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2,336,600 |
Implementation of informed consent for a cystic fibrosis newborn screening program in France: low refusal rates for optional testing.
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The French Association for Neonatal Screening implemented cystic fibrosis neonatal screening (CF NBS) region by region in France, from the beginning of the year 2002 to early 2003. The program uses an immunoreactive trypsinogen/DNA testing algorithm on dried blood samples obtained at 3 days of age. Incorporation of DNA testing necessitated compliance with official regulations and French "bioethics" laws: the need for a written consent from the patient/guardian and specific circulation of the prescription, sample, and results. To fulfill these obligations, the Ethics and Genetics committee of the French Association for Neonatal Screening recommended that informed consent should be obtained for all neonates at birth by having the parents sign directly on the sampling paper. This study was designed to evaluate the effect of the educational efforts used to obtain informed consent on acceptance of CF NBS.</AbstractText>Data from the screening center in Lille, France, were analyzed to determine the rate of refusal of CF NBS in the 18 months after initiation of the informed consent process.</AbstractText>The number of refusals for CF NBS declined from 0.8% at the start of the program to 0.2% at the end of the first year of the new process for obtaining written consent.</AbstractText>Efforts to inform parents and professionals resulted in a significant decrease in the number of refusals for CF NBS.</AbstractText>
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2,336,601 |
ApoE gene and familial risk of Alzheimer's disease as predictors of odour identification in older adults.
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The study examined odour identification ability in healthy older adults at increased risk for developing Alzheimer's disease (AD). We recruited a sample (n = 24) of siblings related to probable AD cases and an age-matched control sample (n = 47). All participants were genotyped for the presence of the ApoE epsilon4 allele. Performance on a simple olfactory task of odour identification was compared according to positive family history of AD and ApoE epsilon4 status. The sibling group showed an odour identification deficit compared to the control group. Whilst there was no independent influence of ApoE epsilon4 status on odour identification, there was a significant interaction between positive family history and ApoE epsilon4 status. Sibling epsilon4 carriers showed the greatest odour identification deficit and their performance was significantly poorer than both the sibling non-epsilon4 carrier and control epsilon4 carrier groups. Odour identification deficits like those reported here are considered to be early cognitive markers of incipient AD. In this respect, these findings support the need to both monitor individuals at increased risk of the disease and introduce olfactory-mediated cognitive tasks into the diagnostic setting.
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2,336,602 |
Different real time PCR approaches for the fine quantification of SNP's alleles in DNA pools: assays development, characterization and pre-validation.
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Single nucleotide polymorphisms (SNPs) are becoming the most common type of markers used in genetic analysis. In the present report a SNP has been chosen to test the applicability of Real Time PCR to discriminate and quantify SNPs alleles on DNA pools. Amplification Refractory Mutation System (ARMS) and Mismatch Amplification Mutation Assay (MAMA) has been applied. Each assay has been pre-validated testing specificity and performances (linearity, PCR efficiency, interference limit, limit of detection, limit of quantification, precision and accuracy). Both the approaches achieve a precise and accurate estimation of the allele frequencies on pooled DNA samples in the range from 5 % to 95 % and don't require standard curves or calibrators. The lowest measurement that could be significantly distinguished from the background noise has been determined around the 1 % for both the approaches, allowing to extend the range of quantifications from 1 % to 99 %. Furthermore applicability of Real Time PCR assays for general diagnostic purposes is discussed.
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2,336,603 |
Sequence diversity within the HA-1 gene as detected by melting temperature assay without oligonucleotide probes.
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The minor histocompatibility antigens (mHags) are self-peptides derived from common cellular proteins and presented by MHC class I and II molecules. Disparities in mHags are a potential risk for the development of graft-versus-host disease (GvHD) in the recipients of bone marrow from HLA-identical donors. Two alleles have been identified in the mHag HA-1. The correlation between mismatches of the mHag HA-1 and GvHD has been suggested and methods to facilitate large-scale testing were afterwards developed.</AbstractText>We used sequence specific primer (SSP) PCR and direct sequencing to detect HA-1 gene polymorphisms in a sample of 131 unrelated Italian subjects. We then set up a novel melting temperature (Tm) assay that may help identification of HA-1 alleles without oligonucleotide probes.</AbstractText>We report the frequencies of HA-1 alleles in the Italian population and the presence of an intronic 5 base-pair deletion associated with the immunogeneic allele HA-1H. We also detected novel variable sites with respect to the consensus sequence of HA-1 locus. Even though recombination/gene conversion events are documented, there is considerable linkage disequilibrium in the data. The gametic associations between HA-1R/H alleles and the intronic 5-bp ins/del polymorphism prompted us to try the Tm analysis with SYBR Green I. We show that the addition of dimethylsulfoxide (DMSO) during the assay yields distinct patterns when amplicons from HA-1H homozygotes, HA-1R homozygotes, and heterozygotes are analysed.</AbstractText>The possibility to use SYBR Green I to detect Tm differences between allelic variants is attractive but requires great caution. We succeeded in allele discrimination of the HA-1 locus using a relatively short (101 bp) amplicon, only in the presence of DMSO. We believe that, at least in certain assets, Tm assays may benefit by the addition of DMSO or other agents affecting DNA strand conformation and stability.</AbstractText>
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2,336,604 |
Chloroplast and microsatellite DNA diversities reveal the introduction history of Brazilian peppertree (Schinus terebinthifolius) in Florida.
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Brazilian peppertree (Schinus terebinthifolius) is a woody perennial that has invaded much of Florida. This native of northeastern Argentina, Paraguay, and Brazil was brought as an ornamental to both the west and east coasts of Florida at the end of the 19th century. It was recorded as an invader of natural areas in the 1950s, and has since extended its range to cover over 280 000 ha. Our goals were to understand the history of this invasion, as one step toward understanding why this exotic was so successful, and ultimately to improve development of biological control agents. We sampled plants from the native and exotic ranges, particularly Florida, and genotyped these individuals at nuclear and chloroplast loci. Nuclear microsatellite and cpDNA loci reveal strong genetic population structure consistent with limited dispersal in the introduced and native ranges. Bayesian clustering of microsatellite data separates the east and west coast plants in Florida into distinct populations. The two chloroplast haplotypes found in Florida are also concordant with this separation: one predominates on the east coast, the other on the west coast. Analysis of samples collected in South America shows that haplotypes as distinct as the two in Florida are unlikely to have come from a single source population. We conclude that the genetic evidence supports two introductions of Brazilian peppertree into Florida and extensive hybridization between them. The west coast genotype likely came from coastal Brazil at about 27 degrees south, whereas the east coast genotype probably originated from another, as yet unidentified site. As a result of hybridization, the Florida population does not exhibit low genetic variation compared to populations in the native range, possibly increasing its ability to adapt to novel environments. Hybridization also has important consequences for the selection of biocontrol agents since it will not be possible to identify closely co-adapted natural enemies in the native range, necessitating more extensive host testing.
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2,336,605 |
Reference materials (RMs) for analysis of the human factor II (prothrombin) gene G20210A mutation.
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The Scientific Committee of Molecular Biology Techniques (C-MBT) in Clinical Chemistry of the IFCC has initiated a joint project in co-operation with the European Commission, Joint Research Centre, Institute of Reference Materials and Measurements to develop and produce plasmid-type reference materials (RMs) for the analysis of the human prothrombin gene G20210A mutation. Although DNA tests have a high impact on clinical decision-making and the number of tests performed in diagnostic laboratories is high, issues of quality and quality assurance exist, and currently only a few RMs for clinical genetic testing are available. A gene fragment chosen was produced that spans all primer annealing sites published to date. Both the wild-type and mutant alleles of this gene fragment were cloned into a pUC18 plasmid and two plasmid RMs were produced. In addition, a mixture of both plasmids was produced to mimic the heterozygous genotype. The present study describes the performance of these reference materials in a commutability study, in which they were tested by nine different methods in 13 expert laboratories. This series of plasmid RMs are, to the best of our knowledge, the first plasmid-type clinical genetic RMs introduced worldwide.
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2,336,606 |
A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk.
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A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes.</AbstractText>We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6-3.2], CT genotype 2.6 mg/d [95% CI: 2.1-3.1], TT genotype 1.4 mg/d [95 % CI: 1.1-1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9-3.5], CT genotype 2.3 mg/d [95% CI: 2.1-2.5], TT genotype 1.7 mg/d [95% CI: 1.3-2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2-5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6-2.3).</AbstractText>These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.</AbstractText>
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2,336,607 |
Fragile X syndrome: a clinico-genetic study of mentally retarded patients in Kuwait.
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In a prospective study in Kuwait, 182 mentally retarded male patients who fulfilled 5 or more clinical criteria of fragile X syndrome were screened using polymerase chain reaction (PCR) testing. Twenty patients (11%) were highly suspected of having fragile X syndrome due to mutation at the FRAXA locus; none had mutation at the FRAXE locus. Of these, 11 (55%) were confirmed fragile-X-positive by both cytogenetic and PCR techniques. The most frequent clinical features were: prominent forehead, high arched palate, hyperextensible joints, long ears, prominent jaw, height > 10th centile and attention-deficit hyperactivity. Less common were avoidance of eye contact (45%), autism (45%) and seizures (30%). Large testes were found in 55% of cases. Pre-pubertal and post-pubertal clinical criteria were different.
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2,336,608 |
[Intrathecal baclofen for children with chronic pain related to severe spasticity: advantages of tunneling the catheter in the testing phase].
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To document the effectiveness and safety of intrathecal baclofen administered through a tunneled catheter during a diagnostic procedure, prior to implantation of a subcutaneous pump, in children with chronic pain due to severe spasticity.</AbstractText>This was a retrospective study of 6 children with intense chronic pain due to spasticity caused by cerebral palsy or genetic dystonia. Increasing doses of intrathecal baclofen in continuous perfusion through a tunneled catheter were tested.</AbstractText>Lumbar intrathecal catheters were tunneled for 48 to 80 hours in 5 males and 1 female aged 8 to 18 years old. Intrathecal baclofen was administered in continuous perfusion up to maximum rates that ranged between 105 and 570 microg/day. For 5 patients the score on the visual analog pain scale (0-10) changed from over 7 to 0 by the end of the test. In 2 patients, side effects of analgesia were noted, specifically sedation, bradycardia, and bradypnea. No serious complications, such as meningitis, spinal abscess, or hematoma, were reported. The families of 4 patients chose to accept implantation of a subcutaneous pump. Pump therapy remained effective and free of complications when checked 23 or 55 months after placement.</AbstractText>Performing a trial of increasing doses of intrathecal baclofen therapy in continuous perfusion through a tunneled catheter facilitated selection of patients for whom chronic administration of intrathecal baclofen is effective and free of complications.</AbstractText>
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2,336,609 |
Association between PADI4 and rheumatoid arthritis: a replication study.
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The peptidylarginine deiminase type 4 gene (PADI4) was recently reported to be associated with rheumatoid arthritis (RA) in a Japanese population. The presence of a single-nucleotide polymorphism (SNP) located in intron 3 of PADI4 provided the strongest evidence of this association. Moreover, functional haplotypes that affect stability of transcripts were identified. However, subsequent research failed to confirm the observed association in a UK population. The present study was undertaken to further investigate the association of PADI4 with RA, using a series of population-based samples from subjects with the same ethnic background as the subjects in the original study.</AbstractText>DNA samples were obtained from 1,230 Japanese RA patients and 948 ethnically matched controls. Genotyping was performed using 5' allele discrimination assays. All samples were genotyped for 3 SNPs on PADI4 (padi4_94, padi4_104, and padi4_102), which comprised the reported haplotypes. Chi-square testing was performed for a case-control study and the PENHAPLO program was used for haplotype estimation.</AbstractText>All tested SNPs were found to show significant differences in frequency between cases and controls (P = 0.010-0.0008), which confirmed the association observed in the original study. Odds ratios calculated for allele frequencies were 1.23, 1.21, and 1.36 in padi4_94, padi4_104, and padi4_102 respectively.</AbstractText>Replication of association in individual samples strongly suggests that PADI4 is a true susceptibility gene for RA.</AbstractText>
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2,336,610 |
The pituitary in klinefelter syndrome.
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Klinefelter syndrome is a genetically determined primary gonadal defect characterized by the XXY karyotype. The testes are small, blood testosterone levels are low, and blood gonadotropin levels are elevated. Pituitary changes in patients with Klinefelter syndrome have not been evaluated in detail.</AbstractText>The first patient, a 76-yr-old man, was operated for a large sellar mass. The second and third patients, a 62- and a 52-yr-old man, respectively, died of cardiac failure. Both the latter pituitaries were normal-sized and removed at autopsy. The diagnosis of Klinefelter syndrome was confirmed by genetic testing in all three cases. The formalin-fixed and paraffin-embedded pituitaries of three patients were evaluated for adenohypophysial hormone immunoreactivity. For immunohistochemistry, the streptavidin- biotin-peroxidase (ABC) complex method was applied.</AbstractText>In case 1, histology and immunohistochemistry revealed an oncocytic gonadotroph macroadenoma immunoreactive for FSH and alpha subunit. No pituitary gland was evident. The pituitary of case 2 featured hyperplasia of gonadotrophs, some with features of "gonadal deficiency cells," and a microadenoma immunoreactive for GH. The pituitary of case 3 similarly showed hyperplasia of gonadotrophs and the formation of gonadal deficiency cells.</AbstractText>Protracted stimulation of gonadotrophs due to lack of androgen feedback might have been a factor in the formation of the gonadotroph adenoma in case 1 and in the development of gonadotroph hyperplasia in cases 2 and 3. The clinically silent GH microadenoma of case 2 was regarded as an incidental finding.</AbstractText>
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2,336,611 |
Research for newborn screening: developing a national framework.
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Newborn metabolic screening represents the largest application of genetic testing in medicine. As new technologies are developed, the number of conditions amenable to newborn screening (NBS) will continue to expand. Despite the scope of these programs, the evidence base for a number of NBS applications remains relatively weak. This article briefly reviews the evidence base for several conditions. The article then develops a proposal for a structured sequence of research protocols to evaluate potential applications for NBS before their formal implementation in public health programs. Such a framework for research will require collaboration between states and the federal government, a collaboration that is emerging through recent federal legislation and funding.
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2,336,612 |
ACOG committee opinion. Number 318, October 2005. Screening for Tay-Sachs disease.
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Tay-Sachs disease (TSD) is a severe progressive neurologic disease that causes death in early childhood. Carrier screening, should be offered before pregnancy to individuals and couples at high-risk, including those of Ashkenazi Jewish, French-Canadian, or Cajun descent and those with a family history consistent with TSD. If both partners are determined to be carriers of TSD, genetic counseling and prenatal diagnosis should be offered.
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2,336,613 |
Preimplantation HLA typing: having children to save our loved ones.
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Preimplantation tissue typing has been proposed as a method for creating a tissue matched child that can serve as a haematopoietic stem cell donor to save its sick sibling in need of a stem cell transplant. Despite recent promising results, many people have expressed their disapproval of this method. This paper addresses the main concerns of these critics: the risk of preimplantation genetic diagnosis (PGD) for the child to be born; the intention to have a donor child; the limits that should be placed on what may be done to the donor child, and whether the intended recipient can be someone other than a sibling. The author will show that these concerns do not constitute a sufficient ground to forbid people to use this technique to save not only a sibling, but also any other loved one's life. Finally, the author briefly deals with two alternative scenarios: the creation of a human leukocyte antigen (HLA) matched child as an insurance policy, and the banking of HLA matched embryos.
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2,336,614 |
Genetic analysis identifies a function for the queC (ybaX) gene product at an initial step in the queuosine biosynthetic pathway in Escherichia coli.
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Queuosine (Q), one of the most complex modifications occurring at the wobble position of tRNAs with GUN anticodons, is implicated in a number of biological activities, including accuracy of decoding, virulence, and cellular differentiation. Despite these important implications, its biosynthetic pathway has remained unresolved. Earlier, we observed that a naturally occurring strain of Escherichia coli B105 lacked Q modification in the tRNAs. In the present study, we developed a genetic screen to map the defect in E. coli B105 to a single gene, queC (renamed from ybaX), predicted to code for a 231-amino-acid-long protein with a pI of 5.6. As analyzed by mobility of tRNA(Tyr) on acid urea gels and two-dimensional thin-layer chromatography of the modified nucleosides, expression of QueC from a plasmid-borne copy confers a Q+ phenotype to E. coli B105. Further, analyses of tRNA(Tyr) from E. coli JE10651 (queA mutant), its derivative generated by deletion of chromosomal queC (queA deltaqueC), and E. coli JE7325, deficient in converting preQ0 to preQ1, have provided the first genetic evidence for the involvement of QueC at a step leading to production of preQ0, the first known intermediate in the generally accepted pathway that utilizes GTP as the starting molecule. In addition, we discuss the possibilities of collaboration of QueC with other cellular proteins in the production of preQ0.
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2,336,615 |
Large genomic deletions inactivate the BRCA2 gene in breast cancer families.
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BRCA1 and BRCA2 are the two major genes responsible for the breast and ovarian cancers that cluster in families with a genetically determined predisposition. However, regardless of the mutation detection method employed, the percentage of families without identifiable alterations of these genes exceeds 50%, even when applying stringent criteria for family selection. A small but significant increase in mutation detection rate has resulted from the discovery of large genomic alterations in BRCA1. A few studies have addressed the question of whether BRCA2 might be inactivated by the same kinds of alteration, but most were either done on a relatively small number of samples or employed cumbersome mutation detection methods of variable sensitivity.</AbstractText>To analyse 121 highly selected families using the recently available BRCA2 multiplex ligation dependent probe amplification (MLPA) technique.</AbstractText>Three different large genomic deletions were identified and confirmed by analysis of the mutant transcript and genomic characterisation of the breakpoints.</AbstractText>Contrary to initial suggestions, the presence of BRCA2 genomic rearrangements is worth investigating in high risk breast or ovarian cancer families.</AbstractText>
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2,336,616 |
Identification of novel mutations in the SEMA4A gene associated with retinal degenerative diseases.
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Semaphorins are a large family of transmembrane proteins. The gene for SEMA4A encodes a transmembrane protein comprising 760 amino acids. To investigate its association with human retinal degeneration, mutation screening of the SEMA4A gene was carried out on 190 unrelated patients suffering from a variety of eye diseases. We report the first observation of the involvement of SEMA4A gene mutations causing retinitis pigmentosa (RP) and cone rod dystrophy (CRD). We screened the DNA of 135 patients with RP, 25 patients with CRD, and 30 with LCA using SSCP and direct DNA sequencing for mutations in the SEMA4A gene. Two mutations, p.D345H and p.F350C, were observed only in affected patients; they were not observed in any of the normal members or the 100 control subjects. Both mutations identified occur in the conserved semaphorin domain. Multiple sequence alignments using Clustal analysis showed that R713Q is a conserved substitution and D345H is a semi-conserved substitution. We conclude that these mutations are a cause of various retinal degenerations.
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2,336,617 |
Subtelomere FISH analysis of 11 688 cases: an evaluation of the frequency and pattern of subtelomere rearrangements in individuals with developmental disabilities.
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Subtelomere fluorescence in situ hybridisation (FISH) analysis has increasingly been used as an adjunct to routine cytogenetic testing in order to detect small rearrangements. Previous reports have estimated an overall abnormality rate of 6%, with a range of 2-29% because of different inclusion criteria.</AbstractText>This study presents data compiled from 11 688 cases referred for subtelomere FISH testing in three clinical cytogenetic laboratories.</AbstractText>In this study population, the detection rate for clinically significant subtelomere abnormalities was approximately 2.5%, with an additional 0.5% detection of presumed familial variants. Approximately half of the clinically significant abnormalities identified were terminal deletions, the majority of which were de novo. Most of the remaining cases were unbalanced translocations between two chromosomes or two arms of the same chromosome. Approximately 60% of the unbalanced translocations were inherited from a parent carrying a balanced form of the rearrangement. Other abnormalities identified included tandem duplications, apparently balanced translocations, partial deletions, and insertions. Interestingly, 9 cases (0.08%) were found to have interstitial deletions of non-telomeric control loci, either BCR on 22q or PML on 15q. The most common clinically significant imbalances found were deletions of 1p, 22q, 4p, 9q, 8p, 2q and 20p. The most common familial variants were a deletion or duplication of 10q, deletion of 4q, deletion of Yq, and duplication of X/Yp onto Xq.</AbstractText>This study of subtelomere rearrangements is a 20 fold increase in number over the previously reported largest study and represents an unbiased analysis of subtelomere rearrangements in a large, unselected patient population.</AbstractText>
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2,336,618 |
Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype.
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Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain. At birth, nearly 50% of children with HPE have cytogenetic anomalies. Approximately 20% of infants with normal chromosomes have sequence mutations in one of the four main HPE genes (SHH, ZIC2, SIX3, and TGIF). The other non-syndromic forms of HPE may be due to environmental factors or mutations in other genes, or potentially due to submicroscopic deletions of HPE genes. We used two complementary assays to test for HPE associated submicroscopic deletions. Firstly, we developed a multicolour fluorescent in situ hybridisation (FISH) assay using probes for the four major HPE genes and for two candidate genes (DISP1 and FOXA2). We analysed lymphoblastoid cell lines (LCL) from 103 patients who had CNS findings of HPE, normal karyotypes, and no point mutations, and found seven microdeletions. We subsequently applied quantitative PCR to 424 HPE DNA samples, including the 103 samples studied by FISH: 339 with CNS findings of HPE, and 85 with normal CNS and characteristic HPE facial findings. Microdeletions for either SHH, ZIC2, SIX3, or TGIF were found in 16 of the 339 severe HPE cases (that is, with CNS findings; 4.7%). In contrast, no microdeletion was found in the 85 patients at the mildest end of the HPE spectrum. Based on our data, microdeletion testing should be considered as part of an evaluation of holoprosencephaly, especially in severe HPE cases.
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2,336,619 |
A unique gene expression signature discriminates familial Alzheimer's disease mutation carriers from their wild-type siblings.
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Alzheimer's disease (AD) is a neurodegenerative disease with an insidious onset and progressive course that inevitably leads to death. The current diagnostic tools do not allow for diagnosis until the disease has lead to irreversible brain damage. Genetic studies of autosomal dominant early onset familial AD has identified three causative genes: amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2). We performed a global gene expression analysis on fibroblasts from 33 individuals (both healthy and demented mutation carriers as well as wild-type siblings) from three families segregating the APP(SWE), APP(ARC) and PSEN1 H163Y mutations, respectively. The mutations cause hereditary progressive cognitive disorder, including typical autosomal dominant AD. Our data show that the mutation carriers share a common gene expression profile significantly different from that of their wild-type siblings. The results indicate that the disease process starts several decades before the onset of cognitive decline, suggesting that presymptomatic diagnosis of AD and other progressive cognitive disorders may be feasible in the near future.
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2,336,620 |
Sperm aneuploidy in fathers of Klinefelter's syndrome offspring assessed by multicolour fluorescent in situ hybridization using probes for chromosomes 6, 13, 18, 21, 22, X and Y.
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It is still unclear if a recurrence risk would exist in fathers of an aneuploid offspring of paternal origin. We have studied disomy frequencies in spermatozoa from fathers having Klinefelter syndrome (KS) offspring or miscarriages. The effect of paternal age on sperm disomy percentages is also analysed.</AbstractText>Parental origin of 17 KS patients was carried out by amplification of X chromosome polymorphisms. Spermatozoa from their fathers were studied by multicolour fluorescent in situ hybridisation (FISH) using probes for chromosomes 6, 13, 18, 21, 22, X and Y.</AbstractText>In 53% of KS cases studied the additional X chromosome was of paternal origin. The paternally transmitted KS group of fathers showed significantly higher frequencies for XY disomy sperm as compared to fathers of the maternal-origin group. A correlation between paternal age and XY disomy frequencies was only found in the paternally derived cases. In contrast, similar disomy frequencies for all autosomes analysed were found in both groups of fathers.</AbstractText>XY disomy frequencies increase with advancing paternal age only in fathers with paternally inherited KS offspring.</AbstractText>
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2,336,621 |
Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone.
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Paget's disease of bone (PDB) is a common metabolic bone disease of late onset with a strong genetic component. Rarely, PDB can occur as part of a syndrome in which the disease is accompanied by inclusion body myopathy and frontotemporal dementia (inclusion body myopathy, Paget's disease and frontotemporal dementia, IBMPFD). Recently, IBMPFD has been shown to be caused by mutations in Valosin-containing Protein (VCP), which is required for the proteasomal degradation of phosphorylated IkappaB-alpha, a necessary step in the activation of the transcription factor NF-kappaB. Here, we evaluated the role of VCP in the pathogenesis of typical PDB. We conducted mutation screening of VCP in 44 kindreds with familial Paget's disease recruited mainly through clinic referrals in the UK, Australia and New Zealand. We also performed an association study of VCP haplotypes in patients with PDB who did not have a family history of the disease (sporadic PDB). No mutations were found in VCP in three PDB families where there was evidence of allele sharing between affected subjects in the VCP critical region on chromosome 9p13. We failed to detect disease-associated mutations in any of the three exons previously reported to contain IBMPFD mutations in a further 41 PDB families. We found no evidence of allelic association between common VCP haplotypes in a case-control study of 179 sporadic PDB patients and 172 age- and sex-matched controls. Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia.
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2,336,622 |
Novel compound heterozygous mutations in sacsin-related ataxia.
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High prevalence of a form of autosomal recessive spastic ataxia with early onset was originally described among French Canadians in the Charlevoix-Saguenay region, in northeastern Quebec. Since the responsible gene (SACS) was identified, mutations in the SACS gene have been described in Tunisia, Italy, Turkey, and Japan. The mutation sites found outside Quebec are different from the ones in Quebec. All patients outside Quebec, except one Italian patient, have been reported to have homozygous mutations. The authors report here identical twin sisters with novel compound heterozygous mutations (c.[2951_2952delAG]+[3922delT]) in the SACS gene.
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2,336,623 |
Genetic susceptibility testing from a stress and coping perspective.
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Four theories of health behavior and of stress and coping are reviewed for their ability to illuminate interest in uptake and outcomes of genetic testing for adult-onset diseases. These theories are the Health Belief Model, the Theory of Planned Behavior (TPB), the Common Sense Model of Self-regulation (CSM), and the Transactional Model of Stress and Coping (TMSC). Basic concepts of each theory are discussed, followed by evidence from the literature supporting the relevance of these concepts to the understanding of genetic testing for four adult-onset diseases: Huntington's disease, Alzheimer's disease, hereditary breast/ovarian cancer, and hereditary colorectal cancer. Emphasis is placed on the finding that a decision to undergo genetic testing may be considered as a way to cope with both the cognitive and affective concerns that arise from living at increased risk of developing a disease in the future. The potential value of genetic testing for reducing uncertainty about and gaining a sense of control over one's risk of developing a chronic disease is highlighted. We argue that theories which focus on stress and coping provide a useful framework for future studies of genetic testing decisions for adult-onset disease risk.
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2,336,624 |
Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD.
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Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported.</AbstractText>To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes.</AbstractText>We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases.</AbstractText>These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.</AbstractText>
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2,336,625 |
New approaches to drug development in pediatric oncology.
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This article reviews the changing paradigm of new drug development for childhood cancer. Although there have been dramatic improvements in the treatment and outcome for childhood cancer over the past 50 years, in some cancers, only limited progress has been made. New strategies to improve the outcome for poor-prognosis tumors and to minimize the long-term sequelae associated with therapy are required. Such strategies include a new pediatric-specific initiative for the preclinical testing of anticancer drugs for childhood malignancies, and ongoing research into the molecular heterogeneity of childhood tumors to facilitate the evaluation of molecularly targeted drugs. In addition, continued investigation into the genetic basis underlying interpatient variability in drug exposure and response is a priority. The goal of these initiatives is to improve the overall outcome for childhood cancer while minimizing the short and long-term sequelae associated with current treatment strategies.
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2,336,626 |
Inherited susceptibility for pediatric cancer.
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The percentage of childhood cancers that are caused by a clearly inherited predisposition varies significantly from only a few percent to more than 50% with individual tumor types. Recent advances in genetic testing and studies of cohorts of cancer patients have demonstrated the likelihood of identifying a cancer susceptibility mutation for numerous childhood cancers. Inherited predisposition to cancer is frequently the result of dominant constitutional mutations in tumor suppressor genes, which can be inherited from an affected parent or occur de novo during gametogenesis. In this article, we review the childhood malignancies that are associated with at least a 10% likelihood of being caused by a genetic susceptibility to cancer and therefore warrant consideration for a genetic evaluation; these malignancies include retinoblastoma, adrenocortical carcinoma, atypical teratoid and malignant rhabdoid tumors, optic pathway tumors, juvenile myelomonocytic leukemia, malignant peripheral nerve sheath tumors, vestibular schwannomas, endolymphatic sac tumors, hemangioblastomas, medullary thyroid cancer, pheochromocytomas, and paragangliomas. Children with other malignancies may also warrant genetic evaluation if there is the co-occurrence of malignancy and two or more congenital anomalies, or malignancy and a significant family history of related cancers. We also review the importance of the correct genetic diagnosis in order to ensure appropriate treatment and ongoing cancer surveillance for the child with cancer and closely related family members (e.g., parents and siblings).
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2,336,627 |
Pharmacodiagnostic testing in breast cancer: focus on HER2 and trastuzumab therapy.
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Pharmacogenomics is defined as research into inherited genetic variations that determine an individual's response to therapeutic agents. In oncology, pharmacogenomics based on somatic molecular alterations inherited by subsequent cancer cell generations forms the basis of molecular targeting of novel therapeutic agents. What has emerged from clinical experience with such agents is the need for appropriate pharmacodiagnostic approaches to ensure the drugs are correctly targeted. Given the broad range of pharmacogenomic agents currently under evaluation for cancer therapy, it appears that a rapid extension of pharmacodiagnostic profiling will be required in the next 5-10 years, if not sooner. If this is to be successfully achieved, lessons learned in the past, particularly during the development of HER2 (ERBB2) testing for directing trastuzumab therapy in breast cancer, may provide a valuable framework for the development of future pharmacodiagnostic assays system. This article reviews the biological and clinical rationale for targeting breast cancer with trastuzumab and the steps taken to validate and improve pharmacodiagnostic procedures for testing tumor HER2 protein expression and HER2 gene amplification. Attention is given to quality assurance and reproducibility of testing approaches and the optimal selection of patients for response to trastuzumab. This approach serves as a paradigm for the future development of pharmacodiagnostic tests in oncology.
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2,336,628 |
Detection of resistance to imatinib by metabolic profiling: clinical and drug development implications.
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Acquired resistance to imatinib mesylate is an increasing and continued challenge in the treatment of BCR-ABL tyrosine kinase positive leukemias as well as gastrointestinal stromal tumors. Stable isotope-based dynamic metabolic profiling (SIDMAP) studies conducted in parallel with the development and clinical testing of imatinib revealed that this targeted drug is most effective in controlling glucose transport, direct glucose oxidation for RNA ribose synthesis in the pentose cycle, as well as de novo long-chain fatty acid synthesis. Thus imatinib deprives transformed cells of the key substrate of macromolecule synthesis, malignant cell proliferation, and growth. Tracer-based magnetic resonance spectroscopy studies revealed a restitution of mitochondrial glucose metabolism and an increased energy state by reversing the Warburg effect, consistent with a subsequent decrease in anaerobic glycolysis. Recent in vitro SIDMAP studies that involved myeloid cells isolated from patients who developed resistance against imatinib indicated that non-oxidative ribose synthesis from glucose and decreased mitochondrial glucose oxidation are reliable metabolic signatures of drug resistance and disease progression. There is also evidence that imatinib-resistant cells utilize alternate substrates for macromolecule synthesis to overcome limited glucose transport controlled by imatinib. The main clinical implications involve early detection of imatinib resistance and the identification of new metabolic enzyme targets with the potential of overcoming drug resistance downstream of the various genetic and BCR-ABL-expression derived mechanisms. Metabolic profiling is an essential tool used to predict, clinically detect, and treat targeted drug resistance. This need arises from the fact that targeted drugs are narrowly conceived against genes and proteins but the metabolic network is inherently complex and flexible to activate alternative macromolecule synthesis pathways that targeted drugs fail to control.
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2,336,629 |
Factors influencing uptake of genetic testing for colorectal cancer risk in an Australian Jewish population.
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There is a significant excess of colorectal cancer in the Australian Ashkenazi Jewish community. This excess can partially be attributed to inherited factors that are over represented in this population, such as the APC variant I1307K, which is associated with a modest increase in colorectal cancer risk. There is currently only sporadic clinical genetic testing offered for this variant, as neither the exact increase in cancer risk and therefore the appropriate screening strategies for I1307K carriers, nor the acceptability of such testing in Jewish communities have been determined. This study reports a high acceptability of such genetic testing within a community sample of 300 Australian Jewish individuals--94% of participants would have a test for predisposition to colorectal cancer and a majority would make this decision based on the desire for information for their families and to decrease their own cancer risk. Some concerns were noted about genetic testing for cancer predisposition, including insurance discrimination, test accuracy and confidentiality.
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2,336,630 |
Comparing knowledge of beta-thalassemia in samples of Italians, Italian-Americans, and non-Italian-Americans.
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The purpose of this study was to determine the level of beta-thalassemia awareness among Italians living on the eastern side of Sicily (Bronte, Catania, and Tortorici, Messina), Italian-Americans, and Americans of other ethnic backgrounds (Other-Americans). A questionnaire was developed which asked respondents knowledge questions about both beta-thalassemia and Down Syndrome. Five hundred questionnaires were distributed, and 456 were ultimately returned and analyzed (150 Italians, 156 Italian-Americans, 150 Other-Americans). Italians answered an average of 55% of the beta-thalassemia correctly compared to scores of 17 and 24% for the Italian-Americans and Other-Americans, respectively. The groups did not differ in their knowledge of Down Syndrome (all answered between 58 and 60% of the questions correctly on average). Over 80% of the Italian respondents had heard of beta-thalassemia compared to only 19% of the Italian-Americans. beta-Thalassemia education programs in Italy appear to have dramatically increased awareness of the disorder. Similar programs need to be developed for at-risk populations in the United States.
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2,336,631 |
Predictive genetic testing for hereditary breast and ovarian cancer: psychological distress and illness representations 1 year following disclosure.
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This prospective study evaluates emotional functioning and illness representations in 68 unaffected women (34 carriers/34 noncarriers) 1 year after predictive testing for BRCA1/2 mutations when offered within a multidisciplinary approach. Carriers had higher subjective risk perception of breast cancer than noncarriers. Carriers who did not have prophylactic oophorectomy had the highest risk perception of ovarian cancer. No differences were found between carriers and noncarriers regarding perceived seriousness and perceived control of breast and ovarian cancer. Mean levels of distress were within normal ranges. Only few women showed an overall pattern of clinically elevated distress. Cancer-specific distress and state-anxiety significantly decreased in noncarriers from pre- to posttest while general distress remained about the same. There were no significant changes in distress in the group of carriers except for ovarian cancer distress which significantly decreased from pre- to posttest. Our study did not reveal adverse effects of predictive testing when offered in the context of a multidisciplinary approach.
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2,336,632 |
To test or not to test? Moderators of the relationship between risk perceptions and interest in predictive genetic testing.
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The moderating effects of motivational factors (illness prevention vs. emotional reassurance), regulatory focus (health vs. illness orientations), and cancer anxiety on the relationship between risk perceptions and women's interest in predictive genetic testing for breast cancer were studied among 102 women with no history of breast cancer. Risk perceptions per se were unrelated to testing interests. Perceptions of higher personal risk for developing breast cancer were positively related to women's interest in testing only among women whose dominant motivation was not emotional reassurance, who were not oriented towards ruling-out disease, and who were not highly anxious about breast cancer. These findings pointed to conditions under which risk perceptions may enhance screening behaviors, and other conditions under which they may not.
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2,336,633 |
Significant association of interleukin 8 -251T/A polymorphism with smoking behavior in a Japanese population.
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Accumulating evidence indicates that the genotype may impact on smoking behavior and a deeper understanding of the molecular basis could lead to more effective strategies for preventing initiation of the habit and to help smokers to quit. Since individual variation in airway responsiveness to cigarette smoke might have an important influence, we have focused on associations between smoking behavior and polymorphisms affecting the inflammatory cytokine, IL-8. In the present study, 453 Japanese non-cancer outpatients (191 males and 262 females) who visited Aichi Cancer Center Hospital were genotyped for the IL8 -251T/A polymorphism, and age- and sex-adjusted odds ratios (aORs) for smoking were estimated using a logistic regression model. The aORs for IL8 251-TA and AA combined, genotypes associated with high production of IL-8, were 0.52 (95% CI 0.33-0.82, P=0.004) for ever having smoked and 0.55 (0.33-0.92, P=0.023) for being a current smoker. Our results suggest that the inflammatory-prone genotype of IL8 may act to deter initiation or characteristics of the smoking habit.
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2,336,634 |
Optic atrophies in metabolic disorders.
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Optic nerve involvement in metabolic disorders often results from apoptosis of cells that form or support the optic nerve, the retinal ganglion cell (RGC) axons, the myelin-forming oligodendrocytes, or the supporting vascular system. Given their high energy demands and the long course of their axons, RGCs are particularly sensitive to intracellular metabolic defects. Defects in energy metabolism, formation of reactive oxygen species, and storage of metabolites can all cause apoptosis of RGCs, decreased myelin formation of oligodendrocytes and increased pressure on the optic nerve. Clinically, the loss of RGC axons manifests as pale optic nerves. In general, the ophthalmologist can identify the underlying cause of an optic atrophy by careful examination, neuro-imaging, and family history. In some cases, however, the diagnosis proves elusive. In these instances, and especially when optic atrophy is accompanied by other systemic involvement, a metabolic disorder should be considered. Here, we review the underlying mechanisms of optic atrophy and its significance in metabolic disorders. Early identification of optic atrophy aids the diagnosis and subsequent management of the underlying condition, including anticipation of symptoms, genetic counseling, and possible therapeutic interventions. For many metabolic disorders, molecular testing is available.
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2,336,635 |
The effects of a genetic information leaflet on public attitudes towards genetic testing.
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Genetics opinion surveys often include information to ensure that respondents have sufficient understanding to give informed responses. The information is assumed to be neutral but may skew responses. We assessed the impact of a seemingly "neutral" information leaflet on attitudes towards genetic testing among 1,024 survey respondents, half of whom received the leaflet. The leaflet group reported higher levels of subjective understanding of genetic testing (68 percent vs. 53 percent), were mre interested in genetic testing (81 percent vs. 77 percent), and held more positive attitudes towards genetics than people who did not receive the leaflet. Information leaflets may have the intended effect of increasing understanding, but may also unintentionally influence reported views of genetics. In the light of the weight given to public consultation in today's governance and regulation of human genetics, increased awareness of how even seemingly neutral information can influence public attitudes is recommended.
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2,336,636 |
The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis.
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Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are associated with cystic fibrosis (CF)-related monosymptomatic conditions, including idiopathic pancreatitis. We evaluated prospectively enrolled patients who had idiopathic recurrent acute pancreatitis or idiopathic chronic pancreatitis, healthy controls, CF heterozygotes, and CF patients (pancreatic insufficient or sufficient) for evidence of CFTR gene mutations and abnormalities of ion transport by sweat chloride and nasal potential difference testing. DNA samples from anonymous blood donors were controls for genotyping. At least one CFTR mutation or variant was carried in 18 of 40 patients (45%) with idiopathic chronic pancreatitis and in 6 of 16 patients (38%) with idiopathic recurrent acute pancreatitis but in only 11 of the 50 controls (22%, P=0.005). Most identified mutations were rare and would not be identified in routine genetic screening. CFTR mutations were identified on both alleles in six patient (11%). Ion transport measurements in patients with pancreatitis showed a wide range of results, from the values in patients with classically diagnosed CF to those in the obligate heterozygotes and healthy controls. In general, ion channel measurements correlated with the number and severity of CFTR mutations. Twelve of 56 patients with pancreatitis (21%) fulfilled current clinical criteria for the diagnosis of CF, but CFTR genotyping alone confirmed the diagnosis in only two of these patients. We concluded that extensive genotyping and ion channel testing are useful to confirm or exclude the diagnosis of CF in the majority of patients with idiopathic pancreatitis.
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2,336,637 |
Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus.
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Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus. Cubicin (daptomycin-for-injection) was approved in 2003 by the FDA to treat skin and skin structure infections caused by Gram-positive pathogens. Daptomycin is particularly significant in that it represents the first new natural product antibacterial structural class approved for clinical use in three decades. The daptomycin gene cluster contains three very large genes (dptA, dptBC, and dptD) that encode the nonribosomal peptide synthetase (NRPS). The related cyclic lipopeptide A54145 has four NRPS genes (lptA, lptB, lptC, and lptD), and calcium dependent antibiotic (CDA) has three (cdaPS1, cdaPS2, and cdaPS3). Mutants of S. roseosporus containing deletions of one or more of the NRPS genes have been trans-complemented with dptA, dptBC, and dptD by inserting these genes under the control of the ermEp* promoter into separate conjugal cloning vectors containing phiC31 or IS117 attachment (attP int) sites; delivering the plasmids into S. roseosporus by conjugation from Escherichia coli; and inserting the plasmids site-specifically into the chromosome at the corresponding attB sites. This trans-complementation system was used to generate subunit exchanges with lptD and cdaPS3 and the recombinants produced novel hybrid molecules. Module exchanges at positions D: -Ala(8) and D: -Ser(11) in the peptide have produced additional novel derivatives of daptomycin. The approaches of subunit exchanges and module exchanges were combined with amino acid modifications of Glu at position 12 and natural variations in lipid side chain starter units to generate a combinatorial library of antibiotics related to daptomycin. Many of the engineered strains produced levels of novel molecules amenable to isolation and antimicrobial testing, and most of the compounds displayed antibacterial activities.
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2,336,638 |
Health beliefs of women with and without breast cancer seeking genetic cancer risk assessment.
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Genetic cancer risk assessment (GCRA) is increasingly being incorporated into clinical care. Planning supportive nursing care for women seeking GCRA requires knowledge of their health beliefs. We described and compared the cancer risk-related beliefs of 134 women with a personal history of breast cancer (affected group) and 80 women without breast cancer who had a family history of the disease (unaffected group), prior to risk assessment, using a mailed survey. This article reports their demographics, health characteristics, family history, and beliefs about cancer risk, risk factors, and genetic testing. Most participants were in their 40s (mean age = 47.9), Caucasian (79%), married (66%), and college-educated (60%), and had children (78%). Most women (87%) had a close relative with breast cancer and/or ovarian cancer. In general, both groups greatly overestimated near-term and lifetime cancer risk. Significantly more unaffected women believed they were at higher risk for breast cancer than affected women. Both groups expressed desire for, but lacked knowledge of, genetic testing. Nurses are in a prime position to assist women seeking GCRA by providing accurate information and emotional support regarding cancer risk, risk factors, and genetic testing.
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2,336,639 |
Male infertility in reciprocal translocation carriers: the sex body affair.
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Previous reports have linked chromosomal reorganization and spermatogenic failure. In this context, it has long been known that reciprocal translocation carriers are more likely to have anomalies in the meiotic process, including fertility failures. It has also been proposed that this fertility failure may be a consequence of an association between the translocated chromosomes and the sex body. In this work, we review different hypotheses explaining meiotic failure in these carriers, and propose a model that relates meiotic abnormalities with both sex body-translocation association and different checkpoints that are known to operate during meiosis.
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2,336,640 |
Sperm studies in heterozygote inversion carriers: a review.
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The risk of producing unbalanced gametes in heterozygous inversion carriers mostly depends on the occurrence of recombination events within the inverted segment. Recombination determines the possibility of producing chromosomes with duplications/deficiencies (pericentric inversions) or with duplications/deficiencies which furthermore appear as dicentric and acentric fragments (paracentric inversions). In this work, a general description of the close relationship between the occurrence of crossovers in pericentric and paracentric inversions and the final segregation outcome is presented. After this introduction, a compilation of inversion segregation data and interchromosomal effect results from previously published sperm studies have been reviewed. Segregation results indicate a great heterogeneity in the percentage of unbalanced gametes, from 0 to 37.38%. The size of the inverted segments and their proportion in the chromosome are two parameters closely related with the incidence of recombination (P < 0.0001; using a quadratic model and Pearson's correlation test). These results suggest that the production of a significant level of unbalanced gametes would require a minimum inversion size of 100 Mbp and the inversion of at least 50% of the chromosome. Interchromosomal effects are seldom observed in chromosomal inversions. Finally, implications of the meiotic behavior of the inversions in the progeny of the carriers and the incorporation of sperm FISH segregation analysis for reproductive genetic counseling are discussed.
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2,336,641 |
Segregation of chromosomes in sperm of Robertsonian translocation carriers.
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Robertsonian translocations are the most frequent structural chromosomal abnormalities in humans and can affect fertility, with various degrees of sperm alterations in men; or the pregnancy outcome of the carriers. The studies on meiotic segregation of chromosomes in sperm of Robertsonian translocation males find a majority of normal or balanced spermatozoa for the chromosomes related to the translocation (mean 85.42%; range 60-96.60%). Furthermore, recent studies suggest an interchromosomal effect. Studies on spermatozoa from translocation carriers, and in mouse models help the comprehension of the meiotic segregation mechanisms. Results of meiotic segregation analysis in man could be integrated in genetic counselling especially when assisted reproductive technology is required.
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2,336,642 |
A developmental and genetic classification for malformations of cortical development.
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Increasing recognition of malformations of cortical development and continuing improvements in imaging techniques, molecular biologic techniques, and knowledge of mechanisms of brain development have resulted in continual improvement of the understanding of these disorders. The authors propose a revised classification based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories are based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In those cases in which the precise developmental and genetic features are uncertain, classification is based on known relationships among the genetics, pathologic features, and neuroimaging features. The major change since the prior classification has been a shift to using genotype, rather than phenotype, as the basis for classifying disorders wherever the genotype-phenotype relationship is adequately understood. Other substantial changes include more detailed classification of congenital microcephalies, particularly those in which the genes have been mapped or identified, and revised classification of congenital muscular dystrophies and polymicrogyrias. Information on genetic testing is also included. This classification allows a better conceptual understanding of the disorders, and the use of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.
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2,336,643 |
Is cannabis a gateway drug? Testing hypotheses about the relationship between cannabis use and the use of other illicit drugs.
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We outline and evaluate competing explanations of three relationships that have consistently been found between cannabis use and the use of other illicit drugs, namely, (1) that cannabis use typically precedes the use of other illicit drugs; and that (2) the earlier cannabis is used, and (3) the more regularly it is used, the more likely a young person is to use other illicit drugs. We consider three major competing explanations of these patterns: (1) that the relationship is due to the fact that there is a shared illicit market for cannabis and other drugs which makes it more likely that other illicit drugs will be used if cannabis is used; (2) that they are explained by the characteristics of those who use cannabis; and (3) that they reflect a causal relationship in which the pharmacological effects of cannabis on brain function increase the likelihood of using other illicit drugs. These explanations are evaluated in the light of evidence from longitudinal epidemiological studies, simulation studies, discordant twin studies and animal studies. The available evidence indicates that the association reflects in part but is not wholly explained by: (1) the selective recruitment to heavy cannabis use of persons with pre-existing traits (that may be in part genetic) that predispose to the use of a variety of different drugs; (2) the affiliation of cannabis users with drug using peers in settings that provide more opportunities to use other illicit drugs at an earlier age; (3) supported by socialisation into an illicit drug subculture with favourable attitudes towards the use of other illicit drugs. Animal studies have raised the possibility that regular cannabis use may have pharmacological effects on brain function that increase the likelihood of using other drugs. We conclude with suggestions for the type of research studies that will enable a decision to be made about the relative contributions that social context, individual characteristics, and drug effects make to the relationship between cannabis use and the use of other drugs.
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2,336,644 |
Population genetic analysis of 15 autosomal STRs loci in the central region of Argentina.
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Allele frequencies, together with some parameters of forensic interest, for 15 STRs included in the Powerplex-16 System (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, Penta D, Penta E, TH01, TPOX and VWA) were estimated from a sample set of 1368 unrelated individuals from three of the most densely populated provinces of Argentina. No deviations from Hardy-Weinberg equilibrium were observed using the Bonferroni correction for the number of loci analyzed. Comparative analyses between our population data and that of other Argentinean databases previously published are presented and discussed. The most informative loci in our data set is the Penta E Loci with discrimination power larger than 0.98 and typical paternity index larger than 4.3. Our results demonstrate that these loci are robust since different laboratories and sample sets provided highly consistent results. This observation underscores the usefulness of these markers systems for human identification and parentage testing.
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2,336,645 |
Diagnosis and management of rheumatoid arthritis.
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Rheumatoid arthritis is a chronic inflammatory disease characterized by uncontrolled proliferation of synovial tissue and a wide array of multisystem comorbidities. Prevalence is estimated to be 0.8 percent worldwide, with women twice as likely to develop the disease as men. Untreated, 20 to 30 percent of persons with rheumatoid arthritis become permanently work-disabled within two to three years of diagnosis. Genetic and environmental factors play a role in pathogenesis. Although laboratory testing and imaging studies can help confirm the diagnosis and track disease progress, rheumatoid arthritis primarily is a clinical diagnosis and no single laboratory test is diagnostic. Complications of rheumatoid arthritis may begin to develop within months of presentation; therefore, early referral to or consultation with a rheumatologist for initiation of treatment with disease-modifying antirheumatic drugs is recommended. Several promising new disease-modifying drugs recently have become available, including leflunomide, tumor necrosis factor inhibitors, and anakinra. Nonsteroidal anti-inflammatory drugs, corticosteroids, and nonpharmacologic modalities also are useful. Patients who do not respond well to a single disease-modifying drug may be candidates for combination therapy. Rheumatoid arthritis is a lifelong disease, although patients can go into remission. Physicians must be aware of common comorbidities. Progression of rheumatoid arthritis is monitored according to American College of Rheumatology criteria based on changes in specific symptoms and laboratory findings. Predictors of poor outcomes in early stages of rheumatoid arthritis include low functional score early in the disease, lower socioeconomic status, early involvement of many joints, high erythrocyte sedimentation rate or C-reactive protein level at disease onset, positive rheumatoid factor, and early radiologic changes.
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2,336,646 |
Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples.
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Cystic fibrosis (CF) is one of the most common monogenic diseases affecting Caucasians and has an incidence of approximately 1:3,300 births. Currently recommended screening panels for mutations in the responsible gene (CF transmembrane regulator gene, CFTR) do not detect all disease-associated mutations. Our laboratory offers extensive sequencing of the CFTR (ABCC7) gene (including the promoter, all exons and splice junction sites, and regions of selected introns) as a clinical test to detect mutations which are not found with conventional screening. The objective of this report is to summarize the findings of extensive CFTR sequencing from our first 157 consecutive patient samples. In most patients with classic CF symptoms (18/24, 75%), extensive CFTR sequencing confirmed the diagnosis by finding two disease-associated mutations. In contrast, only 5 of 75 (7%) patients with atypical CF had been identified with two CFTR mutations. A diagnosis of CF was confirmed in 10 of 17 (58%) newborns with either positive sweat chloride readings or positive immunoreactive trypsinogen (IRT) screen results. We ascertained ten novel sequence variants that are potentially disease-associated: two deletions (c.1641AG>T, c.2949_2853delTACTC), seven missense mutations (p.S158T, p.G451V, p.K481E, p.C491S, p.H949L, p.T1036N, p.F1099L), and one complex allele ([p.356_A357del; p.358I]). We ascertained three other apparently novel complex alleles. Finally, several patients were found to carry partial CFTR gene deletions. In summary, extensive CFTR gene sequencing can detect rare mutations which are not found with other screening and diagnostic tests, and can thus establish a definitive diagnosis in symptomatic patients with previously negative results. This enables carrier detection and prenatal diagnosis in additional family members.
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2,336,647 |
Prothrombin G20210A mutation in cases with recurrent miscarriage: a study of the mediterranean population.
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Thrombophilic predisposition may be one of the underlying causes of recurrent miscariage (RM). The purpose of this study was to evaluate the Prothrombin G20210A mutation in cases with history of RM.</AbstractText>A total of 104 cases, 55 with diagnosis of RM and 49 control cases, were included in this controlled study. In all cases, in addition to full examination tests, Prothrombin 20210A mutation analysis was carried out by means of Polymerase Chain Reaction (PCR).</AbstractText>Mean number of the abortion was 3.51 +/- 0.74 in the RM group and 0.08 +/- 0.27 in the control group (p < 0.05). As a consequence of comprehensive examinations, in 24 (43.6%) of 55 RM cases at least one etiologic factor was put forth. Prothrombin G20210A mutation was observed in six (10.9%) cases of the RM group and one (2.04%) in the control group (p < 0.05). Four of the six cases (66.7%) of Prothrombin G20210A mutation had a subsequent pregnancy. Among these four pregnancies, there was one spontaneous loss at 14 weeks of gestation and one severe pre-eclampsia.</AbstractText>Our data together with literature suggest that Prothrombin G20210A mutation may be associated with RM. We recommend this genetic testing as a screening tool for women with history of RM.</AbstractText>
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2,336,648 |
Biased estimators of quantitative trait locus heritability and location in interval mapping.
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In many empirical studies, it has been observed that genome scans yield biased estimates of heritability, as well as genetic effects. It is widely accepted that quantitative trait locus (QTL) mapping is a model selection procedure, and that the overestimation of genetic effects is the result of using the same data for model selection as estimation of parameters. There are two key steps in QTL modeling, each of which biases the estimation of genetic effects. First, test procedures are employed to select the regions of the genome for which there is significant evidence for the presence of QTL. Second, and most important for this demonstration, estimates of the genetic effects are reported only at the locations for which the evidence is maximal. We demonstrate that even when we know there is just one QTL present (ignoring the testing bias), and we use interval mapping to estimate its location and effect, the estimator of the effect will be biased. As evidence, we present results of simulations investigating the relative importance of the two sources of bias and the dependence of bias of heritability estimators on the true QTL heritability, sample size, and the length of the investigated part of the genome. Moreover, we present results of simulations demonstrating the skewness of the distribution of estimators of QTL locations and the resulting bias in estimation of location. We use computer simulations to investigate the dependence of this bias on the true QTL location, heritability, and the sample size.
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2,336,649 |
Susceptibility patterns and molecular identification of Trichosporon species.
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The physiological patterns, the sequence polymorphisms of the internal transcriber spacer (ITS), and intergenic spacer regions (IGS) of the rRNA genes and the antifungal susceptibility profile were evaluated for their ability to identify Trichosporon spp. and their specificity for the identification of 49 clinical isolates of Trichosporon spp. Morphological and biochemical methodologies were unable to differentiate among the Trichosporon species. ITS sequencing was also unable to differentiate several species. However, IGS1 sequencing unambiguously identified all Trichosporon isolates. Following the results of DNA-based identification, Trichosporon asahii was the species most frequently isolated from deep sites (15 of 25 strains; 60%). In the main, other Trichosporon species were recovered from cutaneous samples. The majority of T. asahii, T. faecale, and T. coremiiforme clinical isolates exhibited resistance in vitro to amphotericin B, with geometric mean (GM) MICs >4 mug/ml. The other species of Trichosporon did not show high MICs of amphotericin B, and GM MICs were <1 mug/ml. Azole agents were active in vitro against the majority of clinical strains. The most potent compound in vitro was voriconazole, with a GM MIC </=0.14 mug/ml. The sequencing of IGS correctly identified Trichosporon isolates; however, this technique is not available in many clinical laboratories, and strains should be dispatched to reference centers where these complex methods are available. Therefore, it seems to be more practical to perform antifungal susceptibility testing of all isolates belonging to Trichosporon spp., since correct identification could take several weeks, delaying the indication of an antifungal agent which exhibits activity against the infectious strain.
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2,336,650 |
TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments.
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TMC125 is a potent new investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that is active against human immunodeficiency virus type 1 (HIV-1) with resistance to currently licensed NNRTIs. Sequential passage experiments with both wild-type virus and NNRTI-resistant virus were performed to identify mutations selected by TMC125 in vitro. In addition to "classic" selection experiments at a low multiplicity of infection (MOI) with increasing concentrations of inhibitors, experiments at a high MOI with fixed concentrations of inhibitors were performed to ensure a standardized comparison between TMC125 and current NNRTIs. Both low- and high-MOI experiments demonstrated that the development of resistance to TMC125 required multiple mutations which frequently conferred cross-resistance to efavirenz and nevirapine. In high-MOI experiments, 1 muM TMC125 completely inhibited the breakthrough of resistant virus from wild-type and NNRTI-resistant HIV-1, in contrast to efavirenz and nevirapine. Furthermore, breakthrough of virus from site-directed mutant (SDM) SDM-K103N/Y181C occurred at the same time or later with TMC125 as breakthrough from wild-type HIV-1 with efavirenz or nevirapine. The selection experiments identified mutations selected by TMC125 that included known NNRTI-associated mutations L100I, Y181C, G190E, M230L, and Y318F and the novel mutations V179I and V179F. Testing the antiviral activity of TMC125 against a panel of SDMs indicated that the impact of these individual mutations on resistance was highly dependent upon the presence and identity of coexisting mutations. These results demonstrate that TMC125 has a unique profile of activity against NNRTI-resistant virus and possesses a high genetic barrier to the development of resistance in vitro.
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2,336,651 |
SIMPROT: using an empirically determined indel distribution in simulations of protein evolution.
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General protein evolution models help determine the baseline expectations for the evolution of sequences, and they have been extensively useful in sequence analysis and for the computer simulation of artificial sequence data sets.</AbstractText>We have developed a new method of simulating protein sequence evolution, including insertion and deletion (indel) events in addition to amino-acid substitutions. The simulation generates both the simulated sequence family and a true sequence alignment that captures the evolutionary relationships between amino acids from different sequences. Our statistical model for indel evolution is based on the empirical indel distribution determined by Qian and Goldstein. We have parameterized this distribution so that it applies to sequences diverged by varying evolutionary times and generalized it to provide flexibility in simulation conditions. Our method uses a Monte-Carlo simulation strategy, and has been implemented in a C++ program named Simprot.</AbstractText>Simprot will be useful for testing methods of analysis of protein sequence families particularly alignment methods, phylogenetic tree building, detection of recombination and horizontal gene transfer, and homology detection, where knowing the true course of sequence evolution is essential.</AbstractText>
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2,336,652 |
The genetic factors in cancer development and their implications for cancer prevention and detection.
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Experimental data from laboratory animals indicate that the same extent of DNA damage or the same mutations in oncogenes and tumor suppressor genes in different hosts result in widely differing cancer development because of numerous polymorphic tumor susceptibility genes. Similarly, recent epidemiological data indicate that susceptibility to common, "sporadic" cancers in humans is influenced considerably by multiple polymorphic host genes with relatively weak effects. This indicates that in addition to hereditary familial cancer syndromes, the sporadic cancer is also under strong genetic control. The multiplicity of genes involved, variation in exposure to environmental carcinogens, and small sizes of cancer families prevent efficient searches for the responsible genes in humans. Therefore, an alternative strategy based on the definition of susceptibility genes in experimental animals and the subsequent study of their human homologues has been successfully employed by several groups. This strategy also helped reveal several important features of cancer susceptibility, including mutual interactions of cancer susceptibility genes, their functional heterogeneity, and the existence of stage-specific control of cancer development. This latter phenomenon is especially important, because the susceptibility to early stages of cancer development may be quite different from that of late stages of cancer development. This needs to be taken into account when introducing preventive testing of biomarkers of early preneoplastic lesions or early cancers, because their predictive value is greatly influenced by the genetically determined individual tendency to proceed toward a more advanced form of neoplasia. Therefore, genetic testing of persons in danger of being exposed to carcinogenic factors should be an important part of the personnel selection.
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2,336,653 |
Genetic prion disease: the EUROCJD experience.
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A total of 10-15% of human transmissible spongiform encephalopathies (TSEs) or prion diseases are characterised by disease-specific mutations in the prion protein gene (PRNP). We examined the phenotype, distribution, and frequency of genetic TSEs (gTSEs) in different countries/geographical regions. We collected standardised data on gTSEs between 1993 and 2002 in the framework of the EUROCJD collaborative surveillance project. Our results show that clinicopathological phenotypes include genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker disease (GSS). Genetic TSE patients with insert mutation in the PRNP represent a separate group. Point and insertional mutations in the PRNP gene varies significantly in frequency between countries. The commonest mutation is E200K. Absence of a positive family history is noted in a significant proportion of cases in all mutation types (12-88%). FFI and GSS patients develop disease earlier than gCJD. Base pair insertions associated with the Creutzfeldt-Jakob disease (CJD) phenotype, GSS, and FFI cases have a longer duration of illness compared to cases with point mutations and gCJD. Cerebrospinal fluid 14-3-3 immunoassay, EEG, and MRI brain scan are useful in the diagnosis of CJD with point mutations, but are less sensitive in the other forms. Given the low prevalence of family history, the term "gTSE" is preferable to "familial TSE". Application of genetic screening in clinical practice has the advantage of early diagnosis and may lead to the identification of a risk of a TSE.
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2,336,654 |
Clinical myths of the cultural "other": implications for Latino patient care.
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Cultural competency is now a requirement in the curriculum of many health professions. However, clinicians' understandings of cultural difference, the accuracy of those understandings, and their impact on patient care have not yet been carefully explored. The authors conducted an ethnographic study designed to describe clinicians' views of Latino culture in the context of amniocentesis decision making, compared those to patients' discussions of their decision making, and explored how clinicians' views about culture are manifested in consultations with Latinas.</AbstractText>Between 2000 and 2002, semistructured, open-ended interviews were conducted in southern Texas with convenience samples of 50 clinicians who discuss prenatal testing with patients, and 40 self-identified Latina patients who had been offered amniocentesis. Observations were also made of 101 genetic counseling sessions. Content analysis focused on the cultural characteristics clinicians identified as affecting Latinas' decision making, patients' self-reported decision-making processes, and clinician and patient comments and actions observed during genetics counseling sessions.</AbstractText>Most clinicians said Latinas are likely to decline amniocentesis because they are religious, fatalistic, male-dominated, family-centered, and superstitious. However, patients' discussions of their decision making were not consistent with these characterizations. Furthermore, clinicians reported providing less complete information to Latina patients in their efforts to be culturally sensitive.</AbstractText>Comparing patient and clinician interviews bring into question clinicians' notion of Latino culture's role in amniocentesis decision making. Efforts to be "culturally competent," in the absence of a patient-centered approach, may unintentionally encourage stereotyping, thereby negatively affecting the quality and content of clinical care.</AbstractText>
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2,336,655 |
Sensory abnormalities in unaffected relatives in familial adult-onset dystonia.
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Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.
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2,336,656 |
Association of the H63D polymorphism in the hemochromatosis gene with sporadic ALS.
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Iron misregulation promotes oxidative stress and abnormally high iron levels have been found in the spinal cords of patients with ALS. The authors investigated whether HFE gene polymorphisms, linked to hemochromatosis, are associated with ALS using two independent populations of patients with sporadic ALS and controls (totaling 379 patients and 400 controls). They found that the H63D polymorphism is overrepresented in individuals with sporadic ALS (odds ratio 1.85, CI: 1.35 to 2.54).
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2,336,657 |
DigiTag assay for multiplex single nucleotide polymorphism typing with high success rate.
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As a consequence of Human Genome Project and single nucleotide polymorphism (SNP) discovery projects, several millions of SNPs, which include possible susceptibility SNPs for multifactorial diseases, have been revealed. Accordingly, there has been a strong drive to perform the investigation with all candidate SNPs for a certain disease without decreasing the number of analyzed SNPs. We developed DigiTag assay, which uses well-designed oligonucleotides called DNA coded numbers (DCNs) in multiplex SNP genotype analysis. During the analysis, the information of a genotype is converted to one of the DCNs in a one to one manner using oligonucleotide ligation assay (encoding). After the encoding reaction, only the DCNs regions and not the SNP specific regions are amplified using the universal primers and then SNP genotype is read out using DNA capillary arrays. DigiTag assay was found to be successful in SNP genotyping, giving a high success rate (24 of 27 SNPs) for randomly chosen SNPs. Moreover, this assay has the potential to analyze almost all kinds of the target SNPs by applying mismatch-induced probes and redesigned primer pairs at a low-cost.
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2,336,658 |
Distributions of HLA class I alleles and haplotypes in Northern Han Chinese.
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Human leukocyte antigen (HLA) class I allelic genotypes were determined in 105 unrelated Han ethnic individuals inhabiting the northern China area. A total of 19 HLA-A alleles, 49 HLA-B alleles and 24 HLA-Cw alleles were detected. Through the analyses of two and three loci haplotypes of HLA-A, HLA-B, and HLA-C loci, 11 HLA-A-B-Cw haplotypes, 19 HLA-A-B haplotypes, 18 HLA-A-Cw haplotypes, and 24 HLA-B-Cw haplotypes with the frequencies of higher than 0.01 were revealed. The Nei's genetic distance (GD) was estimated, and the NJ dendrogram showed that Northern Han had a higher GD to Southern Han (0.233) than those to the Korean (0.138) or other Northern ethnic groups, suggesting that Northern Han had more mixed blood with the ethnic groups originally in Northeast Asia. Our results provide useful information on the further study of evolution and relationships of Chinese ethnic groups and disease association in terms of HLA class I genes.
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2,336,659 |
Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation.
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Until recently, individuals with premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene were believed to be psychologically unaffected. However, the recent documentation of abnormal elevation of FMR1 mRNA, discovery of fragile X-associated tremor/ataxia syndrome (FXTAS), and reports of psychiatric disorders in children and adults with the premutation have suggested a pathogenic gene-brain-behavior mechanism. In a large collaborative study, 68 men and 144 women with the FMR1 premutation completed a psychological symptoms checklist and FMR1 genetic testing, including determination of CGG repeat size, percentage of FMR1 protein (FMRP)-positive lymphocytes, and FMR1 mRNA levels. Relative to published norms, men and women with FXTAS symptoms reported higher levels of several types of psychological symptoms. In addition, men and women with the premutation and no overt evidence of FXTAS reported higher levels of obsessive-compulsive symptoms. Elevated FMR1 mRNA, but not CGG repeat size or reduced FMRP (as measured by immunocytochemistry), was significantly associated with increased psychological symptoms, predominantly obsessive-compulsive symptoms and psychoticism, in premutation men with and without FXTAS symptoms. There was no relationship between CGG repeat size, FMR1 mRNA or FMRP and psychological symptoms in premutation women unless the sample was restricted to those with skewed X-activation ratio toward >50% active premutation alleles. The results of this study support the hypothesis that FMR1 function is associated with psychological difficulties in individuals with the premutation, and provide evidence concordant with an RNA toxic gain-of-function model in a neuropsychiatric phenotype.
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2,336,660 |
The longitudinal relationship between processing speed and cognitive ability: genetic and environmental influences.
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Goals of the present study were to investigate the relationship between age changes in speed and cognition and the genetic and environmental influences on that relationship. Latent growth models and quantitative genetic methods were applied to data from the Swedish Adoption/Twin Study of Aging. The sample included 778 individuals from both complete and incomplete twin pairs who participated in at least 1 of 4 testing occasions over a 13-year-period. Four factors were constructed from 11 cognitive measures: verbal, spatial, memory, and processing speed. Results indicate that for measures of fluid abilities, the explanatory value of processing speed is paramount for both mean cognitive performance and acceleration with age. A significant proportion of the genetic influences on cognitive ability arose from genetic factors affecting processing speed. For measures of fluid abilities, it is not the linear age changes but the accelerating age changes in cognition that share genetic variance with processing speed.
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2,336,661 |
Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.
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MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.
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2,336,662 |
Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations.
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Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe mental retardation, dysmorphic features, ataxia, seizures, and typical behavioural characteristics, including a happy sociable disposition. AS is caused by maternal deficiency of UBE3A (E6 associated protein ubiquitin protein ligase 3A gene), located in an imprinted region on chromosome 15q11-q13. Although there are four different molecular types of AS, deletions of the 15q11-q13 region account for approximately 70% of the AS patients. These deletions are usually detected by fluorescence in situ hybridisation studies. The deletions can also be subclassified based on their size into class I and class II, with the former being larger and encompassing the latter.</AbstractText>We studied 22 patients with AS due to microdeletions using a microarray based comparative genomic hybridisation (array CGH) assay to define the deletions and analysed their phenotypic severity, especially expression of the autism phenotype, in order to establish clinical correlations.</AbstractText>Overall, children with larger, class I deletions were significantly more likely to meet criteria for autism, had lower cognitive scores, and lower expressive language scores compared with children with smaller, class II deletions. Children with class I deletions also required more medications to control their seizures than did those in the class II group.</AbstractText>There are four known genes (NIPA1, NIPA2, CYFIP1, & GCP5) that are affected by class I but not class II deletions, thus raising the possibility of a role for these genes in autism as well as the development of expressive language skills.</AbstractText>
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2,336,663 |
The role of HLA-G in cytokine homeostasis during early pregnancy complicated with maternal infections: a novel etiopathological approach to the neurodevelopmental understanding of schizophrenia.
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Schizophrenia is perhaps the most enigmatic and tragic psychotic disorder with remarkable mortality and morbidity. Schizophrenia is complex and clinically a heterogeneous disorder. The etiological basis of schizophrenia ranges from autoimmune to neurodevelopmental hypothesis in one hand and involvement of different major gene segment with susceptibility loci on the other. Recently, neurodevelopmental hypothesis gained much impetus over the other domain. To support the neurodevelopmental basis, a number of investigations have shown that maternal infections during pregnancy increases the risk of the offspring developing schizophrenia and other neurodevelopmental disorders. The pathological mechanisms underlying this phenomenon is largely unknown. Many have suggested the involvement of different immune markers and shown that cytokines generated in response to maternal infection alter early brain development through their inflammatory activity. However, these findings have escaped discussion on various important issues related to cytokine homeostasis which depends on a large number of immune parameters including non-classical HLA-G molecules. Infections during early stages of pregnancy may alter cytokine regulation by disturbing the whole uterine immune milieu. To elucidate this issue, authors have tried to correlate the possible relationships between maternal infections and aberration of immune networking at the feto-maternal interface and their subsequent influence on the structural and functional abnormalities of the developing brain. The authors hypothesize that there exists a counter regulatory interaction among proinflammatory cytokines like TNF-alpha, HLA-G molecules and different immune cells like NK cells. We emphasize that HLA-G molecules are the novel immune players which maintain the immune homeostasis during early pregnancy in a manner that it can protect developing fetus from maternal immune attack. However, maternal infections may lead to the disturbance of HLA-G expression which in turn may fail to maintain its otherwise inhibitory potential to down regulate the detrimental inflammatory cytokines. Investigation on such interaction may unravel novel molecular mechanisms of neurodevelopmental basis of schizophrenia. Testing of our proposed hypothesis on animal models and on in vitro derived extravillous trophoblast cell lines holds promise of great insights to usher a new dimension of schizophrenia research and for developing new therapeutic strategies for better treatment and to adopt genetic prediction in schizophrenia management paradigm.
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2,336,664 |
The expected performance of single nucleotide polymorphism loci in paternity testing.
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We discuss the utility of single nucleotide polymorphism loci for full trio and mother-unavailable paternity testing cases, in the presence of population substructure and relatedness of putative and actual fathers. We focus primarily on the expected number of loci required to gain specified probabilities of mismatches, and report the expected proportion of paternity indices greater than three threshold values for these loci.
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2,336,665 |
Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing.
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To estimate cystic fibrosis (CF) birth rates in Canada from 1971 to 2000 and to assess the population impact of genetic testing in families with a history of CF, after identification of the CF transmembrane conductance regulator gene in 1989.</AbstractText>Age-at-diagnosis data were obtained from the Canadian Cystic Fibrosis Foundation Patient Data Registry and Canadian births for the corresponding years from Canadian Vital Statistics. Estimates of the CF birth rate in each year were based on a nonparametric model that allows the birth rate to vary across the years and adjusts for censoring of currently undiagnosed patients.</AbstractText>The overall CF birth rate from 1971-1987 was 1/2714 with no increasing or decreasing trend. Beginning in 1988, 1 year before identification of the CF transmembrane conductance regulator gene, estimated CF birth rates followed a linear decline to an estimated rate of 1/3608 in 2000. CF birth rates may have stabilized in the last few years, but further decline may occur with implementation of carrier screening in the general population.</AbstractText>These results demonstrate the temporal association of genetic testing and declining CF birth rates in Canada. They may assist in decisions relating to the allocation of resources for prenatal and neonatal CF screening programs.</AbstractText>
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2,336,666 |
Combining immunoreactive trypsinogen and pancreatitis-associated protein assays, a method of newborn screening for cystic fibrosis that avoids DNA analysis.
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To evaluate the performance of a strategy in which, after immunoreactive trypsinogen (IRT) determination, genetic analysis is replaced by a biological test, the pancreatitis-associated protein (PAP) enzyme-linked immunosorbent assay (ELISA).</AbstractText>The French newborn screening program includes cystic fibrosis (CF) screening by the IRT/CFTR mutation strategy. PAP was assayed on screening cards, in parallel with IRT, in all newborns from 5 French regions (n = 204,749). Analysis of PAP values in CF and non-CF newborns with elevated IRT allowed direct comparison between the current strategy and the proposed IRT/PAP strategy.</AbstractText>A protocol in which newborns with IRT >50 ng/mL and PAP >1.8 ng/mL and those with IRT >100 ng/mL and PAP >1.0 ng/mL are directly recalled for sweat testing would have the same performance as the IRT/CFTR mutation strategy.</AbstractText>The IRT/PAP strategy is an alternative for CF newborn screening, which avoids the drawbacks of genetic analysis and is cheaper and easier to implement than the current IRT/CFTR mutation strategy.</AbstractText>
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2,336,667 |
Evaluation of cytokine polymorphisms (TNFalpha, IFNgamma and IL-10) in Down patients with coeliac disease.
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In Down syndrome there is an increased prevalence of coeliac disease, but the reasons for this association are yet unknown.</AbstractText>To evaluate a possible correlation between TNFalpha, IFNgamma and IL-10 genotype polymorphisms with the susceptibility to coeliac disease in Down syndrome patients.</AbstractText>Single nucleotide polymorphisms of TNFalpha (-308G-->A promoter region), IFNgamma (+874T-->A promoter region) and IL-10 (-1082G-->A promoter region) have been studied in 10 Down patients with coeliac disease, in 40 Down patients without coeliac disease and in 220 healthy controls. Clinical features were also studied in coeliac disease-Down syndrome patients.</AbstractText>The 10 coeliac disease-Down syndrome patients had a biopsy proven coeliac disease afterward a serological testing positive to antigliadin, antiendomysium and antitransglutaminase antibodies. Intestinal biopsy showed total atrophy in 6/10 and partial villous atrophy in 4/10 of them. All coeliac disease-Down syndrome patients had silent forms of coeliac disease and classical trisomy 21. No significant differences were observed for the IFNgamma and IL-10 polymorphisms in the studied groups. A significant trend for increase of TNFalpha -308A positive frequency was observed in coeliac disease-Down syndrome patients compared to healthy controls (p=0.043).</AbstractText>Single nucleotide polymorphisms of IFNgamma and IL-10 do not play a role in predisposing Down syndrome patients to coeliac disease, while the TNFalpha -308 allele could be an additional genetic risk factor for coeliac disease in trisomy 21.</AbstractText>
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2,336,668 |
Computational prediction of genotoxicity: room for improvement.
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Decades of mutagenesis and clastogenesis studies have yielded enough structure-activity-relationship (SAR) information to make feasible the construction of computational models for prediction of endpoints based on molecular structure and reactivity. Although there is cause for optimism that these approaches might someday reduce or eliminate the need for actual genotoxicity testing, we are in fact a long way from this. We provide an overview of the state of the art of such approaches, dissecting out how these models are suboptimal. It is clear that current programs still have limited predictive capabilities. We propose that one of the major contributing factors for the inherent lack of sensitivity (typically 50-60%) is inadequate coverage of non-covalent DNA interactions. Suboptimal specificity can be partly attributed to chemical space considerations with associated non-causal activity correlations.
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2,336,669 |
Prenatal screening for fetal face and clefting in a prospective study on low-risk population: can 3- and 4-dimensional ultrasound enhance visualization and detection rate?
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A study of 1856 second trimester low-risk pregnancies was conducted over a period of 12 months to evaluate the detection rate of cleft lip and palate by 3- and 4-dimensional (3D, 4D) ultrasonography. To image the fetal face and profile, a protocol regarding the use of external or internal hand stimulation or a repeated scan was followed, and the time taken to perform 3D scan was compared to that of a conventional 2D ultrasound. One case of unilateral right cleft lip and a cleft lip plus cleft palate were both identified, giving a prevalence of 1.1 per 1000 live births and a prenatal detection rate of 100%. The average imaging time for fetal face/profile view was significantly less with 3D when compared to 2D (5.33 vs 6.2 seconds, P < .001) and diagnosis at first scan without external or internal hand stimulation was feasible in 78% by 2D versus 87% by 3D technique (P < .0001). Cleft lip and palate were isolated prenatal findings and newborn karyotyping showed normal chromosomal maps in both cases. With the use of this standardized protocol, we were able to image the fetal face and profile view in all cases. We underline the critical role of sonographic expertise in screening for these anomalies and the great enhancement in imaging soft tissues and bone lesions by using 3D ultrasound. We advocate that screening for cleft lip and palate be included in future standard ultrasound examination in the second trimester of pregnancy.
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2,336,670 |
Evaluation of linkage disequilibrium measures between multi-allelic markers as predictors of linkage disequilibrium between markers and QTL.
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Effectiveness of marker-assisted selection (MAS) and quantitative trait loci (QTL) mapping using population-wide linkage disequilibrium (LD) between markers and QTL depends on the extent of LD and how it declines with distance in a population. Because marker-QTL LD cannot be observed directly, the objective of this study was to evaluate alternative measures of observable LD between multi-allelic markers as predictors of usable LD of multi-allelic markers with presumed biallelic QTL. Observable LD between marker pairs was evaluated using eight existing measures and one new measure. These consisted of two pooled and standardized measures of LD between pairs of alleles at two markers based on Lewontin's LD measure, two pooled measures of squared correlations between alleles, one standardized measure using Hardy-Weinberg heterozygosities, and four measures based on the chi-square statistic for testing for association between alleles at two loci. In simulated populations with a range of LD generated by drift and a range of marker polymorphism, marker-marker LD measured by a standardized chi-square statistic (denoted chi(2')) was found to be the best predictor of useable marker-QTL LD for a group of multi-allelic markers. Estimates of the level and decline of marker-marker LD with distance obtained from chi(2') were linearly and highly correlated with usable LD of those markers with QTL across population structures and marker polymorphism. Corresponding relationships were poorer for the other marker-marker LD measures. Therefore, when LD is generated by drift, chi(2') is recommended to quantify the amount and extent of usable LD in a population for QTL mapping and MAS based on multi-allelic markers.
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2,336,671 |
[The relationship of affective temperament and clinical features in bipolar disorder].
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The aim of the present study was to investigate the relationship between affective temperaments and clinical features in bipolar disorder. Testing the relationships between phenomenological features, course, severity of episodes, overall severity of illness and comorbid conditions would clarify the reliability and validity of affective temperamental descriptions.</AbstractText>One hundred patients with bipolar I disorder were recruited from consecutive admissions and evaluated when euthymic. Affective temperaments were assessed with TEMPS-A Turkish version. Information about the characteristics of each patient's illness was obtained from three main sources; interview with patient (SCID-I), interview with at least one close relative and patient records. We compared the clinical features of patients with and without a specific affective temperament.</AbstractText>Similar rates of cyclothymic, hyperthymic and irritable temperaments were observed in bipolar patients. Five important findings of the present study were (1) hyperthymic temperament was more frequent in males than females; (2) manic switches were more frequent among bipolar patients with hyperthymic temperament; (3) psychotic features were more common in the irritable temperament group; (4) comorbid conditions, (mostly alcohol use disorders) were more common among bipolar patients with cyclothymic temperament; and (5) bipolar patients with irritable temperament were more likely to have a manic episode at the onset of illness.</AbstractText>These findings suggest that affective temperaments have significant clinical implications in bipolar disorder, beyond the genetic basis and predisposing factors. There were significant differences between patients with different affective temperaments in terms of gender, type of first episode, psychotic symptoms, switch and comorbidity.</AbstractText>
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2,336,672 |
Fine mapping of the polled locus to a 1-Mb region on bovine chromosome 1q12.
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The absence of horns in Bos taurus is under genetic control of the autosomal dominant polled locus which has been genetically mapped to the centromeric region of cattle Chromosome 1. Recently a 4-Mb BAC contig of this chromosomal region has been constructed. Toward positional cloning of the bovine polled locus, we identified 20 additional microsatellite markers spread over the contig map by random sequencing of bacterial artificial chromosome (BAC) subclones. A total of 26 markers were genotyped in 30 two-generation half-sib families of six different German cattle breeds segregating for the hornless phenotype including 336 informative meioses for the polled character. Our fine-mapping study involving 19 recombinant haplotypes allowed us to narrow the critical region for the bovine polled locus to a 1-Mb segment with a centromeric boundary at RP42-218J17_MS1 and a telomeric boundary at BM6438. For marker-assisted selection purposes, the first evidence of informative flanking markers helps to predict polled genotypes with a higher degree of accuracy within families until testing of the causative mutation is available.
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2,336,673 |
Effect of neuroprotective drugs on gene expression in G93A/SOD1 mice.
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Gene expression analysis is a powerful tool that has been used to define the pathological processes underlying many diseases. Several laboratories, including our own, have used this approach to identify molecular abnormalities in the G93A/SOD1 mouse, an animal model of amyotrophic lateral sclerosis (ALS). Here, we report the results of analysis of an expanded panel of genes throughout the entire lifetime in the spinal cord of these animals. In addition to upregulation of microglia/neuroinflammatory genes identified previously, we observed upregulation of metallothionein-I and -II (MT-I, MT-II). MT-I and MT-II play an important role in disposition of zinc ion, and other studies have also indicated their levels are altered in development of motor neuron disease in these animals. We also analyzed the effect on these expression profiles of several candidate drugs that have been shown to have neuroprotective effects in vivo or in vitro. That is, we asked whether administration to the G93A/SOD1 mice of any of these drugs could reverse the alterations in gene expression patterns that occur as the animals develop. The mice were given daily doses of these drugs when they were 9-11 weeks old, at a stage early in development of motor neuron disease, continuing for 5 weeks, at which time they were sacrificed. Treatment of the mice with l-carnosine, a dipeptide that scavenges free radicals and chelates zinc, did not affect expression of any of the genes altered in these animals. However, it did upregulate 3 genes unaffected by the presence of the G93A/SOD1 mutation: glial fibrillary acidic protein (GFAP), stroma-derived factor-1 (SDF-1), and excitatory amino acid transporter-2 (EAAT2). In contrast, metallothionein-III (MT-III) was downregulated. Treatment of the animals with baicalein, an herbal extract with anti-inflammatory and numerous other effects, downregulated the microglia markers CD68, CD80, and CD86, all of which were upregulated in untreated mutant animals. Baicalein treatment also downregulated tumor necrosis factor receptor (TNFRp55) and upregulated noninducible nitric oxide synthase (nNOS) and glutamine synthase (GS). These 3 genes were unaffected by the presence of the G93A mutation. We discuss the implication of these results for testing the effects of these and other candidate drugs in mutant SOD1 mice.
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2,336,674 |
Attention deficit hyperactivity disorder with reading disabilities: preliminary genetic findings on the involvement of the ADRA2A gene.
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Attention deficit/hyperactivity disorder (ADHD) and reading disability (RD) tend to co-occur and quantitative genetic studies have shown this to arise primarily through shared genetic influences. However, molecular genetic studies have shown different genes to be associated with each of these conditions. Neurobiological studies have implicated noradrenergic function in the aetiology of ADHD that is comorbid with RD. This paper examines the neurobiological evidence and presents preliminary testing of the hypothesis that the ADRA2A receptor gene is contributing to ADHD and comorbid RD.</AbstractText>One hundred and fifty-two children (140 boys, 12 girls) of British Caucasian origin, aged between 6 and 13 years and with a diagnosis of ADHD, were recruited. The children's reading ability was tested. Children were identified as having ADHD or ADHD plus RD (n=82). DNA was available for 110 parent child trios and 42 parent child duos. Genotyping was undertaken for an ADRA2A polymorphism.</AbstractText>For those with ADHD plus RD there was evidence of association with the alpha 2A adrenergic receptor (ADRA2A) polymorphism with the G allele being preferentially transmitted.</AbstractText>The preliminary evidence together with other neurobiological research findings suggests that the ADRA2A gene may contribute to comorbid ADHD and RD and needs to be properly examined.</AbstractText>
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2,336,675 |
Common variable immunodeficiency: test indications and interpretations.
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Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that can present with multiple phenotypes, all of which are characterized by hypogammaglobulinemia, in a person at any age. A specific genetic defect that accounts for all CVID phenotypes has not been identified, and it is likely that several distinct genetic disorders with similar clinical presentations are responsible for the observed variation. In this review, we summarize the known genetic mutations that give rise to hypogammaglobulinemia and how these gene products affect normal or abnormal B-cell development and function, with particular emphasis on CVID. Additionally, we describe specific phenotypic and genetic laboratory tests that can be used to diagnose CVID and provide guidelines for test interpretation and subsequent therapeutic intervention.
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2,336,676 |
POLG mutations in Alpers syndrome.
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Described are six patients with Alpers syndrome from four unrelated families. Affected individuals harbored the following combinations of POLG mutations: 1) A467T/W1020X, 2) W748S-E1143G/G848S, 3) A467T/A467T, and 4) A467T/G848S. Homozygosity for the A467T allele in one patient was associated with a later age at onset. Mitochondrial respiratory chain studies in skeletal muscle were normal in each case. Nine combinations of mutant POLG alleles that cause Alpers syndrome are summarized.
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2,336,677 |
Supportive evidence for a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis.
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An association between susceptibility to rheumatoid arthritis and the Fc receptor-like 3 gene (FCRL3) has been reported in a Japanese population. A case-control study showed that the strongest evidence of the association was derived from a polymorphism in the promoter region of FCRL3, which has a regulatory effect on the expression of the gene.</AbstractText>To validate the findings of this previous report by examining the -169C-->T single nucleotide polymorphism (SNP) in a large cohort.</AbstractText>752 unrelated cases and 940 controls were genotyped. All the samples were from the same ethnic background as the original study. Genotyping was done using 5' allelic discrimination assays. Association between susceptibility to rheumatoid arthritis and -169C-->T SNP was examined by chi(2) testing.</AbstractText>As in the previous study, the SNP showed significant differences between cases and controls (p = 0.022, odds ratio = 1.18, 95% confidence interval 1.02 to 1.35).</AbstractText>This result supports a genetic association of the FCRL3 promoter polymorphism with rheumatoid arthritis.</AbstractText>
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2,336,678 |
A new genetic test for the rapid identification of shiga-toxines producing (STEC), enteropathogenic (EPEC) E. coli isolates from children.
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Routine bacteriological techniques do not allow detection of the most frequent enteric pathogens in young children: enteropathogenic Escherichia coli (EPEC) and shigatoxinogenic E. coli (STEC/EHEC). Since there is no correlation between serotype and pathotype, a genotypic determination is therefore necessary for the identification of these pathogenic strains. We evaluated the Genotype EHEC test (Hain Life Science, Germany), a new rapid system based on DNA multiplex amplification and further hybridization for the detection of shigatoxin stx1, stx2 genes, intimin eae gene and invasin ipaH gene harbored by Shigella and enteroinvasive E. coli (EIEC). E. coli strains of various serogroups isolated from children with acute gastroenteritis, hemorrhagic colitis or hemolytic-uremic syndrome were tested. Their genotypes were first determined by standard in-house PCR. The strains collection included 11 STEC/EHEC (serogroups O157, O111, O26, O91, O-untypable) and nine EPEC (serogroups O26, O157, O55, O126, O127, O-untypable). The same strains were tested with Genotype EHEC. For all the strains, the hybridization banding pattern obtained by Genotype EHEC correlated with their expected genotypic characteristics. No specific equipment is required, except a thermocycler. Absence of electrophoresis system, of ethidium bromide staining and imaging system is a clear-cut advantage of Genotype EHEC. In addition, the short testing time (less than 2 h) optimizes treatment orientation. The Genotype EHEC test allows an easy and reliable identification of EHEC, STEC, EPEC and also EIEC. As such, it is a useful tool for the rapid diagnosis of diarrheal diseases.
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2,336,679 |
Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers.
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DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9-14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An HIV-1 clade A vaccine in clinical trials: stimulation of HIV-specific T cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004;85:911-9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies.
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2,336,680 |
Recurrent implantation failure in assisted reproduction: how to counsel and manage. B. Treatment options that have not been proven to benefit the couple.
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The success of assisted reproduction, although gradually increasing over the years, is still less than satisfactory. Many couples have benefited from this treatment; however, many have also been left frustrated following multiple failed attempts. Couples who fail to conceive after multiple IVF/intracytoplasmic sperm injection (ICSI) treatments often seek treatment options that are new and that have not been offered before. Some of these include immunological testing and treatment, allogenic lymphocyte therapy, intratubal transfer of zygotes and embryos, blastocyst transfer, sequential embryo transfer, assisted hatching, co-cultures, and preimplantation genetic screening for aneuploidy. Although the evidence behind some of these is more robust, most suffer from lack of well designed randomized trials comparing them with other treatment options. Randomized studies are extremely difficult to conduct, as couples will resist being randomized into a treatment group where previously failed procedures will be repeated. In the mean time, assisted reproduction programmes should resist offering treatment options that are not evidence based, or at least they should share with the couple the information that is available and should stress that none of these is a panacea for their problem.
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2,336,681 |
Preimplantation diagnosis and HLA typing for haemoglobin disorders.
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Haemoglobin disorders are among the most frequent indications for preimplantation genetic diagnosis (PGD), introduced as an important option to couples at risk for producing offspring with thalassaemia and sickle cell disease. Previous experience mainly included PGD for beta-thalassaemia, while PGD for alpha-thalassaemia resulting in an unaffected pregnancy has not been reported. This study presents the results of the world's largest experience of 197 PGD cycles for haemoglobin disorders, which includes PGD for alpha-thalassaemia, resulting in 53 clinical pregnancies and birth of 45 healthy children, with five still ongoing. Fifty-four of these cycles were performed in combination with HLA typing, allowing the birth of thalassaemia-free children who were also HLA identical to the affected sibling, with successful stem cell transplantation in one case. As an increasing proportion of patients requesting PGD with HLA typing are of advanced reproductive age, aneuploidy testing was performed simultaneously with PGD. The results show that PGD has now become a practical approach for prevention of haemoglobin disorders, and is gradually being used also for improving access to HLA compatible stem cell transplantation for this group of diseases.
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2,336,682 |
Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia.
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We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 trios and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family trio and case-control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4-risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over-represented in the cases compared with the controls (0.44 vs. 0.38; A allele; chi(2) 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two-marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (chi(2) 6.8; P = 0.04). None of the full four-marker haplotypes showed association, including the G-G-G-G haplotype previously associated with schizophrenia in more than one sample and the A-T-A-A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4.
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2,336,683 |
ApoE -491A/T promoter polymorphism is not an independent risk factor, but associated with the epsilon4 allele in Hungarian Alzheimer's dementia population.
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Apolipoprotein E gene (Apo(epsilon)) has three common alleles (epsilon2, epsilon3, and epsilon4), of which epsilon4 has been shown to be associated with an increased risk for Alzheimer's disease (AD). Possible additional genetic factors, like the -491A variant of ApoE promoter may modify the development of AD, independently of the ApoE allele status. The objective of this study was to investigate whether A/T allelic polymorphism at site-491 of the ApoE promoter is associated with AD in a Hungarian population. The genomic DNA isolated from peripheral blood lymphocytes of 52 late-onset AD and 53 control individuals was used as a template for the two examined polymorphisms and PCR assay was applied. The epsilon4 allele was significantly over-represented in the AD group (28%) as compared with the control population (7%). No significant differences have been found between the control and the AD populations regarding the occurrence of the promoter A allele frequencies (control: 77%, AD: 70%). However, the AA genotype was more frequent in the AD group (48%) than in the control (10%) when the presence of epsilon4 allele was also considered. It is unlikely therefore that the -491A variant of the ApoE promoter gene is an independent risk factor in the Hungarian AD population, but a linkage disequilibrium exists between the two examined mutations.
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2,336,684 |
Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C.
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Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC-related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC-related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC.
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2,336,685 |
Assessment of the effect of age at onset on linkage to bipolar disorder: evidence on chromosomes 18p and 21q.
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Previous evidence suggests that the inheritance of bipolar disorder (BP) may vary depending on the age at onset (AAO). Therefore, we sought to incorporate AAO as a covariate in linkage analyses of BP using two different methods, LODPAL and ordered-subset analysis (OSA), in genomewide scans of 150 multiplex pedigrees with 874 individuals. The LODPAL analysis identified two loci, on chromosomes 21q22.13 (LOD = 3.29; empirical chromosomewide P value = .009) and 18p11.2 (LOD = 2.83; empirical chromosomewide P = .05), with increased linkage among subjects who had early onset (AAO < or = 21 years) and later onset (AAO >21 years), respectively. The finding on 21q22.13 was significant at the chromosomewide level, even after correction for multiple testing. Moreover, a similar finding was observed in an independent sample of 65 pedigrees (LOD = 2.88; empirical chromosomewide P = .025). The finding on 18p11.2 was only nominally significant and was not observed in the independent sample. However, 18p11.2 emerged as one of the strongest regions in the OSA (LOD = 2.92; empirical P = .001), in which it was the only finding to meet chromosomewide levels of significance after correction for multiple testing. These results suggest that 21q22.13 and 18p11.2 may harbor genes that increase the risks for early-onset and later-onset forms of BP, respectively. There have been previous reports of linkage on 21q22.13 and 18p11.2, but the findings have not been consistent. This inconsistency may be due to differences in the AAO characteristics of the samples examined. Future studies to fine map susceptibility genes for BP on chromosomes 21q22.13 and 18p11.2 should take AAO into account.
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2,336,686 |
Definition of immunogenic carbohydrate epitopes.
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Carbohydrates are known as sources of immunological cross-reactivity of allergenic significance. In celery and in cypress pollen, the major allergens Api g 5 and Cup a 1 are recognised by antisera raised against anti-horseradish peroxidase and by patients' IgE which apparently bind carbohydrate epitopes; mass spectrometric analysis of the tryptic peptides and of their N-glycans showed the presence of oligosaccharides carrying both xylose and core alpha1,3-fucose residues. Core alpha1,3-fucose residues are also a feature of invertebrates: genetic and biochemical studies on the fruitfly Drosophila melanogaster, the parasitic trematode Schistosoma mansoni and the nematode worm Caenorhabditis elegans indicate that these organisms possess core alpha1,3-fucosyltransferases. Various experiments have shown that fucosyltransferases from both fly and worm are responsible in vivo and in vitro for the synthesis of N-glycans which cross-react with anti-horseradish peroxidase; thus, we can consider these enzymes as useful tools in generating standard compounds for testing cross-reactive carbohydrate epitopes of allergenic interest.
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2,336,687 |
Genetics of Parkinson's disease.
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The past few years, mutations in 5 genes (a-synuclein, parkin, DJ-1, PINK1, and LRRK2) have been firmly implicated, and additional chromosomal loci have been mapped for inherited forms of Parkinson's disease (PD). These discoveries have profound implications for both the scientific and clinical communities. First, although some of the Mendelian forms of PD are very rare (including those caused by alfa-synuclein, DJ-1, and PINK1 mutations) they are facilitating greatly the dissection of the molecular pathways that lead to death of dopaminergic neurons; these pathways might also be implicated in the pathogenesis of the common forms of PD. Second, the discoveries of Mendelian forms are challenging the concept of PD as one disease, as well as the validity of the current clinico-pathological disease definition. Last, mutations in 2 of these genes turned out to be frequent enough to have relevance in clinical practice: parkin mutations are common in early-onset familial and sporadic PD; moreover, emerging data delineate mutations in the LRRK2 gene (encoding the dardarin protein) as a frequent cause of the familial late onset PD forms, and even of few late-onset sporadic cases. The importance of genetic testing is expected to increase in the near future in the PD field. Here, the author provides a brief update on the genetics of the monogenic forms of PD.
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2,336,688 |
Expression profiling of colon cancer cell lines and colon biopsies: towards a screening system for potential cancer-preventive compounds.
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Interest in mechanisms of colon cancer prevention by food compounds is strong and research in this area is often performed with cultured colon cancer cells. In order to assess utility for screening of potential cancer-preventive (food) compounds, expression profiles of 14 human cell lines derived from colonic tissue were measured using cDNA microarrays with 4000 genes and compared with expression profiles in biopsies of human colon tumours and normal tissue. Differences and similarities in the gene expression profiles of the cell lines were analysed by clustering and principal component analysis (PCA). Cytoskeleton genes and immune response genes are two functional classes of genes that contributed to the differences between the cell lines. A subset of 72 colon cancer-specific genes was identified by comparing expression profiles in human colon biopsies of tumour tissue and normal tissue. A separation of the cell lines based on the tumour stage of the original adenocarcinoma was observed after PCA of expression data of the subset of colon cancer-specific genes in the cell lines. The results of this study may be useful in the ongoing research into mechanisms of cancer prevention by dietary components.
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2,336,689 |
Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families.
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Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.
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2,336,690 |
Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients.
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Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60).</AbstractText>All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2).</AbstractText>In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives.</AbstractText>HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.</AbstractText>
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2,336,691 |
Systemic lupus erythematosus and the extended major histocompatibility complex--evidence for several predisposing loci.
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Systemic lupus erythematosus (SLE) is an autoimmune disease reported to be associated with several alleles in the HLA complex. The purpose of this study was to systematically examine the extended HLA complex (xMHC) in order to get an overview of the primary predisposing genetic factors.</AbstractText>One hundred and sixty-four SLE patients and 254 healthy, unrelated controls were genotyped for HLA-DRB1, -B and -A alleles, as well as 13 microsatellites markers covering the xMHC. Moreover, we selected 335 additional controls matched with the patients for the HLA haplotypes showing the strongest associations, in order to look for additional predisposing loci.</AbstractText>Two regions of the xMHC showed associations: the region covering DRB1 to B, and the extended class I region. Explicitly, DRB1*03 and B*08 displayed strong associations with SLE, which seem to be independent of each other. Furthermore, associations were seen with alleles at microsatellites D6S2225 and D6S2223, located about 3.6 Mb telomeric of HLA-B, and these were not secondary to the associations found with DRB1*03 and B*08.</AbstractText>Both the DRB1*03 and the B*08 alleles display disease association, either implicating involvement of both alleles or caused by another yet unidentified gene(s) in linkage disequilibrium. The associations found in the extended class I region could be markers for a 'novel' predisposing locus (loci) in SLE, adding to the risk conferred by DRB1*03 and B*08. Interestingly, this region has been shown to also be associated with other autoimmune diseases, hence the gene(s) might confer a general propensity for autoimmunity.</AbstractText>
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2,336,692 |
Will nicotine genetics and a nicotine vaccine prevent cigarette smoking and smoking-related diseases?
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Hall argues that the preventive use of genetic and vaccine biotechnologies is a superficially attractive tobacco policy option of doubtful efficacy, cost-effectiveness, and ethicality.
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2,336,693 |
Assessment of the genetic risk and impact of lateral transmission in a valine-associated scrapie outbreak in sheep.
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To characterize an outbreak of valine-associated scrapie, assess the relative risk of scrapie infection in relation to allele frequency at codon 136, and investigate lateral transmission of infection in a sheep flock within the United States.</AbstractText>1,006 sheep.</AbstractText>To determine genotypes, blood or semen samples were assessed via commercial testing; in 190 slaughtered sheep, scrapie status was determined via immunohistochemical evaluation of tissues. Scrapie-positive sheep born to scrapie-negative dams and sheep infected after 1 year of age were identified to assess lateral transmission.</AbstractText>Genotypes were determined for codon 171 (164 sheep) or codons 136 and 171 (842 sheep). Forty-four of 160 slaughtered sheep of known genotype were scrapie positive. In these sheep, the presence of at least 1 valine allele at codon 136 (V136) was highly correlated with scrapie-positive status. Lateral transmission was the probable source of infection for 4 scrapie-positive sheep born to scrapie-negative dams and for 11 sheep in which scrapie was diagnosed at > 50 months of age.</AbstractText>Results suggest that the outbreak of scrapie was associated with a relatively high frequency of V136 in the flock, introduction of a valine-dependent scrapie strain, and the occurrence of lateral transmission. Genotyping of sheep may assist management decisions following diagnosis of scrapie in a sheep with at least 1 V136. It may be prudent to remove sheep of the diploid genotype AVQR (at codons 136 and 171) from infected flocks.</AbstractText>
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2,336,694 |
Preparing African-American men in community primary care practices to decide whether or not to have prostate cancer screening.
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This study was a randomized trial to test the impact of an informed decision-making intervention on prostate cancer screening use.</AbstractText>The study population included 242 African-American men from three primary care practices who were 40-69 years of age and had no history of prostate cancer. Participants completed a baseline survey questionnaire and were randomly assigned either to a Standard Intervention (SI) group (N=121) or an Enhanced Intervention (EI) group (N=121). An informational booklet was mailed to both groups. EI group men were also offered a screening decision education session. Two outcomes were considered: (1) complete screening (i.e., having a digital rectal exam (DRE) and prostate specific antigen (PSA) testing), and (2) complete or partial screening (i.e., having a PSA test with or without DRE). An endpoint chart audit was performed six months after initial intervention contact. The data were analyzed via exact logistic regression.</AbstractText>Overall, screening use was low among study participants. EI group men had a screening frequency two times greater than that of SI group men, but the difference was not statistically significant: 8% vs. 4 % (OR = 1.94) fo rcomplete screening, and 19% vs. 10% (OR = 2.08) for complete or partial screening. Multivariable analyses showed that being in the EI group and primary care practice were significant predictors of complete or partial screening (OR = 3.9 and OR = 5.64, respectively).</AbstractText>Prostate cancer screening use may be influenced by exposure to decision education and the influence of screening-related primary care practice factors.</AbstractText>
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2,336,695 |
Analysis of drug resistance-associated mutations in treatment-naïve individuals infected with different genetic forms of HIV-1 circulating in countries of the former Soviet Union.
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There are few data on drug resistance-associated mutations in the former Soviet Union since, studies have usually been focused on the env or gag genes for subtype information. This study examines the prevalence and patterns of resistance-associated mutations to reverse transcriptase and protease inhibitors (RTI, PRI) in 278 HIV-1-infected treatment-naïve subjects from countries of Eastern Europe, and defines characteristic polymorphisms of RT and PR sequences in HIV-1 subtype A viruses. Blood samples were collected between 1997 and 2004. Plasma RNA was used for PR-RT amplification by reverse transcription coupled with nested PCR and sequencing. Phylogenetic analysis was done with neighbor-joining trees and bootscanning. Analysis of drug resistance mutations, with Stanford University HIV Drug Resistance Database's algorithm, resulted in an overall prevalence of 12.9% resistance to RTI and 3.9% to PRI. The most frequent substitutions in the RT region were at positions 62 and 236. V77I substitution in PR was found in 47.8% of samples. Polymorphisms in subtype A sequences were identified. This is the first study reporting the prevalence and patterns of both PRI and RTI resistance-associated mutations in naïve HIV-1 infected patients from the former Soviet Union. These data underline the importance of genotypic resistance testing of chronically HIV-1-infected patients before initiating treatment, in order to select the most suitable drug regimen.
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2,336,696 |
The paternal gene of the DDK syndrome maps to the Schlafen gene cluster on mouse chromosome 11.
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The DDK syndrome is an early embryonic lethal phenotype observed in crosses between females of the DDK inbred mouse strain and many non-DDK males. Lethality results from an incompatibility between a maternal DDK factor and a non-DDK paternal gene, both of which have been mapped to the Ovum mutant (Om) locus on mouse chromosome 11. Here we define a 465-kb candidate interval for the paternal gene by recombinant progeny testing. To further refine the candidate interval we determined whether males from 17 classical and wild-derived inbred strains are interfertile with DDK females. We conclude that the incompatible paternal allele arose in the Mus musculus domesticus lineage and that incompatible strains should share a common haplotype spanning the paternal gene. We tested for association between paternal allele compatibility/incompatibility and 167 genetic variants located in the candidate interval. Two diallelic SNPs, located in the Schlafen gene cluster, are completely predictive of the polar-lethal phenotype. These SNPs also predict the compatible or incompatible status of males of five additional strains.
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2,336,697 |
A review of family donor constructs: current research and future directions.
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This review addresses research on gamete donors, recipients, and offspring and demonstrates that the foci on all three within the triad are largely directed at disclosure or anonymity; and each in turn centers on the perceived importance of the genetic link. The importance attached to genetics has led some countries to review the ethics of anonymous gamete donation (e.g. New Zealand's 'open system' of information sharing) and has led other countries (Sweden, Austria, Victoria, Australia; the Netherlands, the UK) to change their laws allowing donor gamete offspring the right to obtain identifying information about their genetic parent. This review demonstrates that genealogical inconsistencies between and within members of the triad are common regardless of legislation. A discussion of future trends and concerns, relating to the use of gamete donation and the effects legislation is likely to have on the donor triads in the UK following 2005, is provided. The review also addresses the importance of testing theoretical models within future research, and argues this would lead to a better understanding of the underlying problems encountered at a psychosocial level, such as continued preference for anonymity in donors and denial in large numbers of users of the involvement of a donor in conception. Lack of disclosure effectively prevents true implementation of legislation; if a child is not informed, it is the result of donated gametes, it cannot take up the legally available option of finding out identifiable information about their genetic parent(s).
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2,336,698 |
ProbeMaker: an extensible framework for design of sets of oligonucleotide probes.
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Procedures for genetic analyses based on oligonucleotide probes are powerful tools that can allow highly parallel investigations of genetic material. Such procedures require the design of large sets of probes using application-specific design constraints.</AbstractText>ProbeMaker is a software framework for computer-assisted design and analysis of sets of oligonucleotide probe sequences. The tool assists in the design of probes for sets of target sequences, incorporating sequence motifs for purposes such as amplification, visualization, or identification. An extension system allows the framework to be equipped with application-specific components for evaluation of probe sequences, and provides the possibility to include support for importing sequence data from a variety of file formats.</AbstractText>ProbeMaker is a suitable tool for many different oligonucleotide design and analysis tasks, including the design of probe sets for various types of parallel genetic analyses, experimental validation of design parameters, and in silico testing of probe sequence evaluation algorithms.</AbstractText>
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2,336,699 |
[Implications of pharmacogenetics in every-day practice].
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Pharmacogenetics as one of the areas of clinical pharmacology addresses hereditary factors involved in individually different responses to drugs. Clinical trials combined with molecular genetics seek for underlying reasons influencing efficacy and toxicity of drugs. The declared goal of pharmacogenetics is to provide physicians with knowledge and tools to allow an individualized patient-directed pharmacotherapy. This concept is best evolved for clinical practice in the field of drug-metabolizing enzymes, especially for the cytochromes P450 (CYP) 2D6, CYP2C19 and thiopurine S-methyltransferase (TPMT). Patients with inherited enzyme deficiencies are at risk to accumulate excessive drug concentrations when treated with standard doses which may lead to adverse drug reactions or even to life-threatening conditions. Genetic factors are also involved in drug-target interactions (e. g. receptors). Prospective controlled clinical trials are needed to evaluate the benefit of pharmacogenetics for therapy outcome and to define its role in clinical practice.
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