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2,337,400 |
Balancing selection in the wild: testing population genetics theory of self-incompatibility in the rare species Brassica insularis.
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Self-incompatibility (SI) systems are widespread mechanisms that prevent self-fertilization in angiosperms. They are generally encoded by one genome region containing several multiallelic genes, usually called the S-locus. They involve a recognition step between the pollen and the pistil component and pollen is rejected when it shares alleles with the pistil. The direct consequence is that rare alleles are favored, such that the S-alleles are subject to negative frequency-dependent selection. Several theoretical articles have predicted the specific patterns of polymorphism, compared to neutral loci, expected for such genes under balancing selection. For instance, many more alleles should be maintained and populations should be less differentiated than for neutral loci. However, empirical tests of these predictions in natural populations have remained scarce. Here, we compare the genetic structure at the S-locus and microsatellite markers for five natural populations of the rare species Brassica insularis. As in other Brassica species, B. insularis has a sporophytic SI system for which molecular markers are available. Our results match well the theoretical predictions and constitute the first general comparison of S-allele and neutral polymorphism.
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2,337,401 |
Comparison between immunohistochemistry and chromogenic in situ hybridization in assessing HER-2 status in breast cancer.
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Human epidermal growth factor receptor-2 (HER-2) is usually determined as a potential target for breast cancer therapy. The purpose of the present study was to compare chromogenic in situ hybridization (CISH) with immunohistochemistry (IHC) in determination of HER-2 status, in metastatic breast cancer patients screened for the clinical study of chemotherapy +/- herceptin. It was possible to assess both CISH and IHC in 56 cases, using CISH Detection Kit (Zymed) and HercepTest (DakoCytomation), respectively. HER-2 was amplified by CISH in 32 cases (57%) while 33 (59%) were HER-2-positive by IHC. A concordance between HER-2 status determined by CISH and IHC was noted in 43 of 56 cases (77%; P = 0.00008). Gene amplification was observed in 6/16 cases (37.5%) in IHC-negative subgroup (1+), while no amplification was observed in 5/10 cases (50%) in the IHC-positive subgroup (2+). These results suggest that there was a greater heterogeneity on the genetic level and that simple IHC classification was not sufficient. It is suggested that CISH could be considered as a useful additional method to IHC in determining HER-2 status in breast cancer patients, with a recommendation for testing not only the 2+ but also the 1+ subgroup of patients.
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2,337,402 |
Does genetic counseling have any impact on management of breast cancer risk?
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Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.
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2,337,403 |
Preconception cystic fibrosis carrier screening: costs and consequences.
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The objective of the study was to determine net costs of four potential preconception cystic fibrosis (CF) carrier screening strategies, and to identify the most important cost-related parameters. An estimate was made of the costs of screening carried out during general practitioner (GP) consultations, and screening carried out during group educational sessions. Two test strategies were evaluated: single-entry two-step (SETS) and double- entry two-step (DETS). Several sensitivity analyses were performed. Under the baseline assumptions, SETS screening during GP consultations was the least expensive (net costs US dollar 1,111,354 per year). The sensitivity analysis showed that the costs depend greatly on the estimated lifetime costs of care for a CF patient and the strategy used to inform the target population. Adaptations could be made to the screening program, resulting in economic savings while the primary goal of the screening--to enable participants to make an autonomous informed choice--is guaranteed.
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2,337,404 |
Gender differences in attitudes among those at risk for Huntington's disease.
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This report presents and discusses selected findings regarding gender differences from an Australian-based study that investigated attitudes of individuals at risk for Huntington's disease (HD) towards genetic risk and predictive testing. Clear gender differences emerged regarding perceived coping capacity with regard to predictive testing, as well as disclosure of the genetic risk for HD to others. Female participants were more likely to disclose their genetic risk to others, including their medical practitioners, while male participants were three times more fearful of disclosing their genetic risk to others. These findings are of interest in light of gender differences that have consistently been reported regarding the uptake of predictive testing for HD, other genetic conditions, and health services more generally. While gender differences cannot provide a fully explanatory framework for differential uptake of predictive genetic testing, men and women may experience and respond differently to the genetic risk for HD and possibly other inherited disorders. The meanings of genetic risk to men and women warrants further exploration, given anticipated increases in genetic testing for more common conditions, especially if post-test interventions are possible. These issues are also relevant within the context of individuals' concerns about the potential for discrimination on the basis of genetic risk or genetic test information.
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2,337,405 |
Germline mutations in the MYH gene in Swedish familial and sporadic colorectal cancer.
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Biallelic germline mutations in the base excision repair gene MYH have been shown to predispose to a proportion of multiple colorectal adenomas and cancer. To evaluate the contribution of MYH mutations to non- FAP, non-HNPCC familial colorectal cancer, 84 unrelated Swedish individuals affected with colorectal cancer from such families were screened for germline mutations in the coding sequence of the gene. None of the cases was found to carry any pathogenic sequence change. We then determined the prevalence of the two most common pathogenic MYH mutations found in Caucasians, Y165C and G382D, in 450 Swedish sporadic colorectal cancer cases and 480 Swedish healthy controls. The frequency of both variants in Swedish cases and controls was similar to those previously reported. In addition, we found that previously unknown sequence variations at the position of amino acid 423 (R423Q, R423P, and R423R) appear to occur more frequently in cases than in controls (p = 0.02), a finding that warrants future studies.
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2,337,406 |
Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families.
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Hereditary nonpolyposis colorectal cancer (HNPCC) is due to defects in DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and to a lesser extent PMS2. Of 466 suspected HNPCC families, we defined 54 index patients with either tumors of high microsatellite instability (MSI-H) and/or loss of expression for either MLH1, MSH2, and/or MSH6, but without a detectable pathogenic point mutation in these genes. This study cohort was augmented to 64 patients by 10 mutation-negative index patients from Amsterdam families where no tumors were available. Deletion/duplication screening using the multiplex ligation-dependent probe amplification (MLPA) revealed 12 deletions in MSH2 and two deletions in MLH1. These deletions constitute 17% of pathogenic germline alterations but elucidate the susceptibility to HNPCC in only 22% of the mutation-negative study cohort, pointing towards other mutation mechanisms for an inherited inactivation of MLH1 or MSH2. We describe here four novel deletions. One novel and one known type of deletion were found for three and two unrelated families, respectively. MLPA analysis proved a reliable method for the detection of genomic deletions in MLH1 and MSH2; however, sequence variations in the ligation-probe binding site can mimic single exon deletions.
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2,337,407 |
Genetic analysis carried out on blood-spots of phenylalanine hydroxylase-deficient newborns detected by northeastern Italian neonatal screening.
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The aim of this work was to perform genetic analysis on 18 different blood-spot samples collected from neonates detected as hyperphenylalaninemic by Northeastern Italian screening program. DNA was extracted from blood-spots. Exons/introns of PAH gene were amplified by polymerase chain reaction (PCR), and PCR products were purified and sequenced with both forward and reverse primers. The most frequent mutations were IVS12nt1g>a (16.7%) and R408W, P281L and L48S (all together 11.1%). As expected, compound heterozygosity was the usual finding; homozygosity was found only in two patients with R158Q and IVS2nt5g>c mutations. The V230I mutation was reported for the first time in Italy. We found six previously described polymorphisms (V245V, IVS4nt47c>t, IVS2nt19t>c, IVS3nt-22c>t, IVS5nt-54a>g, and E280>Q280). To our knowledge, four genotypes were not previously described: R158Q/V230I present in one patient with classical PKU; and L48S/R408Q, A403V/IVS2nt-13t>g, and G272X/V230I present in patients showing HPA phenotype. Most of the mutations were located in the exons 12 and 7 and in exon/intron 2 (83.3% detection of total mutations in PKU or HPA patients of Northeastern Italy). From a practical viewpoint, the genetic analysis of blood-spots collected on Guthrie cards for neonatal screening for PKU could be a simple method to establish the genotype of neonates. Consequently, the genotype/phenotype correlation could lead to a more accurate diagnosis and prognosis for families.
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2,337,408 |
The Arg482His mutation in the beta-galactosidase gene is responsible for a high frequency of GM1 gangliosidosis carriers in a Cypriot village.
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GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of beta-galactosidase. It is mainly characterized by progressive neurodegeneration, and in its most severe infantile form, it leads to death before the age of 4. The GLB1 gene gives rise to two alternatively spliced mRNAs that encode the beta-galactosidase and the elastin binding protein (EBP). The diagnosis of two patients with the infantile form of GM1 gangliosidosis and 11 carriers in a small mountainous village in Cyprus prompted us to carry out a study in order to establish the frequency of carriers in the village and identify the mutations involved. Carrier detection was initially based on the measurement of beta-galactosidase activity in leucocytes. Among 85 random samples from the village, 10 were classified as carriers. Sequencing of the GLB1 gene in a Cypriot patient identified the missense mutation c.1445G>A (p.Arg482His) in the homozygous state. Seven of the 10 carriers identified using the enzyme assay were found to carry the same mutation by NspI restriction enzyme analysis. The three individuals who were negative for the c.1445G>A had borderline enzyme results and were probably wrongly classified as carriers. The frequency of GM1 gangliosidosis carriers in this village is approximately 8% (1:12). Western blot analysis showed a marked decrease of the 64-kDa mature form of the enzyme protein and a similar reduction of the 67-kDa EBP. Our results indicate that the c.1445G>A mutation, which appears to be responsible for all GM1 gangliosidosis alleles in this Cypriot village, affects protein conformation.
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2,337,409 |
The implication of de novo 21-hydroxylase mutation in clinical and prenatal molecular diagnoses.
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We studied 37 unrelated families with a history of 21-hydroxylase deficiency (CYP21D) for eight common mutations and gene deletions in the 21-hydroxylase (CYP21) gene. We found de novo mutations in the CYP21 gene in two CYP21D patients. Analysis for eight common mutations in the 21-hydroxylase gene as well as large gene deletions was accomplished using polymerase chain reaction (PCR) followed by amplified created restriction site (ACRS) or restriction fragment length polymorphism (RFLP) and Southern blot followed by hybridization to a CYP21-specific probe. Linkage analysis was performed using microsatellite markers flanking the CYP21 gene. Ten short tandem repeat (STR) markers were used to confirm parentage in the two de novo mutation cases. In two prenatal diagnosis cases, an intron 2-13A/C>G mutation was identified in the proband, but not in the fetus, although the proband and fetus had identical linkage markers. Subsequently, the mutation was confirmed to be absent in the parents' genome and misparentage was ruled out. Our findings are consistent with previous studies showing a de novo mutation frequency of approximately 1.0-1.5% in the CYP21 gene. This new mutation rate is high relative to the rate of approximately one in one million for other autosomal recessive disorders. Thus, the de novo mutation rate in the CYP21 gene is not negligible. It must be considered and discussed in prenatal diagnosis and genetic counseling for this relatively common inherited disorder.
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2,337,410 |
Specific triplex binding capacity of mixed base sequence duplex nucleic acids used for single-nucleotide polymorphism detection.
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Specific base recognition and binding between native double-stranded DNA (dsDNA) and complementary single-stranded DNA (ssDNA) of mixed base sequence is presented. Third-strand binding, facilitated and stabilized by a DNA intercalator, YOYO-1, occurs within 5 min at room temperature. This triplex binding capability has been used to develop a homogeneous assay that accurately detects 1-, 2-, or 3-bp mutations or deletions in the dsDNA target. Every type of 1-bp mismatch can be identified. The assay can reliably distinguish homozygous from heterozygous polymerase chain reaction (PCR)-amplified genomic dsDNA, thus providing a highly sensitive clinical diagnostic assay.
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2,337,411 |
A typing system for the major histocompatibility complex class I chain related genes A and B using polymerase chain reaction with sequence-specific primers.
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The Major Histocompatibility Complex (MHC) class I chain related (MIC) A and B genes are important additional loci within the MHC. We have developed a MICA and MICB typing system using the polymerase chain reaction with sequence-specific primers (PCR-SSP), which operates under the same conditions as our routine HLA-A, -B, and -C typing method. We designed 95 primers in 84 SSP mixtures for MICA and 39 primers in 29 mixtures for MICB. This detected and differentiated all 55 MICA and 19 MICB alleles (except MICA*00701 from MICA*026, MICA*00201 from MICA*020, and three MICB alleles, which are intronic variations). A computer program confirmed the MICA amplification reactivity of each SSP mixture and evaluated the typing set for MICA allele combination ambiguities. Seventy-six "reference" DNA samples were used for validation: 50 from International Histocompatibility Workshop B lymphoblastoid cell lines (IHW BCLs) and 26 MICA-typed samples from two laboratories. The reference material identified 28 out of the 55 MICA alleles and 13 of the 19 MICB alleles, and directly validated 62 of the 84 MICA and 20 of the 29 MICB SSP mixtures. Our genotyping agreed with 283 out of the 286 (98.95%) MICA and MICB reference laboratories' allele assignments or the consensus assignments. Two of the discrepancies remain unresolved, whereas one was probably due to a reference laboratory's failure to differentiate alleles differing in exon 5 of the MICA gene. A comparison of the MICA and MICB allele assignments between laboratories identified a "disagreement rate" of 19.4% for MICA alleles and 13.1% for MICB alleles. Accordingly, we have compiled "consensus" MICA and MICB genotypes for the 50 IHW BCLs tested, which have been confirmed by our typing. We also typed 166 random blood donors. Their MICA and MICB carriage and allele frequencies and HLA-B, MICA, MICB linkage disequilibrium parameters and haplotype frequencies largely concurred with other published data on United Kingdom subjects, further supporting the validity of our typing system. This PCR-SSP system is a simple, reliable and rapid technique for typing MICA and MICB alleles. It is easily updated as new alleles are identified but clearly requires a continuing validation review until all known MICA and MICB alleles have been identified.
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2,337,412 |
Evolutionary combinatorial chemistry, a novel tool for SAR studies on peptide transport across the blood-brain barrier. Part 2. Design, synthesis and evaluation of a first generation of peptides.
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The use of high-throughput methods in drug discovery allows the generation and testing of a large number of compounds, but at the price of providing redundant information. Evolutionary combinatorial chemistry combines the selection and synthesis of biologically active compounds with artificial intelligence optimization methods, such as genetic algorithms (GA). Drug candidates for the treatment of central nervous system (CNS) disorders must overcome the blood-brain barrier (BBB). This paper reports a new genetic algorithm that searches for the optimal physicochemical properties for peptide transport across the blood-brain barrier. A first generation of peptides has been generated and synthesized. Due to the high content of N-methyl amino acids present in most of these peptides, their syntheses were especially challenging due to over-incorporations, deletions and DKP formations. Distinct fragmentation patterns during peptide cleavage have been identified. The first generation of peptides has been studied by evaluation techniques such as immobilized artificial membrane chromatography (IAMC), a cell-based assay, log Poctanol/water calculations, etc. Finally, a second generation has been proposed.
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2,337,413 |
The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series.
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To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations in Arab patients.</AbstractText>The study was performed in the pediatric FMF clinic of Jordan University Hospital over a period of 4 years. Patients were referred by their physicians for diagnosis, management, genetic study, and counseling. A diagnosis of FMF was made according to published criteria. Screening for 5 mutations, namely M694V, V726A, M694I, M680I, and E148Q, was performed by amplification refractory mutation system (ARMS) for the first 4 and by restriction endonuclease testing for E148Q.</AbstractText>Of the 407 unrelated patients investigated, 239 (59%) had 1 or 2 mutations and 168 (41%) had none of the studied mutations detected. Of those with mutations, 92 were homozygous, 53 were compound heterozygotes, 3 had complex alleles, and 91 patients had only 1 identifiable mutation. Of the mutations, M694V, V726A, M694I, M680I, and E148Q accounted for 38, 26, 14, 10 and 13%, respectively. Twelve of our patients developed the protracted febrile myalgia syndrome (PFMS) of whom 5 (42%) were homozygous for M694V. Only 2 developed chronic renal failure, both of whom were homozygous for M694V and were not on colchicine prophylaxis. However, 43 patients had a family history of chronic renal failure, and 15 (35%) were homozygous for M694V.</AbstractText>Our data indicate that the 5 MEFV mutations are well distributed in Arabs. They also show that M694V is the most common mutation in Arab patients with FMF and seems to have an association with the development of amyloidosis and the PFMS. The high frequency of V726A, and the unique high frequency of M694I in Arabs compared with 3 other ethnic groups, are confirmed.</AbstractText>
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2,337,414 |
CGH analysis of familial non-BRCA1/BRCA2 breast tumors and mutation screening of a candidate locus on chromosome 17q11.2-12.
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Mutations in the known predisposing breast cancer genes BRCA1 and BRCA2 account for only a small proportion (<10%) of breast cancer families in the Stockholm region of Sweden. This study aims to identify novel predisposing genes in non-BRCA1/BRCA2 breast cancer families. We have employed comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) data in combination with data from a recently carried out genome wide linkage scan, in an effort to identify chromosomal regions harboring potential breast cancer genes. CGH revealed loss of chromosome 17 and chromosome 6q to be a frequent event in high-risk breast cancer families, while gain of 8q was most prevalent in low-risk families. The loss of chromosome 17 was consistent with previous LOH studies and so this region was investigated further. Disease was shown to be linked to chromosome 17 in those families exhibiting loss of the chromosome in both CGH and LOH analyses. An overlapping region of linkage was determined to lie between markers D17S1294 and D17S1293, fine mapping of the region delineated a region between markers D17S1880 and D17S1293. Ten genes were determined to lie within this 1.5 Mb region and families were screened for germline mutations in these genes. In conclusion, we have investigated one possible small region on chromosome 17 for its involvement in high-risk non-BRCA1/BRCA2 breast cancer families. No predisposing mutations were identified in the 10 genes investigated in this study, however further analysis of chromosome 17 is warranted.
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2,337,415 |
Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.
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Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation.
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2,337,416 |
Sex differences in the genetic basis of morning serum cortisol levels: genome-wide screen identifies two novel loci specific to women.
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Relatively little is known about the influence of specific genes on cortisol levels, particularly morning cortisol levels.</AbstractText>The objective of this study was to identify quantitative trait loci associated with morning serum cortisol levels.</AbstractText>We carried out a genome screen for morning serum cortisol using linkage and association methods tailored for use in large pedigrees. We conducted these analyses both in the whole sample and partitioned by sex.</AbstractText>This study was conducted on nine communal Hutterite farms in South Dakota.</AbstractText>The Hutterites are a young founder population who practice a communal, farming lifestyle in the western United States and in Canada. Hutterites (n = 504, 53% female) aged 11-89 yr from a single pedigree participated in this study.</AbstractText>The main outcome measures were markers significantly linked or associated with variation in morning serum cortisol levels.</AbstractText>One genome-wide significant association was identified in the whole sample on 11p (D11S1981, P = 0.000092). Results of sex-partitioned analyses indicated that this association was restricted to females (females, P = 0.000084; males, P = 0.20). The 146-bp allele at this locus accounted for 7% of the variance in morning cortisol values in females, and females homozygous for the allele had an 89% increase in morning cortisol levels compared with female noncarriers. A second genome-wide significant association in females was identified on 14q (D14S74, P = 0.000091).</AbstractText>Our results suggest that the genetic determinants of morning cortisol levels may be different for men and women and that loci on 11p and 14q influence morning cortisol levels in women.</AbstractText>
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2,337,417 |
[From gene to disease; congenital adrenal hypoplasia and the DAX-1 gene].
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Congenital adrenal hypoplasia is an X-linked disorder resulting in adrenocortical deficiency, failure to complete puberty due to hypogonadotrophic hypogonadism, and infertility. The disease is caused by mutations in the DAX-1 gene. The DAX-1 protein is a transcription inhibitor; it represses the transcription of other, as yet mostly unknown, genes. Mutation analysis can confirm a clinical diagnosis of congenital adrenal hypoplasia. An early diagnosis might prevent critical damage due to an adrenal crisis in an undiagnosed patient. Molecular testing can be used for carrier detection and genetic counselling.
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2,337,418 |
Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22.
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Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16-q21 (MLS=2.61) and 4q12-q21 (MLS=2.38). 6q16-q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male-male pairs. Our scan also provides support for linkage (MLS> or =1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14-p12 and 18q22.
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2,337,419 |
Genetic tests of biologic systems in affective disorders.
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To liberate candidate gene analyses from criticisms of inexhaustiveness of examination of specific candidate genes, or incompleteness in the choice of candidate genes to study for specific neurobiological pathways, study of sizeable sets of genes pertinent to each putative pathophysiological pathway is required. For many years, genes have been tested in a 'one by one' manner for association with major affective disorders, primarily bipolar illness. However, it is conceivable that not individual genes but abnormalities in several genes within a system or in several neuronal, neural, or hormonal systems are implicated in the functional hypotheses for etiology of affective disorders. Compilation of candidate genes for entire pathways is a challenge, but can reasonably be carried out for the major affective disorders as discussed here. We present here five groupings of genes implicated by neuropharmacological and other evidence, which suggest 252 candidate genes worth examining. Inexhaustiveness of gene interrogation would apply to many studies in which only one polymorphism per gene is analyzed. In contrast to whole-genome association studies, a study of a limited number of candidate genes can readily exploit information on genomic sequence variations obtained from databases and/or resequencing, and has an advantage of not having the complication of an extremely stringent statistical criterion for association.
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2,337,420 |
Maximal metabolic rates during voluntary exercise, forced exercise, and cold exposure in house mice selectively bred for high wheel-running.
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Selective breeding for high wheel-running activity has generated four lines of laboratory house mice (S lines) that run about 170% more than their control counterparts (C lines) on a daily basis, mostly because they run faster. We tested whether maximum aerobic metabolic rates (V(O2max)) have evolved in concert with wheel-running, using 48 females from generation 35. Voluntary activity and metabolic rates were measured on days 5+6 of wheel access (mimicking conditions during selection), using wheels enclosed in metabolic chambers. Following this, V(O2max) was measured twice on a motorized treadmill and twice during cold-exposure in a heliox atmosphere (HeO2). Almost all measurements, except heliox V(O2max), were significantly repeatable. After accounting for differences in body mass (S < C) and variation in age at testing, S and C did not differ in V(O2max) during forced exercise or in heliox, nor in maximal running speeds on the treadmill. However, running speeds and V(O2max) during voluntary exercise were significantly higher in S lines. Nevertheless, S mice never voluntarily achieved the V(O2max) elicited during their forced treadmill trials, suggesting that aerobic capacity per se is not limiting the evolution of even higher wheel-running speeds in these lines. Our results support the hypothesis that S mice have genetically higher motivation for wheel-running and they demonstrate that behavior can sometimes evolve independently of performance capacities. We also discuss the possible importance of domestication as a confounding factor to extrapolate results from this animal model to natural populations.
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2,337,421 |
Effects of chronic alcohol treatment on acoustic startle reactivity during withdrawal and subsequent alcohol intake in high and low alcohol drinking rats.
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The purpose of the present study is to determine whether the inverse genetic association between alcohol withdrawal magnitude and genetic propensity for alcohol drinking that we have previously identified in alcohol-naive rats given alcohol acutely, would also be seen following chronic alcohol exposure. The effect of forced, chronic alcohol treatment on subsequent voluntary alcohol drinking was also examined.</AbstractText>Male rats from the high alcohol drinking (HAD2) and low alcohol drinking (LAD2) lines received two intragastric (IG) infusions of alcohol (3.0 g/kg BW; 25% v/v) or an equal volume of water, separated by 5 h, every day for 20 consecutive days (chronic alcohol treatment). Acoustic startle reactivity was assessed at 10, 14, and 18 h after the second infusion on days 1, 5, 10, 15, and 20. After acoustic startle testing was completed, all rats received two IG infusions of 3.0 g alcohol/kg BW, separated by 5 h, and blood alcohol content was assessed at 10, 14, and 18 h after the second alcohol infusion. All rats were then given a 24 h free-choice between alcohol and water for 8 weeks.</AbstractText>Startle magnitude to a 120 dB tone was suppressed during alcohol withdrawal in both alcohol-treated HAD2 and LAD2 rats after 5, 10, and 15 days of alcohol treatment. Forced, chronic alcohol treatment produced metabolic tolerance in both the HAD2 and LAD2 lines and significantly suppressed subsequent voluntary alcohol intake in rats of the HAD2 line.</AbstractText>Reduced acoustic startle reactivity during alcohol withdrawal in both HAD2 and LAD2 rats is consistent with our previous findings in the HAD2 but not the LAD2 line and may reflect reduced CNS excitability during withdrawal from forced alcohol exposure. Forced alcohol exposure robustly retarded the expression of a genetic predisposition toward alcohol drinking in rats selectively bred for high alcohol intake.</AbstractText>
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2,337,422 |
Identification, characterization and forensic application of novel Y-STRs.
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Y-chromosomal polymorphic STRs are a powerful tool for forensic and evolutionary studies. Within the last decade, a series of Y-STR systems have been developed and demonstrated to be suitable for a variety of forensic applications including sexual assault cases and paternity testing. This review describes our recent studies on novel male-specific Y-STRs, involving identification, development of a multiplex-PCR system, population study and forensic application.
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2,337,423 |
Improvements to the throughput of recombinant protein expression in the baculovirus/insect cell system.
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Recombinant baculoviruses have proved to be a very useful means to express many proteins over the last 20 years. Since their introduction, there have been a number of significant improvements that have simplified and speeded up the construction of baculoviruses. One of the most commonly used methods relies upon recombination with the baculovirus genome maintained in Escherichia coli. In this paper, we report the conversion of nearly all the steps in this process including the expression testing and purification to a multi-well plate format. This enables a significant increase in the number of constructs that can be processed in a shorter period of time and an order of magnitude increase in the number of expression conditions that can be analysed. A key step in our process is that the transfection is done in suspension rather than adherent cells, which gives a much higher virus titre than in the standard methods.
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2,337,424 |
Molecular and haematological characterization of compound Hb E/Hb Pyrgos and Hb E/Hb J-Bangkok in Thai patients.
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We describe haematological and DNA characterization of haemoglobinopathies in Thai adolescents caused by compound heterozygosities for Hb E [beta26(B8) Glu-Lys] and two other beta-globin chain variants, Hb Pyrgos [beta83(EF7) Gly-Asp] and Hb J Bangkok [beta56(D7) Gly-Asp]. Hb analysis demonstrated that although these two beta-chain variants have separated elution profiles on liquid chromatography-based Hb analysis, they have similar alkaline electrophoretic mobilities on cellulose acetate electrophoresis. Haematological data associated with these two previously undescribed conditions were compared with those of pure carriers of the variants found in other unrelated Thai individuals. beta-Globin gene haplotypes linked to these two beta-chain variants and a simple DNA testing based on multiplex allele-specific polymerized chain reaction for differential diagnosis are presented.
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2,337,425 |
Psychological impact of genetic testing for cancer susceptibility: an update of the literature.
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This article presents an overview of the rapidly evolving body of literature on the psychological impact of genetic testing for hereditary breast/ovarian cancer susceptibility, hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). Uptake of genetic testing for BRCA1/2 and HNPCC-related mutations is more consistently related to psychological factors, rather than sociodemographic variables. Most studies on the psychological impact of genetic testing amongst individuals who have never been affected by cancer demonstrate that non-carriers derive significant psychological benefits from genetic testing, while no adverse effects have been observed amongst carriers. These benefits are more clear-cut for HNPCC, compared to hereditary breast/ovarian cancer, reflecting differences in risk management options. The few studies available on individuals affected with cancer indicate that the impact of genetic testing is mediated and amplified by their former experience of cancer. Future directions and challenges of research in this area are reviewed. In particular, more empirical data are needed on the broader impact of genetic testing on those with inconclusive results or results of uncertain significance. As genetic testing is becoming available for other types of familial cancer, additional investigations will be needed as there is evidence to suggest that the impact of genetic testing may be unique to each type of familial cancer.
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2,337,426 |
Molecular basis of oculocutaneous albinism type 1 in Lebanese patients.
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Oculocutaneous albinism type 1 (OCA1) results from mutations in the tyrosinase gene, which lead to partial or complete loss of activity of the corresponding enzyme. A large number of mutations have been identified worldwide, providing insight into the pathogenesis of the disorder. We performed ophthalmic and dermatological exams on 30 Lebanese subjects with oculocutaneous albinism, then screened for mutations in the tyrosinase gene in an effort to establish the molecular basis of the disorder in our population and correlate it with phenotypic findings. The five exons of the gene together with the exon-intron boundaries and part of the promoter region were sequenced. Mutations were found in a total of 14 patients (47%) while no mutation was identified in the sequenced regions in 53% of patients. Fourteen different mutations were identified of which eight were novel while six had been previously reported. Mutations were mainly seen in patients with clinical findings, suggestive of OCA1A (64% of patients with OCA1A versus 25% of patients with OCA1B); therefore, the absence of mutations in some of the other patients may indicate the involvement of other genes.
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2,337,427 |
Genomic screening and replication using the same data set in family-based association testing.
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The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations that achieve genome-wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease-susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease-susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype-tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome-wide significance, as population-based designs do.
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2,337,428 |
Audiological features of GJB2 (connexin 26) deafness.
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The aim of the present study was to characterize audiological profiles in patients with GJB2 deafness</AbstractText>We screened DNA from 399 individuals with nonsyndromic deafness for mutations in the connexin 26 gene (GJB2) by sequence analysis. A total of 77 (19%) of these deaf individuals were biallelic GJB2 mutations (either homozygous or compound heterozygous mutations) (GJB2 deafness). Using the audiological classification criteria of genetic deafness proposed by the European Workshop on Genetic Hearing Loss, we analyzed audiograms of these patients to characterize audiological features of the GJB2 deafness. In addition, we reviewed audiological data of 411 deafness cases from the literature providing details of audiological data (including 157 with GJB2 deafness).</AbstractText>All categories of hearing loss severity were found, with significant differences in the findings from GJB2 cases: 1 (4.5%) of 22 individuals with mild hearing loss, 10 (13.3%) of 75 with moderate loss, 14 (14.9%) of 94 with severe loss, and 52 (25%) of 208 with profound deafness (Chi-square test, 3 df, p = 0.016). 81.6% of patients with GJB2 mutations had severe to profound loss, 18.4% with mild to moderate loss (Chi-square test, p = 0.014). The 235delC mutation was always associated with profound deafness. The main audiogram shapes found were residual/sloping (72.7%) and flat (23.4%). There were no differences in the severity and audiogram shapes of the hearing impairment between homozygous and compound heterozygous GJB2 deafness (Chi-square test, p > 0.05).</AbstractText>Our study shows that the probability of finding biallelic GJB2 mutations increases with the severity of hearing loss. Audiograms associated with GJB2 deafness were usually nonspecific. Patients with unknown causes of severe or profound hearing loss should be routinely tested for GJB2 mutations, but due to the variability in hearing loss, individuals with lesser degrees of hearing loss should not be precluded from testing.</AbstractText>
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2,337,429 |
Paternal history of asthma and airway responsiveness in children with asthma.
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Little is known regarding the relationship between parental history of asthma and subsequent airway hyperresponsiveness (AHR) in children with asthma.</AbstractText>We evaluated this relationship in 1,041 children with asthma participating in a randomized trial of antiinflammatory medications (the Childhood Asthma Management Program [CAMP]).</AbstractText>Methacholine challenge testing was performed before treatment randomization and once per year over an average of 4.5 years postrandomization. Cross-sectional and longitudinal repeated measures analyses were performed to model the relationship between PC20 (the methacholine concentration causing a 20% fall in FEV1) with maternal, paternal, and joint parental histories of asthma. Models were adjusted for potential confounders.</AbstractText>At baseline, AHR was strongly associated with a paternal history of asthma. Children with a paternal history of asthma demonstrated significantly greater AHR than those without such history (median log(e)PC20, 0.84 vs. 1.13; p = 0.006). Although maternal history of asthma was not associated with AHR, children with two parents with asthma had greater AHR than those with no parents with asthma (median log(e)PC20, 0.52 vs. 1.17; p = 0.0008). Longitudinal multivariate analysis of the relation between paternal history of asthma and AHR using repeated PC20 measurements over 44 months postrandomization confirmed a significant association between paternal history of asthma and AHR among children in CAMP.</AbstractText>Our findings suggest that the genetic contribution of the father is associated with AHR, an important determinant of disease severity among children with asthma.</AbstractText>
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2,337,430 |
Identification of the omega4406 regulatory region, a developmental promoter of Myxococcus xanthus, and a DNA segment responsible for chromosomal position-dependent inhibition of gene expression.
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When starved, Myxococcus xanthus cells send signals to each other that coordinate their movements, gene expression, and differentiation. C-signaling requires cell-cell contact, and increasing contact brought about by cell alignment in aggregates is thought to increase C-signaling, which induces expression of many genes, causing rod-shaped cells to differentiate into spherical spores. C-signaling involves the product of the csgA gene. A csgA mutant fails to express many genes that are normally induced after about 6 h into the developmental process. One such gene was identified by insertion of Tn5 lac at site omega4406 in the M. xanthus chromosome. Tn5 lac fused transcription of lacZ to the upstream omega4406 promoter. In this study, the omega4406 promoter region was identified by analyzing mRNA and by testing different upstream DNA segments for the ability to drive developmental lacZ expression in M. xanthus. The 5' end of omega4406 mRNA mapped to approximately 1.3 kb upstream of the Tn5 lac insertion. A 1.0-kb DNA segment from 0.8 to 1.8 kb upstream of the Tn5 lac insertion, when fused to lacZ and integrated at a phage attachment site in the M. xanthus chromosome, showed a similar pattern of developmental expression as Tn5 lac Omega4406. The DNA sequence upstream of the putative transcriptional start site was strikingly similar to promoter regions of other C-signal-dependent genes. Developmental lacZ expression from the 1.0-kb segment was abolished in a csgA mutant but was restored upon codevelopment of the csgA mutant with wild-type cells, which supply C-signal, demonstrating that the omega4406 promoter responds to extracellular C-signaling. Interestingly, the 0.8-kb DNA segment immediately upstream of Tn5 lac omega4406 inhibited expression of a downstream lacZ reporter in transcriptional fusions integrated at a phage attachment site in the chromosome but not at the normal omega4406 location. To our knowledge, this is the first example in M. xanthus of a chromosomal position-dependent effect on gene expression attributable to a DNA segment outside the promoter region.
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2,337,431 |
Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.
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Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations of mismatch repair genes, usually in hMLH1 or hMSH2. All earlier studies on penetrance except one population based study were conducted in HNPCC families and did not correct for the way in which these families were ascertained.</AbstractText>To obtain estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease causing mutations of the hMSH2 and hMLH1 genes.</AbstractText>Families with known germline mutations of hMLH1 (n = 39) and hMSH2 (n = 45) were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for cancer of the colorectum and endometrium.</AbstractText>Both loci were analysed jointly as there was no significant difference in risk (p = 0.08). At age 70, colorectal cancer risk for men was 26.7% (95% confidence interval, 12.6% to 51.0%) and for women, 22.4% (10.6% to 43.8%); the risk for endometrial cancer was 31.5% (11.1% to 70.3%).</AbstractText>Current estimates of the CRC risk of mutations to the hMLH1 and hMSH2 locus should be replaced by considerably lower risks which account for the selection of the families.</AbstractText>
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2,337,432 |
Ticks and tick-borne disease in Guatemalan cattle and horses.
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Blood samples and ticks were collected from 48 cattle and 74 horses from seven sites in the Peten region of Guatemala. Data on body condition, mucous membrane capillary refill time and tick infestation levels were recorded for each animal in the study. Horses had significantly higher levels of tick infestation than cattle, as well as poorer body condition scores. Seroprevalence of Babesia spp. was 95.8% for B. bovis in cattle, 89.6% for B. bigemina in cattle, and 92.7% for B. equi in horses. Seroprevalence of Anaplasma marginale in cattle was 87.5%, similar to reports in animals from other regions of Central America. This is the first time that A. phagocytophilum has been reported in animals from this region, with overall PCR-prevalence of 27.6% in cattle and horses, and seroprevalence of 28.4% (52% in cattle and 13% in horses). An agent was identified with serological cross-reactivity and close genetic relatedness to Ehrlichia ruminantium, but further testing confirmed that the agent in Guatemalan cows was not the agent of heartwater. Ticks were identified to species with the predominant species identified on cattle as Boophilus microplus and Amblyomma cajennense, while Anocentor nitens and A. cajennense were most commonly found on horses. Prevalence of infection, tick infestation levels, host factors and environmental data were analyzed for association; A. nitens was significantly associated with A. phagocytophilum prevalence by village.
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2,337,433 |
Spine biomechanics.
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Current trends in spine research are reviewed in order to suggest future opportunities for biomechanics. Recent studies show that psychosocial factors influence back pain behaviour but are not important causes of pain itself. Severe back pain most often arises from intervertebral discs, apophyseal joints and sacroiliac joints, and physical disruption of these structures is strongly but variably linked to pain. Typical forms of structural disruption can be reproduced by severe mechanical loading in-vitro, with genetic and age-related weakening sometimes leading to injury under moderate loading. Biomechanics can be used to quantify spinal loading and movements, to analyse load distributions and injury mechanisms, and to develop therapeutic interventions. The authors suggest that techniques for quantifying spinal loading should be capable of measurement "in the field" so that they can be used in epidemiological surveys and ergonomic interventions. Great accuracy is not required for this task, because injury risk depends on tissue weakness as much as peak loading. Biomechanical tissue testing and finite-element modelling should complement each other, with experiments establishing proof of concept, and models supplying detail and optimising designs. Suggested priority areas for future research include: understanding interactions between intervertebral discs and adjacent vertebrae; developing prosthetic and tissue-engineered discs; and quantifying spinal function during rehabilitation. "Mechanobiology" has perhaps the greatest future potential, because spinal degeneration and healing are both mediated by the activity of cells which are acutely sensitive to their local mechanical environment. Precise characterisation and manipulation of this environment will be a major challenge for spine biomechanics.
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2,337,434 |
Estimating the probability of identity in a random dog population using 15 highly polymorphic canine STR markers.
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Dog DNA-profiling is becoming an important supplementary technology for the investigation of accident and crime, as dogs are intensely integrated in human social life. We investigated 15 highly polymorphic canine STR markers and two sex-related markers of 131 randomly selected dogs from the area around Innsbruck, Tyrol, Austria, which were co-amplified in three PCR multiplex reactions (ZUBECA6, FH2132, FH2087Ua, ZUBECA4, WILMSTF, PEZ15, PEZ6, FH2611, FH2087Ub, FH2054, PEZ12, PEZ2, FH2010, FH2079 and VWF.X). Linkage testing for our set of marker suggested no evidence for linkage between the loci. Heterozygosity (HET), polymorphism information content (PIC) and the probability of identity (P((ID)theoretical), P((ID)unbiased), P((ID)sib)) were calculated for each marker. The HET((exp))-values of the 15 markers lie between 0.6 (VWF.X) and 0.9 (ZUBECA6), P((ID)sib)-values were found to range between 0.49 (VWF.X) and 0.28 (ZUBECA6). Moreover, the P((ID)sib) was computed for sets of loci by sequentially adding single loci to estimate the information content and the usefulness of the selected marker sets for the identification of dogs. The estimated P((ID)sib) value of all 15 markers amounted to 8.5 x 10(-8). The presented estimations turned out to be a helpful approach for a reasonable choice of markers for the individualisation of dogs.
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2,337,435 |
Identification of HLA-DQalpha and -DRbeta residues associated with susceptibility and protection to epithelial ovarian cancer.
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Substantial evidence has been accumulated suggesting that T cells in patients with epithelial ovarian carcinoma (EOC) exhibit an antigen-driven immune response directed against the tumor cells. In the context of human leukocyte antigen (HLA), this suggests its possible involvement in the disease. Therefore, we examined the distribution of the HLA-DRB1*, -DQA1*, and -DQB1* alleles in 47 patients with EOC and 67 healthy Caucasian women. The frequency of D(70) and E(71) polymorphic residues of the DRB1 alleles was significantly reduced in EOC patients versus controls (pD(70)E(71) = 0.009), suggesting a protective role against the disease. The DQalpha residues R(52) and Y(11)R(55) were increased in the patients (p = 0.008 and 0.012, respectively). Because residues 11 and 55 participate in the formation of pocket 1, they may be functionally important amino acid positions that influence disease susceptibility. The frequency of the DQalpha susceptibility epitope (R(52)Y(11)R(55)) among the DRbetaD(70)E(71)-positive EOC patients was increased when compared with DRbetaD(70)E(71)-positive controls (EOC, 100%; control, 52%; p = 0.028). Among individuals without the DQalpha susceptibility epitope, the distribution of DRbetaD(70)E(71)-positive cases was significantly different between EOC patients and controls (EOC, 0%; control, 60%; p = 0.039). Therefore, it appears that the presence of DQalpha susceptibility elements overrides the protective effect of the DRbetaD(70)E(71) epitope and suggests an interactive relationship between DRbeta and DQalpha epitopes that may be of importance for disease susceptibility. Because positions DRbeta 70,71 and DQalpha 52 have been implicated in immunologic diseases, it is likely that besides being critical for T-cell recognition, they may also play a role in T-cell development and acquisition of the T-cell repertoire.
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2,337,436 |
Sequence-based typing of the HLA-A10/A19 group and confirmation of a pseudogene coamplified with A*3401.
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The strategy for sequencing human leukocyte antigen (HLA)-A was based on separate amplification of exons 2 and 3, followed by forward and reverse heterozygous sequencing of the alleles. Validation of the method was obtained by sequencing 11 individuals carrying alleles from all different HLA-A allele groups, except *43. All alleles could be correctly identified except A*3401. Unexpected polymorphic positions were identified in exon 3, even in individuals homozygous for A*3401. In addition, the pseudogene HLA-COQ or HLA-DEL linked to A*3401 was coamplified and sequenced. The problem was solved by using different amplification primers for exon 3 with mismatches for the two pseudogenes. A total of 252 unrelated individuals with at least one allele belonging to the A10 or A19 group were typed for HLA-A by this strategy. Ten different alleles were identified in the A10 group and 14 in the A19 group. As second allele a further 30 different subtypes from all different groups were sequenced. In 21 individuals, sequencing exon 1 was necessary to distinguish A*7401 from A*7402. The sequencing strategy, with separate amplification of the exons, has proven to be a robust method, resulting in reliable and efficient high-resolution HLA-A typing.
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2,337,437 |
Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma.
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Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis.</AbstractText>We genotyped six single nucleotide polymorphisms (SNPs) in the STAT3 gene in a cohort of 401 Caucasian adult asthmatics. The associations between each SNP and forced expiratory volume in 1 second (FEV1), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV1 were conducted with mixed linear models. Haplotype analyses were conducted using imputed haplotypes. We completed a second association study by genotyping the same six polymorphisms in a cohort of 652 Caucasian children with asthma.</AbstractText>We found that three polymorphisms were significantly associated with baseline FEV1: homozygotes for the minor alleles of each polymorphism had lower FEV1 than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV1 over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV1. Among the childhood asthmatics, one polymorphism was associated with both baseline FEV1 and the repeated measures of FEV1 over 4 years.</AbstractText>Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV1 in both adults and children with asthma, and suggest that STAT3 may participate in inflammatory pathways that have an impact on level of lung function.</AbstractText>
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2,337,438 |
Adoption of array technologies into the clinical laboratory.
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Array-based methods are making substantial contributions to the discovery of disease biomarkers and are fueling the growth of multianalyte testing for disease diagnosis and treatment. The distillation of high-density array results into sets of signature markers promises to improve disease staging, risk stratification and treatment decisions. To accommodate the growing requirement for multiplex testing, clinical laboratories are converting several single-analyte tests into array-based formats. However, adoption of array technologies provides several challenges to the laboratory, which must evaluate these new formats, train laboratory personnel, market the new services and obtain reimbursement for new analytes. Liquid-bead arrays are an attractive format for routine clinical diagnostics due to a combination of appropriate analyte density, simultaneous array decoding and detection, and flexibility for rapid customization. In this review, the suitability of several array platforms to diagnostic testing and applications of liquid-bead arrays for cystic fibrosis testing, multidisease carrier status assays and leukemia subtyping are discussed. As our understanding of the clinical utility of new or established biomarkers and recommendations for testing change, flexibility and adaptability of array platforms will be imperative. Future development of novel assay formats and improved quantitation will expand the number of diseases tested and lead to further integration into the diagnostic laboratory.
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2,337,439 |
A single-component CD40-targeted adenovirus vector displays highly efficient transduction and activation of dendritic cells in a human skin substrate system.
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Dendritic cell (DC) based tumor vaccination usually involves the administration of ex vivo generated autologous DC. Transduction of DC by viral vectors in vivo has been proposed as a more standardized and easily clinically applicable approach. Previously, we have reported that an Ad5 vector targeted to CD40 via genetic capsid incorporation of CD40L achieves selective transduction of DC in vitro. In the present study, we evaluate the ability of this vector to deliver transgenes in a stringent human substrate system. We report the capacity of this CD40-targeted vector to infect, with high efficiency, cutaneous DC resident in human skin explants, while simultaneously inducing their activation and maturation. This latest generation of single-component, fully targeted vectors should make feasible the clinical testing of in vivo DC-targeted vaccines.
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2,337,440 |
Whole-genome screening for susceptibility genes in multicase families with Behçet's disease.
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Behçet's disease is generally considered to be a multifactorial disease with important genetic and environmental components. A strong association between an HLA class I antigen, HLA-B51, and Behçet's disease has long been known. However, analysis of multicase families has suggested a substantial contribution of non-HLA loci. The aim of this study was to perform a whole-genome linkage analysis for identification of other susceptibility loci for Behçet's disease in multicase families.</AbstractText>The study group comprised a total of 193 individuals (90 male, 103 female) from 28 multicase families of Turkish origin; 83 of the subjects (50 males, 33 females) fulfilled the International Study Group criteria for Behçet's disease. Three hundred ninety-five highly informative microsatellite markers spanning the genome were genotyped using fluorescent polymerase chain reaction primers and a fully automated electrophoresis platform. After the first analysis, 33 additional markers that were located close to the peak linkage areas were genotyped in all individuals. Nonparametric multipoint linkage analysis was carried out using GeneHunter version 2.1 software.</AbstractText>Evidence for linkage (P < or = 0.05) was obtained in 16 chromosome regions: 1p36, 4p15, 5q12, 5q23, 6p22-24, 6q16, 6q25-26, 7p21, 10q24, 12p12-13, 12q13, 16q12, 16q21-23, 17p13, 20q12-13, and Xq26-28. After the addition of further markers, the maximum nonparametric linkage score increased from 3.5 to 3.94 at 12p12-13 (D12S77; P = 0.0002) and from 3.07 to 3.70 at 6p22-24 (D6S285; P = 0.0005).</AbstractText>This study is the first systematic genome screen in Behçet's disease and provides evidence of linkage to several non-HLA susceptibility loci in a cohort of Turkish multicase families. This represents the first step toward the identification of novel Behçet's disease susceptibility genes.</AbstractText>
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2,337,441 |
Observation of a parental inversion variant in a rare Williams-Beuren syndrome family with two affected children.
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The Williams-Beuren syndrome (WBS) region at 7q11.23 is subject to several genomic rearrangements, one of which, the WBSinv-1 variant, is an inversion polymorphism. The WBSinv-1 chromosome has been shown to occur frequently in parents of individuals with WBS, implying that it predisposes the region to the WBS deletion. Here we investigate two WBS families with multiple affected children, and show that in one family, both siblings have a deletion on a WBSinv-1 chromosome background that arose due to interchromosomal recombination. These results suggest that the two WBS deletions in this family were independent events, and that there is likely a significant increase in the risk of deletion of the WBS region associated with the WBSinv-1 chromosome. The rarity of multiplex WBS families would suggest that the overall risk of having a child with WBS is still relatively low; however, families with an existing member with WBS may choose to opt for WBSinv-1 testing and genetic counseling.
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2,337,442 |
Sanfilippo type B syndrome: five patients with an R565P homozygous mutation in the alpha-N-acetylglucosaminidase gene from the Okinawa islands in Japan.
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Sanfilippo type B syndrome (mucopolysaccharidosis type IIIB; MPS IIIB) is an autosomal recessive lysosomal storage disorder that is caused by defective alpha- N-acetylglucosaminidase (NAGLU). We performed NAGLU gene analysis in five patients with MPS IIIB whose respective parents from the Okinawa islands in Japan were not apparently consanguineous. We found a missense mutation (R565P) in all five patients (all homozygotes). We screened this mutation in 200 healthy subjects and found one heterozygote (none of the subjects were related to the patients). These results suggest that there may be a founder effect that results in the accumulation of R565P mutation in this area.
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2,337,443 |
The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications.
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Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of high-grade, highly proliferating, estrogen receptor- and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor- and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma.
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2,337,444 |
Psychosocial aspects of risk communication and mutation testing in familial breast-ovarian cancer.
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As cancer genetics services develop, psychosocial research evaluating risk communication and mutation testing for familial breast-ovarian cancer has expanded rapidly. It is timely to review findings in key areas. These will inform risk counselling practice and help prepare women making risk management decisions.</AbstractText>The psychological effect of risk communication and genetic counselling has been elucidated and women's risk perceptions explored. Knowledge of optimal risk communication strategies is lacking, but recent research shows both consistency in information giving and deficiencies in specific communication skills; the need for personally tailored risk information, which addresses counsellees' concerns, is highlighted. Outcome assessments of risk communication, such as risk perception and psychological distress, are useful but insufficient to evaluate the complex communication process, and decision making in this context is underresearched. Subsequent diffusion of risk information and interfamily communication pose difficulties for high-risk individuals. The short-term psychological consequences of predictive mutation testing are an important focus of research and are largely reassuring, but long-term outcomes are sparse.</AbstractText>Our understanding of the psychological benefits and limitations of risk counselling and mutation testing can now inform clinical practice, but insufficient knowledge exists of long-term outcomes. Most women are unlikely to be distressed following risk communication, but some may need psychosocial support in the short term following predictive testing for BRCA1/2. Different approaches to risk communication need to be developed and evaluated in parallel with communications skills training to ensure an adequate focus on the women's agenda.</AbstractText>
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2,337,445 |
Genetic diversity and antibiotic resistance patterns in a campylobacter population isolated from poultry farms in Switzerland.
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The diversity and genetic interrelation of Campylobacter jejuni and C. coli isolated from Swiss poultry were assessed by three independent typing methods. Samples were derived prior to slaughter from 100 randomly selected flocks (five birds per flock) raised on three different farm types. The observed flock prevalence was 54% in total, with 50% for conventional and 69% for free-range farms. Birds held on farms with a confined roaming area had the lowest prevalence of 37%. Campylobacter isolates were characterized by amplified fragment length polymorphism (AFLP), restriction fragment length polymorphism of flaA PCR fragments (flaA-RFLP), and disk diffusion testing for eight antimicrobial agents that are commonly used in veterinary or human medicine in Switzerland. Analysis of the genotypic results indicates that the Campylobacter population in Swiss poultry is genetically highly diverse. Nevertheless, occasionally, isolates with identical or nearly identical characteristics were isolated from different farms or farm types in different locations. Genetic typing by AFLP and flaA-RFLP was found to be complementary. The majority of isolates (67%) were susceptible to all tested antibiotics; however, single, double, and triple resistances were observed in 7%, 23%, and 2% of the strains, respectively. There was no correlation between genotype and antibiotic resistance. Surprisingly, sulfonamide resistance was frequently found together with streptomycin resistance. Our findings illustrate the results of common genetic exchange in the studied bacterial population.
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2,337,446 |
Impact of self-reported familiarity with guidelines for cystic fibrosis carrier screening.
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To assess the impact of self-reported familiarity with published guidelines on knowledge, implementation, and opinions of obstetrician-gynecologists regarding carrier screening for cystic fibrosis.</AbstractText>A questionnaire pertaining to cystic fibrosis screening guidelines was mailed to 1,165 members of the American College of Obstetricians and Gynecologists.</AbstractText>Sixty-four percent of questionnaires were returned. Statistical analyses were limited to the 632 respondents whose primary medical specialty was gynecology (GynOnly) or obstetrics and gynecology (ObGyns). More ObGyns had thoroughly read or skimmed the guidelines (67.1%) than had GynOnlys (41.6%). Correctly responding to basic questions regarding cystic fibrosis was associated with having read the guidelines, although responding to a more complex question was not. Familiarity with the guidelines was associated with correctly identifying the recommendations for offering screening, with practice implementation of cystic fibrosis screening, and with self-ratings of qualifications and training to offer screening and to provide counseling. In contrast, familiarity with the guidelines was not associated with ObGyn's opinion that burden of disease is likely to be influential in patient acceptance of screening. Physicians who had thoroughly read the guidelines were more likely to disagree that the cystic fibrosis screening test is too inaccurate to risk influencing reproductive decision making (thoroughly read = 79% disagree, skimmed = 69%, not read = 58%, not heard of it = 50%).</AbstractText>There was a strong association between self-reported familiarity with the American College of Obstetricians and Gynecologists/American College of Medical Genetics guidelines and physicians' knowledge, implementation, and ratings of training for offering cystic fibrosis carrier screening.</AbstractText>
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2,337,447 |
Sequence analysis of the MHC class II DPB1 gene in chimpanzees (Pan troglodytes).
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The diversity of the MHC class II region in non-human primates is a focus of biomedical research because this region plays a crucial role in the recognition of antigens in the immune system. In particular, the chimpanzee [Pan troglodytes (Patr)], which belongs to the superfamily Hominoidea, has been used as a human model for the study of diseases such as human hepatitis C virus (HCV), human hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, to which only humans and chimpanzees are susceptible. In the present study, polymorphisms of the MHC-DPB1 gene (Patr-DPB1) in a chimpanzee colony in Japan were examined using a stepwise polymerase chain reaction (PCR) technique. In order to design a suitable primer pair which would amplify exon 2 of the Patr-DPB1 gene, a fragment of approximately 8 kb from exon 1 to exon 3 was amplified from chimpanzee genomic DNA. After designing a 500-bp primer pair at the 3' region of intron 1 and the 5' region of intron 2, analysis of DPB1 exon 2 alleles of each chimpanzee was carried out. Twenty-two chimpanzees were used in our study, and we identified seven alleles by sequence analysis on the Patr-DPB1 gene, including one new allele. The obtained nucleotide sequence patterns suggest that Patr-DPB1 alleles emerge by genetic variations such as the exchange of sequence motifs and the accumulation of point mutations.
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2,337,448 |
Inherited corneal disease: the evolving molecular, genetic and imaging revolution.
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Advances in molecular genetics and in vivo ocular imaging modalities have enhanced our understanding of the corneal dystrophies. To date at least 11 genes have been identified, in which mutations manifest in corneal disease. In addition there are at least eight other loci identified to which corneal dystrophies have been linked. The information gained from the knowledge of gene function, aberrant protein production, or altered enzyme activity in the cornea, has resulted in greater knowledge of the pathophysiological mechanisms in these disorders. In vivo confocal microscopy has recently enabled microstructural study of dystrophic corneas throughout the disease course, rather than being limited to histopathological analysis of tissue removed at corneal transplantation. This perspective article summarizes the current knowledge, with emphasis on the genes, mutant proteins and resultant mechanisms that lead to manifestations of disease, along with characteristic findings with in vivo confocal microscopy.
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2,337,449 |
Human leucocyte antigen determinants of susceptibility to Barrett's oesophagus in Asians--a preliminary study.
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Characteristic immune profiles have been demonstrated in gastro-oesophageal reflux disease. However, the genetic basis of gastro-oesophageal reflux disease remains unclear.</AbstractText>To investigate whether certain human leucocyte antigen genes are associated with Barrett's oesophagus.</AbstractText>Asian patients of Malay, Chinese and Indian descent with Barrett's oesophagus (n = 59) and those without reflux symptoms and a normal oesophagus (n =60) were recruited prospectively using endoscopic and histopathological criteria. Human leucocyte antigen class I and II typing was performed using a polymerase chain reaction sequence-specific primers method.</AbstractText>The HLA-B7 allele was present in 17% (10 of 59) of patients with Barrett's oesophagus when compared with 0% (zero of 60) of controls [P = 0.0006, corrected P = 0.0171, OR = 25.67]. Subgroup analysis revealed that the HLA-B7 allele was confined almost exclusively to Indians with Barrett's oesophagus, 43% (nine of 21) vs. 0% (zero of 19) Indian controls (P = 0.0014, corrected P = 0.0406, OR = 29.64). No class II associations, protective human leucocyte antigens or extended haplotypes for disease susceptibility were identified.</AbstractText>Barrett's oesophagus in Asians, particularly Indians, is strongly positively associated with HLA-B7; reinforcing a genetic component to gastro-oesophageal reflux disease. A larger sample size and different ethnic populations should be genotyped to further confirm this association and identify possible additional risk factors in the human leucocyte antigen locus.</AbstractText>
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2,337,450 |
Germline susceptibility to colorectal cancer due to base-excision repair gene defects.
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DNA repair is a key process in the maintenance of genome integrity. Here, we present a large, systematically collected population-based association study (2,239 cases; 1,845 controls) that explores the contribution to colorectal cancer incidence of inherited defects in base-excision repair (BER) genes. We show that biallelic MUTYH defects impart a 93-fold (95% CI 42-213) excess risk of colorectal cancer, which accounts for 0.8% of cases aged <55 years and 0.54% of the entire cohort. Penetrance for homozygous carriers was almost complete by age 60 years. Significantly more biallelic carriers had coexisting adenomatous polyps. However, notably, 36% of biallelic carriers had no polyps. Three patients with heterozygous MUTYH defects carried monoallelic mutations in other BER genes (OGG1 and MTH1). Recessive inheritance accounted for the elevated risk for those aged <55 years. However, there was also a 1.68-fold (95% CI 1.07-2.95) excess risk for heterozygous carriers aged >55 years, with a population attributable risk in this age group of 0.93% (95% CI 0%-2.0%). These data provide the strongest evidence to date for a causative role of BER defects in colorectal cancer etiology and show, to our knowledge for the first time, that heterozygous MUTYH mutations predispose to colorectal cancer later in life. These findings have clinical relevance for BER gene testing for patients with colorectal cancer and for genetic counseling of their relatives.
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2,337,451 |
Novel management of oral cancer: a paradigm of predictive oncology.
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The rationale for molecular-targeted prevention of oral cancer is strong. Oral cancer is a major global threat to public health with 300,000 new cases diagnosed worldwide on an annual basis. Notably, the great morbidity and mortality rates of this devastating disease have not improved in decades. Oral cancer development is a tobacco-related multistep and multifocal process involving field carcinogenesis and intraepithelial clonal spread. Biomarkers of genomic instability, such as aneuploidy and allelic imbalance, can accurately measure the cancer risk of oral premalignant lesions or intraepithelial neoplasia (IEN). Retinoid-oral IEN studies (e.g., retinoid acid receptor-beta, p53, genetic instability, loss of heterozygosity, and cyclin D1) have advanced the overall understanding of the biology of intraepithelial carcinogenesis and preventive agent molecular mechanisms and targets, important advances for monitoring preventive interventions, assessing cancer risk, and pharmacogenomics. Clinical management of oral IEN varies from watchful waiting to complete resection, although complete resection does not prevent oral cancer in high-risk patients. New approaches, such as interventions with molecular-targeted agents and agent combinations in molecularly defined high-risk oral IEN patients, are urgently needed to reduce the devastating worldwide consequences of oral cancer.
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2,337,452 |
Genetics of prostate cancer.
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Prostate cancer is the most frequently diagnosed visceral cancer of men, responsible for approximately 40,000 deaths in adult males per year. To identify the genetic causes of prostate cancer, we performed a whole genome scan of affected sib pairs, using DNA markers spaced evenly across the human genome. We demonstrated that regions on chromosomes 1, 4, 5, 7, 8, 11, 16 and 19 might harbor genes that predispose individuals to prostate cancer and may affect tumor growth rate and tumor aggressiveness. Here we present DNA sequence analysis of KIAA 0872 and 17-beta hydroxysteroid dehydrogenase that are located on chromosome 16 within the mapped region, and we demonstrate that neither of these genes carries mutations in the protein coding region or their splice junction sites. These results suggest that these genes are less likely to be associated with the cause of familial prostate cancer.
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2,337,453 |
Impaired motor learning in mice expressing torsinA with the DYT1 dystonia mutation.
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Primary early-onset generalized dystonia is an autosomal dominant disorder caused by a deletion (DeltaGAG) in the DYT1 gene encoding torsinA. The gene defect has incomplete penetrance, with approximately 30% of carriers developing clinically evident dystonia. We describe lines of transgenic mice that express either human mutant torsinA (hMT) or human wild-type (hWT) torsinA. All mice demonstrated moderately increased levels of torsinA in the brain by Western blot analysis and normal subcellular distribution of torsinA in neurons by confocal microscopy. No animals had dystonic features. However, mice overexpressing hMT, but not hWT, torsinA displayed a reduced ability to learn motor skills in an accelerating rotarod paradigm. This pattern resembles the impaired motor sequence learning demonstrated in human nonmanifesting carriers of the DeltaGAG mutation. Open-field testing showed no differences in spontaneous activity between transgenic mice and their nontransgenic littermates, indicating that mice overexpressing hMT torsinA did not develop overtly abnormal motor behavior. Together, these data suggest that these transgenic mice provide a useful model of the DeltaGAG carrier state that can be used to probe genetic and environmental factors that can trigger the dystonic state.
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2,337,454 |
Bladder cancer outcome and subtype classification by gene expression.
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Models of bladder tumor progression have suggested that genetic alterations may determine both phenotype and clinical course. We have applied expression microarray analysis to a divergent set of bladder tumors to further elucidate the course of disease progression and to classify tumors into more homogeneous and clinically relevant subgroups. cDNA microarrays containing 10,368 human gene elements were used to characterize the global gene expression patterns in 80 bladder tumors, 9 bladder cancer cell lines, and 3 normal bladder samples. Robust statistical approaches accounting for the multiple testing problem were used to identify differentially expressed genes. Unsupervised hierarchical clustering successfully separated the samples into two subgroups containing superficial (pT(a) and pT(1)) versus muscle-invasive (pT(2)-pT(4)) tumors. Supervised classification had a 90.5% success rate separating superficial from muscle-invasive tumors based on a limited subset of genes. Tumors could also be classified into transitional versus squamous subtypes (89% success rate) and good versus bad prognosis (78% success rate). The performance of our stage classifiers was confirmed in silico using data from an independent tumor set. Validation of differential expression was done using immunohistochemistry on tissue microarrays for cathepsin E, cyclin A2, and parathyroid hormone-related protein. Genes driving the separation between tumor subsets may prove to be important biomarkers for bladder cancer development and progression and eventually candidates for therapeutic targeting.
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2,337,455 |
Psychosocial risk associated with newborn screening for cystic fibrosis: parents' experience while awaiting the sweat-test appointment.
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The psychosocial effects on parents of infants with abnormal results in cystic fibrosis (CF) newborn screening (NBS) that uses genetic testing remain unclear.</AbstractText>Twenty-eight individuals representing 14 families participated in grounded theory interviews approximately 6 months after their child's positive NBS results for CF. Participants also completed the Center for Epidemiologic Studies Depression Scales (CES-D) at their infant's sweat-test appointment (n = 51) and/or approximately 6 months after the sweat test (n = 35).</AbstractText>Most parents experienced high levels of emotional distress during their wait for the sweat-test appointment (CES-D score, mean +/- SD: 16.5 +/- 6.7; 43.1% in the clinical range; median wait: 7 days; range: 3-35 days). CES-D scores of these parents were also significantly higher than those of comparison parents. Interviews showed that parental cognitive uncertainty and emotional distress were influenced by the parents' prior knowledge of NBS, CF, and their carrier status; parents' adjustment to their new baby; and the physicians' approach to informing parents. Parents' coping strategies involved requesting a sweat test as soon as possible, searching for information, assessing the infant's risk/health, seeking support, praying, or not talking with others.</AbstractText>The waiting period from notification regarding positive NBS results to diagnostic test results can be psychologically distressing to parents, causing depressive symptoms that vary depending on their perceptions about the likelihood that their infant has CF. Implications for future research examining psychosocial interventions for NBS are discussed.</AbstractText>
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2,337,456 |
A GFP-based genetic screen reveals mutations that disrupt the architecture of the zebrafish retinotectal projection.
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The retinotectal projection is a premier model system for the investigation of molecular mechanisms that underlie axon pathfinding and map formation. Other important features, such as the laminar targeting of retinal axons, the control of axon fasciculation and the intrinsic organization of the tectal neuropil, have been less accessible to investigation. In order to visualize these processes in vivo, we generated a transgenic zebrafish line expressing membrane-targeted GFP under control of the brn3c promoter/enhancer. The GFP reporter labels a distinct subset of retinal ganglion cells (RGCs), which project mainly into one of the four retinorecipient layers of the tectum and into a small subset of the extratectal arborization fields. In this transgenic line, we carried out an ENU-mutagenesis screen by scoring live zebrafish larvae for anatomical phenotypes. Thirteen recessive mutations in 12 genes were discovered. In one mutant, ddl, the majority of RGCs fail to differentiate. Three of the mutations, vrt, late and tard, delay the orderly ingrowth of retinal axons into the tectum. Two alleles of drg disrupt the layer-specific targeting of retinal axons. Three genes, fuzz, beyo and brek, are required for confinement of the tectal neuropil. Fasciculation within the optic tract and adhesion within the tectal neuropil are regulated by vrt, coma, bluk, clew and blin. The mutated genes are predicted to encode molecules essential for building the intricate neural architecture of the visual system.
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2,337,457 |
Mutations in hepatocyte nuclear factor-1beta and their related phenotypes.
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Hepatocyte nuclear factor-1 beta (HNF-1beta) is a widely distributed transcription factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct. Thirty HNF-1beta mutations have been reported in patients with renal cysts and other renal developmental disorders, young-onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities.</AbstractText>We sequenced the HNF-1beta gene in 160 unrelated subjects with renal disease, 40% of whom had a personal/family history of diabetes.</AbstractText>Twenty three different heterozygous HNF-1beta mutations were identified in 23/160 subjects (14%), including 10 novel mutations (V61G, V110G, S148L, K156E, Q176X, R276Q, S281fsinsC, R295P, H324fsdelCA, Q470X). Seven (30%) cases were proven to be due to de novo mutations. Renal cysts were found in 19/23 (83%) patients (four with glomerulocystic kidney disease, GCKD) and diabetes in 11/23 (48%, while three other families had a family history of diabetes. Only 26% of families met diagnostic criteria for maturity-onset diabetes of the young (MODY) but 39% had renal cysts and diabetes (RCAD). We found no clear genotype/phenotype relationships.</AbstractText>We report the largest series to date of HNF-1beta mutations and confirm HNF-1beta mutations as an important cause of renal disease. Despite the original description of HNF-1beta as a MODY gene, a personal/family history of diabetes is often absent and the most common clinical manifestation is renal cysts. Molecular genetic testing for HNF-1beta mutations should be considered in patients with unexplained renal cysts (including GCKD), especially when associated with diabetes, early-onset gout, or uterine abnormalities.</AbstractText>
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2,337,458 |
Impact of homozygosity for an amyloidogenic transthyretin mutation on phenotype and long term outcome.
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Although amyloidogenic transthyretin (ATTR) mutations are common in several populations, such as black Americans, the small number of diagnosed patients homozygous for TTR amyloid and the short follow up in most studies has until now prevented an analysis of their phenotype. In Sweden, nine homozygous patients from eight families carrying the ATTR mutation Val30Met, which gives rise to fatal neuropathic amyloidosis (FAP), have been identified and have now been followed for up to 15 years. This has enabled an analysis of the phenotype of homozygous patients. Genetic testing and detection of amyloid deposits in the vitreous body or in intestinal or skin biopsies confirmed the diagnosis in all patients. The patients' symptoms were obtained from medical records. For comparison, we used a group of 35 heterozygous non-transplanted patients with FAP (18 men and 17 women), who had been evaluated at the Department of Medicine, Umeå University Hospital before their deaths. Vitreous amyloidosis was the most prevalent symptom in the homozygous group, and in two patients it was the only manifestation of the disease during their lifetime. The age at onset was not different from that of heterozygous patients, and their survival tended not to be shorter but actually longer than for heterozygotes. Homozygosity for the mutation associated with FAP, ATTR Val30Met, does not implicate a more severe phenotype for Swedish patients. The most common symptom was vitreous opacity, which may be the only manifestation of the disease. These findings point to the possibilities of different pathways for amyloid formation, or the presence of hitherto unknown genes operating in amyloid formation.
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2,337,459 |
Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data.
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Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH.</AbstractText>We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France.</AbstractText>In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10(-5)), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004).</AbstractText>This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients.</AbstractText>
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2,337,460 |
AVID: an integrative framework for discovering functional relationships among proteins.
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Determining the functions of uncharacterized proteins is one of the most pressing problems in the post-genomic era. Large scale protein-protein interaction assays, global mRNA expression analyses and systematic protein localization studies provide experimental information that can be used for this purpose. The data from such experiments contain many false positives and false negatives, but can be processed using computational methods to provide reliable information about protein-protein relationships and protein function. An outstanding and important goal is to predict detailed functional annotation for all uncharacterized proteins that is reliable enough to effectively guide experiments.</AbstractText>We present AVID, a computational method that uses a multi-stage learning framework to integrate experimental results with sequence information, generating networks reflecting functional similarities among proteins. We illustrate use of the networks by making predictions of detailed Gene Ontology (GO) annotations in three categories: molecular function, biological process, and cellular component. Applied to the yeast Saccharomyces cerevisiae, AVID provides 37,451 pair-wise functional linkages between 4,191 proteins. These relationships are approximately 65-78% accurate, as assessed by cross-validation testing. Assignments of highly detailed functional descriptors to proteins, based on the networks, are estimated to be approximately 67% accurate for GO categories describing molecular function and cellular component and approximately 52% accurate for terms describing biological process. The predictions cover 1,490 proteins with no previous annotation in GO and also assign more detailed functions to many proteins annotated only with less descriptive terms. Predictions made by AVID are largely distinct from those made by other methods. Out of 37,451 predicted pair-wise relationships, the greatest number shared in common with another method is 3,413.</AbstractText>AVID provides three networks reflecting functional associations among proteins. We use these networks to generate new, highly detailed functional predictions for roughly half of the yeast proteome that are reliable enough to drive targeted experimental investigations. The predictions suggest many specific, testable hypotheses. All of the data are available as downloadable files as well as through an interactive website at http://web.mit.edu/biology/keating/AVID. Thus, AVID will be a valuable resource for experimental biologists.</AbstractText>
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2,337,461 |
Genetic analyses in consecutive israeli jewish colorectal cancer patients.
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Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse.</AbstractText>To assess the contribution of E1317Q to CRC development in the Jewish population.</AbstractText>A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined.</AbstractText>The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation.</AbstractText>In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.</AbstractText>
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2,337,462 |
Characterization of complete HIV type 1 genomes from non-B subtype infections in U.S. military personnel.
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Infections with non-B HIV-1 subtypes are rare in the United States, but comprise a significant percentage of infections among U.S. military personnel. Risk behavior while on overseas deployment correlates with non-B infection in this population. Extensive genetic characterization will be required to define HIV-1 diversity, and to effectively evaluate requirements for HIV-1 vaccines and other prevention strategies in this group. From 1997 to 2000, 520 recent seroconverters, identified through routine HIV-1 testing in the U.S. active military force, volunteered for a prospective study. V3 loop serology or partial genome sequencing identified 28 non- B subtype infections; 14 were studied by full genome sequencing and phylogenetic analysis. Five strains were CRF01_AE. Four of these clustered with CM240 from Thailand, and one clustered with African CRF01_AE. Four strains were CRF02_AG, prevalent in West and West Central Africa. Two strains were subtype C. One strain was a unique recombinant between CRF01_AE and subtype B, and another was a complex unique recombinant between subtype A and D. The final strain was a member of a complex circulating recombinant first identified in Senegal, CRF09_cpx, incorporating subtypes A, F, G, and an unclassified genome. This diversity of non-B subtype HIV-1 strains, encompassing three globally prevalent non-B strains and including rare or even possibly unique strains, illustrates the breadth of U.S. military exposure while deployed and sets the bar higher for breadth of cross-subtype protection to be afforded by an HIV-1 vaccine.
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2,337,463 |
Confronting the emergence of drug-resistant HIV type 1: impact of antiretroviral therapy on individual and population resistance.
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Resistance to antiretroviral agents, and in particular the increasing levels of transmitted resistant virus could offset the substantial gains won with potent antiretroviral therapy. Primary and acquired antiretroviral resistance rates reflect the relative usage of different antiretroviral drugs in the population, as well as the inherent genetic barrier to the development of resistance associated with individual drugs. Data on antiretroviral resistance rates, gleaned from the growing HIV-1-infected population treated with a continuously increasing number of antiretroviral drugs and drug combinations, provide insights into patient management approaches for delaying the emergence of resistance and minimizing the degree of resistance. Evolving data suggest that the relative ease by which HIV-1 escapes the selective pressure of chronic drug exposure varies for the different antiretroviral drug classes and individual antiretroviral drugs. The development of resistance in vivo can be anticipated based on these data, in conjunction with the individuals treatment history and resistance testing results. These in turn can guide the judicious use of antiretroviral drugs to attain optimal treatment responses and to preserve therapeutic options for the time when antiretroviral-resistant strains emerge. The recent developments of new antiretroviral drugs, including the use of boosted protease inhibitors, suggest that treatment strategies can limit the development of resistance.
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2,337,464 |
Molecular pathology and clinical characteristics of oligodendroglial neoplasms.
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To evaluate the role of molecular genetics in the routine clinic, we investigated allelic imbalance at 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in 100 oligodendroglial neoplasms diagnosed at a single treatment center between 2000 and 2003. The -1p/-19q genotype, seen in 64, 34, 77, and 30% of OII, OAII, OIII, and OAIII respectively, was inversely related to p53 mutation and 17p13 loss. Genotype was unrelated to tumor location and could not distinguish high-grade tumors that presented de novo from those that progressed from a previous lower grade malignancy. Presentation with seizures was more common in cases with the -1p/-19q genotype, and these remained stable for longer before treatment. In longitudinal samples, 74% retained their initial histological differentiation, whereas 29% showed new genetic alterations, the -1p/-19q genotype being acquired in three cases. Loss of 1p36 and 19q13, 17p13, chromosome 10, and p53 mutation were significantly associated with survival from presentation in Kaplan-Meier analysis (p < 0.01), and loss of 1p36 and 19q13 and loss of 17p13 retained significance in multivariate analysis. In this recently diagnosed unselected series, clinical differences in tumors with and without the -1p/-19q genotype support a genetic approach to aid diagnosis and prognostication for oligodendroglial neoplasms.
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2,337,465 |
Effects of alginate encapsulation on mitochondrial activity.
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The long-term objective of our research is to study the biochemical consequences of primary genetic defects of the Pyruvate Dehydrogenase Complex, a key mitochondrial enzyme complex, by NMR spectroscopy. An established method to obtain energetic and metabolic information from intact cells involves the use of 31P and 13C NMR spectroscopic techniques. NMR spectra from live and fully functional cells can be obtained from cells encapsulated within alginate beads and maintained in a perfusion bioreactor throughout the NMR experiment. However, before spectroscopic studies can commence, the effects of alginate encapsulation on the general metabolism and mitochondrial activity of fibroblasts need to be determined. in this study we report glucose consumption and flow cytometry measurements (with the fluorescent markers MitoTracker GreenFM and Nonyl-acridine Orange to determine the mitochondrial status and mass) of healthy human fibroblasts encapsulated in a mannuronic acid-rich alginate matrix. The results show that alginate encapsulation of fibroblasts does not affect the glucose consumption, the mitochondrial integrity, or the mitochondrial mass during 21 days of in vitro culture.
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2,337,466 |
Cancer as a risk factor for long-term cognitive deficits and dementia.
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Previous studies have shown that cancer survivors frequently experience short-term cognitive deficits, but it is unknown how long these deficits last or whether they worsen over time. Using a co-twin control design, the cognitive function of 702 cancer survivors aged 65 years and older was compared with that of their cancer-free twins. Dementia rates were also compared in 486 of the twin pairs discordant for cancer. Cancer survivors overall, as well as individuals who had survived cancer for 5 or more years before cognitive testing, were more likely than their co-twins to have cognitive dysfunction (odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.36 to 3.24; P<.001; and OR = 2.71, 95% CI = 1.47 to 5.01; P<.001, respectively). Cancer survivors were also twice as likely to be diagnosed with dementia as their co-twins, but this odds ratio did not reach statistical significance (OR = 2.0, 95% CI = 0.86 to 4.67; P = .10). These results suggest that cancer patients are at increased risk for long-term cognitive dysfunction compared with individuals who have never had cancer, even after controlling for the influence of genetic factors and rearing environment.
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2,337,467 |
Cancer risks and mortality in heterozygous ATM mutation carriers.
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Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain.</AbstractText>Cancer incidence and mortality information for 1160 relatives of 169 UK A-T patients (including 247 obligate carriers) was obtained through the National Health Service Central Registry. Relative risks (RRs) of cancer in carriers, allowing for genotype uncertainty, were estimated with a maximum-likelihood approach that used the EM algorithm. Maximum-likelihood estimates of cancer risks associated with three groups of mutations were calculated using the pedigree analysis program MENDEL. All statistical tests were two-sided.</AbstractText>The overall relative risk of breast cancer in carriers was 2.23 (95% confidence interval [CI] = 1.16 to 4.28) compared with the general population but was 4.94 (95% CI = 1.90 to 12.9) in those younger than age 50 years. The relative risk for all cancers other than breast cancer was 2.05 (95% CI = 1.09 to 3.84) in female carriers and 1.23 (95% CI = 0.76 to 2.00) in male carriers. Breast cancer was the only site for which a clear risk increase was seen, although there was some evidence of excess risks of colorectal cancer (RR = 2.54, 95% CI = 1.06 to 6.09) and stomach cancer (RR = 3.39, 95% CI = 0.86 to 13.4). Carriers of mutations predicted to encode a full-length ATM protein had cancer risks similar to those of people carrying truncating mutations.</AbstractText>These results confirm a moderate risk of breast cancer in A-T heterozygotes and give some evidence of an excess risk of other cancers but provide no support for large mutation-specific differences in risk.</AbstractText>
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2,337,468 |
Genomic analysis of Drosophila chromosome underreplication reveals a link between replication control and transcriptional territories.
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In Drosophila polytene chromosomes, most late-replicating regions remain underreplicated. A loss-of-function mutant of the suppressor of underreplication [Su(UR)] gene suppresses underreplication (UR), whereas extra copies of this gene enhance the level and number of regions showing UR. By combining DNA microarray analysis with manipulation of the number of Su(UR) gene copies, we achieved genomic-scale molecular identification of 1,036 genes that are arranged in clusters located in 52 UR chromosomal regions. These regions overlap extensively (96%) but are not completely identical with late-replicating regions of mitotically dividing Kc cells in culture. Reanalysis of published gene expression profiles revealed that genomic regions defined by replication properties include clusters of coordinately expressed genes. Genomic regions that are UR in polytene chromosomes and late replicated in Kc cell chromosomes show a particularly common association with transcriptional territories that are expressed in testis/males but not ovary/females or embryos. An attractive hypothesis for future testing is that factors involved in replication control, such as SU(UR), may interact physically with those involved in epigenetic silencing of transcription territories.
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2,337,469 |
Emerging trends in genetic-based medical diagnostics.
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Prior to the publication of the sequencing of the human genome in April 2003, approximately 1,000 genetic tests were available for monogenetic diseases, i.e., those diseases that emanate from a single gene. The Human Genome Project (HGP) offers the data needed to elucidate the more difficult polygenetic diseases and genetic predisposition to diseases, and help explain variability in drug response. Microarray technology utilizing HGP data has made it possible to survey a person's genome. The applications of this technology include minimizing drug reactions and deriving cancer prognoses. This article will address the role of genetic testing in diagnosing and predicting disease now and in the near future.
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2,337,470 |
Analysis of SNP profiles in patients with major depressive disorder.
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The present study focused on 91 single-nucleotide polymorphisms (SNPs) in 21 candidate genes to find associations with major depressive disorder (MDD). In total, 160 healthy controls and 177 patients with MDD were studied. We applied arrayed primer extension (APEX) based genotyping technology followed by association and haplotype analysis. SNPs in CCKAR, DRD1, DRD2, and HTR2C genes showed nominally significant associations with MDD. None of these associations remained significant after adjustment for multiple testing. Haplotype analysis revealed CCKAR haplotypes to be associated with MDD (global p=0.004). More precisely, we found the GAGT haplotype to be associated with increased risk for MDD (OR 7.42, 95% CI 2.13-25.85, p=0.002). This haplotype effect remained significant after Bonferroni correction (p=0.04 after Bonferroni's adjustment). Altogether we were able to find some nominal associations, but due to small sample size these results should be taken as exploratory. However, the effect of GAGT haplotype on the CCKAR gene may be considered as increasing the risk for MDD.
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2,337,471 |
Longitudinal assessment of PCBs and chlorinated pesticides in pregnant women from Western Canada.
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Maternal exposures to organochlorines prior to pregnancy are considered a risk to neonatal welfare, specifically in relation to neurocognitive functions. There is growing interest in the evaluation of maternal blood testing as a marker for fetal exposure as well as the variable geographic distribution of these priority chemicals.</AbstractText>Three hundred and twenty-three women in the second trimester of pregnancy entered the study at a prenatal clinic providing genetic counselling information. Subjects who had an indication for genetic amniocentesis based on late maternal age were eligible to participate. Two hundred and thirty-eight completed an environmental questionnaire. A sample of amniotic fluid was taken for karyotype analysis in 323 women and blood samples during pregnancy (209), at birth (105) and from the umbilical cord (97) and breast milk (47) were also collected. These samples were tested for 29 PCB congeners and organochlorine pesticides.</AbstractText>The concentrations of PCB 153 in these media were relatively low in relation to other studies. Sigma PCBs measurements in samples taken during the second trimester of pregnancy, at birth and in the umbilical cord were strongly correlated. Specific measurements of PCB 153 and PCB 180 among those subjects with completed sampling of blood samples from mothers and cord samples were significantly correlated. The concentrations of PCBs and pesticides did not differ in relation to prior spontaneous abortion history. There were no organochlorines present in the amniotic fluid at the current level of quantification.</AbstractText>Pregnant women from the Western Canada region of Calgary, Alberta are exposed to relatively low concentrations of organochlorines. Measurement of maternal blood during the second trimester of pregnancy can reliably estimate the fetal exposure to PCBs. This estimate is reliable for Group 2 and 3 PCBs as well as PCB 153 and PCB 180. The amniotic fluid does not contain measurable concentrations of pesticides and PCBs under the conditions of the levels of quantification.</AbstractText>
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2,337,472 |
Experimental evidence for multivariate stabilizing sexual selection.
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Stabilizing selection is a fundamental concept in evolutionary biology. In the presence of a single intermediate optimum phenotype (fitness peak) on the fitness surface, stabilizing selection should cause the population to evolve toward such a peak. This prediction has seldom been tested, particularly for suites of correlated traits. The lack of tests for an evolutionary match between population means and adaptive peaks may be due, at least in part, to problems associated with empirically detecting multivariate stabilizing selection and with testing whether population means are at the peak of multivariate fitness surfaces. Here we show how canonical analysis of the fitness surface, combined with the estimation of confidence regions for stationary points on quadratic response surfaces, may be used to define multivariate stabilizing selection on a suite of traits and to establish whether natural populations reside on the multivariate peak. We manufactured artificial advertisement calls of the male cricket Teleogryllus commodus and played them back to females in laboratory phonotaxis trials to estimate the linear and nonlinear sexual selection that female phonotactic choice imposes on male call structure. Significant nonlinear selection on the major axes of the fitness surface was convex in nature and displayed an intermediate optimum, indicating multivariate stabilizing selection. The mean phenotypes of four independent samples of males, from the same population as the females used in phonotaxis trials, were within the 95% confidence region for the fitness peak. These experiments indicate that stabilizing sexual selection may play an important role in the evolution of male call properties in natural populations of T. commodus.
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2,337,473 |
Parental attitudes and beliefs regarding the genetic testing of children.
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To explore parental attitudes and beliefs about genetic testing of children for conditions that present throughout the life cycle.</AbstractText>Twelve semi-structured focus groups with black and white parents were conducted.</AbstractText>Across racial groups, most respondents want access to genetic testing and believe that parents should be the final decision-makers. While most respondents believe it is important to share genetic information with relatives, white respondents want physicians to respect confidentiality absolutely, whereas some black respondents accept physician disclosures in specific situations.</AbstractText>Professional policy statements are restrictive about access to predictive genetic testing of children. This conflicts with parental attitudes about who should have decisional authority. While there is consensus among respondents that genetic information should be shared with relatives, respondents disagree as to who should be responsible for disclosure, and when professionals should breach patient confidentiality.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,337,474 |
The educational needs and professional roles of Canadian physicians and nurses regarding genetic testing and adult onset hereditary disease.
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To investigate the knowledge, professional involvement and confidence of Canadian nurses and physicians in providing genetic services for adult onset hereditary disease.</AbstractText>1,425 physicians and 1,425 nurses received a mailed questionnaire with reminders. The response rates were 50% (n = 543) and 79% (n = 975), respectively.</AbstractText>Forty-eight percent of physicians and 31% of nurses lacked formal education in genetics. Respondents reported being involved in caring for people at risk for adult onset hereditary disease. Their levels of confidence that they could perform tasks, such as counselling about predictive genetic tests, however, were lower than their levels of expectation that it would be important for them to provide these services.</AbstractText>The expected roles and educational needs of Canadian nurses and physicians have broad areas of overlap suggesting the possibility of combined professional education programs and multiple ways of organizing teams to provide genetic services to people at risk for adult onset hereditary disease.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,337,475 |
Economic evaluation of prenatal population screening for fragile X syndrome.
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This paper models costs and benefits of a population screening programme for pregnant women to detect fragile X syndrome. Given the high lifetime costs of fragile X and the high sensitivity and specificity of testing, such a programme may seem attractive.</AbstractText>Economic evaluation.</AbstractText>Our base case results indicate that such a programme seems close to cost neutral, so may indeed seem attractive for this reason. However, sensitivity analysis shows that assumptions regarding lifetime costs are crucial to results; our results suggest if lifetime costs are under AUD 2.5 million, costs of screening will exceed future costs avoided.</AbstractText>Economic modelling of screening programmes reveals valuable information which might have an influence on the debate on the social value of a population screening programme for fragile X in pregnant women.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,337,476 |
Coeliac disease: is it time for mass screening?
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Screening studies indicate a prevalence of coeliac disease (CD) of up to 1% in populations of European ancestry, yet the majority of cases remain undiagnosed. Serological markers for CD now available have high sensitivity and specificity, offering the option of mass population screening. The principles of disease screening as set out by Wilson and Jugner can be applied to CD to predict whether this is appropriate. CD is an important health problem for the individual and the community because of high prevalence, associated specific and non-specific morbidity, and long-term complications of which the most important are gut malignancy and osteoporosis. However, recent studies indicate that the prevalence of malignancy and the health impact of osteoporosis are much less than previously supposed, so the prophylactic benefits of early diagnosis through screening may be low. While CD has an accepted and effective treatment, dietary gluten exclusion, this is difficult for the individual and asymptomatic cases may be poorly motivated to comply. Diagnosis of CD is by histological confirmation on duodenal biopsy. We now recognise milder degrees of gluten sensitive enteropathy without villous atrophy (Marsh I, II lesions) and the benefits to the individual by identifying these early lesions through screening is unknown: whether to treat such individuals needs to be agreed before programmes commence. Screening with serum antibodies is relatively non-invasive but may have to be repeated during each individual's lifetime. HLA typing beforehand to identify the 30% of the population with DQ2 or DQ8, who are at potential risk of CD, will allow one-off exclusion of a large percentage of the population but like all genetic testing has ethical implications. The economic costs of screening and treatment versus morbidity prevented have not been calculated.
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2,337,477 |
Time to reconsider subcutaneous mastectomy for breast-cancer prevention?
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Genetic testing for women at increased risk of developing breast cancer has moved from the research setting to become part of established clinical practice. By testing for inherited mutations in BRCA1 and BRCA2, we are identifying more and more women who have an 80% or more lifetime risk of developing breast cancer. Since the discovery of BRCA1 in 1994, several clinical studies have led to strategies for reducing the risk of developing breast cancer, including prophylactic mastectomy, prophylactic oophorectomy, and preventive tamoxifen. We believe that in 2005, all prophylactic options, including subcutaneous and total mastectomy should be discussed and made available to women who find themselves unfortunate enough to have inherited a BRCA mutation.
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2,337,478 |
Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations.
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We present five families of paediatric patients suffering from choroid plexus carcinoma in which we found germline TP53 mutations. Only one of the families conformed to the criteria of Li-Fraumeni syndrome and only three (including the Li-Fraumeni syndrome family) met the Chompret criteria for germline TP53 mutation testing. In the remaining two families no family history of cancer was identified and/or the parents of the patient were shown not to carry the mutation. Our results give further support to the notion that the occurrence of this rare paediatric tumour, especially in combination with a positive family history of cancer, but possibly also without any family history, may be an indicator of a germline TP53 mutation. The identification of this genetic defect has important consequences for cancer prevention and treatment in affected families.
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2,337,479 |
Genetics of essential hypertension.
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To inform healthcare providers of the genetics involved in the development of essential hypertension and to illustrate the role the healthcare provider has in the management of patients with essential hypertension.</AbstractText>Research-based articles in the medical literature, selected published literature in refereed journals, and Internet sites.</AbstractText>Essential hypertension is a complex chronic disease that affects many people and has grave implications for the patient. Genetics involved in the development of essential hypertension and treatment choices is evolving; therefore, the healthcare provider must be knowledgeable in these areas to effectively care for patients with hypertension.</AbstractText>Essential hypertension is a chronic disease that affects over 50 million people in the United States. Advances in genetics are allowing scientists to discover the genetic basis of hypertension. With knowledge of genetics and environmental factors involved in the development of essential hypertension, healthcare providers will be able to more effectively screen, manage, and treat individuals with hypertension.</AbstractText>
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2,337,480 |
Ethical decision making in first trimester pregnancy screening.
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Many couples enter pregnancy without an intricate understanding of the potential maternal and fetal/newborn complications. While it is reasonable for expectant couples to consider only the positive outcomes, it is the role of the healthcare professional to educate the parents on the options for fetal screening and testing. Once couples have this information, it is their opportunity to consider the options according to their beliefs and values. In reviewing the principles of ethics, healthcare professionals will gain a better understanding of their role in the couple's decision making. Recommendations are made for maintaining and improving optimal patient care in first trimester pregnancy screening.
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2,337,481 |
The unwitting sacrifice problem.
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The diagnosis of bipolar disorder has been linked to giftedness of various sorts and this raises a special problem in that it is likely that the condition has a genetic basis. Therefore it seems possible that in the near future we will be able to detect and eliminate the gene predisposing to the disorder. This may mean, however, that, as a society, we lose the associated gifts. We might then face a difficult decision either way in that it is unclear that we are preventing an unalloyed bad when we diagnose and eliminate bipolar disorder through prenatal genetic testing and yet if we allow the individual to be born we are condemning that person to being an unwitting sacrifice in that they might well suffer considerable net distress as a result of our need to keep our gene pool enriched in the relevant way.
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2,337,482 |
Real-time PCR methods for monitoring antimalarial drug resistance.
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Drug-resistant Plasmodium falciparum is a challenge to malaria control programs. Policy makers currently depend on in vivo (and, sometimes, in vitro) resistance testing to set treatment guidelines. Molecular markers such as mutations in dhfr, dhps, pfcrt and pfmdr1 represent potential surveillance tools. In this article, we describe newer high-throughput methods for detecting these molecular markers. One method, 5' nuclease real-time polymerase chain reaction, is discussed in detail.
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2,337,483 |
Development of comprehensive functional genomic screens to identify novel mediators of osteoarthritis.
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The aim of this study was to develop high-throughput assays for the analysis of major chondrocyte functions that are important in osteoarthritis (OA) pathogenesis and methods for high-level gene expression and analysis in primary human chondrocytes.</AbstractText>In the first approach, complementary DNA (cDNA) libraries were constructed from OA cartilage RNA and full-length clones were selected. These cDNAs were transferred into a retroviral vector using Gateway Technology. Full-length clones were over-expressed in human articular chondrocytes (HAC) by retroviral-mediated gene transfer. The induction of OA-associated markers, including aggrecanase-1 (Agg-1), matrix metalloproteinase-13 (MMP-13), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), collagen IIA and collagen X was measured by quantitative real-time polymerase chain reaction (QPCR). Induction of a marker gene was verified by independent isolation of 2-3 clones per gene, re-transfection followed by QPCR as well as nucleotide sequencing. In the second approach, whole cDNA libraries were transduced into chondrocytes and screened for chondrocyte cluster formation in three-dimensional agarose cultures.</AbstractText>Using green fluorescent protein (eGFP) as a marker gene, it was shown that the retroviral method has a transduction efficiency of >90%. A total of 40 verified hits were identified in the QPCR screen. The first set of 19 hits coordinately induced iNOS, COX-2, Agg-1 and MMP-13. The most potent of these genes were the tyrosine kinases Axl and Tyro-3, receptor interacting kinase-2 (RIPK2), tumor necrosis factor receptor 1A (TNFR1A), fibroblast growth factor (FGF) and its receptor FGFR, MUS81 endonuclease and Sentrin/SUMO-specific protease 3. The second set of seven hits induced both Agg-1 and MMP-13 but none of the other markers. Five of these seven genes regulate the phosphoinositide-3-kinase pathway. The most potently induced OA marker was iNOS. This marker was induced 20-500 fold by seven genes. Collagen IIA was also induced by seven genes, the most potent being transforming growth factor beta (TGFbeta)-stimulated protein TSC22, vascular endothelial growth factor (VEGF) and splicing factor 3a. This screening assay did not identify inducers of collagen X. The second chondrocyte cluster formation screen identified 14 verified hits. Most of the genes inducing cluster formation were kinases. Additional genes had not been previously known to regulate chondrocyte cluster formation or any other chondrocyte function.</AbstractText>The methods developed in this study can be applied to screen for genes capable of inducing an OA-like phenotype in chondrocytes on a genome-wide scale and identify novel mediators of OA pathogenesis. Thus, coordinated functional genomic approaches can be used to delineate key genes and pathways activated in complex human diseases such as OA.</AbstractText>
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2,337,484 |
[Study on genetic diagnosis and prenatal diagnosis of alpha-thalassemia].
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To develop a single-tube multiplex polymerase chain reaction (mPCR) technique to detect three common deletional alpha-thalassemias (alpha-Thal) in Chinese, and to perform genetic diagnosis and prenatal diagnosis for an alpha-Thal family from Hebei province, China.</AbstractText>Fourty-two blood samples including samples from one alpha-Thal family from Hebei province were assayed. The mPCR containing 7 primers, gel electrophoresis and DNA sequencing were used for the genetic diagnosis and prenatal diagnosis.</AbstractText>The gene types of the fourty-two DNA samples analyzed by the mPCR-gel electrophoresis technique were in accordance with the results by Southern blot and three separate PCR techniques. A HbH child and a fetus of the alpha-Thal family were diagnosed as--(SEA)/alpha(cs)alpha and alpha alpha/alpha alpha respectively by using the mPCR and DNA sequencing. The result of postnatal analysis of the cord blood was consistent with the prenatal result (alpha alpha/alpha alpha).</AbstractText>The developed mPCR technique can be used for genetic diagnosis and prenatal diagnosis of the 3 deletional alpha-Thal in Chinese.</AbstractText>
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2,337,485 |
Recurrent miscarriage.
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Recurrent miscarriage, the occurrence of three consecutive first-trimester losses of pregnancy, affects 1% of women. The purported causes of recurrent miscarriage include chromosomal abnormalities, thrombophilia, metabolic disorders, anatomical causes and immune factors. At present, the only recommended investigations are testing for lupus anticoagulant and anticardiolipin antibody levels (to diagnose antiphospholipid syndrome, an acquired thrombophilia) and the karyotyping of both parents for chromosomal abnormalities. Women with antiphospholipid syndrome should be offered treatment with aspirin and low molecular weight heparin. Couples with chromosomal abnormalities should be referred to a clinical geneticist with whom the options of prenatal diagnosis, pre-implantation genetic diagnosis, donor gametes and adoption in subsequent pregnancies should be discussed. Couples with unexplained recurrent miscarriage should be offered appropriate emotional support and reassurance that they have a good prognosis for future pregnancies.
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2,337,486 |
Considerations when using the significance analysis of microarrays (SAM) algorithm.
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Users of microarray technology typically strive to use universally acceptable data analysis strategies to determine significant expression changes in their experiments. One of the most frequently utilised methods for gene expression data analysis is SAM (significance analysis of microarrays). The impact of selection thresholds, on the output from SAM, may critically alter the conclusion of a study, yet this consideration has not been systematically evaluated in any publication.</AbstractText>We have examined the effect of discrete data selection criteria (qualification criteria for inclusion) and response thresholds (out-put filtering) on the number of significant genes reported by SAM. The use of a reduced data set by applying arbitrary restrictions vis-à-vis abundance calls (e.g. from D-chip) or application of the fold change (FC) option within SAM (named the FC hurdle hereafter), can substantially alter the significant gene list when running SAM in Microsoft Excel. We determined that for a given final FC criteria (e.g. 1.5 fold change) the FC hurdle applied within Microsoft Excel SAM alters the number of reported genes above the final FC criteria. The reason is that the FC hurdle changes the composition of the control data set, such that a different significance level (q-value) is obtained for any given gene. This effect can be so large that it changes subsequent post hoc analysis interpretation, such as ontology overrepresentation analysis.</AbstractText>Our results argue for caution when using SAM. All data sets analysed with SAM could be reanalysed taking into account the potential impact of the use of arbitrary thresholds to trim data sets before significance testing.</AbstractText>
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2,337,487 |
A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia?
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We screened 100 children with acute lymphoblastic leukemia (ALL) to assess the incidence of single amino acid change A91V in perforin. Heterozygous A91V was found in 12/100 patients and 5/127 controls (OR, 3.4; 95%CI: 1.15-9.95; p=0.014). A91V is a novel and frequent predisposing factor for childhood ALL.
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2,337,488 |
Molecular genotyping of the Italian cohort of patients with hemophilia B.
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The aim of the study, funded by the Italian Ministry of Health, was to identify the causative mutation in all known patients with hemophilia B in Italy.</AbstractText>Overall, 269 patients followed by 25 regional centers were considered in the study; after exclusion of the related individuals, 238 unrelated patients were analyzed (153 with severe, 59 with moderate and 26 with mild hemophilia B). Screening of the factor IX gene was performed using conformation sensitive gel electrophoresis (CSGE) followed by denaturing high performance liquid chromatography (dHPLC) or direct sequencing in negative cases, or by dHPLC/sequencing (36 cases).</AbstractText>A mutation was identified in 236 of the 238 patients: 6 had large gene deletions (4 total and 2 partial), 14 small deletions, 1 combined deletion/insertion and 215 single nucleotide substitutions. A correlation was observed between the type of mutation and severity of hemophilia; however, a number of patients with the same genotype had varying severities of the disease. Eight of the 169 patients with severe hemophilia B (4.7%) developed inhibitors: 2 of these had a complete gene deletion, 1 had a large partial deletion (from exon A to part of exon H) while 5 had 3 different nonsense mutations. One patient with a nonsense mutation developed anaphylaxis. We also studied 65 families with hemophilia B involving 144 females (14 obligatory carriers, 85 carriers and 45 non-carriers) and performed 12 antenatal diagnoses.</AbstractText>The data have been used to build the Italian mutation database to provide each family with knowledge of the disease-causing defect for genetic counseling. This Italian study confirms the marked heterogeneity of factor IX mutations in the population and the presence of a degree of genotype/phenotype discordance. The identification of the mutation can also be used to predict risk of inhibitor development.</AbstractText>
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2,337,489 |
Two new delta-globin mutations: Hb A2-Ninive [delta133(H11)Val-Ala] and a delta(+)-thalassemia mutation [-31 (A --> G)] in the TATA box of the delta-globin gene.
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Two new delta-globin gene mutations have been detected: one leads to a fairly stable Hb A2 variant differing electrophoretically only minimally from normal Hb A2, and the second causes a delta(+)-thalassemia (thal) phenotype.
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2,337,490 |
Rapid iterative negative geotaxis (RING): a new method for assessing age-related locomotor decline in Drosophila.
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Age-related behavioral declines are common manifestations of aging in animals. Negative geotaxis, an innate escape response during which flies ascend the wall of a cylinder after being tapped to its bottom, is one of the behaviors that senesces in Drosophila. Many laboratories, including ours, have used a variety of negative geotaxis assays based on the performance of single flies. To circumvent limitations of single-fly assays, we developed a new method for assessing negative geotaxis called rapid iterative negative geotaxis (RING). In RING assays, digital photography is used to document negative geotaxis in multiple groups of animals simultaneously. We show that performance in RING assays is not influenced by the density of flies being tested, the time of day, or repeated testing. We used the RING assay to demonstrate that negative geotaxis declines with the age of animals as previously shown in single fly studies and that senescence of negative geotaxis is sensitive to genetic background. Finally, we used RING assays to show that long-lived Indy and chico mutants exhibit delayed senescence of negative geotaxis. Our results demonstrate that RING is a powerful method for assessing negative geotaxis that should facilitate the search for manipulations that influence behavioral aging in Drosophila.
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2,337,491 |
[Pulmonary hypertension: pathophysiology, genetics and functional genomics].
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Novel discoveries of the genetic basis of pulmonary hypertension have recently inspired a whole new area of research in pulmonary medicine. The finding that germ-line mutations in the BMPR2 locus, encoding a transmembrane receptor of the TGF beta superfamily, are the cause for familial and partly idiopathic pulmonary arterial hypertension has provided new clues for our understanding of this complex, yet highly localized disease. The TGF beta superfamily comprises more than 40 different growth and differentiation factors essential in the control of proliferation and differentiation of most cell types. In this review, we summarize the novel genetic and functional genomic findings to provide an outlook for the understanding of this disease.
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2,337,492 |
Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788-3790del mutation.
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Fanconi anemia (FA) is an autosomal recessive genetic disease characterized by progressive bone marrow failure, susceptibility to cancer and multiple congenital anomalies. There is important clinical variability among patients and the knowledge of factors which might predict outcome would greatly help the decision making regarding the choices of treatment and the appropriate time to start it. Future studies of the possible correlation between specific mutations with specific clinical presentations will provide the answer to one of these factors. At our Center we standardized a rapid and precise screening test using a mismatch PCR assay for a specific mutation (3788-3790del in exon 38 of gene FANCA) in Brazilian FA patients. We present the results obtained after screening 80 non-consanguineous FA patients referred from all regions of Brazil with a clinical diagnosis of FA supported by cellular hypersensitivity to diepoxybutane. We were able to detect the 3788-3790del allele in 24 of the 80 (30%) FA patients studied. Thirteen of the 80 (16.25%) were homozygotes and 11 of the 80 (13.75%) were compound heterozygotes, thus confirming the high frequency of the FANCA 3788-3790del mutation in Brazilian FA patients. The identification of patients with specific mutations in the FA genes may lead to a better clinical description of this condition, also providing data for genotype-phenotype correlations, to a better understanding of the interaction of this specific mutation with other mutations in compound heterozygote patients, and ultimately to the right choices of treatment for each patient with improvement of the prognosis on future studies.
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2,337,493 |
Phenotypic and molecular characterization of Mycobacterium tuberculosis isolates resistant to both isoniazid and ethambutol.
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In performing radiometric susceptibility testing on over 2,000 patient isolates of Mycobacterium tuberculosis during the past 6 years, we found that resistance to 7.5 microg/ml ethambutol (EMB) occurred only in isolates that are also resistant to 0.4 microg/ml isoniazid (INH). Using 157 selected isolates in the present study, we performed radiometric and agar proportion susceptibility tests and DNA sequencing of genetic regions associated with resistance to these two drugs. The goal was to study the occurrence of the common mutations associated with resistance to each drug and also to determine whether any particular INH-resistance-associated mutation occurred more often in combination with any particular EMB-resistance-associated mutation. In an analysis of 128 isolates resistant to 0.4 microg/ml INH, we found that a mutation at katG Ser315 was more common in isolates also resistant to 7.5 microg/ml EMB (61 of 67=91.0%) than in isolates either susceptible to EMB or resistant to 2.5 microg/ml EMB (39 of 60=65.0%). These observations suggest that INH-resistant strains with a mutation at katG Ser315 are more likely to acquire resistance to 7.5 microg/ml EMB than are isolates with INH-resistance-associated mutations at other sites. In addition, we found that 64 of 67 (95.5%) isolates resistant to 7.5 microg/ml EMB contained a mutation in either codon 306 or codon 406 of embB. Met306Val was the most common embB mutation, present in 52 (77.6%) of the 67 isolates. Most occurrences of this mutation (49 of 52=94.2%) were found in isolates that also contained the katG Ser315Thr mutation. Finally, sequencing this region of embB appears to be sufficiently sensitive for use as a rapid screening tool for detection of high-level resistance to EMB.
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2,337,494 |
Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?
|
Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and response to eight different antimalarial drugs. However, the consistent association observed between a 3-bp indel in G7 and AS response merits further investigation.
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2,337,495 |
Human p53 knock-in (hupki) mice do not differ in liver tumor response from their counterparts with murine p53.
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Mouse models are important tools in toxicologic research. Differences between species in pathways contributing to tumor development, however, raise the question in how far mouse models are valid for human risk assessment. One striking difference relates to the frequency of spontaneous liver cancer which is high in certain mouse strains but rather low in humans. Similarly, mutation frequencies in cancer genes are characteristically different, i.e. P53 mutations are frequent in human but very rare in murine liver tumors, whereas Ras genes are often mutated in mouse liver tumors but hardly ever in human liver cancers. Since P53 has been shown to control oncogenic RAS in human cells, we hypothesized that this function of the tumor suppressor could differ in mouse hepatocytes. To test this hypothesis, we used hupki (human p53 knock-in) mice which carry a partly humanized P53 sequence (P53KI). In this study, we report the results of the first hepatocarcinogenesis experiment with this strain of mice. Mice of the genotypes P53KI/KI, P53WT/KI and P53WT/WT were treated with N-nitrosodiethylamine at 2 weeks of age and killed 35 weeks later. The frequency of liver tumors and glucose-6-phosphatase-altered liver lesions was almost identical in all three P53 genotypes and approximately 40-50% of liver tumors showed activating mutations in codon 61 of the Ha-Ras gene independent of genotype. Moreover, only very few P53-positive lesions were observed but without nuclear localization of the protein, suggesting the absence of P53 mutations. These data suggest that the hupki allele behaves like its murine ortholog in mouse hepatocarcinogenesis.
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2,337,496 |
Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer's disease.
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Linkage studies suggest the presence of putative risk and/or age-at-onset genes for Alzheimer's disease on Chromosome 10. Recently, a genomic converging approach using a combination of linkage, expression and association studies has reported significant associations of the glutathione S-transferase omega 1 and 2 (GSTO1 and GSTO2) genes and possibly the protease serine 11 (PRSS11) gene on chromosome 10 with age-at-onset, but not risk, for Alzheimer's disease (AD) and Parkinson disease. We investigated the association of the reported three polymorphisms in 990 sporadic late-onset AD cases (26% autopsy confirmed) and 735 controls. In our sample, we found no association either with age-at-onset in AD cases or with disease risk in the case-control cohort. However, haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). Additional markers in these genes need to be screened to explore their role in the etiology of AD.
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2,337,497 |
Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease.
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Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.
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2,337,498 |
Genetic susceptibility to simple febrile seizures: interleukin-1beta promoter polymorphisms are associated with sporadic cases.
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Febrile seizures (FSs) are the commonest form of convulsions. A genetic predisposition to FSs is known, based on family studies, twin studies, and complex segregation analysis. Simple FSs may be more homogenous in their clinical manifestations, and show better agreement with the multifactorial inheritance theory than the complex type. Interleukin-1 (IL-1) beta is one of the pro-inflammatory cytokines that are postulated to be involved in the development of FSs. To determine whether or not function-related polymorphisms of the IL-1beta (IL1B) gene are associated with susceptibility to simple FSs, the genotypes for two biallelic polymorphisms in the promoter region at positions -31 and -511 of the IL1B gene were determined by means of PCR-restriction fragment length polymorphism in 229 FS patients (108 sporadic and 60 familial simple FS, and 61 complex FS patients) and 158 controls. IL1B -31C/T, a TATA box polymorphism, has been found to be in complete linkage disequilibrium with the IL1B -511C/T polymorphism. Sporadic simple FS patients exhibited significantly higher frequencies of IL1B -31C/-511T alleles and homozygotes than controls (uncorrected p = 0.0094 and 0.0029, corrected p = 0.038 and 0.035, respectively), while no differences were observed in patients with all or familial simple FSs versus controls. There were no significant differences in the frequencies of -31C/T and -511C/T in the IL-1beta promoter gene between complex FS patients and controls. The present study suggests that the IL-1beta gene contributes to a genetic susceptibility to the development of simple FSs of sporadic occurrence.
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2,337,499 |
Sample genetic policy language for research conducted with native communities.
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[corrected] We have been repeatedly asked to clarify genetic issues that have cultural ramifications for Native communities.</AbstractText>In the following commentary, we explain selected genetic issues that may vary among tribal nations; nonetheless, scientists should allocate sufficient time to meet with the tribal leaders and/or members of the tribal institutional review board prior to designing a genetic study to learn how selected issues are perceived by that specific tribal nation.</AbstractText>Tribal nations generally encourage and mandate community-based participatory research methodology.</AbstractText>We have included in this commentary draft language for study protocols to support researchers and tribal nations when developing studies pertaining to genetic issues.</AbstractText>
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