that will delineate the role of other putative virulence factors in this significant pathogen.
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2,336,917 |
Genetic resistance to bovine tuberculosis in the Iberian wild boar.
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Bovine tuberculosis (bTB) is an important re-emerging zoonotic disease, causing major economic losses and constraining international trade of animals and their products. Despite eradication programmes, some countries continue to encounter outbreaks, mainly due to wildlife acting as primary hosts or reservoirs. While the genetic component of tuberculosis in humans and cattle is well documented, the role of genetic factors as modulators of bTB resistance remains unclear for natural populations. To address this issue, we investigated the relative contribution of host genetic variability to susceptibility to bTB infection and disease progression in wild boars from southern Spain. We found that genetic heterozygosity is an important predictor of bTB, not only modulating resistance to infection but also influencing containment of disease progression in infected individuals. Our results provide further evidence that host genetic variability plays a central role in natural populations. Testing each marker separately reveals evidence of both general and single-locus associative effects on bTB and several loci reveal high homology to regions of the genome with known immune function. Our results may prove to be crucial for understanding outbreaks of bTB in wildlife that could potentially affect domestic livestock and humans.
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2,336,918 |
Genetic testing for inherited breast cancer risk in African Americans.
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As genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations is increasingly integrated into the clinical management of high-risk women, it will be important to understand barriers and motivations for genetic counseling among women from underserved minority groups to ensure equitable access to these services. Therefore, the purpose of this review was to synthesize literature on knowledge and attitudes about genetic counseling and testing for inherited breast cancer risk in African Americans. We also review studies that evaluated genetic testing intentions in this population. We conducted a search of the PubMed database to identify studies related to BRCA1/2 testing in African Americans that were published between 1995 and 2003. Overall, studies have evaluated ethnic differences in knowledge and attitudes about genetic testing or have compared African American and Caucasian women in terms of genetic testing intentions. These studies have shown that knowledge about breast cancer genetics and exposure to information about the availability of testing is low among African Americans, whereas expectations about the benefits of genetic testing are endorsed highly. However, much less is known about the psychological and behavioral impact of genetic testing for BRCA1/2 mutations in African Americans. Additional research is needed to understand barriers and motivations for participating in genetic testing for inherited cancer risk in African Americans. The lack of studies on psychological functioning, cancer surveillance, and preventive behaviors following testing is a significant void; however, for these studies to be conducted, greater access to genetic counseling and testing in African Americans will be needed.
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2,336,919 |
Family history: the three-generation pedigree.
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The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial relationships as part of a family genogram. The three-generation pedigree provides a pictorial representation of diseases within a family and is the most efficient way to assess hereditary influences on disease. Two recent events have made family history assessment more important than ever: the completion of the Human Genome Project with resultant identification of the inherited causes of many diseases, and the establishment of national clinical practice guidelines based on systematic reviews of preventive interventions. The family history is useful in stratifying a patient's risk for rare single-gene disorders and more common diseases with multiple genetic and environmental contributions. Major organizations have endorsed using standardized symbols in pedigrees to identify inherited contributions to disease.
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2,336,920 |
African Jordanian population genetic database on fifteen short tandem repeat genetic loci.
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To establish a genetic database of the African-Jordanian population for forensic and paternity testing purposes.</AbstractText>Allelic distribution at fifteen short tandem repeat (STR) loci was determined for 95 healthy unrelated African-Jordanians. The 15 autosomal STR loci, included within the GenePrint PowerPlex 16 system, were amplified from the subset of the 95 DNA extracts isolated from the population sample. Electrophoresis for each polymerase chain reaction (PCR) product was carried out using the ABI Prism 310 Genetic Analyzer and the length of the amplified DNA fragments was determined using the Genotype 2.0 and PowerTyper 16 Macro softwares. Calculations of allelic frequencies, forensic efficiency parameters, Hardy-Weinberg departure, and quantitative analysis of the allele frequencies in various populations were determined.</AbstractText>DNA extracts were successfully amplified and the genetic database was compiled. All tested loci showed no significant statistical deviation from Hardy-Weinberg expectations. Furthermore, no significant difference was observed between the sample population under investigation and other population genetic databases.</AbstractText>The loci investigated here proved to be sufficiently polymorphic for forensic purposes, since the forensic efficiency values suggest that they are very discriminating in the African-Jordanian subpopulation.</AbstractText>
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2,336,921 |
RETIRED: Fetal soft markers in obstetric ultrasound.
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This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.
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2,336,922 |
HaploChIP: an in vivo assay.
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The characterization of protein-deoxyribonucleic acid (DNA) interactions occurring at an allele-specific level is important to resolving the functional consequences of genetic variation in non-coding DNA for gene expression and regulation. The approach of haplotype-specific chromatin immunoprecipitation (i.e., haploChIP) resolves in living cells relative protein-DNA binding to a particular allele through immunoprecipitation of proteins crosslinked to DNA. Single-nucleotide polymorphisms present in a heterozygous form are used as markers to differentiate allelic origin. This in turn allows resolution of specific haplotypes showing differences in relative protein occupancy. The haploChIP approach allows testing of in vitro hypotheses that a transcription factor protein shows haplotype specific occupancy. In addition, the haploChIP approach allows screening of haplotypes for differences in relative gene expression by immunoprecipitation using antibodies to phosphorylated Pol II.
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2,336,923 |
Measuring paternal discrepancy and its public health consequences.
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Paternal discrepancy (PD) occurs when a child is identified as being biologically fathered by someone other than the man who believes he is the father. This paper examines published evidence on levels of PD and its public health consequences. Rates vary between studies from 0.8% to 30% (median 3.7%, n = 17). Using information from genetic and behavioural studies, the article identifies those who conceive younger, live in deprivation, are in long term relationships (rather than marriages), or in certain cultural groups are at higher risk. Public health consequences of PD being exposed include family break up and violence. However, leaving PD undiagnosed means cases having incorrect information on their genetics and fathers continuing to suspect that children may not be theirs. Increasing paternity testing and use of DNA techniques in clinical and judicial procedures means more cases of PD will be identified. Given developing roles for individual's genetics in decisions made by health services, private services (for example, insurance), and even in personal lifestyle decisions, the dearth of intelligence on how and when PD should be exposed urgently needs addressing.
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2,336,924 |
Genetic and economic evaluation of Japanese Black (Wagyu) cattle breeding schemes.
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Deterministic simulation was used to evaluate 10 breeding schemes for genetic gain and profitability and in the context of maximizing returns from investment in Japanese Black cattle breeding. A breeding objective that integrated the cow-calf and feedlot segments was considered. Ten breeding schemes that differed in the records available for use as selection criteria were defined. The schemes ranged from one that used carcass traits currently available to Japanese Black cattle breeders (Scheme 1) to one that also included linear measurements and male and female reproduction traits (Scheme 10). The latter scheme represented the highest level of performance recording. In all breeding schemes, sires were chosen from the proportion selected during the first selection stage (performance testing), modeling a two-stage selection process. The effect on genetic gain and profitability of varying test capacity and number of progeny per sire and of ultrasound scanning of live animals was examined for all breeding schemes. Breeding schemes that selected young bulls during performance testing based on additional individual traits and information on carcass traits from their relatives generated additional genetic gain and profitability. Increasing test capacity resulted in an increase in genetic gain in all schemes. Profitability was optimal in Scheme 2 (a scheme similar to Scheme 1, but selection of young bulls also was based on information on carcass traits from their relatives) to 10 when 900 to 1,000 places were available for performance testing. Similarly, as the number of progeny used in the selection of sires increased, genetic gain first increased sharply and then gradually in all schemes. Profit was optimal across all breeding schemes when sires were selected based on information from 150 to 200 progeny. Additional genetic gain and profitability were generated in each breeding scheme with ultrasound scanning of live animals for carcass traits. Ultrasound scanning of live animals was more important than the addition of any other traits in the selection criteria. These results may be used to provide guidance to Japanese Black cattle breeders.
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2,336,925 |
Disgust in pre-clinical Huntington's disease: a longitudinal study.
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Emotion recognition from both face and voice and experience of emotions were investigated in a group of non-symptomatic people at risk of carrying the Huntington's disease gene who presented for genetic testing. Based on the results of the DNA test, a group of people carrying the Huntington's disease gene (HD+), and a group of non-carriers (HD-) were formed. Since we were especially interested in the time course of possible deficits in emotion recognition, all people at risk were reassessed 6 and 12 months after the initial assessment. Recognising facial expressions of disgust was significantly impaired on all three assessments in the HD+ group, while recognition of vocal emotions and the experience of emotions were largely unaffected, confirming that deficits in recognition of facial expressions of disgust are an early correlate of carrying the gene for Huntington's disease. The inclusion of a healthy control group (n = 37) further allowed an estimate of the genetic and environmental contribution to deficits in facial emotion recognition.
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2,336,926 |
An exploratory comparison of genetic counselling protocols for HNPCC predictive testing.
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Most UK genetics centres offering predictive testing for hereditary non-polyposis colorectal cancer (HNPCC) use an extended counselling protocol originally developed for Huntington's disease. Shortened counselling may be more appropriate in the context of treatable genetic conditions such as HNPCC. Twenty-six high-risk individuals were randomized to extended genetic counselling (two sessions of education and reflection held 1 month apart) or shortened genetic counselling (a single educational session) prior to HNPCC testing. Prospective questionnaires, interviews and transcripts of counselling sessions were analysed. Participants were unsure what to expect prior to genetic counselling and had already decided to undergo genetic testing. There was no evidence of psychological harm caused by shortened genetic counselling, with a high level of satisfaction with the counselling received in both groups. Reflective counselling occurred in both groups but was framed in terms of practical action and information. Participants expressed differing preferences for the level of information received. This exploratory study indicates that shortened genetic counselling may be an appropriate means of supporting decisions already made by individuals about HNPCC testing. However, participants would benefit from preparatory information to help them reflect on issues not previously considered, which can then be explored more fully as part of a tailored counselling approach.
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2,336,927 |
A novel locus for autosomal dominant hereditary gingival fibromatosis, GINGF3, maps to chromosome 2p22.3-p23.3.
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Hereditary gingival fibromatosis (HGF) is a rare, benign disorder characterized by slowly progressive fibrous overgrowth of the gingiva. To date, two loci have been mapped in familial cases with autosomal dominant non-syndromic HGF: GINGF (MIM 135300) on chromosome 2p21-p22 and GINGF2 (MIM 605544) on chromosome 5q13-q22. Of the two loci, only SOS1 (son of sevenless one, MIM 182530) gene underlying GINGF locus has been identified. Ascertainment of a large Chinese family has allowed the mapping of a novel locus to 2p22.3-p23.3, GINGF3. Haplotype construction and analysis localized the new locus to an 11.4-cM interval between markers D2S2221 (telomeric) and D2S1788 (centromeric). The maximum two-point limit of detection (LOD) score of 3.45 (theta=0) and multipoint LOD score of 5.00 for marker D2S390 strongly supported linkage to this region. Thus, this genetic interval is distal to and does not overlap with the previously described locus, GINGF, on 2p21-p22.
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2,336,928 |
'Indirect' BRCA1/2 testing: a useful approach in hereditary breast and ovarian cancer families without a living affected relative.
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We report an approach for BRCA1/2 testing whereby genetic testing can be offered to families at high risk of hereditary breast and ovarian cancer but where no DNA from affected relatives is available. By testing two or more unaffected relatives at 50% risk of being heterozygous for a potential BRCA1/2 mutation, there is a chance of up to 99% of finding a mutation that would have been detectable in an affected individual from the same family. The overall likelihood of identifying a mutation is dependent on the family history, and therefore 'indirect' testing would be most applicable for families with a very high risk of carrying a BRCA1/2 mutation. Using this approach also requires balancing issues of testing resource limitations, family dynamics and adequate preparation of unaffected persons for a positive test, with the advantages of targeting screening and prophylactic surgery.
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2,336,929 |
Psychological functioning in African American women at an increased risk of hereditary breast and ovarian cancer.
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Despite attention to psychological issues during genetic counselling and testing for hereditary breast and ovarian cancer risk, limited information is available on cancer-specific distress among African American women being targeted for participation in counselling and testing. Therefore, the purpose of this study is to examine cancer-specific distress in African American women at an increased risk of hereditary breast and ovarian cancer and to identify factors having significant associations with distress in this population. Respondents were 141 African American women identified for participation in genetic counselling and testing for BRCA1/2 mutations. Overall, respondents reported moderate levels of cancer-specific distress. Younger age (coefficient=6.0, p=0.001), being unemployed (coefficient=-5.0, p=0.01), and having a personal history of cancer (coefficient=5.0, p=0.02) had significant associations with intrusion. Younger age was also associated significantly with greater avoidance (r=6.0, p=0.02). These results suggest that African American women aged 50 and younger, those who are unemployed and women with a personal history of breast or ovarian cancer may be the most vulnerable to experiencing elevated levels of distress during genetic counselling and testing. Greater attention to psychological issues, including concerns about cancer and cancer risks, may be needed during genetic counselling and testing for BRCA1/2 mutations with these women.
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2,336,930 |
Phaeochromocytoma: current concepts.
|
The discovery of novel mutations in genes encoding succinate dehydrogenase subunits has revealed that familial phaeochromocytomas are much more common than previously thought. Genetic screening should be offered to patients with apparently sporadic phaeochromocytomas and their first-degree relatives. An increasing proportion of phaeochromocytomas present preclinically on genetic testing or as "incidentalomas" on abdominal imaging, rather than with classic symptoms and signs. Clinical suspicion should prompt measurement of plasma levels of free metanephrine or 24-hour urinary catecholamine and metanephrine levels, followed, if positive, by tumour localisation studies. With appropriate perioperative care, surgical management of phaeochromocytomas is safe and effective. Most tumours can be removed laparoscopically.
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2,336,931 |
Early effect of gene therapy on a direct muscle neurotization model.
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Direct nerve-to-muscle neurotization has been the subject of both clinical and experimental studies. In this study, the authors report a new animal model to test the regenerative properties of a nerve (musculocutaneous) implanted in a muscle (biceps). They also report the early effects of the application at the implantation site of exogenously administered Brain Derived Nerve Factor (BDNF) and of endogenously produced BDNF, via the administration of an adenoviral construct with a tissue-specific promotor for muscle cells (AdRSV), and containing the BDNF gene. Evaluation included behavioral testing (grooming test), electrical stimulation, Western blot analysis of the distal implanted nerve to determine the presence of locally produced BDNF, and motor end-plate staining of the biceps muscle. At the early time point of 1 week following the musculocutaneous nerve to biceps muscle implantation, there was no increased production of recombinant BDNF at the distal implanted musculocutaneous nerve, as assessed by Western blot analysis. Therefore, there was no significant difference in the behavioral evaluation of the animals at 1 week; the Terzis grooming test showed no statistical difference among groups, but a trend toward better function for the BDNF and the high-dose AdRSV-BDNF groups, compared to the control groups. There was also no difference in the histologic appearance and number of the motor end-plates at the implantation site, compared to the controls. The electrical stimulation of the MC nerve did not produce statistically significant results among the experimental groups. In this direct nerve to muscle neurotization model, the application of AdRSV-BDNF at 3 x 10 (9) pfu/ul did not show enhanced production of BDNF at 1 week.
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2,336,932 |
Haplotyping of STR cluster DXS6801-DXS6809-DXS6789 on Xq21 provides a powerful tool for kinship testing.
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Short tandem repeat (STR) markers DXS6801 (GATA41B11), DXS6809 (GATA69B129) and DXS6789 (GATA31F01) are located in a 3-Mb region on human chromosome Xq21, spanning approximately 3-6 cM. Theoretically, this cluster could give rise to 1,144 different haplotypes in the German population. In fact, genotyping of 806 males revealed the presence of 207 different haplotypes. Since the three STRs have been shown to be in strong linkage disequilibrium (LD), haplotype frequencies cannot be computed on the basis of single locus allele frequencies alone, but have to be estimated directly instead. In this work, we present data on linkage, haplotype frequencies and LD in the German population. To highlight the potential of the STR cluster for forensic analysis, we also report two examples of its successful application in pedigree-based kinship testing.
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2,336,933 |
The shared epitope is a marker of severity associated with selection for, but not with response to, infliximab in a large rheumatoid arthritis population.
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To determine whether joint destruction, indication for, and response to infliximab in rheumatoid arthritis are associated with the shared epitope (SE) or selected cytokine gene polymorphisms (interleukin (IL) 1B, IL1-RN, and tumour necrosis alpha).</AbstractText>In a large rheumatoid arthritis population of 930 patients from the same area (Rhône-Alpes, France), patients with (n = 198) or without infliximab treatment (n = 732) were compared according to their genetic status. Clinical, biological, and radiological data were collected. Typing for SE status and cytokine polymorphisms was carried out using enzyme linked oligosorbent assay. Statistical analysis was by chi(2) testing and calculation of odds ratios (OR).</AbstractText>A dose relation was observed between the number of SE copies and joint damage in the whole rheumatoid population (OR, 1 v 0 SE copy = 2.38 (95% confidence interval, 1.77 to 3.19), p<0.001; OR 2 v 0 SE copy = 3.92 (2.65 to 5.80), p<0.001. The SE effect increased with disease duration but was not significant before two years. Selection for infliximab treatment (n = 198) was associated with increased disease activity, joint damage, and the presence of the SE with a dose effect. In all, 66.2% patients achieved an ACR20 improvement. No clinical or genetic factors were able to predict the clinical response to infliximab.</AbstractText>This post-marketing study in a large cohort of rheumatoid arthritis patients indicates a linkage between rheumatoid arthritis severity, selection for treatment with infliximab, and the presence and dose of the SE.</AbstractText>
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2,336,934 |
Genetics education in a culturally diverse population--lessons learnt, future directions.
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To provide equitable genetics education services, the needs of a culturally and linguistically diverse (CALD) population must be addressed. The mission of the Centre for Genetics Education (CGE) in Australia articulates a commitment to fostering community partnerships, implementing educational strategies and evaluating the impact of genetics information and technology on society. The aim of this report is to review the ways in which CALD groups have been partners in the planning and implementation of genetics educational strategies of the Centre. Responding to the community and respecting its contribution has helped forge these partnerships and implement appropriate and relevant educational strategies. The partnerships have been effective in modulating both the protocols used in producing resources, the resource content itself, and the provision of more appropriately targeted resources for these community groups.
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2,336,935 |
Strategies for the prevention of hereditary diseases in a highly consanguineous population.
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Autosomal recessive hereditary diseases are relatively common in the Saudi population. The consanguinity rate is in excess of 50% and is a practice that remains strongly embedded within Saudi culture. The impact of this practice is recognized and is being addressed. Early detection and treatment of diseases can reduce mortality and minimize morbidity. This is the basis of successful neonatal screening for inborn errors of metabolism where treatment or modification of lifestyle can modulate disease. Ultimately, understanding the genetics of these diseases will provide opportunities for prevention. Options such as prenatal screening can be used to reduce the incidence of live births with inherited diseases. However, prenatal diagnosis and associated intervention is unacceptable to wide sections of all societies. Carrier detection and genetic counselling programmes have been very successful in reducing the incidence of inherited disorders in many populations. These programmes are most successful when they are sensitive to the cultural backgrounds of populations in which they are applied. In Saudi society, premarital screening to identify carrier status and the provision of appropriate counselling has tremendous potential to prevent inherited disease.
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2,336,936 |
Prevention of thalassaemia and haemoglobinopathies in remote and isolated communities--the Maldives experience.
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The Maldives comprises 1192 islands covering a land mass that amounts to under 1% of the total geographical territory of the country. The population of 280,000 is dispersed across 200 isolated communities, with an average of 1000 people per community. Recent progress in health terms include a reduction in the infant mortality rate from 62 in 1992 to 14 in 2003, and 95% coverage in child immunization. In 1992, SHE a non-governmental organization established that the beta-thalassaemia prevalence rate was 18.1% (1 in 5) and on the basis of the result, launched a nationwide awareness and population screening programme, visiting each island in the Maldives every 5 years and targeting 12-35-year-olds. Screening of 100 cord blood samples indicated a 28% incidence of alpha-thalassaemia. Screening results highlighted significantly high incidence of more than one haemoglobinopathy on individual islands. This is of particular importance given the norm of intra-island marriages. Specific mutation analysis showed that three mutations accounted for more than 95% of the thalassaemia genes, ensuring a high detection rate and cost effectiveness of a prenatal diagnosis programme. Outcomes of the screening programme include screening of more than 25% of the target population; the establishment of a Government National Thalassaemia Centre; inclusion of thalassaemia into the school curriculum; the legal requirement for screening prior to marriage; legalization of prenatal diagnosis and medical termination of pregnancy; and the commencement of prenatal diagnostic services. The programme successes include effective advocacy, resource mobilization, motivation for screening, voluntary blood donation, and thalassaemia becoming a household word in the country.
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2,336,937 |
Alpha-thalassaemia and population health in Southeast Asia.
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Alpha-thalassaemia mutations are common. In Southeast Asia, they cause Hb H disease and Hb Barts hydrops fetalis. Fetuses with the devastating Hb Barts hydrops fetalis due to the complete lack of alpha-globin gene die in utero or shortly after birth, often during the second or third trimesters. Recent findings on patients with Hb H disease who have only one active alpha-globin gene suggest that it is not necessarily a benign disorder as previously thought. The disease burden of these syndromes and their public health importance have been largely neglected. We review the population carrier frequencies of alpha-thalassaemia, and summarize the clinical features, diagnostic approaches, counselling and management of these common genetic disorders. Several practical proposals are made that, if implemented, can begin to address the issues of collaboration and improvement for care of these common diseases in the region.
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2,336,938 |
Cancer-specific gene therapy.
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Cancer cells transcriptionally activate many genes that are important for uncontrolled proliferation and cell death. Deregulated transcriptional machinery in tumor cells usually consists of increased expression/activity of transcription factors. Ideally, cancer-specific killing can be achieved by delivering a therapeutic gene under the control of the DNA elements that can be activated by transcription factors that are overexpressed and/or constitutively activated in cancer cells. Additionally, tumor-specific translation of tumor-killing genes has been also exploited in cancer gene therapy. Based on these rationales, cancer-specific expression of a therapeutic gene has emerged as a potentially successful approach for cancer gene therapy. To achieve tumor-specific expression, cancer-specific vectors are generally composed of promoters, enhancers, and/or 5'-UTR that are responsive to tumor-specific transcription factors. A number of cancer-specific promoters have been reported, such as those of probasin, human telomerase reverse transcriptase, survivin, ceruloplasmin, HER-2, osteocalcin, and carcinoembryonic antigen. Evidences suggest that the enhancer element targeted by beta-catenin can be useful to target colon cancer cells. The 5'-UTR of the basic fibroblast growth factor-2 has been reported to provide tumor specificity. Moreover, a variety of therapeutic genes demonstrated direct antitumor effects such as those encoding proapoptotic proteins p53, E1A, p202, PEA3, BAX, Bik, and prodrug metabolizing enzymes, namely thymidine kinase and cytosine deaminase. As cancerous cells of different origins vary significantly in their genetic, transcriptional/translational, and cellular profiles, the success of a cancer gene therapy will not be promised unless it is carefully designed based on the biology of a specific tumor type. Thus, tremendous research efforts have been focused on the development of non-viral vectors that selectively target various tumors resulting in minimal toxicity in the normal tissues. Significant progresses were also made in the exploitation of various novel apoptotic, cytotoxic genes as therapeutic tools that suppress the growth of different tumors. Together, these recent advances provide rationales for future clinical testing of transcriptionally targeted non-viral vectors in cancer patients.
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2,336,939 |
DNA sequence variations in the prolyl isomerase Pin1 gene and Alzheimer's disease.
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Senile plaques and neurofibrillary tangles (NFT) are the prominent lesions in the brain of Alzheimer's disease (AD) patients. NFT are mainly composed of an abnormally phosphorylated form of tau protein, which has lost its function to bind microtubules and promote their assembly. Tau hyperphosphorylation critically decreases tau function and precedes neurodegeneration. The majority of tau phosphorylation sites are Ser/Thr-Pro motifs, which are known to exist in two distinct cis and trans conformations. The prolyl isomerase Pin1 catalyses the conversion of those conformations. Pin1 binds to tau specifically at the Thr231-Pro site and restores tau function, either by inducing conformational changes or facilitating dephosphorylation. It has been shown that Pin1 expression levels inversely correlate with the predicted vulnerability of different brain areas to neurodegeneration and soluble Pin1 is depleted in neurons from AD brains; furthermore, Pin1 knock-out mice develop signs and symptoms of tau-related pathologies late in life. It seems that Pin1 plays an important role in maintaining tau function, thereby preserving neuronal homeostasis and preventing age-dependent neurodegeneration. DNA sequence variations in Pin1 gene may affect its expression level or function and influence the individual risk for developing AD. We screened by denaturing high performance liquid chromatography the genomic DNA of 120 AD subjects and 134 age-matched controls and we found very few and rare sequence variations in the promoter region and in exons 2 and 3. We conclude that Pin1 is a very well conserved gene, whose rare nucleotide variations have no effect on the individual genetic risk for AD.
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2,336,940 |
Polymerase chain reaction screening for DNA viruses in paraffin-embedded brains from dogs with necrotizing meningoencephalitis, necrotizing leukoencephalitis, and granulomatous meningoencephalitis.
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The objective of this investigation was to determine whether or not herpesvirus (herpes-), adenovirus (adeno-), or canine parvovirus DNA is present in the brains of dogs with necrotizing meningoencephalitis (NME), necrotizing leukoencephalitis (NLE), and granulomatous meningoencephalitis (GME). Paraffin-embedded brain specimens from 12 histopathologically confirmed dogs with NME, 3 with NLE, and 7 with GME were screened for viral DNA with degenerate herpes- and adenovirus polymerase chain reaction (PCR) and a canine parvovirus-specific PCR. Positive-control specimens included genomic viral DNA and paraffin-embedded tissues from dogs with confirmed herpes-, adeno-, or canine parvovirus infections. Herpes-, adeno-, or canine parvovirus DNA was amplified by PCR from the corresponding positive-control specimens. Negative controls included 7 dogs with various brain disorders and produced no viral amplicons. The 22 dogs with NME, NLE, and GME were negative for viral DNA. Additional studies testing for other viruses or inherited genetic mutations are warranted to gain insight into the etiologies of NME, NLE, and GME. We discuss potential etiologies and provide a clinical and histopathologic overview of these common canine encephalitides.
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2,336,941 |
Exact family-based association tests for biallelic data.
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Family-based study designs have an important role in the search for association between disease phenotypes and genetic markers. Unlike traditional case-control methods, family-based tests use within-family data to avoid identification of spurious associations that may result from population admixture. Many family-based association tests have been proposed to accommodate a variety of ascertainment schemes and patterns of missing data. In this report, we describe exact family-based association tests for biallelic data. Specifically, we discuss test of the null hypotheses "no linkage and no association" and "linkage, but no association". These tests, which are valid under various models for inheritance and patterns of missingness, utilize the procedure proposed by Rabinowitz and Laird [2000: Hum Hered 50:211-223] that provides a unified framework for family based association testing (FBAT). The conditioning approach implemented in FBAT makes an exact test conceptually straightforward, but computationally difficult since the minimum sufficient statistics upon which we condition do not have a conventional form. An exact test may be especially critical when accurate computation of the extreme area of the FBAT statistic is needed, such as when the study design necessitates multiple comparisons adjustments. We describe the exact approach as a useful alternative to the asymptotic test and show that the exact tests for biallelic data may be most useful for the recessive disease model.
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2,336,942 |
Identification, characterization, and association analysis of novel genes from the bipolar disorder susceptibility locus on chromosome 4q35.
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The cause of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical, biochemical, or genetic defect. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. We previously identified a bipolar disorder susceptibility locus on chromosome 4q35 and refined the interval harboring this susceptibility gene to approximately 5 Mb, a size that is amenable to positional cloning. Several independent studies have reported the presence of a susceptibility gene at this locus. To identify candidate genes for testing for association with bipolar disorder, we previously established a transcript map that encompasses the candidate interval. We have continued to seek novel genes from this region in order to expand this transcript map. Here, we describe the further identification and characterization of eight novel genes from the chromosome 4q35 bipolar candidate interval. Expression analysis determined that six of these novel genes are expressed in the brain, and these genes were therefore analyzed for association with bipolar disorder. Single nucleotide polymorphisms were identified from the candidate genes and tested for association in our case-control cohort. Our data suggest that the six candidate genes analyzed can be excluded from involvement in the disorder.
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2,336,943 |
Familial autoinflammatory diseases: genetics, pathogenesis and treatment.
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The systemic autoinflammatory diseases are characterized by seemingly unprovoked inflammation, without major involvement of the adaptive immune system. This review focuses mainly on a subset of these illnesses, the hereditary recurrent fevers, which include familial Mediterranean fever, the tumor necrosis factor receptor-associated periodic syndrome, the hyperimmunoglobulinemia D with periodic fever syndrome, and cryopyrin-associated periodic syndromes. This review elucidates how recent advances have impacted diagnosis, pathogenesis, and treatment.</AbstractText>More than 170 mutations have been identified in the four genes underlying the six hereditary recurrent fevers. Genetic testing has broadened the clinical and geographic boundaries of these illnesses, given rise to the concept of the cryopyrin-associated periodic syndromes as a disease spectrum, and permitted diagnosis of compound heterozygotes for mutations in two different hereditary recurrent fever genes. Genetics has also advanced our understanding of amyloidosis, a complication of the hereditary recurrent fevers, and suggested a possible role for common hereditary recurrent fever variants in other inflammatory conditions. Recent advances in molecular pathophysiology include the elucidation of the N-terminal PYRIN domain in protein-protein interactions, the description of the NALP3 (cryopyrin) inflammasome as a macromolecular complex for interleukin-1beta activation, and the identification of signaling defects other than defective receptor shedding in patients with tumor necrosis factor receptor-associated periodic syndrome. These molecular insights form the conceptual basis for targeted biologic therapies.</AbstractText>Advances in molecular genetics extend our ability to recognize and treat patients with systemic autoinflammatory diseases and inform our understanding of the regulation of innate immunity in humans.</AbstractText>
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2,336,944 |
Microsatellite genotyping for genetic quality testing using sperm cells in the mouse.
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We attempted to determine the number of sperm cells required for genotyping of one microsatellite marker. The crude genomic DNA extracted from about 760 or more sperm cells gave sufficient quantity of PCR product using a 20 microl-scale PCR. We also studied the effects of non-ionic detergents on extraction of crude sperm genomic DNA. PCR products amplified with the crude sperm genomic DNA extracted using the lysis buffer supplemented with non-ionic detergents showed much clear bands. In conclusion, our results suggest that a small part of the frozen sperm, which is less than 1/10 of the original volume (10 microl), provides sufficient quantity of template DNA for genetic quality testing.
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2,336,945 |
Biochemical and biomechanical properties of lesion and adjacent articular cartilage after chondral defect repair in an equine model.
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Chondral defects may lead to degradative changes in the surrounding cartilage, predisposing patients to developing osteoarthritis.</AbstractText>To quantify changes in the biomechanical and biochemical properties of the articular cartilage adjacent to chondral defects after experimental defect repair.</AbstractText>Controlled laboratory study.</AbstractText>Specimens were harvested from tissue within (lesion), immediately adjacent to, and at a distance from (remote area) a full-thickness cartilage defect 8 months after cartilage repair with genetically modified chondrocytes expressing insulin-like growth factor-I or unmodified, control chondrocytes. Biomechanical properties, including instantaneous Young's and equilibrium aggregate moduli, were determined by confined compression testing. Biochemical properties, such as water and proteoglycan content, were also measured.</AbstractText>The instantaneous Young's modulus, equilibrium modulus, and proteoglycan content increased, whereas water content decreased with increasing distance from the repaired lesion. The instantaneous Young's and equilibrium moduli of the adjacent articular cartilage were 80% and 50% that of remote area samples, respectively, whereas water content increased 0.9% and proteoglycan content was decreased by 35%. No significant changes in biomechanical and biochemical properties were found either in the lesion tissue or in adjacent cartilage with genetic modification of the chondrocytes.</AbstractText>Articular cartilage adjacent to repaired chondral defects showed significant remodeling 8 months after chondral defect repair, regardless of whether genetically modified or unmodified cells were implanted.</AbstractText>Changes in the biochemical and biomechanical properties of articular cartilage adjacent to repaired chondral defects may represent remodeling as part of an adaptive process or degeneration secondary to an altered distribution of joint forces. Quantification of these changes could provide important parameters for assessing progress after operative chondral defect repair.</AbstractText>
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2,336,946 |
SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.
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ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in two highly homologous variants: SMN1, the causative gene responsible for the production of the majority of functional SMN protein, and SMN2, responsible for the production of less protein but sufficient for modifying the SMA phenotype.</AbstractText>To test whether SMN genotypes are associated with susceptibility to and severity of sporadic ALS.</AbstractText>We performed competitive quantitative PCR analysis for both SMN1 and SMN2 genes in 242 clinically well-defined ALS patients and 175 controls. The combined determination of SMN1 and SMN2 copies also allowed for an estimation of the level of SMN for each patient (estimated SMN protein level = SMN1 copy number + 0.20 x SMN2 copy number).</AbstractText>One copy of SMN1 was associated with an increased risk of developing ALS (odds ratio = 4.1, 95% CI = 1.2 to 14.2, p = 0.02) and ALS patients carried fewer SMN2 copy numbers (p < 0.001). Sixty-one percent of patients had an estimated protein SMN level < or = 2.2 vs only 36% of controls (p = 0.0000004). Multivariate Cox regression analyses showed that lower SMN2 copy numbers and lower levels of estimated SMN protein (hazard ratio = 1.3, 95% CI = 1.1 to 1.6, p = 0.03) were associated with an increased mortality rate.</AbstractText>SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.</AbstractText>
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2,336,947 |
Evaluation of offspring and maternal genetic effects on disease risk using a family-based approach: the "pent" design.
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Diseases that develop during gestation may be influenced by the genotype of the mother and the inherited genotype of the embryo/fetus. However, given the correlation between maternal and offspring genotypes, differentiating between inherited and maternal genetic effects is not straightforward. The two-step transmission disequilibrium test was the first, family-based test proposed for the purpose of differentiating between maternal and offspring genetic effects. However, this approach, which requires data from "pents" comprising an affected child, mother, father, and maternal grandparents, provides biased tests for maternal genetic effects when the offspring genotype is associated with disease. An alternative approach based on transmissions from grandparents provides unbiased tests for maternal and offspring genetic effects but requires genotype information for paternal grandparents in addition to pents. The authors have developed two additional, pent-based approaches for the evaluation of maternal and offspring genetic effects. One approach requires the assumption of genetic mating type symmetry (pent-1), whereas the other does not (pent-2). Simulation studies demonstrate that both of these approaches provide valid estimation and testing for offspring and maternal genotypic effects. In addition, the power of the pent-1 approach is comparable with that of the approach based on data using all four grandparents.
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2,336,948 |
Limb-girdle muscular dystrophy in childhood.
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LGMD refers to a class of muscular dystrophies with onset in the proximal muscles. They are genetically heterogeneous, with both autosomal recessive and dominant forms. The autosomal recessive forms are more common and in general follow a more severe course compared to the dominant forms. It is important to reach a specific genetic diagnosis beyond making a group diagnosis of LGMD to provide adequate genetic counseling, to predict risks for the patient such as the development of cardiomyopathy, and to be able to take advantage of specific treatments when they become available. Establishing a specific diagnosis requires knowledge about the individual clinical features, expert analysis of the muscule biopsy, and the guided initiation of appropriate genetic testing.
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2,336,949 |
The diagnosis of muscular dystrophy.
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Pediatricians should be familiar with the common presenting signs and symptoms of MD so that they can make a clinical diagnosis of possible MD based on the patient's medical history, a physical examination, and a CK screen. Appropriate referral to a neuromuscular specialist will then enable the precise diagnosis of MD to be made with definitive histologic, biochemical, and genetic testing.
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2,336,950 |
[Chronic beryllium disease: a model of interaction between environmental exposure and genetic predisposition. Pathogenesis and clinical features (Part 2)].
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Chronic beryllium disease (CBD) is an occupational lung disease caused by the inhalation of beryllium dust, fumes or metallic salts.</AbstractText>Beryllium affects the lungs via particles deposited in the pulmonary alveoli. These are ingested by alveolar macrophages which act as antigen presenting cells to CD4+ T lymphocytes. T lymphocytes proliferate in response to beryllium antigens and combined with macrophages produce numerous epithelioid granulomas with the release of inflammatory cytokines (IFNgamma, IL-2, TNFalpha and IL6) and growth factors. Beryllium induces macrophage apoptosis which reduces its clearance from the lung which in turn contributes to the host's continual re-exposure and thus a chronic granulomatous disorder. Pulmonary granulomatous inflammation is the primary manifestation of CBD, but the disease occasionally involves other organs such as the liver, spleen, lymph nodes and bone marrow. The clinical, radiological, and histopathological features of CBD can be difficult to distinguish from sarcoidosis. The Beryllium lymphocyte proliferation test (BeLPT) demonstrates a beryllium specific immune response, confirms the diagnosis of CBD, and excludes sarcoidosis.</AbstractText>CBD provides a human model of pulmonary granulomatous disease produced by an occupational exposure, occurring more frequently in those with a genetic pre-disposition. It can be differentiated from sarcoidosis by specific immunological testing.</AbstractText>
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2,336,951 |
IL-2 and IL-4 polymorphisms as candidate genes in schizophrenia.
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An immune process, characterized by a relative predominance of the T helper-2 (Th2) system and possibly induced by a viral infection,may be involved in the pathophysiology of schizophrenia. In this context, functional polymorphisms in the Interleukin-2 (IL-2) and Interleukin-4 (IL-4) genes appear to be principal candidates for genetic schizophrenia research. Further evidence for these candidate genes comes from several linkage analyses, pointing to susceptibility gene loci on chromosomes 4q and 5q, where the genes coding for IL- 2 and IL-4 are located. We carried out a case-control study including 230 schizophrenic patients and 251 healthy persons, investigating the IL-2 -330 T/G single nucleotide polymorphism (SNP) and the IL-4 -590 C/T SNP. A significant association of the IL-2 -330 TT genotype and of the IL-4 -590 CC genotype with schizophrenia could be identified. Our findings may partly account for the relative predominance of the Th2 system in schizophrenia, although they cannot directly explain this immunological imbalance, but may be related to an altered antiviral immune response in patients with schizophrenia.
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2,336,952 |
Chromosomal aberrations in squamous cell carcinomas of the upper aerodigestive tract: biologic insights and clinical opportunities.
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Oncogenesis results from a progressive accumulation of genetic aberrations consequent to a complex interplay between carcinogenic factors and innate infidelity of DNA surveillance mechanisms. Although the development of genetic aberrations is random, those conferring survival advantages are selected for in a Darwinian manner, thus allowing continuous adaptation to selection pressures. Chromosomal aberrations are a prominent manifestation of genetic damage, which can be closely linked with tumor behavior and outcome as exemplified by curative treatment of chronic myelogenous leukemia resulting from targeting the BCR-ABL translocation. In the case of head and neck squamous cell carcinomas (HNSCC), chromosomal changes are detectable at all stages of tumor development, providing excellent opportunities for genomic prognostication and therapy. Several studies have shown that the overall genomic profile of HNSCC is highly consistent, but individual tumors vary significantly in their complement of genetic alterations, thereby confounding clinical correlation. The application of modern genetic and bioinformatic analytic approaches has facilitated the identification of critical genomic changes in HNSCC, many of which have been linked to clinical outcome. These genetic aberrations represent excellent targets for novel therapeutics, but require validation. The initiation of phase III trials evaluating the therapeutic utility of genetic aberrations suggests a promising future for genome-based treatment of HNSCC.
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2,336,953 |
DNA hybridization detection at heated electrodes.
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The detection of DNA hybridization is of central importance to the diagnosis and treatment of genetic diseases. Due to cost limitations, small and easy-to-handle testing devices are required. Electrochemical detection is a promising alternative to evaluation of chip data with optical readout. Independent of the actual readout principle, the hybridization process still takes a lot of time, hampering daily use of these techniques, especially in hospitals or doctor's surgery. Here we describe how direct local electrical heating of a DNA-probe-modified gold electrode affects the surface hybridization process dramatically. We obtained a 140-fold increase of alternating current voltammetric signals for 20-base ferrocene-labeled target strands when elevating the electrode temperature during hybridization from 3 to 48 degrees C while leaving the bulk electrolyte at 3 degrees C. At optimum conditions, a target concentration of 500 pmol/L could be detected. Electrothermal regeneration of the immobilized DNA-probe strands allowed repetitive use of the same probe-modified electrode. The surface coverage of DNA probes, monitored by chronocoulometry of hexaammineruthenium(III), was almost constant upon heating to 70 degrees C. However, the hybridization ability of the probe self-assembled monolayer declined irreversibly when using a 70 degrees C hybridization temperature. Coupling of heated electrodes and highly sensitive electrochemical DNA hybridization detection methods should enhance detection limits of the latter significantly.
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2,336,954 |
High prevalence of the W24X mutation in the gene encoding connexin-26 (GJB2) in Spanish Romani (gypsies) with autosomal recessive non-syndromic hearing loss.
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Molecular testing for mutations in the gene encoding connexin-26 (GJB2) at the DFNB1 locus has become the standard of care for genetic diagnosis and counseling of autosomal recessive non-syndromic hearing impairment (ARNSHI). The spectrum of mutations in GJB2 varies considerably among the populations, different alleles predominating in different ethnic groups. A cohort of 34 families of Spanish Romani (gypsies) with ARNSHI was screened for mutations in GJB2. We found that DFNB1 deafness accounts for 50% of all ARNSHI in Spanish gypsies. The predominating allele is W24X (79% of the DFNB1 alleles), and 35delG is the second most common allele (17%). An allele-specific PCR test was developed for the detection of the W24X mutation. By using this test, carrier frequencies were determined in two sample groups of gypsies from different Spanish regions (Andalusia and Catalonia), being 4% and 0%, respectively. Haplotype analysis for microsatellite markers closely flanking the GJB2 gene revealed five different haplotypes associated with the W24X mutation, all sharing the same allele from marker D13S141, suggesting that a founder effect for this mutation is responsible for its high prevalence among Spanish gypsies.
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2,336,955 |
Novel EXT1 and EXT2 mutations identified by DHPLC in Italian patients with multiple osteochondromas.
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We describe the results of an optimised DHPLC-based mutation screening of the EXT1 and EXT2 genes in Italian patients affected by multiple osteochondromas [MO; also referred to as hereditary multiple exostoses (HME) in the literature], using a multistep approach. We first analysed 36 unrelated probands for EXT1 mutations by DHPLC analysis and subsequent direct sequencing of all samples with abnormal elution profile. Negative cases were then screened for EXT2 mutations using the same approach. In patients who tested normal at DHPLC screening, all EXT1 and EXT2 exons and splice-site junctions were directly sequenced. In 7 informative families, we also performed a pre-screening linkage analysis to selectively focus the DHPLC testing on the EXT1 or EXT2 gene. We detected 31 MO-related mutations, of which 23 (74%) were novel. Seven polymorphisms were also found. Twenty-four mutations (77%) were found in EXT1 and 7 (23%) in EXT2. No disease-causing mutations were detected in five of 36 patients, with a mutation frequency of 86%. According with previous studies, most mutations (90%) are loss of function. Neither false positive nor false negative results were obtained. This multistep method can be considered a fast and reliable diagnostic strategy for the detection of EXT1/2 mutations, with excellent sensitivity and specificity.
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2,336,956 |
Genetic diversity of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and its effect on the performance of PfHRP2-based rapid diagnostic tests.
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Rising costs of antimalarial agents are increasing the demand for accurate diagnosis of malaria. Rapid diagnostic tests (RDTs) offer great potential to improve the diagnosis of malaria, particularly in remote areas. Many RDTs are based on the detection of Plasmodium falciparum histidine-rich protein (PfHRP) 2, but reports from field tests have questioned their sensitivity and reliability. We hypothesize that the variability in the results of PfHRP2-based RDTs is related to the variability in the target antigen. We tested this hypothesis by examining the genetic diversity of PfHRP2, which includes numerous amino acid repeats, in 75 P. falciparum lines and isolates originating from 19 countries and testing a subset of parasites by use of 2 PfHRP2-based RDTs. We observed extensive diversity in PfHRP2 sequences, both within and between countries. Logistic regression analysis indicated that 2 types of repeats were predictive of RDT detection sensitivity (87.5% accuracy), with predictions suggesting that only 84% of P. falciparum parasites in the Asia-Pacific region are likely to be detected at densities < or = 250 parasites/microL. Our data also indicated that PfHRP3 may play a role in the performance of PfHRP2-based RDTs. These findings provide an alternative explanation for the variable sensitivity in field tests of malaria RDTs that is not due to the quality of the RDTs.
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2,336,957 |
Genetics of cystic fibrosis.
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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which encodes a protein expressed in the apical membrane of exocrine epithelial cells. CFTR functions principally as a cyclic adenosine monophosphate (cAMP)-induced chloride channel and appears capable of regulating other ion channels. Mutations affect CFTR through a variety of molecular mechanisms, which can produce little or no functional gene product at the apical membrane. More than 1000 different disease-causing mutations within the CFTR gene have been described. The potential of a mutation to contribute to the phenotype depends on its type, localization in the gene, and the molecular mechanism as well as on interactions with secondary modifying factors. Genetic testing can confirm a clinical diagnosis of CF and can be used for infants with meconium ileus, for carrier detection in individuals with positive family history and partners of proven CF carriers, and for prenatal diagnostic testing if both parents are carriers. Studies of clinical phenotype in correlation with CFTR genotype have revealed a very complex relationship demonstrating that some phenotypic features are closely determined by the underlying mutations, whereas others are modulated by modifier genes, epigenetic mechanisms, and environment.
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2,336,958 |
A review of alpha-1 antitrypsin deficiency.
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Alpha-1 antitrypsin (AAT) is a protein that prevents enzymes such as elastin from degrading normal host tissue. Individuals who are deficient in AAT (those with levels < 11 micromol/L) are at risk for developing such clinical manifestations as emphysema, cirrhosis, panniculitis, and anticytoplasmic neutrophilic antibody (C-ANCA)-positive vasculitis (Wegener's granulomatosis). Estimates suggest that 75 to 85% of those with severe deficiency of AAT will develop emphysema. Smoking appears to be the most important risk factor for the development of emphysema among AAT deficient persons. Severe deficiency of AAT also seems to be associated with a shorter lifespan. Among smokers, mild to moderate reductions in AAT levels may be associated with a more rapid decline in lung function. Diagnosis of AAT deficiency is made by measuring serum levels of AAT and, if reduced, an effort should then be made to identify the genetic abnormality responsible for the reduction. A recent evidence-based review has offered testing recommendations for AAT deficiency and includes the recommendation that all patients with COPD be tested for AAT deficiency. Augmentation with an intravenous form of purified pooled human plasma has been shown to increase the serum levels of AAT among deficient patients and its use appears to impact the rate of forced expiratory volume in 1 second (FEV (1)) decline and overall survival; to date, no confirmatory, large, prospective, randomized trials are available.
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2,336,959 |
Segregation of microsatellite alleles in gynogenetic diploid Pacific abalone (Haliotis discus hannai).
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Inheritance of 9 microsatellite loci was examined in 3 families of gynogenetic Pacific abalone Haliotis discus hannai produced by fertilizing eggs with UV-irradiated sperm followed by inhibition of the second meiotic division. The proportion of heterozygous progeny was used to estimate marker-centromere (M-C) distances. All loci conformed to Mendelian segregation in the control crosses when null alleles were accounted for. The absence of paternal alleles confirmed the gynogenetic origin of the offspring and indicated 100% success for 3 families. Estimated recombinant frequencies ranged from 0.10 to 0.60, which is lower than those observed in other gynogenetic diploid animals. The mean recombination frequency was 0.22, corresponding to a fixation index of 0.78 in one generation. This is 3.12 times the increase in homozygosity expected after one generation of sib mating (0.25), suggesting meiotic gynogenesis may be an effective means of rapid inbreeding in the abalone. M-C map distances for the 9 loci varied between 5 and 30 cM under the assumption of complete interference. The information about M-C distances will be useful for future gene mapping in H. discus hannai.
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2,336,960 |
Differential gene expression in ovarian tumors reveals Dusp 4 and Serpina 5 as key regulators for benign behavior of serous borderline tumors.
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Ovarian serous borderline tumors (SBT) are characterized by arborizing papillae lined by stratified epithelial cells, varying atypia, and absence of stromal invasion. Originally, these tumors have been classified as borderline because they behaved in a remarkably indolent manner, even with widespread tumor deposits called implants and the presence of lymph node involvement. The molecular biology of these lesions has just begun to be explored. High prevalence of B-RAF/K-RAS mutations in SBTs in contrast to serous carcinomas (SCAs) indicates that the mitogenic RAS-RAF-MEK-ERK-MAP kinase pathway is crucial for the pathogenesis of SBTs. The purpose of this study was to further unravel the genetic pathways through which SBTs develop, with a special focus on explaining the generally benign SBT behavior.</AbstractText>We generated RNA expression profiles of 38 ovarian serous neoplasms. Global Test pathway analysis and significance analysis of microarrays (SAM) of the expression profiles was performed.</AbstractText>SAM and Global Testing showed that although the mitogenic pathway is activated in SBTs, activation of downstream genes involved in extracellular matrix (ECM) degradation is absent, suggesting an uncoupling of both events. In addition, we show that two genes involved in regulating this uncoupling, ERK-inhibitor Dusp 4 and uPA-inhibitor Serpina 5, are downregulated in SCAs in contrast to SBTs. In SCAs, this was associated with downstream MMP-9 activation at both mRNA and protein level.</AbstractText>We propose that the putative tumor suppressor genes Dusp 4 and Serpina 5 provide a major clue to the indolent behavior of SBTs.</AbstractText>
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2,336,961 |
Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population.
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Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy.</AbstractText>To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families.</AbstractText>Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA.</AbstractText>All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family.</AbstractText>The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability.</AbstractText>
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2,336,962 |
Mutation analysis of the small heat shock protein 27 gene in chinese patients with Charcot-Marie-Tooth disease.
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Charcot-Marie-Tooth (CMT) disease, the most common hereditary peripheral neuropathy, is highly clinically and genetically heterogeneous, and mutations in at least 18 genes have been identified. Recently, mutations in small heat shock protein 27 (Hsp27) were reported to cause CMT disease type 2F and distal hereditary motor neuropathy.</AbstractText>To investigate the frequency and phenotypic features of an Hsp27 mutation in Chinese patients with CMT disease.</AbstractText>DNA samples from 114 unrelated patients with CMT disease were screened for mutations in Hsp27 by polymerase chain reaction and direct sequencing. A cosegregated study was performed using the MbiI restriction endonuclease, and 50 healthy control subjects were analyzed. Haplotype analysis was performed using 5 short tandem repeat markers to analyze whether the families with the same mutation probably had a common ancestor.</AbstractText>One missense mutation, C379T, was detected in 4 autosomal dominant families with CMT disease type 2, and haplotype analysis indicated that the 4 families probably had a common founder. The frequency of the Hsp27 mutation is 0.9% (1/111) in Chinese patients with CMT disease in our study, and the phenotypes were characterized by later onset (age, 35-60 years) and mild sensory impairments. Electrophysiological findings showed moderately to severely slowed nerve conduction velocities in lower limb nerves but normal or mildly reduced velocities in upper limb nerves.</AbstractText>To our knowledge, this is the first report of an Hsp27 mutation in the People's Republic of China. The C379T mutation in Hsp27 also causes CMT disease type 2, except for distal hereditary motor neuropathy, and the phenotypes are distinct from the family with CMT disease type 2F described previously. A mutation of Hsp27 may be uncommon in Chinese patients with CMT disease.</AbstractText>
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2,336,963 |
Tandem repeat copy-number variation in protein-coding regions of human genes.
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Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles.</AbstractText>Protein-coding tandem repeat copy-number polymorphisms were detected in 249 tandem repeats found in 218 UniGene clusters; observed length differences ranged from 2 to 144 nucleotides, with unit copy lengths ranging from 2 to 57. This corresponded to 1.59% (218/13,749) of proteins investigated carrying detectable polymorphisms in the copy-number of protein-coding tandem repeats. We found no evidence that tandem repeat copy-number polymorphism was significantly elevated in defense-response proteins (p = 0.882). An association with the Gene Ontology term 'protein-binding' remained significant after covariate adjustment and correction for multiple testing. Combining this analysis with previous experimental evaluations of tandem repeat polymorphism, we estimate the approximate mean frequency of tandem repeat polymorphisms in human proteins to be 6%. Because 13.9% of the polymorphisms were not a multiple of three nucleotides, up to 1% of proteins may contain frameshifting tandem repeat polymorphisms.</AbstractText>Around 1 in 20 human proteins are likely to contain tandem repeat copy-number polymorphisms within coding regions. Such polymorphisms are not more frequent among defense-response proteins; their prevalence among protein-binding proteins may reflect lower selective constraints on their structural modification. The impact of frameshifting and longer copy-number variants on protein function and disease merits further investigation.</AbstractText>
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2,336,964 |
Identification of mislabeled specimen by molecular methods: case report and review.
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Specimen misidentification is a common cause of errors in surgical pathology. We report a case where bone-marrow biopsies from patients of different genders were mislabeled and molecular methods were applied to resolve the identity. A short tandem repeat (STR)-polymerase chain reaction-based assay, commonly used in paternity testing, was employed in an attempt to assign the correct identity to the specimens. However, the specimens had been processed by decalcification and the DNA yield was poor. One of the markers in the assay is the non-STR amelogenin locus that distinguishes the X and Y chromosomes. This amelogenin marker results in a product of low molecular weight, enabling unequivocal resolution of identity despite a poor DNA yield. The prevalence of errors in pathology due to specimen misidentifications is reviewed.
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2,336,965 |
Genetic markers for retinitis pigmentosa.
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To review recent advances in the molecular genetics of retinitis pigmentosa with emphasis on the development of genetic markers that aids diagnosis and prognosis.</AbstractText>Literature search of MEDLINE from 1988 to 2005 using the following key words: 'retinitis pigmentosa', 'rhodopsin', 'RP1', 'RPGR', and 'genetic counseling'. References of two genes--RHO and RP1--causing retinitis pigmentosa in the Chinese population were reviewed.</AbstractText>Literature and data related to genetic markers for retinitis pigmentosa.</AbstractText>The genetics of retinitis pigmentosa is complex. It can be sporadic or familial, with heterogeneous transmission modes. Retinitis pigmentosa is associated with nearly 40 chromosomal loci, where 32 candidate genes have been identified. A large number of mutations are known to cause retinitis pigmentosa. But no single mutation alone accounts for more than 10% of unrelated retinitis pigmentosa patients. Genetic tests for retinitis pigmentosa require screening for a consort of mutations in a large number of genes. High throughput screening technology such as denaturing high performance liquid chromatography and automated DNA sequencing should make such tests feasible.</AbstractText>Rapid developments in the understanding of the genetics of retinitis pigmentosa have helped to establish genetic tests of clinical value. The complex mode of inheritance nonetheless makes genetic counselling difficult, even in the presence of positive genetic screening results.</AbstractText>
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2,336,966 |
Using progenitor strain information to identify quantitative trait nucleotides in outbred mice.
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We have developed a fast and economical strategy for dissecting the genetic architecture of quantitative trait loci at a molecular level. The method uses two pieces of information: mapping data from crosses that involve more than two inbred strains and sequence variants in the progenitor strains within the interval containing a quantitative trait locus (QTL). By testing whether the strain distribution pattern in the progenitor strains is consistent with the observed genetic effect of the QTL we can assign a probability that any sequence variant is a quantitative trait nucleotide (QTN). It is not necessary to genotype the animals except at a skeleton of markers; the genotypes at all other polymorphisms are estimated by a multipoint analysis. We apply the method to a 4.8-Mb region on mouse chromosome 1 that contains a QTL influencing anxiety segregating in a heterogeneous stock and show that, under the assumption that a single QTN is present and lies in a region conserved between the human and mouse genomes, it is possible to reduce the number of variants likely to be the quantitative trait nucleotide from many thousands to <20.
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2,336,967 |
Ochronotic rheumatism in Algeria: clinical, radiological, biological and molecular studies--a case study of 14 patients in 11 families.
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To confirm alkaptonuria and ochronotic arthropathy diagnosis by mutation screening of the homogentisate 1,2-dioxygenase (HGD) gene. Try to establish a genotype-phenotype correlation in the five subjects with a molecular study on HGD gene.</AbstractText>We report 14 alkaptonuria cases (10 men and four women) in 11 Algerian families. Consanguineous matings were evidenced in only three families (F = 1/16). Molecular analysis was performed by sequencing genomic DNA in order to identify the mutations of the HGD gene.</AbstractText>Alkaptonuria was always confirmed by urinary homogentisic acid determination. Four different mutations of the HGD gene were found: an homozygous missense mutation, Serine189Isoleucine in two sisters with a mild phenotype; an homozygous splice site mutation (IVS1-1G > A) in a man with a severe phenotype (death at 61 years old from renal failure); a silent mutation, Alanine470Alanine at the heterozygous state in a man with a mild phenotype; a 'G' deletion at the position c.819 which causes a frameshift after Gly217(Gly217fs) that runs into a stop codon at c. 850. This mutation is novel and was found in heterozygosis in a woman with a mild phenotype.</AbstractText>The two homozygous mutations were associated, respectively, with a severe and a mild phenotype but no genotype-phenotype correlation could be found.</AbstractText>
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2,336,968 |
Risks and benefits of population-based genetic testing for Mendelian subsets of common diseases were examined using the example of colorectal cancer risk.
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Genetic testing for adult-onset, common diseases is becoming more commonplace in clinical medicine. We modeled the proportions of hypothetic populations that would potentially benefit or suffer harm from widespread predisposition testing.</AbstractText>Using the traditional two-by-two table from the discipline of epidemiology, we modeled three hypothetic populations using the example of genetic testing for hereditary colorectal cancer in three groups: the general population, a genetically increased-risk population, and a population at increased risk due to nongenetic factors.</AbstractText>We demonstrate that the potential benefits are increased and risks are reduced when testing is limited to those at increased genetic risk when compared with testing in the general population. Where disease incidence is increased due to nongenetic factors, genetic testing has the potential to detract from the detection and reduction of other potentially important risk factors.</AbstractText>While targeted testing can benefit those truly at increased risk, broadly applied genetic testing can do more harm than good.</AbstractText>
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2,336,969 |
A buccal cell model comet assay: development and evaluation for human biomonitoring and nutritional studies.
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The comet assay is a widely used biomonitoring tool for DNA damage. The most commonly used cells in human studies are lymphocytes. There is an urgent need to find an alternative target human cell that can be collected from normal subjects with minimal invasion. There are some reports of buccal cells, collected easily from the inside of the mouth, being used in studies of DNA damage and repair, and these were of interest. However, our preliminary studies following the published protocol showed that buccal cells sustained massive damage and disintegrated at the high pH [O. Ostling, K.J. Johanson. Microelectrophoretic study of radiation-induced DNA damages in individual mammalian cells. Biochem. Biophys. Res. Commun. 123 (1984) 291-298] used, but that at lower pH were extremely resistant to lysis, an essential step in the comet assay. Therefore, the aims of this study were to develop a protocol than enabled buccal cell lysis and DNA damage testing in the comet assay, and to use the model to evaluate the potential use of the buccal cell model in human biomonitoring and nutritional study. Specifically, we aimed to investigate intra- and inter-individual differences in buccal cell DNA damage (as strand breaks), the effect of in vitro exposure to both a standard oxidant challenge and antioxidant treatment, as well as in situ exposure to an antioxidant-rich beverage and supplementation-related effects using a carotenoid-rich food. Successful lysis was achieved using 0.25% trypsin for 30 min followed by proteinase K (1mg/ml) treatment for 60 min. When this procedure was performed on cells pre-embedded in agarose on a microscope slide, followed by electrophoresis (in 0.01 M NaOH, 1mM EDTA, pH 9.1, 18 min at 12 V), a satisfactory comet image was obtained, though inter-individual variation was quite wide. Pre-lysis exposure of cells to a standard oxidant challenge (induced by H2O2) increased DNA strand breaks in a dose related manner, and incubation of cells in Trolox (a water soluble Vitamin E analogue) conferred significant protection (P<0.05) against subsequent oxidant challenge. Exposure of buccal cell in situ (i.e. in the mouth) to antioxidant-rich green tea led to an acute decrease in basal DNA strand breaks. In a controlled human intervention trial, buccal cells from 14 subjects after 28 days' supplementation with a carotenoid-rich berry (Fructus barbarum L.) showed a small but statistically significant (P<0.05) decrease in DNA strand breaks. These data indicate that this buccal cell comet assay is a feasible and potentially useful alternative tool to the usual lymphocyte model in human biomonitoring and nutritional work.
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2,336,970 |
Tissues from population-based cancer registries: a novel approach to increasing research potential.
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Population-based cancer registries, such as those included in the Surveillance, Epidemiology, and End-Results (SEER) Program, offer tremendous research potential beyond traditional surveillance activities. We describe the expansion of SEER registries to gather formalin-fixed, paraffin-embedded tissue from cancer patients on a population basis. Population-based tissue banks have the advantage of providing an unbiased sampling frame for evaluating the public health impact of genes or protein targets that may be used for therapeutic or diagnostic purposes in defined communities. Such repositories provide a unique resource for testing new molecular classification schemes for cancer, validating new biologic markers of malignancy, prognosis and progression, assessing therapeutic targets, and measuring allele frequencies of cancer-associated genetic polymorphisms or germline mutations in representative samples. The assembly of tissue microarrays will allow for the use of rapid, large-scale protein-expression profiling of tumor samples while limiting depletion of this valuable resource. Access to biologic specimens through SEER registries will provide researchers with demographic, clinical, and risk factor information on cancer patients with assured data quality and completeness. Clinical outcome data, such as disease-free survival, can be correlated with previously validated prognostic markers. Furthermore, the anonymity of the study subject can be protected through rigorous standards of confidentiality. SEER-based tissue resources represent a step forward in true, population-based tissue repositories of tumors from US patients and may serve as a foundation for molecular epidemiology studies of cancer in this country.
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2,336,971 |
Preimplantation genetic diagnosis for aneuploidy screening in women older than 37 years.
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To provide background information about the average aneuploidy and implantation rates of older patients after IVF with preimplantation genetic diagnosis for aneuploidy screening (PGD-AS) when the patients are subdivided into age categories; and to compare pregnancy outcome data after PGD-AS in this group of patients with a similar control group.</AbstractText>Retrospective clinical study.</AbstractText>Patients in an academic reproductive medicine unit.</AbstractText><AbstractText Label="PATIENT(S)" NlmCategory="METHODS">All patients 37 years or older who had PGD-AS between October 1999 and December 2003 and all pregnant patients 37 years or older who had IVF/intracytoplasmic sperm injection without PGD-AS during the same period of time.</AbstractText><AbstractText Label="INTERVENTION(S)" NlmCategory="METHODS">IVF with PGD-AS.</AbstractText><AbstractText Label="MAIN OUTCOME MEASURE(S)" NlmCategory="METHODS">Aneuploidy rate, miscarriage rate, live birth rate, implantation rate, multiple pregnancy rate, and prenatal testing.</AbstractText><AbstractText Label="RESULT(S)" NlmCategory="RESULTS">Three hundred ninety-four PGD-AS cycles of patients between 37 and 46 years of age were analyzed. The aneuploidy rate gradually increased with age. The implantation rate remained similar over all age groups. There was a trend to a lower miscarriage and multiple pregnancy rate in the PGD-AS group and a higher delivery/live birth rate. There were five elective terminations of pregnancy after prenatal testing and three late miscarriages due to prenatal testing in the control group.</AbstractText><AbstractText Label="CONCLUSION(S)" NlmCategory="CONCLUSIONS">Preimplantation genetic diagnosis for aneuploidy screening can give valuable information to older patients concerning the reason why their IVF cycles are unsuccessful and whether it is worthwhile to continue IVF treatment, and it can help patients to avoid the emotional trauma that can occur after prenatal testing during the second trimester of pregnancy.</AbstractText>
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2,336,972 |
Genome-wide scan for myopia in the Old Order Amish.
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To identify myopia susceptibility genes influencing common myopia in 34 Old Order Amish families, a genetically well-defined founder population.</AbstractText>A prospective study of families with myopia consisting of a minimum of two individuals affected with myopia.</AbstractText>Extended families consisting of at least two siblings affected with myopia were ascertained. A genome-wide linkage scan using 387 markers was conducted by the Center for Inherited Disease Research (CIDR). Linkage analyses were conducted with parametric (autosomal dominant, fixed penetrance model) and nonparametric methods. Model-free linkage analysis was also performed maximizing over penetrance and over dominance (that is, fitting a wide range of both dominant and recessive models).</AbstractText>Under the fixed penetrance model, the maximum two-point heterogeneity LOD score (HLOD) was 1.59 at D20S451 and the maximum multipoint HLOD was 1.92 at D6S1021. The nonparametric maximum multipoint (NPL) at D3S2427 had a P-value of .0005. Under the model-free analysis, multipoint heterogeneity LOD scores of 2.03 were observed on both chromosomes 8 (under a recessive model between D8S1130 and D8S1106) and X (under a recessive model between DXS6800 and DXS6789). Reanalyses of chromosomes 3, 6, 8, 20, and X using the best penetrance models resulted in maximum multipoint HLODs of 1.84 at D3S3053; 1.84 at D3S2427; 2.04 at D8S1130; and 2.34 at DXS6800.</AbstractText>The locus on chromosome 8p23 independently confirms a report by Hammond and associates mapping a myopia quantitative trait loci (QTL) to this region.</AbstractText>
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2,336,973 |
Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson's disease.
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Glial cell-line derived neurotrophic factor (GDNF) is a good candidate agent for restoring functional reinnervation and/or neuroprotection of dopamine (DA) nigrostriatal system and thus for the treatment of Parkinson's disease (PD). Viral delivery is currently the most likely in vivo strategy for delivery of the therapeutic protein into the brain for treatment of neurological diseases. However, one of the important unresolved issues for this strategy is the threshold number of DA nigral neurons and/or of striatal DA terminals necessary for optimal benefit from GDNF therapy. In this study, we examined the intrastriatal neurotrophic effects of long-term GDNF delivery using a lentiviral vector in a new rat model of early PD. Lenti-GDNF was injected into the striatum 4 weeks after partial substantia nigra pars compacta 6-hydroxydopamine-induced lesion. Striatal denervation was evaluated by assessing tyrosine hydroxylase-positive DA fiber density and corroborated by testing motor deficit by means of a staircase test. GDNF treatment restored complete striatal DA innervation in the previously denervated area and this was associated with significant behavioral improvements.
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2,336,974 |
High follicular phase luteinizing hormone levels in young healthy BRCA1 mutation carriers: implications for breast and ovarian cancer risk.
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BRCA1 mutation carriers have up to 80% life-time risk of developing breast cancer and 20-40% risk of developing ovarian cancer. High LH levels have been linked to increased risks of both breast and ovarian cancers in some studies and it is unknown whether gonadotropin levels are associated with BRCA1 mutation status. The aim of the study was to explore whether gonadotropin levels were associated with BRCA1 mutation status among healthy 40-year-old-women from hereditary breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured height, weight, breast volumes, and plasma levels of LH, FSH, and estradiol (E2) once during menstrual cycle days 5-10 and once again during cycle days 18-23 in 43 non-carriers from BRCA1 families, 20 BRCA1 mutation carriers, and 101 women from non-BRCA1/2 families. The strongest predictors of high LH levels among BRCA1 mutation carriers and non-carriers during cycle days 5-10 were being a BRCA1 mutation carrier (p=0.002), lack of current OC use (p=0.003), and being nulliparous (p=0.01), adjusted for age and menstrual cycle day when the samples were obtained. This association was seen both in non-OC users and current OC users but was only significant in the former group (p=0.005). Because of multiple analyses it is possible that our finding is a result of a Type 1 statistical error. After a permutation test the new adjusted p value in non-OC users was 0.05. FSH and E2 were similar in non-carriers, BRCA1 mutation carriers and women from non-BRCA1/2 families. We found significantly elevated LH levels in the follicular phase among young healthy BRCA1 mutation carriers compared with non-carriers from BRCA1 families. This is a small study and confirmatory studies are warranted to establish whether elevated LH levels are part of the BRCA1 phenotype and may be manipulated in order to reduce cancer risks in BRCA1 mutation carriers.
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2,336,975 |
Prenatal diagnosis in laminin alpha2 chain (merosin)-deficient congenital muscular dystrophy: a collective experience of five international centers.
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The congenital muscular dystrophies (CMD) are clinically and genetically heterogeneous. The merosin (laminin alpha2 chain) deficient form (MDC1A), is characterized clinically by neonatal hypotonia, delayed motor milestones and associated contractures. It is caused by deficiency in the basal lamina of muscle fibers of the alpha2 chain of laminins 2 and 4 (LAMA2 gene at 6q22-23). Laminin alpha2 chain is also expressed in fetal trophoblast, which provides a suitable tissue for prenatal diagnosis in families where the index case has total deficiency of the protein. This article reports the collective experience of five centers over the past 10 years in 114 prenatal diagnostic studies using either protein analysis of the chorionic villus (CV) of the trophoblast plus DNA molecular studies with markers flanking the 6q22-23 region and intragenic polymorphisms (n=58), or using only DNA (n=44) or only protein (n=12) approaches. Of the 102 fetuses studied by molecular genetics, 27 (26%) were predicted to be affected while 75 (74%) were considered as unaffected, with 52 (51%) being heterozygous, thus conforming closely to an autosomal recessive inheritance. In 18 of the 27 affected fetuses, the trophoblast was studied by immunocytochemistry and there was a total or only traces deficiency of the protein in CV basement membrane in all. In 10 cases material from the presumably affected fetus was available for analysis after termination of the pregnancy and immunohistochemical study confirmed the diagnosis in all of them. Prenatal studies of 'at risk' pregnancies in the five centers produced neither false negative (merosin-deficiency in CVs in a normal fetus), nor false positive (normal merosin expression in CVs and affected child), indicating the reliability of the technique, when all the necessary controls are done. Our experience suggests that protein and DNA analysis can be used either independently or combined, according to the facilities of each center, to provide accurate prenatal diagnosis of the MDC1A, and have an essential role in genetic counseling.
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2,336,976 |
Chemical stress sensitive luminescent human cells: molecular biology approach using inducible Drosophila melanogaster hsp22 promoter.
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A whole-cell bioassay has been developed for the total toxicity testing of liquid samples. The method is based on the induction of the bioluminescent activity of genetically manipulated mammalian cells. For that purpose, transfection was used to introduce, in HeLa cells, a DNA sensing element that responds to chemical stress agents (heavy metals, genotoxic agents, and endocrine-disrupting chemicals). Such element was designed to direct the expression of a reporting gene (firefly luciferase) through the activation of Drosophila melanogaster hsp22 promoter. A molecular approach was conducted to optimize hsp22 promoter element in order to decrease the background expression level of the reporting gene and to increase the sensitivity of the bioassay for testing endocrine disruptors. As a result, in the presence of 20-100 microM cadmium chloride, a 6-fold increase in luciferase expression was obtained using a specially designed truncated hsp22 promoter construction. The following chemicals known to be found in the polluted samples were tested: CdCl2, Cd(NO3)2, NaAsO2, alachlore, fentine acetate, thiram, and maneb. The stressing effect of each of them was sensitively detected by the present bioassay in the 0.05-50 microM concentration range.
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2,336,977 |
Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry.
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<AbstractText Label="BACKGROUND & AIMS" NlmCategory="OBJECTIVE">Previous uncontrolled studies have suggested that patients with hepatic iron overload have a poor outcome after liver transplantation. We examined the effect of HFE mutations on posttransplantation survival in patients with hepatic iron overload.</AbstractText>Two hundred sixty patients with end-stage liver disease and hepatic iron overload were enrolled from 12 liver transplantation centers. Hepatic iron concentration (HIC), hepatic iron index (HII), HFE mutation status, and survival after liver transplantation were recorded.</AbstractText>HFE-associated hemochromatosis (HH) defined as homozygosity for the C282Y (n = 14, 7.2%) mutation or compound heterozygosity for the C282Y/H63D (n = 11, 5.6%) mutation was identified in 12.8% of patients. Survival postliver transplantation was significantly lower among patients with HH (1-, 3-, and 5-year survival rates of 64%, 48%, 34%, respectively) compared with simple heterozygotes (C282Y/wt or H63D/wt) or wild-type patients. Patients with HH had a hazard ratio for death of 2.6 (P = .002) after adjustment for age, United Network for Organ Sharing status, year of transplantation, and either elevated HII or HIC. Non-HH patients with hepatic iron overload also had significantly decreased survival when compared with the overall population undergoing liver transplantation (OR = 1.4, 95% CI: 1.15-1.61, P < .001).</AbstractText>One- and 5-year survivals after liver transplantation are significantly lower among patients with HFE-associated HH. Our data also suggest that hepatic iron overload may be associated with decreased survival after liver transplantation, even in patients without HH. Early diagnosis of hepatic iron overload using HFE gene testing and iron depletion prior to liver transplantation may improve posttransplantation survival, particularly among patients with HH.</AbstractText>
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2,336,978 |
Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset.
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<AbstractText Label="BACKGROUND & AIMS" NlmCategory="OBJECTIVE">Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Currently, cancer risks for individuals with HNPCC are based on data from clinically ascertained families. The purpose of this study was to re-examine the penetrance in HNPCC using a comprehensive dataset from a geographically defined region.</AbstractText>A combined dataset of 70 HNPCC families ascertained by traditional high-risk criteria and by molecular screening comprising 88 probands and 373 mutation-positive family members was used. Statistical methods were modified survival analysis techniques.</AbstractText>In mutation-positive relatives (excluding probands), the median age at diagnosis of CRC was 61.2 years (confidence interval [CI], 56.3-68.0 y). The lifetime risk for CRC was 68.7% (CI, 58.6%-78.9%) for men and 52.2% (CI, 37.6%-66.9%) for women. Considering only probands, the median age at diagnosis of CRC was 44.0 years (CI, 41.0-46.3 y). Median age of onset of EC was 62.0 years (CI, 55.9 y to an upper limit too high to calculate) with a lifetime cancer risk of 54% (CI, 41.9%-66.1%).</AbstractText>A markedly later age of onset for CRC at 61 y than previously reported (approximately 44 y) is suggested, resulting mainly from a more rigorous method of analysis in which all gene-positive individuals (both affected and unaffected with cancer) are considered. Lifetime cancer risks may be lower for CRC and endometrial cancer than presently assumed. If confirmed, these data suggest a need to alter counseling practices, and to consider HNPCC in older individuals than before.</AbstractText>
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2,336,979 |
Diagnosing protan heterozygosity using the Medmont C-100 colour vision test.
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A surprisingly high 15 per cent of women in Caucasian societies are carriers of the genes for abnormal colour vision but there is no clinical method to identify them. It has long been known that heterozygotes for the protan colour vision deficiencies can demonstrate a reduced luminous sensitivity to red light. This is known as Schmidt's sign, which is thought to arise from mosaicism (Lyonisation). The Medmont C-100 colour vision test measures relative spectral sensitivity using flicker photometry to differentiate protans and deutans. It should be able to diagnose Schmidt's sign.</AbstractText>We tested six known protan heterozygotes (four whose sons have a protan colour vision deficiency and two whose fathers are protan) with the Medmont C-100 test.</AbstractText>All six heterozygotes made average settings of -1.75 or more negative at the Medmont C-100 test, settings which are at or beyond the boundary of the distribution of settings made by observers with normal colour vision. There have been two previous cases reported in the literature of protan heterozygotes, who made protan settings on the Medmont C-100 or its predecessor test, the OSCAR. We also tested six daughters of the known heterozygotes, 50 per cent of whom are likely to be heterozygotes. Four of the six (66 per cent) made protan settings on the Medmont C-100. The other two made normal 0.0 settings.</AbstractText>We conclude that the Medmont C-100 can be used clinically to diagnose carriers of protan colour vision deficiency.</AbstractText>
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2,336,980 |
The use and control of heel prick blood samples.
|
The human body is assuming new meanings and value. When tissue, such as hair, blood and saliva is subjected to DNA analysis, detailed intimate information can be revealed about a person that may predict information about behavioural traits and future disorders. Such genetic information may lead to the development of beneficial therapeutic treatments, but it may also lead to employment or insurance discrimination. Human tissue is commonly used by law enforcement agencies to detect perpetrators of crimes and to identify corpses. There are many sources of such tissue samples. One is from samples routinely collected from newborn babies for a test known as the "Guthrie test" or heel prick test. At about two days of age the child's heel is pricked and the resultant drops of blood are applied to filter paper attached to a test card. This is dried and analysed and, in New Zealand, the cards are stored indefinitely. The potential range of research purposes using such blood samples is increasing, and expanding markets have increased their value. This paper considers the status of the samples in light of recent developments in New Zealand and suggests appropriate approaches for retention and further use of the samples, or third party access to them.
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2,336,981 |
A patient with mosaic partial trisomy 18 resulting from dicentric chromosome breakage.
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We present a patient with minor dysmorphic features and a mosaic karyotype with two different abnormal cell lines, both involving abnormalities of chromosome 18. Twenty percent of cells studied (4/20) had 46 chromosomes with a large derivative pseudoisodicentric chromosome 18. This chromosome was deleted for 18pter and duplicated for part of proximal 18p (18p11.2 based on fluorescence in situ hybridization (FISH) studies and all of 18q. The two copies of portions of chromosome 18 were fused in an inverted fashion (duplicated for 18qter->18p11.3). The smaller der(18) was present in 80% of cells studied (16/20) and had a normal q-arm, while the p-arm was missing the subtelomere region but had duplication of a part of 18p. FISH studies showed that the larger derivative 18 contained the 18q subtelomere at each end, but the 18p subtelomere was absent, consistent with fusion of two regions within 18p resulting in deletion of the subtelomeric regions. The smaller der(18) was also missing the 18p subtelomere (with normal 18q as expected). Further testing with BAC clones mapping within 18p11.2 showed that these sequences were duplicated and inverted in both of the der(18)s. These findings lead us to hypothesize that the smaller der(18) was derived from the larger, dicentric 18 following anaphase bridge formation, with breakage distal to the duplicated segment.
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2,336,982 |
No association of serotonin transporter gene (SLC6A4) with schizophrenia and bipolar disorder in Japanese patients: association analysis based on linkage disequilibrium.
|
Serotonin transporter gene (SLC6A4) is one of the most promising candidate genes for psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP). Two functional polymorphisms, 5HTTLPR and 5HTTVNTR, have been a focus for genetic association analyses; however, no conclusive results have been obtained. We conducted, 1) a mutation search of SLC6A4, 2) LD mapping to select 'tagging' markers (10 SNPs and 5HTTVNTR, while 5HTTLPR was treated as an independent marker because of its allelic form), and 3) association analysis of these 'tagging' markers and independent markers (5HTTLPR and Asn605Lys) with SCZ and BP in Japanese patients. In this mutation search, a nonsynonymous SNP, Asn605Lys, was detected. No associations of 'tagging' markers and independent markers with such conditions were found. These results indicate that SLC6A4 might not play a major role in SCZ and BP in Japanese patients, a finding that agrees with both the common disease-common variant hypothesis and common disease-rare variant hypothesis.
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2,336,983 |
Comparison of cryopreservation techniques for long-term storage of ash (Fraxinus excelsior L.).
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The main purpose of this study was to develop a cryopreservation protocol for ash and to highlight the importance of testing different clones and plant material of different ontogenetic states. In vitro-grown ash (Fraxinus excelsior L.) shoot tips were successfully cryopreserved following optimization of the PVS2-vitrification protocol. Pretreatment conditions were optimized and three cryopreservation techniques (encapsulation/dehydration, PVS2-vitrification and encapsulation-vitrification) were tested one after another. PVS2-vitrification proved to be the most suitable technique. In vitro-grown shoot tips of ash were successfully cryopreserved with a mean regrowth of 73% for juvenile clones and 67% for selected mature trees. The optimum preculture conditions and the initial protocol were: 10 days cold hardening, preculture for 2 days on medium with 0.8 M glycerol, incubation in 2 M glycerol solution for 20 min at 22 degrees C followed by PVS2 for 25 min at 0 degrees C on ice and direct immersion in liquid nitrogen. Warming was carried out in 43 degree C water for 1 min followed by 22 degree C water for 10 sec. The encapsulation/dehydration method was not successful for shoot tips of F. excelsior because the shoots were sensitive to osmotic dehydration. The encapsulation/vitrification method resulted in a mean regrowth of only 16%. PVS2 vitrification can now be used to store important ash germplasm of either juvenile or mature trees.
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2,336,984 |
Factor XI mutation in a Holstein cow with repeat breeding in Japan.
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Factor XI deficiency is an autosomal recessive coagulopathy in Holstein cattle. Affected cows have a tendency to show repeat breeding. Forty repeat breeding Holstein Friesian cows were selected and tested for the Factor XI mutation. Genomic DNA was isolated from the blood of the cows (n=40). Exon 12 of the Factor XI gene of the cows was amplified by PCR. One repeat breeding cow was heterozygous to the Factor XI mutation as indicated by the presence of two DNA fragments of 320 bp and 244 bp. The insertion of the 76 bp in the heterozygous cow was confirmed by DNA sequencing. The heterozygous cow was in her fourth lactation. She gave birth to male twins at the last calving. She was inseminated artificially four times after the last calving. Factor XI deficiency in cattle has been reported in different countries. However, no case was reported in Japan. This might be the first to report Factor XI mutation in Holstein cattle in Japan.
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2,336,985 |
Modern diagnostics of Chlamydia trachomatis infections.
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Chlamydia trachomatis (C. trachomatis) is the most common agent of sexually transmitted infections. The clinical spectrum of the disease ranges from urethritis to infertility in women and to trachoma. Intracellular localisation of the pathogen creates a challenge for routine diagnostics. In this review possible diagnostic tests have been presented, varying from classic cell culture analysis and serodiagnostics (Enzyme-linked Immunoassays, Indirect Immunofluorescence) to the most sophisticated nucleic acid analyses (hybridisation, Polymerase Chain Reaction, Transcription Mediated Amplification, Ligase Chain Reaction), Advantages and disadvantages of the leading tests are discussed. Possible reasons of false positive as well as false negative results of genetic testing are presented.
|
2,336,986 |
Model for assessment of proficiency of human immunodeficiency virus type 1 sequencing-based genotypic antiretroviral assays.
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Use of sequencing-based genotyping as a diagnostic assay for human immunodeficiency virus (HIV) antiretroviral resistance is increasing. Periodic evaluation of the proficiency of laboratories performing this assay should be established. It is important to identify components of the assay that influence the generation of reliable sequencing data and that should and can be monitored. A model was developed to determine what parameters were reasonable and feasible for assessing the performance of genotyping assays. Ten laboratories using the genotyping platform, HIV-1 Genotyping System (HGS) v. 1 and software versions 1.1 or 2.0, participated in two rounds of testing. For each round, each group was sent a panel consisting of three clinical samples to sequence in real time. Six months later, seven laboratories using the TRUGENE HIV-1 Genotyping Kit participated in a separate round, working with both panels at the same time. Analysis of the data showed that one main indicator of genotyping proficiency was achievement of > or =98% sequence homology of a sample tested to a group consensus sequence for that sample. A second was concordant identification of codons at sites identified with resistance mutations in the sample, although scoring of these criteria is still undetermined from this study. These criteria are applicable to all sequence-based genotyping platforms and have been used as a baseline for assessing the performance of genotyping for the determination of antiretroviral resistance in our ongoing proficiency program.
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2,336,987 |
Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease.
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Lyme disease (LD) is caused by Borrelia burgdorferi and displays different stages, including localized, early disseminated, and persistent infection, all of which are associated with profound inflammatory reactions in the host. Induction of proinflammatory cytokines by B. burgdorferi is mainly mediated by outer surface proteins interacting with TLR-2/TLR-1 heterodimers. In this study, we show that TNF-alpha induction by Borrelia lysate was impaired in heterozygous TLR-2 knockout mice, while reactivity to lipoteichoic acid, another TLR-2 ligand signaling via TLR-2/TLR-6 heterodimers, was unaffected. Blood from individuals heterozygous for the TLR-2 polymorphism Arg753Gln was tested for cytokine release upon stimulation with Borrelia lysate, and induction of TNF-alpha and IFN-gamma was significantly lower as compared with individuals not exhibiting this variation. Overexpression of TLR-2 carrying the Arg753Gln polymorphism in HEK 293 cells led to a significantly stronger impairment of activation by TLR-2/TLR-1 ligands as compared with TLR-2/TLR-6 ligands. To study whether heterozygosity for the Arg753Gln variant of TLR-2 influenced susceptibility for LD, we analyzed 155 patients for this polymorphism. The Arg753Gln variant occurs at a significantly lower frequency in LD patients as compared with matched controls (5.8 vs 13.5%, odds ratio 0.393, 95% confidence interval 0.17-0.89, p = 0.033), with an even more pronounced difference when late stage disease was observed (2.3 vs 12.5%, odds ratio 0.163, 95% confidence interval 0.04-0.76, p = 0.018). These data suggest that Arg753Gln may protect from the development of late stage LD due to a reduced signaling via TLR-2/TLR-1.
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2,336,988 |
Circulating placental RNA in maternal plasma is associated with a preponderance of 5' mRNA fragments: implications for noninvasive prenatal diagnosis and monitoring.
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The molecular characteristics of placental RNA circulating in maternal plasma are unknown. We investigated the integrity of circulating placental RNA in maternal plasma and tested the relevance of plasma RNA integrity for noninvasive prenatal diagnosis.</AbstractText>Six different placental transcripts and mRNA of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were quantified for the 5' and 3' regions in maternal plasma by 1-step real-time reverse transcription-PCR (RT-PCR) assays. This quantitative strategy was validated by 2-step RT-PCR and serial dilution experiments. The rates of detection by the 5' and 3' assays for the beta-subunit of human chorionic gonadotropin (beta hCG) were assessed in maternal plasma samples collected from different gestational periods.</AbstractText>For 5 of the 7 genes, the plasma mRNA concentrations measured by the 5' amplicons were significantly higher than those measured by the corresponding 3' amplicons. Every transcript under study demonstrated a higher rate of detection in the 5' assay than in the 3' assay in maternal plasma. In particular, the detection rate of beta hCG mRNA in maternal plasma was increased throughout gestation when the 5' assay was used.</AbstractText>Circulating placental RNA is associated with a preponderance of 5' mRNA fragments in maternal plasma. Apart from its intrinsic biological interest, this information could have important implications for the development of new assays targeting fetal RNA markers for noninvasive prenatal diagnosis and monitoring.</AbstractText>
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2,336,989 |
The codon for the methionine at position 129 (M129) in the human prion protein provides an alternative initiation site for translation and renders individuals homozygous for M129 more susceptible to prion disease.
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Single amino-acid substitutions in the prion protein have been found to lead to resistance or susceptibility to amyloid fibril formation. In humans, the presence of methionine at position 129 in the prion protein results in increased susceptibility to prion disease, while the presence of valine at that position appears to be protective. It is hypothesized that the codon for M129 is an alternative initiation site for translation, which results in a truncated molecule that is missing the first 128 amino acids, including the signal peptide. This N-terminal truncated form of the prion molecule will not be transported to the extracellular space and thus will accumulate in the cytosol where it is more susceptible to fibril formation and aggregation; this aggregation could hinder normal degradation processes and cause disease. The results of experimental studies on truncated prion molecules support this hypothesis. To test the hypothesis, a gene segment, which when transcribed would result in a prion molecule starting at methionine 129, could be introduced into a convenient experimental animal to see if there is increased incidence of prion disease. Or, fibrils from the brains of affected M129/M129 homozygous individuals could be isolated and the molecules in the fibrils analyzed to determine the identity of the N-terminal amino acid(s). We predict that those isolates will have a preponderance of molecules that start with the methionine at position 129 in the intact protein.
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2,336,990 |
Fluorescent multiplex PCR--fast method for autosomal dominant spinocerebellar ataxias screening.
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Expansion of CAG trinucleotide repeats has been shown to cause a number of autosomal dominant spinocerebellar ataxias such as SCA1, SCA2, SCA3/MJD, SCA6 and SCA7. These disorders are characterized by a wide inter- and intrafamiliar variation in clinical features. The same mutation can result in different phenotypes and the very similar phenotypes can be caused by different mutations. Therefore it is necessary to investigate more SCA genes (according to prevalence) to identify the causal elongation. We developed a fast and efficient screening method based on touchdown multiplex PCR with fluorescent labelled primers for the most common types of SCAs (SCA 1, 2, 3 and 7). It has been reliable in 113 probands tested. Fragment analysis was performed by using 6% denaturing polyacrylamide gel and employing the automated DNA sequencer. This method considerably shortens the process of molecular genetic screening of SCAs and might be used as a tip for designing other SCA screening sets.
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2,336,991 |
Carotid body paraganglioma and SDHD mutation in a Greek family.
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Carotid body (CB) is a highly specialized paraganglion originating from the neural crest ectoderm. CB paraganglion can be caused either by a genetic predisposition (hereditary paraganglia) or by chronic hypoxic stimulation. Germline mutations in any of the following genes: SDHD, SDHC, SDHB, PGL2 or other unknown genes, can cause paragangliomas (PGLs).</AbstractText>We studied a Greek family in which the two daughters had carotid body paraganglioma, whereas both parents did not. RNA extraction, reverse transcriptase polymerase chain reaction and direct DNA sequencing were performed, in order to identify SDHD mutations in all four exons.</AbstractText>Our results revealed the existence of the missense mutation Y114C, in exon-4 of the SDHD gene, in the unaffected father and both affected sisters.</AbstractText>DNA testing was performed, for the first time in Greece, on patients with carotid body tumor. This marks a new geographical location, in the literature, for this mutation.</AbstractText>
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2,336,992 |
[Practical usefulness of the IDENTIFILER system for paternity testing in the Central Poland population].
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The usefulness of the IDENTIFILER multiplex system for paternity testing in the Central Poland population was examined. One hundred excluding cases and one hundred including cases were analysed and the results were estimated for two different types of cases: trios (standard cases) and duos (motherless cases). Efficiency of exclusion and paternity index were analysed for each locus as well as for the entire set of the fifteen STR markers.
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2,336,993 |
[Frequency quotient of paternity index Qf in a case of replacement of the natural father within a trio with his brother].
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Cases of trios in which the natural father's near blood-relative instead of the natural father are among the hardest to give an expert opinion on. The goal of this study was to determine with what frequencies specific given values of paternity index appear in trios with the natural father and with the natural father's brother, and whether these frequencies can be the basis for discovering the substitution of the natural father by a brother in a given trio examined. The study material was the population of genotypes investigated in the AmpF/STR SGM Plus system. It was seen that the higher the paternity index values, the more frequently they appear in trios with the natural father, and less frequently in trios with the natural father's brother. This dependency has a general character and obtained in all the systems studied. The frequency quotients Qf (defined as the frequency of a given PI value in trios with the natural father in relation to the "reduced" frequency of the PI value in trios with the brother of the natural father) are found in the region of c. 0.6 to c. 1.4, whereby extreme values are rare, and the most frequent are cases where Qf oscillates within modest limits around the value 1. This fact shows that the majority of cases, calculated Qf values contribute little to resolving the question of whether the defendant--or his brother--is the child's father.
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2,336,994 |
Familial transmission of a dysmorphic syndrome: a variant example of Kabuki syndrome?
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Familial transmission of a dysmorphic syndrome: a variant example of Kabuki syndrome?: We report a Romanian family with a dysmorphic syndrome in three generations: a boy, his mother and maternal grandfather, who all presented with the typical facial appearance, characteristic skeletal and dermatoglyphic findings of Kabuki syndrome, but no mental retardation, short stature and visceral abnormalities. The phenotype observed in this family may represent the mild end of a spectrum of clinical manifestations described in this condition. This report provides a further evidence for autosomal dominant transmission of the disorder.
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2,336,995 |
A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis.
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Spondyloepiphyseal dysplasia (SED) encompasses a heterogeneous group of disorders characterized by shortening of the trunk and limbs. The autosomal dominant SED type Kimberley (SEDK) is associated with premature degenerative arthropathy and has been previously mapped in a multigenerational family to a novel locus on 15q26.1. This locus contains the gene AGC1, which encodes aggrecan, the core protein of the most abundant proteoglycan of cartilage. We screened AGC1 for mutations and identified a single-base-pair insertion, within the variable repeat region of exon 12 in affected individuals from the family with SEDK, that introduces a frameshift of 212 amino acids, including 22 cysteine residues, followed by a premature stop codon. This is the first identification of an AGC1 mutation causing a human disorder. This finding extends the spectrum of mutated genes that may cause SED and thus will aid in the molecular delineation of this complex group of conditions.
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2,336,996 |
A high-density screen for linkage in multiple sclerosis.
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To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.
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2,336,997 |
Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin.
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Mutations in the catalytic subunit of the mitochondrial DNA polymerase gamma (POLG) have been found to be an important cause of neurological disease. Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G. Here, we studied the frequency of this allele and found it to be among the most common genetic causes of inherited ataxia in Finland. We identified 27 patients with mitochondrial recessive ataxia syndrome (MIRAS) from 15 Finnish families, with a carrier frequency in the general population of 1 : 125. Since the mutation pair W748S+E1143G has also been described in European patients, we examined the haplotypes of 13 non-Finnish, European patients with the W748S mutation. Haplotype analysis revealed that all the chromosomes carrying these two changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common, northern haplotypes, outside the core haplotype, could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicate that this newly identified ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes.
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2,336,998 |
Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.
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Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.
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2,336,999 |
An algorithm to construct genetically similar subsets of families with the use of self-reported ethnicity information.
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We present a simple algorithm that uses self-reported ethnicity information, pedigree structure, and affection status to group families into genetically more homogeneous subsets. This algorithm should prove useful to researchers who wish to perform genetic analyses on more-homogeneous subsets when they suspect that ignoring heterogeneity could lead to false-positive results or loss of power. We applied our algorithm to the self-reported ethnicity information of 159 families from the Veterans Affairs Cooperative Study of schizophrenia. We compared these estimates of population membership with those obtained using the program structure in an analysis of 378 microsatellite markers. We found excellent concordance between family classifications determined using self-reported ethnicity information and our algorithm and those determined using genetic marker data and structure; 158 of the 159 families had concordant classifications. In addition, the degree of admixture estimated using our algorithm and self-reported ethnicity information correlated well with that predicted using the genotype information.
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