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2,337,900 |
Identification of two novel genes for blackleg resistance in Brassica napus.
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Blackleg, caused by Leptosphaeria maculans, is a major disease of Brassica napus. Two populations of B. napus DH lines, DHP95 and DHP96, with resistance introgressed from B. rapa subsp. sylvestris, were genetically mapped for resistance to blackleg disease with restriction fragment length polymorphism markers. Examination of the DHP95 population indicated that a locus on linkage group N2, named LepR1, was associated with blackleg resistance. In the DHP96 population, a second locus on linkage group N10, designated LepR2, was associated with resistance. We developed BC1 and F2 populations, to study the inheritance of resistance controlled by the genes. Genetic analysis indicated that LepR1 was a dominant nuclear allele, while LepR2 was an incompletely dominant nuclear resistance allele. LepR1 and LepR2 cotyledon resistance was further evaluated by testing 30 isolates from Canada, Australia, Europe, and Mexico. The isolates were from B. napus, B. juncea, and B. oleracea and represented different pathogenicity groups of L. maculans. Results indicated that LepR1 generally conferred a higher level of cotyledon resistance than LepR2. Both genes exhibited race-specific interactions with pathogen isolates; virulence on LepR1 was observed with one isolate, pl87-41, and two isolates, Lifolle 5, and Lifolle 6, were virulent on LepR2. LepR1 prevented hyphal penetration, while LepR2 reduced hyphal growth and inhibited sporulation. Callose deposition was associated with resistance for both loci.
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2,337,901 |
Unsuspected Klinefelter syndrome diagnosed during oncologic evaluation: a case series.
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Klinefelter syndrome is an underdiagnosed chromosomal disorder that has significant implications for health and for medical management. This report presents 5 adult male patients diagnosed with previously unsuspected Klinefelter syndrome as a result of cytogenetic testing for suspected hematologic malignancies. This case series highlights the importance of maintaining a comprehensive and holistic approach to medical care. The medical, genetic, and psychosocial implications of the Klinefelter diagnosis are discussed.
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2,337,902 |
Developing the use of mismatch binding proteins for discovering rare somatic mutations.
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A method for detecting rare, unknown, somatic mutations could allow presymptomatic cancer screening from human fluids. Immobilized mismatch binding protein can bind DNA heteroduplexes while allowing homoduplexes to be washed away, thus enriching for rare mutations. We examined the potential use, for mutation enrichment, of a fusion protein of maltose binding protein and the mismatch binding protein TaqMutS (MBP-MutS). Unlabeled and fluorescent-labeled oligonucleotides, either perfectly complementary or with single nucleotide mismatches or deletions, were combined to form homo- or heteroduplexes that were then mixed at low ratios of hetero- to homoduplexes and enriched for heteroduplexes. Enrichment was observed using a capillary DNA sequencer. A single base deletion oligonucleotide was enriched by a factor of 29, and a mismatch oligonucleotide was enriched by a factor of 2. N-1 oligonucleotide synthesis fragments were enriched more than were mismatches, suggesting that these deletion fragments may compete for MutS and impede enrichment of mismatches. Purification of oligonucleotides by high pressure liquid chromatography or polyacrylamide gel electrophoresis failed to remove n-1 fragments, thus overcoming this obstacle to enrichment of mismatch mutations may require alternative strategies, such as developing new purification methods or avoiding the use of synthetic oligonucleotides before enrichment.
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2,337,903 |
A novel optical biosensor format for the detection of clinically relevant TP53 mutations.
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The TP53 gene has been the subject of intense research since the realisation that inactivation of this gene is common to most cancer types. Numerous publications have linked TP53 mutations in general or at specific locations to patient prognosis and therapy response. The findings of many studies using general approaches such as immunohistochemistry or sequencing are contradictory. However, the detection of specific mutations, especially those occurring in the structurally important L2 and L3 zinc binding domains, which are the most common sites of TP53 mutations, have been linked to patient prognosis and more strongly to radiotherapy and chemotherapy resistance in several major cancers. In this study, the TI-SPR-1 surface plasmon resonance system and Texas Instruments Spreeta chips were used to develop a DNA biosensor based on thiolated probes complementary to these domains. The sensors were able to detect these mutations in both oligonucleotides and PCR products with normal and mutant TP53 DNA, but the difference in hybridisation signal was small. Preliminary experiments to enhance the signal using Escherichia coli mismatch repair proteins, MutS and single strand binding protein were carried out. It was found that MutS was unable to bind to mismatch oligonucleotides, but single strand binding protein was able to bind to single stranded probes, which had not hybridised to the target, resulting in a three-fold increase in the sensitivity of the biosensor. While further work needs to be carried out to optimise the system, these preliminary experiments indicate that the TI-SPR-1 can be used for the detection of clinically relevant mutations in the TP53 gene and that the sensitivity can be increased significantly using single strand binding protein. This system has a number of advantages over current mutation detection technologies, including lower cost, ease of sensor preparation and measurement procedures, technical simplicity and increased speed due to the lack of need for gel electrophoresis.
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2,337,904 |
Sampling strategies for detecting rare impurities: an application in gene therapy products.
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Detection of rare impurities in drug products presents special challenges. Replication competent adenovirus (RCA) is a rare impurity found in adenovirus-based gene therapy products. Various methods are used for detection of RCAs. We primarily focus on qualitative assays. Acceptance sampling plans for detecting RCAs in batches of gene therapy products are discussed. Assuming that the number of RCA units per patient dose follows a Poisson distribution, operating characteristics (OC) of these sampling plans can be studied. The OC curves display the acceptance probabilities for batches with specific true but unknown level of RCA and can be used to assess the specificity and sensitivity of the test strategies. Application of Bayesian methodologies in the assessment of RCA levels in drug batches is also discussed. Using observed data and prior belief, a 95% credible region for the number of RCA units per patient dose can be constructed. Both classical and Bayesian calculations display the impact of sample size, sampling fraction, and assay quality on the detection of RCA. For better sensitivity, the largest possible sampling fraction that does not interfere with the logistics and the performance of the assay should be used. The choice of sample size will depend on the upper limit of the biologically safe level of RCA, the testing strategy, the desired level of sensitivity and specificity, and also on practical issues.
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2,337,905 |
A paternally inherited duplication in the Prader-Willi/Angelman syndrome critical region: a case and family study.
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The Prader-Willi/Angelman Critical Region (PWACR; Chromosome 15q11-13) is of interest as a potential locus for genes conferring susceptibility to autism spectrum disorders (ASD). This report describes a female proband referred for evaluation of a possible ASD. Genetic analyses indicated that the proband, her father and one of her sisters, carried a paternally derived interstitial duplication involving 15q11-13. The proband showed evidence of ASD (PDD-NOS), borderline mental retardation, mild hypotonia and joint laxity. Her father and her sister were of normal intelligence and neither was thought to have an ASD, although speech/language difficulties and some autistic type behaviours were reported to have been present early in the development of the sister. This is one of the first reports of a child with a paternal duplication and an autism spectrum disorder. More research is required to determine whether paternally derived duplications that involve 15q11-13 are associated with developmental impairments.
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2,337,906 |
Physicians and genetic malpractice.
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Primary care physicians are unprepared for the increase in demands for prenatal genetic testing. Often, they do not possess the necessary knowledge, skills or attitudes to provide genetic counselling. Yet, since the demand for prenatal genetic services is growing faster than the number of genetic professionals, the responsibility of genetic counselling will fall to these physicians. Physicians who lack genetic literacy may find themselves the targets of lawsuits for wrongful birth and wrongful life. Wrongful birth and wrongful life claims (in the context of genetics) both assert that but for the physician's negligence, the handicapped child would not have been born. Such medical malpractice suits against physicians exist in the United States, the United Kingdom, Canada and Australia. This paper discusses the case law on wrongful birth/life cases in these four countries. The authors conclude that as the number and availability of prenatal genetic tests increases, so too will the number of genetic malpractice claims, unless the education of physicians and medical students in genetics is promoted, possibly with the Internet as the new educational paradigm.
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2,337,907 |
Molecular genetic confirmatory testing from newborn screening samples for the common African-American, Asian Indian, Southeast Asian, and Chinese beta-thalassemia mutations.
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beta-Thalassemia is a serious health problem in the United States, especially in California, due to increased Asian immigration. Neonatal screening by using high-performance liquid chromatography (HPLC) or isoelectric focusing (IEF) may lead to confusion due to interactions of various hemoglobinopathies with beta-thalassemia. Our purpose was to develop single-tube multiplexed PCR assays using original neonatal screening specimens to identify the mutations responsible for beta-thalassemia in order to expedite diagnostic confirmation. Primers were designed for two to six common ethnic-specific mutations using the amplification refractory mutation system (ARMS). This multiplex ARMS approach was standardized using DNA samples with known mutations for beta-thalassemia in those of Asian (Southeast Asian, Chinese, and Asian Indian) and African-American descent. Specimens from African-American neonates were tested for two mutations (-88 and -29); Asian Indians for five mutations (IVSI-1, IVSI-5, codons (Cd) 41/42, Cd 8/9, and 619-bp deletion); Chinese, Taiwanese, and Southeast Asians for seven mutations (Cd 41/42, Cd 17, -28, IVSII-654, Cd 71/72, IVSI-5, and IVSI-1). We identified each of these beta-thalassemia mutations in multiplexed ARMS from positive control samples. We tested 25 anonymized dried blood specimens from neonates who had been diagnosed with beta-thalassemia and who also belonged to these ethnic groups. We detected a mutation specific to the neonate's ethnic group using the ARMS approach in nearly all specimens, and the results were confirmed by sequencing. Multiplexed ARMS for ethnic-specific beta-thalassemia mutations from the original newborn screening dried blood specimens is a rapid and efficient approach for diagnostic confirmation.
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2,337,908 |
Ophthalmoplegia due to mitochondrial DNA disease: the need for genetic diagnosis.
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We describe a patient with chronic progressive external ophthalmoplegia (CPEO) who underwent muscle biopsy for suspected mitochondrial disease. In spite of normal histocytochemical cytochrome c oxidase (COX) activity and respiratory chain enzyme measurements in muscle, subsequent molecular genetic analysis revealed the presence of a single, large-scale deletion of mitochondrial DNA (mtDNA). The case serves to illustrate the importance of pursuing the proposed mitochondrial genetic abnormality, even in patients with normal biopsy findings.
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2,337,909 |
On the theoretical and empirical framework for studying genetic interactions within and among species.
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We present a quantitative genetic (QG) interpretation of the Bateson-Dobzhansky-Muller (BDM) genetic model of speciation in order to unify the theoretical framework for understanding how the genetic differentiation of populations is associated with the process of speciation. Specifically, we compare the QG theory of joint scaling with the Turelli-Orr mathematical formulation of the BDM model. By formally linking the two models, we show that a wealth of empirical methods from QG can be brought to bear on the study of the genetic architecture of hybrid phenotypes to better understand the connections, if any, between microevolution within populations and macroevolution in the origin of species. By integrating the two theories, we make additional novel predictions that enrich the opportunities for empirically testing speciation genetic theory or facets of it, such as Haldane's rule. We show that the connection between the two theories is simple and straightforward for autosomal genes but not for sex-linked genes. Differences between the two approaches highlight key conceptual issues concerning the relevance of epistasis to evolution within and among lineages and to differences in the process of speciation in hermaphrodites and in organisms with separate sexes.
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2,337,910 |
Genetic polymorphism of CYP2C9 in a Vietnamese Kinh population.
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Cytochrome P450 2C9 (CYP2C9) shows genetic polymorphism with high interethnic variation, but no report has addressed the genetic polymorphism in the Vietnamese population. In the present study, the distribution of 2 common allelic variations of CYP2C9 was investigated in Vietnamese Kinh population, a major ethnic group in Vietnam. Genomic DNA from 157 Vietnamese subjects was amplified by polymerase chain reaction, and the presence of CYP2C9*2 and CYP2C9*3 allelic variants was determined by pyrosequencing. Among 157 Vietnamese subjects, no subject with the CYP2C9*2 allele was detected, but 7 subjects were heterozygous for the CYP2C9*3 allele. The allele frequency of CYP2C9*3 was 2.2% in the Vietnamese Kinh population. This genotype distribution was well correlated with previous reports suggesting no occurrence of CYP2C9*2 in Asians. These results suggest that CYP2C9*2 may be absent in Vietnamese Kinh population and that CYP2C9*3 is major allelic variant that causes interindividual variation of drug responses to CYP2C9 substrate drugs in the Vietnamese Kinh population.
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2,337,911 |
gammaAla82Gly represents a common fibrinogen gamma-chain variant in Caucasians.
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Screening of 200 blood donors for the presence of polymorphisms in three fibrinogen genes (FGA, FGB, FGG), revealed two individuals with a heterozygous missense mutation (c.323C > G, gammaAla82Gly) in the FGG gene. This mutation has been reported previously to cause mild hypofibrinogenaemia. Analysis of an additional 416 blood donors showed two more heterozygous gammaAla82Gly mutations, resulting in an overall gammaAla82Gly allele frequency of 0.0032. Haplotype analysis demonstrated that the gammaAla82Gly mutation originated from a common founder. From these data we estimated that homozygous individuals for gammaAla82Gly should occur at a frequency of 1: 95 000, suggesting that hypofibrinogenaemia represents a more frequent condition in the population than so far believed.
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2,337,912 |
Manifestation, management and molecular analysis of candidate genes in two rare cases of thyrotoxic hypokalemic periodic paralysis.
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Hypokalemic periodic paralysis as a complication of thyrotoxicosis (THypoKPP) is common in Asians but not well recognized in Western countries or pediatric patients, where most cases are due to the familial variant (FHypoKPP). Ion channel gene mutations may underlie these diseases. We describe the first pediatric and a rare adult Caucasian case of THypoKPP in Finland.</AbstractText>Manifestation and management of two THypoKPP cases. We studied for possible mutations in KCNE3, KCNJ2, SCN4A and CACNA1S genes.</AbstractText>A 15-year-old Vietnamese boy presented with sudden-onset paralysis and severe hypokalemia, 1.8 mmol/l. The case was first regarded as FHypoKPP, but thyroid function testing revealed a suppressed TSH and highly elevated FT4. A 37-year-old Caucasian male presented with acute tetraparesis. His plasma potassium was only 1.4 mmol/l. Treatment with carbimazole had been initiated two weeks earlier, but FT4 was still elevated. No mutations in KCNE3, KCNJ2, SCN4A or CACNA1S genes were detected.</AbstractText>THypoKPP is a potentially life-threatening condition which bares many similarities with FHypoKPP. THypoKPP is rare in Western countries but should be considered in sudden-onset paralysis, independently of age and especially in males. Mutations in ion channel candidate genes did not underlie the disease in the present cases.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,337,913 |
Specific detection of the PVY(N)-W variant of Potato virus Y.
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PVY(N)-W is one of the variant populations of Potato virus Y (PVY). This variant is of concern in seed potato production and requires a specific diagnosis since it induces more or less symptomless infections and is not detectable easily in field inspections. Moreover, this variant is serologically indistinguishable from the common strain PVY(O). This study describes a simple and specific molecular detection test for the PVY(N)-W variant using a PCR protocol based on the recombinant point within the HC-Pro/P3 region of PVY(N) variants (PVY(NTN), PVY(N)-W). To avoid both detection of recombinant PVY(NTN) and PVY(N)-W isolates, a forward PVY(N)-like primer located in the HC-Pro region coupled to a reverse PVY(O)-like primer located in the NIa region was designed to amplify a specific PCR product of 4114 nt from PVY(N)-W isolates. This technique was assessed on 41 PVY reference and field isolates. Only isolates referenced as PVY(N)-W were amplified and gave the expected PCR product of 4114 nt, whereas no band was obtained from PVY(N), PVY(NTN) or PVY(O) isolates. In conclusion, this PVY(N)-W diagnosis tool is rapid, easy-to-use and suitable for large-scale testing in laboratories of seed potato certification.
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2,337,914 |
Type I spinal muscular atrophy can mimic sensory-motor axonal neuropathy.
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Spinal muscular atrophy is a group of allelic autosomal recessive disorders characterized by progressive motoneuron loss, symmetric weakness, and skeletal muscle atrophy. It is traditionally considered a pure lower motoneuron disorder, for which a current definitive diagnosis is now possible by molecular genetic testing. We report two newborns with a clinical phenotype consistent with that of spinal muscular atrophy type I and nerve conduction studies and electromyography suggesting more extensive sensory involvement than classically described with spinal muscular atrophy. Molecular testing confirmed spinal muscular atrophy in patient 1 but not in patient 2. Thus, in the setting of a suspected congenital axonal neuropathy, molecular testing might be necessary to distinguish spinal muscular atrophy type I from infantile polyneuropathy.
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2,337,915 |
Screening differentially expressed genes in mouse hepatocarcinoma ascites cell line with high potential of lymphatic metastasis.
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To screen genes differentially expressed in mouse hepatocarcinoma ascites cell line with high potential of lymphatic metastasis.</AbstractText>A subtracted cDNA library of mouse hepatocarcinoma cell line with high potential of lymphatic metastatic Hca-F and its synogenetic cell line Hca-P with a low metastatic potential was constructed by suppression subtracted hybridization(SSH) method. The screened clones of the subtracted library were sequenced and GeneBank homology search was performed.</AbstractText>Fourteen differentially expressed cDNA fragments of Hca-F were obtained with two novel genes.</AbstractText>SSH is a useful technique to detect differentially expressioned genes and an effective method to clone novel genes.</AbstractText>
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2,337,916 |
[Screening 21-hydroxylase deficiency carriers in androgen excess women of Chinese Han nationality].
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To gain a primary understanding of the prevalence of 21-hydroxylase deficiency(21-OHD) heterozygote (carrier) among androgen excess women of Chinese Han nationality, compare the molecular genetic changes therein revealed with the results of adrenocorticotropic hormone (ACTH) stimulating test, and assess the carriers' phenotype-genotype correlation.</AbstractText>Eighty-two androgen excess cases and 14 healthy women underwent ACTH stimulating test during the follicular phase. Molecular genetic analysis of CYP21 for 9 common mutations was performed with the method of amplification-created restriction sites.</AbstractText>In androgen excess group, the basal level of F0 (P<0.01), as well as basal 17-OHP0 and the ACTH stimulated concentrations of 17-OHP60 were much higher than controls (P<0.01), and there was no obvious discrepancy in F60 (P>0.05). The net increase of 17-OHP and the ratio of net increase of 17-OHP to net increase of F were also higher than controls (P<0.01). No CYP21 gene mutations were found in control group. Four patients of the androgen excess group were identified as heterozygous carriers of CYP21 mutations. The ACTH stimulating test results from gene normal patients and from carriers overlapped to a certain extent.</AbstractText>Among 82 patients of Chinese Han nationality androgen excess women, 4.9% were 21-OHD heterozygous. The response of serum 17-OHP is not useful for predicting CYP21 gene mutation carrier status. Genotyping is the most reliable method to detect carrier.</AbstractText>
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2,337,917 |
[Genetic polymorphisms of fifteen short tandem repeat loci in Chengdu Han population].
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To acquire the population genetic data of fifteen short tandem repeat (STR) loci in Chengdu Han population.</AbstractText>A total of 210 EDTA-blood specimens were collected from the unrelated individuals in Chengdu Han population. The DNA samples were extracted with Chelex method and amplified by multiplex PCR technique. The PCR products were analyzed by an automatic genetic analyzer; the relative fragment's lengths of PCR products were calculated by gene scan analysis software and afterward genotyped by genotype software.</AbstractText>Fifteen STR loci of the 210 samples showed a successful result of genotyping. The heterozygosities of the fifteen STR loci in Chengdu Han population were found to be 0.529-0.881; the combined exclusion probability and discrimination power for the fifteen STR loci in Chengdu Han population were determined to be 0.999998 and 7.3 x 10 (-17); respectively.</AbstractText>The distinct genotype of fifteen STR loci and the sex of sample could be unveiled just through PCR and electrophoresis once, and a higher measured value could be obtained for both the combined discrimination power and the exclusion probability; the fifteen STR loci can meet the needs of the parentage testing and personal identification in forensic medicine.</AbstractText>
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2,337,918 |
Genetic testing for germline mutations of the APC gene in patients with apparently sporadic desmoid tumors but a family history of colorectal carcinoma.
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Desmoid tumors, also known as aggressive fibromatosis, occur with an incidence of 10 to 15 percent in patients affected by familial adenomatous polyposis, an autosomal inherited disease caused by germline mutations in the APC gene. However, sporadic forms with no hereditary background exist. The aim of this study was to find out whether there are APC germline mutations in apparently sporadic desmoid tumor patients without clinical or familial signs of familial adenomatous polyposis but with a family history of colorectal carcinoma in at least one family member.</AbstractText>Genomic DNA and mRNA were isolated from peripheral blood leukocytes of index patients of eight nonrelated families. Mutation screening was performed using reverse transcriptase polymerase chain reaction-based protein truncation test for APC exons 1-14. The large APC exon 15 was scrutinized by the protein truncation test of four overlapping genomic fragments. Additionally, genomic DNA from five desmoid tumors was analyzed for loss of heterozygosity at D5S346 close to the APC locus.</AbstractText>No translational stop mutations typical for familial adenomatous polyposis could be found in the APC gene in any of the analyzed blood samples from the desmoid tumor patients. Additionally, no loss of heterozygosity at D5S346 was found in four of five desmoids; one tumor was not informative.</AbstractText>These results may suggest that patients with sporadic desmoids and no clinical signs of familial adenomatous polyposis detected on careful examination, esophagogastroduodenoscopy, and complete colonoscopy do not need to be tested routinely for germline mutations of the APC gene. However, as large studies dealing with this problem are absent, it might be more time and cost effective to perform an APC mutational analysis instead.</AbstractText>
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2,337,919 |
Expression of PHA polymerase genes of Pseudomonas putida in Escherichia coli and its effect on PHA formation.
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Poly-3-hydroxyalkanoates (PHAs) are synthesized by many bacteria as intracellular storage material. The final step in PHA biosynthesis is catalyzed by two PHA polymerases (phaC) in Pseudomonas putida. The expression of these two phaC genes (phaC1 and phaC2)was studied in Escherichia coli, either under control of the native promoter or under control of an external promoter. It was found that the two phaC genes are not expressed in E. coli without an external promoter. During heterologous expression of phaC from Plac on a high copy number plasmid, a rapid reduction of the number of colony forming units was observed, especially for phaC2. It appears that the plasmid instability was partially caused by high-level production of PHA polymerase. Subsequently, tightly regulated phaC2 expression systems on a low copy number vector were applied in E. coli. This resulted in PHA yields of over 20 of total cell dry weight, which was 2 fold higher than that obtained from the system where phaC2 is present on a high copy number vector. In addition, the PHA monomer composition differed when different gene expression systems or different phaC genes were applied.
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2,337,920 |
Genome-wide strategies for detecting multiple loci that influence complex diseases.
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After nearly 10 years of intense academic and commercial research effort, large genome-wide association studies for common complex diseases are now imminent. Although these conditions involve a complex relationship between genotype and phenotype, including interactions between unlinked loci, the prevailing strategies for analysis of such studies focus on the locus-by-locus paradigm. Here we consider analytical methods that explicitly look for statistical interactions between loci. We show first that they are computationally feasible, even for studies of hundreds of thousands of loci, and second that even with a conservative correction for multiple testing, they can be more powerful than traditional analyses under a range of models for interlocus interactions. We also show that plausible variations across populations in allele frequencies among interacting loci can markedly affect the power to detect their marginal effects, which may account in part for the well-known difficulties in replicating association results. These results suggest that searching for interactions among genetic loci can be fruitfully incorporated into analysis strategies for genome-wide association studies.
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2,337,921 |
Improving the nutritional value of Golden Rice through increased pro-vitamin A content.
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"Golden Rice" is a variety of rice engineered to produce beta-carotene (pro-vitamin A) to help combat vitamin A deficiency, and it has been predicted that its contribution to alleviating vitamin A deficiency would be substantially improved through even higher beta-carotene content. We hypothesized that the daffodil gene encoding phytoene synthase (psy), one of the two genes used to develop Golden Rice, was the limiting step in beta-carotene accumulation. Through systematic testing of other plant psys, we identified a psy from maize that substantially increased carotenoid accumulation in a model plant system. We went on to develop "Golden Rice 2" introducing this psy in combination with the Erwinia uredovora carotene desaturase (crtI) used to generate the original Golden Rice. We observed an increase in total carotenoids of up to 23-fold (maximum 37 microg/g) compared to the original Golden Rice and a preferential accumulation of beta-carotene.
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2,337,922 |
Maternal efforts to prevent type 1 diabetes in at-risk children.
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The aim of this study was to assess maternal diabetes prevention efforts aimed at children identified as at risk through newborn genetic screening.</AbstractText>A total of 192 mothers of children identified as at risk for type 1 diabetes through newborn genetic screening were administered a structured interview 3.6 +/- 0.8 years after risk notification. The interview assessed possible diabetes prevention behaviors across six domains: health surveillance, diet, physical activity, illness prevention, medications, and stress reduction. A mother's cognitive (diabetes risk perception and perceived control), affective (anxiety), and coping responses to the child's at-risk status were assessed.</AbstractText>A total of 67% of mothers reported one or more diabetes prevention behaviors. Monitoring behaviors (e.g., watching for signs of diabetes and checking blood glucose) were the most common, reported in 59%, followed by modifications in the child's diet in 34% and physical activity in 14%. Potentially harmful prevention behaviors (e.g., limiting contact with other children, delaying immunizations, and giving medications including insulin) were rare. Mothers who engaged in diabetes prevention behaviors reported higher diabetes risk perception, greater anxiety, and more use of certain coping styles. Infants of these mothers were more likely to have a first-degree relative with diabetes.</AbstractText>In the absence of known methods of preventing type 1 diabetes, most mothers of at-risk children report diabetes prevention behaviors. Such behaviors must be more carefully assessed to ensure accurate interpretation of data obtained from natural history studies and prevention trials.</AbstractText>
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2,337,923 |
Long-term monitoring of the mortality trend of Huntington's disease in Austria.
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Recent increasing incidence and prevalence rates of Huntington's disease (HD), a fatal neurodegenerative disorder, prompted us to investigate the epidemiological dynamic of HD in Austria during the period 1970--2001. Our study demonstrated a stable HD mortality rate throughout Austria of 0.125 per 100,000 individuals during the investigated period. The median age at death from HD was 56.5 years for both sexes and remained stable during the entire period observed, indicating no prolonged survival. An above average mortality rate from HD was observed in the north-eastern parts of Austria. Our data reflect the epidemiology of HD prior to and after the availability of genetic testing and provide a solid baseline for future investigations on the epidemiology of HD.
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2,337,924 |
Statistical analysis of diversification with species traits.
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Testing whether some species traits have a significant effect on diversification rates is central in the assessment of macroevolutionary theories. However, we still lack a powerful method to tackle this objective. I present a new method for the statistical analysis of diversification with species traits. The required data are observations of the traits on recent species, the phylogenetic tree of these species, and reconstructions of ancestral values of the traits. Several traits, either continuous or discrete, and in some cases their interactions, can be analyzed simultaneously. The parameters are estimated by the method of maximum likelihood. The statistical significance of the effects in a model can be tested with likelihood ratio tests. A simulation study showed that past random extinction events do not affect the Type I error rate of the tests, whereas statistical power is decreased, though some power is still kept if the effect of the simulated trait on speciation is strong. The use of the method is illustrated by the analysis of published data on primates. The analysis of these data showed that the apparent overall positive relationship between body mass and species diversity is actually an artifact due to a clade-specific effect. Within each clade the effect of body mass on speciation rate was in fact negative. The present method allows to take both effects (clade and body mass) into account simultaneously.
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2,337,925 |
[Clinical, tomographic and immunogenetic study of patients with infantile cerebral palsy].
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A neurovisual and immunogenetic study of patients with different forms of cerebral palsy was conducted. Morphological peculiarities of each form were described. A frequent combination of pathology of cerebrospinal fluid spaces and periventricular area with disruption of neuronal migration and development of brain mass and volume was found. HLA-typing revealed a significant association of the disease with antigen B13. An association of cerebral palsy with particular genetically determined vulnerability of fetal brain to lesions disrupting genetic program for neuroontogenesis is suggested.
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2,337,926 |
[Therapeutic implications of polymorphisms in cytochromes and drug transporters].
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There is great heterogeneity in the way individuals respond to drug therapy. Reasons for this variability include pathophysiological or environmental factors, drug interactions or genetic influences. Among those influences are polymorphisms in drug-metabolizing enzymes, such as Cytochrom-P-450 (CYP) 2D6, CYP2C9 or CYP2C19 or genetic variants in enzymes coding for drug transporters, such as P-Glycoprotein. Polymorphisms might cause changes in drug pharmacokinetics and consequently drug efficacy after administration of recommended standard drug doses. Reduced enzyme activity can either result in a higher percentage of drug side-effects, or an augmented drug response due to increased target site concentrations. Conversely, intensified catalytic enzymatic activity might lead to subtherapeutic drug concentrations. In the future, genetic screening by genotyping before the initiation of pharmacotherapy might help to identify responders or non-responders and might it offer individualized therapies to select patient populations.
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2,337,927 |
Expression profiling using human tissues in combination with RNA amplification and microarray analysis: assessment of Langerhans cell histiocytosis.
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Advances in molecular genetics have led to sequencing of the human genome, and expression data is becoming available for many diverse tissues throughout the body, allowing for exciting hypothesis testing of critical concepts such as development, differentiation, homeostasis, and ultimately, disease pathogenesis. At present, an optimal methodology to assess gene expression is to evaluate single cells, either identified physiologically in living preparations, or by immunocytochemical or histochemical procedures in fixed cells in vitro or in vivo. Unfortunately, the quantity of RNA harvested from a single cell is not sufficient for standard RNA extraction methods. Therefore, exponential polymerase-chain reaction (PCR) based analyses, and linear RNA amplification including amplified antisense (aRNA) RNA amplification and a newly developed terminal continuation (TC) RNA amplification methodology have been used in combination with microdissection procedures such as laser capture microdissection (LCM) to enable the use of microarray platforms within individual populations of cells obtained from a variety of human tissue sources such as biopsy-derived samples {including Langerhans cell histiocytosis (LCH)} as well as postmortem brain samples for high throughput expression profiling and related downstream genetic analyses.
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2,337,928 |
Denaturing gradient-based two-dimensional gene mutation scanning in a polymer microfluidic network.
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An integrated two-dimensional (2-D) DNA separation platform, combining standard gel electrophoresis with temperature gradient gel electrophoresis (TGGE) on a polymer microfluidic chip, is reported. Rather than sequentially sampling DNA fragments eluted from standard gel electrophoresis, size-resolved fragments are simultaneously electrokinetically transferred into an array of orthogonal microchannels and screened for the presence of sequence heterogeneity by TGGE in a parallel and high throughput format. A bulk heater assembly is designed and employed to externally generate a temporal temperature gradient along an array of TGGE channels. Extensive finite element modeling is performed to determine the optimal geometries of the microfluidic network for minimizing analyte band dispersion caused by interconnected channels in the network. A pH-mediated on-chip analyte stacking strategy is employed prior to the parallel TGGE separations to further reduce additional band broadening acquired during the electrokinetic transfer of DNA fragments between the first and second separation dimensions. A comprehensive 2-D DNA separation is completed in less than 5 min for positive detection of single-nucleotide polymorphisms in multiplex PCR products that vary in size and sequence.
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2,337,929 |
Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence.
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We tested six single nucleotide polymorphisms (SNPs) in the alpha4 subunit gene (CHRNA4) and four SNPs in the beta2 subunit gene (CHRNB2) of nicotinic acetylcholine receptors (nAChRs) for association with nicotine dependence (ND), which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) in 2037 subjects from 602 nuclear families of either European-American (EA) or African-American (AA) ancestry. Analysis of the six SNPs within CHRNA4 demonstrated that in the EA sample SNPs rs2273504 and rs1044396 are significantly associated with the adjusted SQ and FTND score, respectively. In the AA samples, SNPs rs3787137 and rs2236196 are each significantly associated with at least two adjusted ND measures. Association of rs2236196 with the adjusted HSI and FTND scores in the AA samples remained significant after correction for multiple testing. Furthermore, analysis revealed gender- and ethnic-specific associations for several SNPs with ND measures in both ethnic samples; however, only the association of SNP rs2236196 with the three adjusted ND measures remained significant after correcting for multiple testing in the AA female samples. Haplotype analysis of rs2273505-rs2273504-rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with three adjusted ND measures in samples from the AA females. A similar analysis for the four SNPs within CHRNB2 did not reveal significant association with the three ND measures. In summary, our findings provide convincing evidence for the involvement of the nAChR alpha4 subunit, but not of the nAChR beta2 subunit, in nicotine addiction.
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2,337,930 |
Delayed gene therapy of glial cell line-derived neurotrophic factor is efficacious in a rat model of Parkinson's disease.
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Gene transfer of glial cell line-derived neurotrophic factor (GDNF) in rodent models of Parkinson's disease (PD) has been shown to protect against neurodegeneration either prior to or immediately after neurotoxin-induced lesions; however, the nigrostriatal pathway was largely intact when gene delivery was completed in these models, which may not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, replication-incompetent adenoviral vectors encoding the rat GDNF gene were administered into the striatum 4 weeks following 6-hydroxydopamine (6-OHDA) injection in the unilateral striatum, more closely resembling fully developed PD. Apomorphine-induced rotational behavior testing was performed every week following 6-OHDA injection. At the 10th week after gene transfer, the striatal dopamine concentrations were measured by HPLC with an electrochemical detector and the number of tyrosine hydroxylase (TH)-positive dopamine neurons in the substantia nigra (SN) was determined by immunohistochemistry. Injection of 6-OHDA into the striatum produced stable increases in rotation, which reached a plateau between 4 and 5 weeks post-injection. The number of TH-positive neuron in the SN and dopamine levels in the striatum was significantly lower in the 6-OHDA group compared to the normal group. Gene transfer of GDNF, but not beta-galactosidase, significantly increased the number of TH-positive neurons and dopamine levels, with a subsequent behavioral recovery between 5 and 10 weeks following GDNF transduction. These findings demonstrate that adenovirus-mediated gene transfer of GDNF is efficacious even in the late stages of 6-OHDA-induced PD rats. They also provide further evidence on the effectiveness of GDNF-based gene therapy for experimental Parkinson's disease.
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2,337,931 |
First molecular screening of deafness in the Altai Republic population.
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We studied the molecular basis of NSHL in Republic of Altai (South Siberia, Russia). The Altaians are the indigenous Asian population of the Altai Mountain region considered as a melting-pot and a dispersion center for world-wide human expansions in the past.</AbstractText>A total of 76 patients of Altaian, Russian or mixed ethnicity and 130 Altaian controls were analyzed by PCR-DHPLC and sequencing in the GJB2 gene. The GJB6 deletion and the common non-syndromic deafness-causing mitochondrial mutations were also tested when appropriate.</AbstractText>8.3% of the Altaian chromosomes were carrying GJB2 mutations versus 46.9% of the Russian chromosomes. The 235delC mutation was predominant among Altaians, whereas the 35delG mutation was most prevalent among Russian patients.</AbstractText>We found an Asian-specific GJB2 diversity among Altaians, and different GJB2 contribution for deafness in the Altaian and Russian patients. The high carrier frequency of 235delC in Altaians (4.6%) is probably defined by gene drift/founder effect in a particular group. The question whether the Altai region could be one of founder sources for the 235delC mutation widespread in Asia is open.</AbstractText>
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2,337,932 |
[Factor V Leiden, FII G20210A, MTHFR C677T mutations as risk factors for venous thrombosis during pregnancy and puerperium].<Pagination><StartPage>201</StartPage><EndPage>205</EndPage><MedlinePgn>201-5</MedlinePgn></Pagination><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Venous thrombosis is the most common cause of obstetric morbidity and mortality during pregnancy and puerperium. The incidence of pregnancy-associated venous thrombosis varies from 1 in 1000 to 1 in 2000 deliveries. Factor V G1691A (FV Leiden), FII G20210A and MTHFR C677T mutations are the most common genetic risk factors for thromboembolism. The aim of this study was to establish the presence of these risk factors in a group of women with an episode of deep venous thrombosis during pregnancy or puerperium.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">The study was carried in a group of 45 women with the first episode of deep venous thrombosis during pregnancy or puerperium. The patients with antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, and autoimmune and malignant diseases were excluded from the study. FV Leiden, FII G20210A, and MTHFR C677T mutations were detected by polymerase chain reaction, followed by digestion with specific restriction enzymes.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">Twenty heterozygous carriers of the FV Leiden mutation and one homozygous carrier were detected, which represents the frequencies of 44.4% and 2.2%, respectively. For the FII G20210A mutation, six heterozygous carriers were identified, giving the frequency of 13.3%. The MTHFR C677T mutation was observed in 31 patients (22 heterozygous and 9 homozygous carriers) which represents the frequencies of 48.9% and 20%, respectively.</AbstractText><AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">Our study suggested that the obligatory testing for FV Leiden and FII G20210A mutations was strongly recommended in women with history of venous thrombosis during pregnancy and puerperium. We found a slight effect of MTHFR 677T allele, but it should be considered in association with other risk factors.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Dordević</LastName><ForeName>Valentina</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Institut za molekularnu genetiku i geneticko inzenjerstvo, Beograd, Klinicki centar Srbije. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rakićević</LastName><ForeName>Ljiljana</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Spasić</LastName><ForeName>Milo</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Miković</LastName><ForeName>Danijela</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Kovać</LastName><ForeName>Mirjana</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Radojković</LastName><ForeName>Dragica</ForeName><Initials>D</Initials></Author></AuthorList><Language>srp</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Serbia</Country><MedlineTA>Vojnosanit Pregl</MedlineTA><NlmUniqueID>21530700R</NlmUniqueID><ISSNLinking>0042-8450</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015415">Biomarkers</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C095381">factor V Leiden</NameOfSubstance></Chemical><Chemical><RegistryNumber>9001-24-5</RegistryNumber><NameOfSubstance UI="D005165">Factor V</NameOfSubstance></Chemical><Chemical><RegistryNumber>9001-26-7</RegistryNumber><NameOfSubstance UI="D011516">Prothrombin</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.5.1.20</RegistryNumber><NameOfSubstance UI="D042965">Methylenetetrahydrofolate Reductase (NADPH2)</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D015415" MajorTopicYN="N">Biomarkers</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="N">analysis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005165" MajorTopicYN="N">Factor V</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D042965" MajorTopicYN="N">Methylenetetrahydrofolate Reductase (NADPH2)</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="Y">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011247" MajorTopicYN="N">Pregnancy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011250" MajorTopicYN="Y">Pregnancy Complications, Hematologic</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011516" MajorTopicYN="N">Prothrombin</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011644" MajorTopicYN="N">Puerperal Disorders</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020246" MajorTopicYN="N">Venous Thrombosis</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>26</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>4</Month><Day>15</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>26</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15790048</ArticleId><ArticleId IdType="doi">10.2298/vsp0503201d</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15790029</PMID><DateCompleted><Year>2005</Year><Month>05</Month><Day>11</Day></DateCompleted><DateRevised><Year>2020</Year><Month>12</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0208-0613</ISSN><JournalIssue CitedMedium="Print"><Issue>1</Issue><PubDate><Year>2005</Year></PubDate></JournalIssue><Title>Molekuliarnaia genetika, mikrobiologiia i virusologiia</Title><ISOAbbreviation>Mol Gen Mikrobiol Virusol</ISOAbbreviation></Journal>[Resistance of Russian isolates of Neisseria gonorrhoeae to fluoroquinolones].
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Fluoroquinolones still belong to the drugs of choice in the treatment of uncomplicated gonorrhea. At the same time, there have been more data on the spreading N. gonorrhoeae strains resistant to fluoroquinolones. A variety of mechanisms, like modification of the target of antibiotic's action (point mutations in genes gyrA and parC), a decreasing permeability of the bacterial cell membrane (amino-acid changes Por protein) and a growing efflux of antibiotic (mutations in the promoter or in the coding region of mtrR) mediate in the shaping resistance of the drugs. The MIC values for four fluoroquinolone-series antibiotics were determined and the gyrA, parC, por and mtrR genes were examined for resistance-responsible mutations in 32 studied clinical strains of N. gonorrhoeae. Strains with high resistance to fluoroquinolones were detected; 3 of them had no common changes in GyrA or ParC, however, amino acid changes and mutations were detected in Por protein and promoter or gene mtrR encoding region, respectively. The paper contains priority data on the detection (in Russia) of N. gonorrhoeae strains with high resistance to fluoroquinolones. Involvement of different mechanisms in the process of resistance shaping is discussed. The results are of practical importance for planning the antibacterial therapy of gonorrhoeae; they point out the need in regional testing of resistance in the N. gonorrhoeae population encountered in Russia.
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2,337,933 |
HFE genotyping demonstrates a significant incidence of hemochromatosis in undifferentiated arthritis.
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Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated to be 1 in 10, while up to 1 in 200 is affected by the disease. Arthropathy is one early clinical manifestation of this disease, but the articular features are often misdiagnosed. In this study the two frequent mutations of the HLA-linked hemochromatosis gene (HFE) were investigated in a rheumatology clinic population.</AbstractText>Two hundred and six consecutive patients (mean age 57.7 years; 38 male/168 female) attending a rheumatology clinic over a period of 14 months were screened for HFE mutations (C282Y and H63D). All standard diagnostic procedures were used to identify the aetiology of the arthropathy. Mutations were evaluated by separation on PAGE of digested PCR amplificates of DNA (by SnapI and Bcl-I, for C282Y and H63D, respectively) obtained from PBMCs.</AbstractText>The C282Y and H63D allele frequencies were 4.5 and 12.8 in patients with rheumatic diseases. Five patients were homozygote for H63D (2.4%), and one for C282Y (0.5%). Five patients were compound heterozygous (2.4%). The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis was 12.9 and exceeded that of healthy subjects (p = 0.01).</AbstractText>Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin, to allow early diagnosis of hemochromatosis.</AbstractText>
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2,337,934 |
(Mis)alignments in counseling for Huntington's Disease predictive testing: clients' responses to reflective frames.
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As a sequel to an earlier paper (Sarangi et al., 2004. J Genet Couns, 13(2), 135-155) examining genetic counselors' initiation of reflective frames, in this paper we analyze the variable ways in which clients respond to such reflective frames in the clinical setting. Of the six types of reflective questions identified, we focus on two types, which recur throughout the counseling protocol: (i) questions about clients' decisions to have genetic testing and (ii) questions exploring the potential impact of a positive or negative test result. The analytic focus here is on the mismatches surrounding clients' apparent readiness to discuss coping with the onset of disease (risk of disease) when they have been asked to discuss coping with genetic test results (risk of knowing). Our theoretical discussion is centered around the notion of alignment as a framework for locating the convergence and divergence of counselors' and clients' agendas in interaction. Drawing on detailed transcripts of 24 Huntington's Disease counseling consultations in South Wales, we analyze 119 counselor-client question-response sequences using the methodology of discourse analysis. Preliminary coding of clients' responses led us to identify three recurrent themes: (a) gaining knowledge as a basis for future action; (b) needing to know as a subjective necessity; and (c) downplaying what can be known. In a further analysis of extended data extracts, we draw attention to how clients display varying degrees of engagement with regard to the testing process and outcomes along the temporal and social axes. At one extreme, clients may take up the opportunity to engage in self-reflection, and thus endorse the legitimacy of the reflective frame. At the other extreme, clients may implicitly or explicitly challenge the relevance of self-reflection, and hence the usefulness of this counselor-initiated routine. We suggest that clients' varied response behaviors result from the perceived need of some clients to display their 'readiness' for predictive testing-an overarching 'meta-question' posed by the very existence of the counseling protocol.
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2,337,935 |
Evaluating the impact of genetic counseling and testing with signal detection methods.
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One measure of the impact of genetic counseling and testing (GCT) is the extent to which it fosters behavioral change that is consistent with mutation status. We describe and illustrate how two different signal detection methods, receiver operating characteristic (ROC) analysis and recursive partitioning, can be used in this context to evaluate the impact of GCT. We analyzed real screening behavior data obtained in the 12 months following GCT for Hereditary Nonpolyposis Colon Cancer (HNPCC) using these two different signal detection approaches. Each approach demonstrated that GCT had an impact on behavioral outcomes, and was effective in fostering behavioral outcomes appropriate to mutation status. The ROC approach demonstrated that GCT was effective because mutation positive and mutation negative individuals could be distinguished on the basis of the number of recommended screening behaviors. The recursive partitioning approach demonstrated that GCT was effective because there were generally high rates of adherence to screening guidelines among subjects. The recursive partitioning technique also identified four subgroups of subjects, each with distinct characteristics, for which tailored interventions could be developed to increase rates of adherence to screening guidelines. Signal detection methods are easily implemented and are useful techniques for evaluating the impact of GCT.
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2,337,936 |
Cystic fibrosis prenatal screening in genetic counseling practice: recommendations of the National Society of Genetic Counselors.
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For over a decade, prenatal screening for cystic fibrosis (CF) has been considered a model for the integration of genetic testing into routine medical practice. Data from pilot studies and public policy discourse have led to recommendations by some professional organizations that CF screening should be offered or made available to pregnant women and their partners, and to couples planning a pregnancy. It is crucial that genetic counselors gain thorough understanding of the complexities of CF and the implications of positive test results, so that they may serve as a reliable, educated referral base and resource for health care providers and their patients. While not all pregnant women will be referred for genetic counseling prior to CF carrier testing, genetic counselors often will be asked to counsel clients after they have a positive test result, or who are found to be at increased risk. Genetic counselors can play an important role in providing accurate and current information as well as support for patients' informed decisions. These recommendations were created by a multicenter working group of genetic counselors with expertise in CF and are based on personal clinical experience, review of pertinent English language medical articles, and reports of expert committees. The recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a particular client.
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2,337,937 |
Selective induction of tumor-associated antigens in murine pulmonary vasculature using double-targeted adenoviral vectors.
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Targeted therapies directed to tumor-associated antigens are being investigated for the treatment of cancer. However, there are few suitable animal models for testing the ability to target these tumor markers. Therefore, we have exploited mice transgenic for the human coxsackie and adenovirus receptor (hCAR) to establish a new model for transient expression of human tumor-associated antigens in the pulmonary vasculature. Systemic administration of Ad in hCAR mice resulted in an increase in transgene expression in the lungs compared to wild-type mice, as determined using a luciferase reporter gene. To reduce transgene expression in the liver, the predominant organ of ectopic Ad localization and transgene expression following systemic administration, we utilized the endothelial-specific flt-1 promoter, which resulted in a further increased lung-to-liver ratio of luciferase expression. Administration of an adenoviral vector encoding the tumor-associated antigen carcinoembryonic antigen (CEA) under transcriptional control of the flt-1 promoter resulted in selective expression of this antigen in the pulmonary vasculature of hCAR mice. Feasibility of targeting to expressed CEA was subsequently demonstrated using adenoviral vectors preincubated with a bifunctional adapter molecule recognizing this tumor-associated antigen, thus demonstrating utility of this transient transgenic animal model.
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2,337,938 |
Introducing the MUC16 gene: implications for prevention and early detection in epithelial ovarian cancer.
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More than 24,000 women in the United States are diagnosed with ovarian cancer every year, and half of these women die from their disease. Stage 1 ovarian cancer is curable in 95% of cases; however, due to inadequate screening tools and lack of symptoms in early disease, ovarian cancer is generally at Stage 3 or 4 when finally diagnosed. CA125 is a tumor antigen used to monitor the progression and regression of epithelial ovarian cancer. When its levels are elevated postsurgery (hysterectomy/salpingo-oophorectomy with or without peritoneal washings and lymph node biopsy) and postchemotherapy, it is suggestive of recurrent disease. Due to its similarly elevated levels in some nonmalignant conditions, however, it is not specific enough to be used for population screening. The CA125 molecule is considered a very large glycoprotein because of its molecular weight, and it has three domains: the carboxy terminal domain, the extracellular domain, and the amino terminal domain. MUC16 is the gene that encodes the peptide moiety of the CA125 molecule. MUC16 domains provide novel opportunities to develop new assays and refine current tools to improve the sensitivity and specificity of CA125 for population-based screening guidelines.
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2,337,939 |
Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers.
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Using a newly developed real-time reverse transcriptase-polymerase chain reaction method, mRNAs were quantitated for CYP3A4, CYP3A5 and CYP3A7 in adult livers from 24 Japanese and 24 Caucasian subjects to elucidate the potential ethnic differences in the expression levels of human cytochrome P450 (CYP) 3As. The expression level of CYP3A4 mRNA in Japanese livers (n = 24) was approximately three times higher than that in Caucasian livers (n = 24, p < 0.001). The mean level of CYP3A5 mRNA was approximately twice higher in Japanese (n = 9) than in Caucasians (n = 5) heterozygous for the CYP3A5 *1 allele (p = 0.057). The CYP3A7 mRNA level was twice higher in Japanese (n = 24) than in Caucasians (n = 22) carrying the CYP3A7 *1A/ *1A genotype (p = 0.042). The level of CYP3A4 mRNA did not correlate with those of CYP3A5 (r = 0.044, n = 24) or CYP3A7 (r = 0.21, n = 24) mRNAs in Japanese livers in contrast to co-regulatory expression of CYP3A4, CYP3A5 and CYP3A7 in Caucasian livers. The results indicate that there are ethnic differences in the expression levels of adult liver CYP3A mRNAs between Japanese and Caucasians, and that the mechanism(s) regulating the hepatic CYP3A expression may be different between these ethnic groups.
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2,337,940 |
Development of a pyrosequencing approach for rapid screening of rifampin, isoniazid and ethambutol-resistant Mycobacterium tuberculosis.
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The need to minimize the transmission of drug-resistant Mycobacterium tuberculosis requires rapid identification procedures.</AbstractText>To develop a pyrosequencing approach for rapid screening of rifampin, isoniazid and ethambutol-resistant M. tuberculosis based on characterization of resistance-associated hot mutations.</AbstractText>Three pairs of PCR primers and three pyrosequencing sequencing primers for detecting mutations at codon 526 and 531 of the rpoB gene, codon 315 of the katG gene, and codon 306 of the embB gene were chosen. The sensitivity of the pyrosequencing approach was determined by assaying PCR products generated from 10-fold serial dilutions of the DNA from the H37Rv strain. The efficacy of the pyrosequencing approach was evaluated by analyzing clinical isolates with a known antibiotic phenotype.</AbstractText>Resistance-associated hot mutations could be determined within 2 h after PCR amplification using pyrosequencing. About 45 fg DNA per reaction was required to obtain sufficient PCR products to produce a clear, accurate pyrosequencing pattern. No mutations were found in all 20 drug-susceptible clinical isolates, while all isolates with mutations showed corresponding drug resistances.</AbstractText>This pyrosequencing approach can be used for rapid screening of rifampin-, isoniazid- and ethambutol-resistant M. tuberculosis prior to standard drug susceptibility testing.</AbstractText>
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2,337,941 |
Distinguishing the four genetic causes of Jouberts syndrome-related disorders.
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Jouberts syndrome-related disorders are a group of recessively inherited conditions showing cerebellar vermis hypoplasia and the molar tooth sign of the midbrain-hindbrain junction. Recent analyses have suggested at least three loci, JBTS1 (9q34.3), -2 (11p11.2-q12.3), and -3 (6q23), but the phenotypic spectrum associated with each locus has not been delineated. In addition, deletions of the NPHP1 gene, usually responsible for isolated juvenile nephronophthisis, are occasionally encountered among Jouberts syndrome-related disorder patients. Here, we describe four novel families showing evidence of linkage to two of these loci, provide a 3.6Mb refinement of the JBTS2 locus, and perform a detailed comparison of all linked families identified so far, to define the clinical and radiographical hallmarks for each genetic condition. We find that JBTS1 and -3 primarily show features restricted to the central nervous system, with JBTS1 showing largely pure cerebellar and midbrain-hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain-hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the central nervous system features, and results in extreme phenotypic variability. This provides a useful framework for genetic testing strategies and prediction of which patients are most likely to experience development of systemic complications.
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2,337,942 |
Nonparametric tests of association of multiple genes with human disease.
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The genetic basis of many common human diseases is expected to be highly heterogeneous, with multiple causative loci and multiple alleles at some of the causative loci. Analyzing the association of disease with one genetic marker at a time can have weak power, because of relatively small genetic effects and the need to correct for multiple testing. Testing the simultaneous effects of multiple markers by multivariate statistics might improve power, but they too will not be very powerful when there are many markers, because of the many degrees of freedom. To overcome some of the limitations of current statistical methods for case-control studies of candidate genes, we develop a new class of nonparametric statistics that can simultaneously test the association of multiple markers with disease, with only a single degree of freedom. Our approach, which is based on U-statistics, first measures a score over all markers for pairs of subjects and then compares the averages of these scores between cases and controls. Genetic scoring for a pair of subjects is measured by a "kernel" function, which we allow to be fairly general. However, we provide guidelines on how to choose a kernel for different types of genetic effects. Our global statistic has the advantage of having only one degree of freedom and achieves its greatest power advantage when the contrasts of average genotype scores between cases and controls are in the same direction across multiple markers. Simulations illustrate that our proposed methods have the anticipated type I-error rate and that they can be more powerful than standard methods. Application of our methods to a study of candidate genes for prostate cancer illustrates their potential merits, and offers guidelines for interpretation.
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2,337,943 |
[Fundus quiz 2004].
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Six cases with characteristic fundus pathologies are presented and discussed using multiple choice questions.
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2,337,944 |
An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia.
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Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed.
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2,337,945 |
CT60 single nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen-4 gene region is associated with Graves' disease in an Italian population.
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Graves' disease (GD) is an autoimmune and polygenic disorder. Several studies have shown that human leukocyte antigen (HLA) class II and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene are involved in the genetic susceptibility. We performed a case control study on 150 patients with GD and 301 controls, matched for age and gender, to verify the association of three polymorphisms located in CTLA-4 region (A49G, [AT](n)-3'UTR, and CT60) and of HLA-DRB1 and DQB1 loci with the disease in an Italian population. The prevalence of patients with GD carrying the G allele of CT60 was significantly higher compared to control subjects (p = 0.02, odds ratio [OR] = 1.82). The allelic frequency of the G allele of CT60 was also significantly higher in patients with GD (p = 0.02). The G allele frequency of A49G in patients was significantly higher compared to control subjects (p = 0.04). The 280 allele phenotype frequency of (AT)(n)-3'UTR was also significantly higher in patients (p = 0.04). The G allele of A49G, the G allele of CT60, and the 280 allele of (AT)(n)-3'UTR microsatellite were significantly increased in patients with GD with thyroid-associated ophthalmopathy (TAO) compared to controls (p = 0.04, p = 0.03, and p = 0.02, respectively), however, we did not find any significant difference between TAO and non-TAO patients. We also found the HLA-DRB1*03 allele to be associated with GD; interestingly, the association of the CTLA-4 markers was independent from the HLA DRB1*03 status. These results highlight the role of the CTLA-4 locus, in addition to HLA, in the susceptibility to GD. Inside the CTLA-4 region, CT60 appears to be the most associated polymorphism to GD, however, further studies are needed to identify the etiologic variant.
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2,337,946 |
Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians.
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Clinically relevant genetics knowledge is essential for appropriate assessment and management of inherited cancer risk, and for effective communication with patients. This national physician survey assessed knowledge regarding basic cancer genetics concepts early in the process of introduction of predictive genetic testing for breast/ovarian and hereditary non-polyposis colorectal cancer (HNPCC) syndromes.</AbstractText>A stratified random sample was selected from the American Medical Association Masterfile of all licensed physicians. In total, 1251 physicians (820 in primary care, 431 in selected subspecialties) responded to a 15 minute questionnaire (response rate 71%) in 1999-2000. Multivariate logistic regression analyses were conducted to identify demographic and practice characteristics associated with accurate response to three knowledge questions.</AbstractText>Of the study population, 37.5% was aware of paternal inheritance of BRCA1/2 mutations, and 33.8% recognised that these mutations occur in <10% of breast cancer patients. Only 13.1% accurately identified HNPCC gene penetrance as >or=50%. Obstetrics/gynaecology physicians, oncologists, and general surgeons were significantly more likely than general and family practitioners to respond accurately to the breast/ovarian questions, as were gastroenterologists to the HNPCC question.</AbstractText>These nationally representative data indicate limited physician knowledge about key cancer genetics concepts in 1999-2000, particularly among general primary care physicians. Specialists were more knowledgeable about syndromes they might treat or refer elsewhere. Recent dissemination of practice guidelines and continued expansion of relevant clinical literature may enhance knowledge over time. In addition to educational efforts to assist physicians with the growing knowledge base, more research is needed to characterise the organisational changes required within the healthcare system to provide effective cancer genetics services.</AbstractText>
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2,337,947 |
High pressure liquid chromatography and electrospray ionization mass spectrometry are advantageously integrated into a two-levels approach to detection and identification of haemoglobin variants.
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Detecting and correctly identifying haemoglobin (Hb) variants is typically achieved by a two-levels laboratory approach. We report our experience in dealing with 91 Hb variants, including a number of frequent and a few rare variants. Screening included akaline agarose gel electrophoresis (AGE), ion-exchange automated high-performance liquid chromatography (HPLC) and a test for deoxyhaemoglobin solubility. Identification was based on electrospray ionization-mass spectrometry (ESI-MS). Our results confirmed the advantages of HPLC over AGE for screening, because of the occurrence of some electrophoretically 'silent' variants. ESI-MS permitted the definitive identification of 90 of the 91 variants included in the study, in some cases (e.g. HbS) through the application of a simple protocol (direct injection of the sample), in other cases requiring the application of more demanding procedures (purification of the variant chain and peptide analysis after enzymatic or chemical cleavage). In an additional case (Hb J-Oxford), ESI-MS assay did not lead to definitive identification, but gave indications for designing the appropriate primers to focus DNA sequence analysis on the specific region of the gene. Deoxyhaemoglobin solubility test was positive only in the presence of HbS. We conclude that HPLC and ESI-MS are advantageously integrated into a two-level analytical system for the detection and confirmation of variant Hbs.
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2,337,948 |
Heat-shock protein 70: molecular supertool?
|
The cellular stress response decreases cellular injury, either via primary induction of cytoresistance or by secondary enhancement of cellular repair mechanisms. The most frequently studied and best understood effectors of the cellular stress response are the heat shock proteins (HSP). HSP are among the oldest tools in the cellular protein machinery, demonstrating extremely high conservation of the genetic code since bacteria. Molecular chaperons, with the HSP-70 being the prototype, cooperate in transport and folding of proteins, preventing aggregation, and even resolubilizing injured proteins. Increasing evidence supports a role for HSP during the recovery from renal ischemia, in particular in cellular salvage from apoptotic cell death and cytoskeletal restoration. Recent studies also report the potential for biomolecular profiling of newborns for the risk of acute renal failure. In peritoneal dialysis novel data suggest the use of HSP expression for biocompatibility testing. More importantly, HSP are prime therapeutic candidates for clinical situations associated with predictable insults, such as organ procurement in transplant medicine and repetitive exposure to hyperosmolar and acidotic peritoneal dialysis fluids. The next challenge will be to define the regulatory pathways of the cellular stress response in these models to introduce novel therapeutic interventions, such as new pharmaceutics enhancing the HSP expression.
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2,337,949 |
Quantification of random genomic mutations.
|
Cancer cells contain numerous clonal mutations. It has been theorized that malignant cells sustain an elevated mutation rate and, as a consequence, harbor yet larger numbers of random point mutations. Testing this hypothesis has been precluded by lack of an assay to measure random mutations-that is, mutations that occur in only one or a few cells of a population. We have established a method that has permitted us to detect and identify rare random mutations in human cells, at a frequency of 1 per 10(8) base pairs. The assay is based on gene capture, by hybridization with a uracil-containing probe, followed by magnetic separation. Mutations that render the mutational target sequence non-cleavable by a restriction enzyme are quantified by dilution to single molecules and real-time quantitative PCR amplification. The assay can be extended to quantify mutation in any DNA-based organism, at different sites in the genome, in introns and exons, in unselected and selected genes, and in proliferating and quiescent cells.
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2,337,950 |
In situ genotyping individual DNA molecules by target-primed rolling-circle amplification of padlock probes.
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Methods are needed to study single molecules to reveal variability, interactions and mechanisms that may go undetected at the level of populations of molecules. We describe here an integrated series of reaction steps that allow individual nucleic acid molecules to be detected with excellent specificity. Oligonucleotide probes are circularized after hybridization to target sequences that have been prepared so that localized amplification reactions can be initiated from the target molecules. The process results in strong, discrete detection signals anchored to the target molecules. We use the method to observe the distribution, within and among human cells, of individual normal and mutant mitochondrial genomes that differ at a single nucleotide position.
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2,337,951 |
LigAmp for sensitive detection of single-nucleotide differences.
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We developed the LigAmp assay for sensitive detection and accurate quantification of viruses and cells with single-base mutations. In LigAmp, two oligonucleotides are hybridized adjacently to a DNA template. One oligonucleotide matches the target sequence and contains a probe sequence. If the target sequence is present, the oligonucleotides are ligated together and detected using real-time PCR. LigAmp detected KRAS2 mutant DNA at 0.01% in mixtures of different cell lines. KRAS2 mutations were also detected in pancreatic duct juice from patients with pancreatic cancer. LigAmp detected the K103N HIV-1 drug resistance mutation at 0.01% in plasmid mixtures and at approximately 0.1% in DNA amplified from plasma HIV-1. Detection in both systems is linear over a broad dynamic range. Preliminary evidence indicates that reactions can be multiplexed. This assay may find applications in the diagnosis of genetic disorders and the management of patients with cancer and infectious diseases.
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2,337,952 |
RNAi living-cell microarrays for loss-of-function screens in Drosophila melanogaster cells.
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RNA interference (RNAi)-mediated loss-of-function screening in Drosophila melanogaster tissue culture cells is a powerful method for identifying the genes underlying cell biological functions and for annotating the fly genome. Here we describe the development of living-cell microarrays for screening large collections of RNAi-inducing double-stranded RNAs (dsRNAs) in Drosophila cells. The features of the microarrays consist of clusters of cells 200 mum in diameter, each with an RNAi-mediated depletion of a specific gene product. Because of the small size of the features, thousands of distinct dsRNAs can be screened on a single chip. The microarrays are suitable for quantitative and high-content cellular phenotyping and, in combination screens, for the identification of genetic suppressors, enhancers and synthetic lethal interactions. We used a prototype cell microarray with 384 different dsRNAs to identify previously unknown genes that affect cell proliferation and morphology, and, in a combination screen, that regulate dAkt/dPKB phosphorylation in the absence of dPTEN expression.
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2,337,953 |
A highly informative SNP linkage panel for human genetic studies.
|
We have developed a highly informative set of single-nucleotide polymorphism (SNP) assays designed for linkage mapping of the human genome. These assays were developed on a robust multiplexed assay system to provide a combination of very high accuracy and data completeness with high throughput for linkage studies. The linkage panel is comprised of approximately 4,700 SNPs with 0.39 average minor allele frequency and 624-kb average spacing. Based on almost 2 million genotypes, data quality was shown to be extremely high, with a 99.94% call rate, >99.99% reproducibility and 99.995% genotypes consistent with mendelian inheritance. We constructed a genetic map with an average 1.5-cM resolution using series of 28 CEPH pedigrees. The relative information content of this panel was higher than those of commonly used STR marker panels. The potent combination of this SNP linkage panel with the multiplexed assay system provides a previously unattainable level of performance for linkage studies.
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2,337,954 |
Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays.
|
We present a genotyping method for simultaneously scoring 116,204 SNPs using oligonucleotide arrays. At call rates >99%, reproducibility is >99.97% and accuracy, as measured by inheritance in trios and concordance with the HapMap Project, is >99.7%. Average intermarker distance is 23.6 kb, and 92% of the genome is within 100 kb of a SNP marker. Average heterozygosity is 0.30, with 105,511 SNPs having minor allele frequencies >5%.
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2,337,955 |
BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes.
|
Recently, it was shown that the oncogenic activation of BRAF, a member of the RAS/RAF family of kinases, by the V600E mutation is characteristic for sporadic colon tumors with microsatellite instability. Further, it was shown to associate with the silencing of the mismatch repair (MMR) gene MLH1 by hypermethylation. Moreover, BRAF mutations proved to be absent in tumors from hereditary nonpolyposis colorectal cancer syndrome (HNPCC) families with germline mutations in the MMR genes MLH1 and MSH2. These data suggest that the oncogenic activation of BRAF is involved only in sporadic colorectal tumorigenesis. In order to further support this hypothesis, we have extended the analysis of the BRAF gene to a different subset of HNPCC families without germline mutations in MLH1 and MSH2. BRAF-V600E mutations were analysed by automatic sequencing in 38 tumors from HNPCC families with germline mutations in the MSH6 gene and also in HNPCC (suspected) families that do not have mutations in the MMR genes MLH1, MSH2 and MSH6. All patients belong to different families. No mutations were detected in 14 tumors from HNPCC patients with germline mutations in MSH6. Further, no mutations of BRAF were found in tumors from 23 MMR-negative families, from which 13 fulfilled the Amsterdam criteria (HNPCC) and 10 were suspected for HNPCC as they were positive for the Bethesda criteria. Overall, our data reinforce the concept that BRAF is not involved in the colorectal tumorigenesis of HNPCC. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer.
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2,337,956 |
Lafora disease due to EPM2B mutations: a clinical and genetic study.
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To study EPM2B gene mutations and genotype-phenotype correlations in patients with Lafora disease.</AbstractText>The authors performed a clinical and mutational analysis of 25 patients, from 23 families, diagnosed with Lafora disease who had not shown mutations in the EPM2A gene.</AbstractText>The authors identified 18 mutations in EPM2B, including 12 novel mutations: 4 nonsense mutations (R265X, C26X, W219X, and E67X), a 6-base pair (bp) microdeletion resulting in a two amino acid deletion (V294_K295del), a 4-bp insertion resulting in a frameshift mutation (S339fs12), and 6 missense mutations (D308A, I198N, C68Y, E67Q, P264H, and D233A). In our data set of 77 families with Lafora disease, 54 (70.1%) tested probands have mutations in EPM2A, 21 (27.3%) in EPM2B, and 2 (2.6%) have no mutations in either gene. The course of the disease was longer in patients with EPM2B mutations vs patients with EPM2A mutations.</AbstractText>Genetic allelic heterogeneity is present in Lafora disease associated with mutations in EPM2B. Patients with mutations in EPM2A and EPM2B express similar clinical manifestation, although patients with EPM2B-associated Lafora disease seem to have a slightly milder clinical course. The lack of mutations in EPM2A and EPM2B in two families could be because of the presence of mutations in noncoding, nontested regions or the existence of an additional gene associated with Lafora disease.</AbstractText>
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2,337,957 |
Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.
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Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented.</AbstractText>The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically.</AbstractText>The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency.</AbstractText>The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.</AbstractText>
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2,337,958 |
Mitochondrial DNA content is decreased in autosomal dominant optic atrophy.
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Autosomal dominant optic atrophy (ADOA) is the commonest form of inherited optic neuropathy. Mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein underlie ADOA and may perturb the biogenesis and maintenance of mitochondria.</AbstractText>To investigate the mutation spectrum of the OPA1 gene and assess alterations in mitochondrial content caused by OPA1 mutations.</AbstractText>Sixteen Korean patients with clinically suspected ADOA were studied. The mutation spectrum of the OPA1 gene was analyzed by PCR single-strand conformation polymorphism and sequencing, and mitochondrial DNA (mtDNA) content was quantified by real-time PCR.</AbstractText>Eight different mutations were found, including five novel mutations. Quantitative real-time PCR analysis showed excellent linearity and precision for the determination of mtDNA copy numbers. The number of mtDNA copies per cell in patients with OPA1 gene mutations (ages 7 to 40) was significantly lower than those in all normal control subjects (p = 0.037), particularly lower than in normal control subjects ages 10 to 39 (p = 0.022).</AbstractText>The mutation spectrum of the OPA1 gene disclosed marked genetic heterogeneity and the mitochondrial DNA content was found to be lower in autosomal dominant optic neuropathy, which provides direct evidence for a pathogenetic role of mutations of the OPA1 gene.</AbstractText>
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2,337,959 |
Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation.
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To explore whether there is an increased prevalence of chronic rhinosinusitis (CRS) in known cystic fibrosis (CF) carriers. Self-reported CRS affects 13% to 14% of the US population and clusters in families, which suggests that genetic factors may play an etiologic role. Cystic fibrosis is an inherited recessive disorder that invariably affects the sinuses. The frequency of CF mutations has been reported to be higher in patients with CRS than in unaffected controls.</AbstractText>Obligate CF carriers (parents of patients with CF) were recruited from the Johns Hopkins CF clinic. The presence of signs and symptoms of CRS was assessed by a sinus disease questionnaire. A subgroup of participants was evaluated by a physician experienced in the diagnosis of CRS.</AbstractText>Fifty-three (36%) of 147 obligate CF carriers who returned a completed questionnaire had self-reported CRS. Twenty-three CF carriers (14 with and 9 without CRS based on self-reporting in the questionnaire) were clinically evaluated. Seven were diagnosed as having CRS (all 7 with self-reported CRS), while another 6 had allergic rhinitis or recurrent acute rhinosinusitis (all 6 with self-reported CRS), and 10 had no evidence of active sinus disease (1 with self-reported CRS). The sensitivity (100%) and specificity (56%) of the questionnaire for physician-diagnosed CRS was similar to that of other survey instruments used to estimate the prevalence of self-reported CRS in the general population.</AbstractText>Carriers of a single CF mutation have a higher prevalence of CRS than the general population.</AbstractText>
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2,337,960 |
Experimental designs for reliable detection of linkage disequilibrium in unstructured random population association studies.
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A method is given for design of experiments to detect associations (linkage disequilibrium) in a random population between a marker and a quantitative trait locus (QTL), or gene, with a given strength of evidence, as defined by the Bayes factor. Using a version of the Bayes factor that can be linked to the value of an F-statistic with an existing deterministic power calculation makes it possible to rapidly evaluate a comprehensive range of scenarios, demonstrating the feasibility, or otherwise, of detecting genes of small effect. The Bayes factor is advocated for use in determining optimal strategies for selecting candidate genes for further testing or applications. The prospects for fine-scale mapping of QTL are reevaluated in this framework. We show that large sample sizes are needed to detect small-effect genes with a respectable-sized Bayes factor, and to have good power to detect a QTL allele at low frequency it is necessary to have a marker with similar allele frequency near the gene.
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2,337,961 |
Immunogenomics of hematopoietic stem cell transplantation.
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Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) incur the risk of graft-versus-host disease even when the donor is a sibling who shares the Major Histocompatibility Antigens. Therefore, even the perfect HLA match does not represent the optimal genetic match between donors and recipients in HSCT. In addition to the HLA complex other genetic systems operate and affect the outcome of HSCT. These include minor histocompatibility systems (Martin P. Applicability of matching for minor histocompatibility antigens in human bone marrow transplantation. In: Roopenian DC, Simpson E, editors. Minor histocompatibility antigens: From the laboratory to the clinic. Georgetown: Landis Bioscience; 2000. p. 97-103) (inducing bona fide allogeneic responses) as well as a series of functional polymorphisms in cytokines and chemokines and receptors genes (Transplantation 1997;64:553). Among the items affecting the outcome of HSCT the incidence and severity of infections have an important impact. Polymorphisms of genes controlling both arms of the immune responses to pathogens (innate versus cognate) are strong candidates for susceptibility factors to infection in allogeneic transplantation. These include the MHC alleles (HLA class I, class II, MIC) CD1, Toll and TLR genes MBP, MPO genes, ...). In addition to the NK alloreactivity induced by HLA class I epitopes mismatching (a common situation in HSCT) variations in the genotype of the KIR genes (Tissue Antigens 2001;57:358) may also be encountered between the donor and the recipient leading to potentially harmful or beneficial combinations. An integrated knowledge of the role and hierarchy of the most important genetic factors (MHC and non-MHC) will provide the rationale for a comprehensive matching in HSCT (Curr Opin Hematol 3 (1996) 416). This short review provides a panorama of this strategic issue for further development of HSCT.
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2,337,962 |
Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome.
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The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms.
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2,337,963 |
Age dependence of strain determinant on mice motor coordination.
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Evaluation of motor coordination and motor learning in mice remains a challenge as many factors may interact with the different tests used. Among these factors, genetic background has been reported to be a major determinant of mice performances in motor coordination tests. However, it is not known if the strain dependence of motor coordination and motor learning remains constant through life. In order to assess this point, we tested during 5 days male and female mice of three different strains (NMRI, C57BL/6J, and C57BL/6J x 129OlaHsd) in runway, rotarod, and thin rod tests at juvenile (first day of testing = postnatal day 19) and adult (3 months) age. We found a strong strain effect on motor performances and motor learning at juvenile age (C57BL/6J performing more poorly than the two other strains), whatever the tests used. Interestingly, the C57BL/6J mice were the best performing mice at the adult age. These strain rankings were observed either in male and female groups. These results demonstrate that the strain determinant on mice performances and motor learning is highly age dependent.
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2,337,964 |
In vitro synthesis of enzymatically active HIV-1 protease for rapid phenotypic resistance profiling.
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Given the expanding antiretroviral therapy, inexpensive and fast HIV drug resistance assays are urgently needed. In this view, we have developed a novel phenotypic resistance test for HIV-1 protease inhibitors (PIs) based on recombinant expression of patient-derived HIV PR in Escherichia coli and subsequent enzymatic testing in a fluorescent readout.</AbstractText>To facilitate and expedite the test procedure, we have introduced coupled in vitro transcription/translation using a commercially available technology called RTS for producing enzymatically active HIV-1 protease (PR).</AbstractText>We expressed one wild type PR and one highly resistant mutant starting from molecular clones as well as three patient-derived PRs. The amplified PR gene was either ligated into an expression vector or directly used as a template for the in vitro transcription/translation reaction. Enzymatic susceptibility data derived from in vitro expressed PRs were correlated to the respective results from E. coli expression and genotypic evaluation.</AbstractText>All tested enzymes were obtained in sufficient quantities for complete resistance profiling to five PIs. The PRs required no purification prior to the enzymatic assay. Inhibition constants and enzymatic resistance factors compared well to corresponding data from PRs expressed in parallel in E. coli. Enzymatic resistance was in good agreement with the respective PR genotype.</AbstractText>The presented in vitro transcription/translation system represents a novel approach for HIV PR expression starting from molecular clones or patient samples. Coupled with the enzyme-kinetic PR assay recently developed in our group it allows to sensitively quantify resistance to PIs. The test system is significantly less laborious and faster than currently available phenotypic drug resistance assays.</AbstractText>
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2,337,965 |
Familiality of temperament in bipolar disorder: support for a genetic spectrum.
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The array of different diagnoses and clinical presentations seen in the family members of bipolar probands suggests a quantitative or spectrum phenotype. Consistent with this idea, it has been proposed that an underlying quantitative variation in temperament may be the primary phenotype that is genetically transmitted and that it in turn predisposes to bipolar disorder (BP). Choosing the appropriate phenotypic model for BP is crucial for success in genetic mapping studies. To test this theory, various measures of temperament were examined in the family members of bipolar probands. We predicted that a gradient of scores would be observed from those with BP to those with major depression to unaffected relatives to controls.</AbstractText>Members of 85 bipolar families and 63 control subjects were administered clinical interviews for diagnosis (SCID) and two temperament assessments, the TEMPS-A and TCI-125. Subjects with BP, major depressive disorder, unaffected relatives, and controls were compared on each temperament scale and on eight factors extracted from a joint factor analysis of the TEMPS-A and TCI-125.</AbstractText>The four groups were found to be significantly different and with the expected order of average group scores for four of the TEMPS-A scales, three of the TCI-125 scales, and one of the extracted factors. On the fifth TEMPS-A scale, hyperthymic, controls scored higher than the other three subject groups contrary to expectations. Significant differences were seen between unaffected relatives and controls on the hyperthymic scale and on the first extracted factor, anxious/reactive.</AbstractText>Controls were mainly recruited through advertisements, which may have introduced an ascertainment bias. It is also possible that mood state at the time of completing the questionnaire influenced subject's rating of their temperament. Additionally, bipolar I and bipolar II subjects were placed in the same group even though they had some differing clinical features.</AbstractText>Our data support the theory that some dimensions of temperament are transmitted in families as quantitative traits that are part of a broader bipolar spectrum. In particular, the hyperthymic scale of the TEMPS-A and the anxious/reactive extracted factor distinguished unaffected relatives from controls. The hyperthymic scale yielded results opposite to expectation with controls higher than any family group. This may be an artifact of the self-rated form of the questionnaire, a consequence of our grouping bipolar I and II subjects together, or the result of a "protective" factor and bears further study. Nevertheless, both of these scales may be useful quantitative traits for genetic mapping studies.</AbstractText>
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2,337,966 |
CDH1 associated gastric cancer: a report of a family and review of the literature.
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Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant inherited form of gastric cancer associated with inactivating germline mutations in the CDH1 gene. We set out to outline the role of CDH1 in HDGC. Investigation of a family suspected as having HDGC is discussed. The role of surgery in the management of affected individuals is then examined.</AbstractText>A search was conducted of Medline and the National Library of Medicine to identify key articles concerning CDH1 gene mutations, familial gastric cancer and gastrectomy. Further, relevant articles were obtained by manual scanning of the reference lists of identified papers. Mutation-specific CDH1 genetic testing was performed on six living family members and on gastric tissue obtained from two deceased members.</AbstractText>CDH1 mutations cause inactivation of the cell adhesion protein E-cadherin. Carriers of the CDH1 germline gene mutation develop an aggressive, diffuse, submucosal gastric cancer at an early age. Current endoscopic screening is ineffective at detecting HDGC. The presence of a CDH1 germline gene mutation was confirmed in both deceased family members and also in four of the six living members tested.</AbstractText>Genetic counselling and CDH1 gene mutation testing is indicated in families with suspected HDGC. In the absence of a satisfactory surveillance mechanism, prophylactic total gastrectomy would appear to be an appropriate therapeutic option in mutation carriers.</AbstractText>
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2,337,967 |
[Ethical aspects of disclosing information on prenatal screening for Down's syndrome].
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Giving detailed information on prenatal screening for Down's syndrome is considered as paramount since this medical procedure intends to enhance the patient's self-governance in reproductive issues. Not only the respect for autonomy, but also the increased maternal anxiety and the reproductive decisions following the positive test result demand from the genetic professional to offer the test through genetic counselling. The counsellor's awareness about the expectations of pregnant women and the clarification of her own attitude concerning the screening can contribute to the effectiveness of counselling. The content of information embraces the technical aspects of screening and its consequences, like the description of Down's syndrome, the method of screening, the way of risk assessment, the detection rate, the false positive and false negative test results, the diagnostic procedures, and the termination of pregnancy. Written information leaflets should be completed by personal communication as the combination of these two forms has proved to be the most useful. The process of consultation is influenced by the communication skill of the genetic professional and the information seeking activity of the patient, so doctors should be trained to communicate better and patients should be encouraged to get more information about the screening.
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2,337,968 |
Selection of predictor variables for pneumonia using neural networks and genetic algorithms.
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Artificial neural networks (ANN) can be used to select sets of predictor variable that incorporate nonlinear interactions between variables. We used a genetic algorithm, with selection based on maximizing network accuracy and minimizing network input-layer cardinality, to evolve parsimonious sets of variables for predicting community-acquired pneumonia among patients with respiratory complaints.</AbstractText>ANN were trained on data from 1044 patients in a training cohort, and were applied to 116 patients in a testing cohort. Chromosomes with binary genes representing input-layer variables were operated on by crossover recombination, mutation, and probabilistic selection based on a fitness function incorporating both network accuracy and input-layer cardinality.</AbstractText>The genetic algorithm evolved best 10-variable sets that discriminated pneumonia in the training cohort (ROC areas, 0.838 for selection based on average cross entropy (ENT); 0.954 for selection based on ROC area (ROC)), and in the testing cohort (ROC areas, 0.847 for ENT selection; 0.963 for ROC selection), with no significant differences between cohorts. Best variable sets based on the genetic algorithm using ROC selection discriminated pneumonia more accurately than variable sets based on stepwise neural networks (ROC areas, 0.954 versus 0.879, p = 0.030), or stepwise logistic regression (ROC areas, 0.954 versus 0.830, p = 0.000). Variable sets of lower cardinalities were also evolved, which also accurately discriminated pneumonia.</AbstractText>Variable sets derived using a genetic algorithm for neural networks accurately discriminated pneumonia from other respiratory conditions, and did so with greater accuracy than variables derived using stepwise neural networks or logistic regression in some cases.</AbstractText>
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2,337,969 |
Evaluation of closed adult nucleus multiple ovulation and embryo transfer and conventional progeny testing breeding schemes for milk production in tropical crossbred cattle.
|
The potential benefits of closed adult nucleus multiple ovulation and embryo transfer (MOET) and conventional progeny testing (CNS) schemes, and the logistics of their integration into large-scale continuous production of crossbred cattle were studied by deterministic simulation. The latter was based on F1 (Bos taurus x Bos indicus) production using AI or natural mating and MOET, and continuous F2 production by mating of F1 animals. The gene flow and the cumulative discounted expressions (CDES) were also calculated. Both schemes had 8, 16, 32, or 64 dams with 2, 4, 8, 16, or 32 sires selected. In the MOET nucleus scheme (MNS), the test capacity was 1, 2, 8, or 16 offspring, and the number of matings per dam per year was 1, 2, or 4. A scheme of 8 sires with 64 dams and a test capacity of 4 female offspring per dam per year resulted in an annual genetic gain (in phenotypic standard deviation) of 0.324 and 0.081 for MNS and CNS, respectively. In the MNS, there was substantial genetic gain with a relatively small number of animals compared with a CNS. The F1 had the highest, and the F2 scheme the lowest CDES. However, a very large number of B. indicus females would be required in the F1 scheme. This scheme may not be practical under conditions in developing countries. The F2 scheme was logistically attractive because it produces its own replacements, and the number of B. taurus females required would be easy to attain. Accompanying technical and financial constraints of nucleus schemes should be addressed before applying them.
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2,337,970 |
Structural characterization and transcriptional regulation of the gene encoding diapause hormone and pheromone biosynthesis activating neuropeptide in the cotton bollworm, Helicoverpa armigera.
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We have cloned the gene encoding the diapause hormone and the pheromone biosynthesis activating neuropeptide in Helicoverpa armigera (Har-DH-PBAN). The Har-DH-PBAN gene contains six exons and five introns that fall in the same positions as in the Bombyx mori DH-PBAN gene (Bom-DH-PBAN). The transcription initiation site lays 29 bp upstream of the translation initiation site. Southern blot analysis suggests that a single copy of this gene is present per haploid genome. A structural comparison of DH-PBAN promoters between H. armigera and B. mori show similarities in the TATA box and in a potential binding site for a POU family transcription factor, POU-M2. However, testing of these DNA regions for factor binding in vitro and transcription assays in cell culture highlight significant differences in their regulation particularly in reference to the POU-M2 sites. Our results uncover common and different regulatory mechanisms at work in the control of DH-PBAN gene expression in H. armigera and B. mori.
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2,337,971 |
Atopic disease in childhood.
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A child with atopy produces IgE antibodies after exposure to common environmental allergens. The atopic diseases (eczema, asthma and rhinoconjunctivitis) are clinical syndromes each defined by a group of symptoms and signs. Not all children with atopy will have atopic disease or develop symptoms after exposure to an allergen. Both genetic and environmental factors determine the development of atopic disease. The presence of specific IgE antibodies to environmental allergens is determined with skin prick or radioallergosorbent testing in children with atopy. Test results should be interpreted in the context of the clinical history and further investigations (eg, allergen avoidance or challenge). Management of atopic disease is frequently symptomatic, but it is important to avoid identified allergen triggers. Immunotherapy may be considered in selected school-age children with severe rhinoconjunctivitis. Preventing atopic disease in high-risk infants and hindering progression of disease in children with established disease are the areas of active research.
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2,337,972 |
Greenberg v. Miami Children's Hospital Research Institute.
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Court Decision: 264 Federal Supplement, 2d Series 1064; 2003 May 29 (date of decision). Plaintiffs in this case were a group of parents of children afflicted with Canavan disease, who provided tissue for research on the disease and aided in identification of other affected families, and three nonprofit organizations that had developed a confidential database and Canavan disease registry. The defendants were physician-researcher Reuben Matalon, who isolated and patented the Canavan gene sequence and developed genetic screening tests for it, and the Miami facilities where he did his research. The U.S. District Court for the Southern District of Florida dismissed several of the plaintiffs' claims, including lack of informed consent, breach of fiduciary duty, fraudulent concealment of the patent, and misappropriation of trade secrets. However, the court upheld the claim of unjust enrichment made by the donors of tissue, on the grounds that "the facts paint a picture of a continuing research collaboration that involved Plaintiffs also investing time and significant resources."
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2,337,973 |
Identification of novel mutations in patients with Shwachman-Diamond syndrome.
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Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease, mainly characterized by exocrine pancreatic insufficiency, hematological dysfunction and skeletal abnormalities. The SDS disease locus was mapped to chromosome 7q11 and disease-associated mutations were reported in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SBDS is a member of a highly conserved protein family with putative orthologs in diverse species including archaea and eukaryotes. It is widely expressed in many tissues and its function is still unknown. In the present study we analyzed the genotype of 15 unrelated Italian SDS patients. After sequencing the whole coding region we were able to complete all genotypes of the SDS patients tested. A total of eleven distinct mutations were identified. The most frequent mutations are due to gene conversion events between SBDS and its unprocessed pseudogene, named SBDSP. We described four new gene conversions involving exon 2 and three novel mutations that are not a result of gene conversion events. In two out of the fifteen cases, the family analysis evidenced an apparently unexpected inheritance of SDS alleles between parents and affected children. In the first case we found a new large gene conversion event, that caused the failure of the amplification of the father's allele and in the second what could be explained as a de novo gene conversion. Both cases have important implications for genetic counseling and molecular genetic analysis. In a disorder caused by gene conversions of variable extension these findings emphasize the necessity of testing patient's parents and the significance of the choice of primers.
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2,337,974 |
Recurrent myoglobinuria due to carnitine palmitoyltransferase II deficiency: clinical, biochemical, and genetic features of adult-onset cases.
|
To create awareness of adult-onset carnitine palmitoyltransferase II (CPT II) deficiency by describing the clinical, biochemical, and genetic features of three New Zealand patients with this disorder.</AbstractText>Review of case notes, creatine kinase (CK) values, CPT II assay results, genetic mutation analyses, and the literature.</AbstractText>Three patients with CPT II deficiency were encountered by the authors over a 7-year period. Onset of symptoms was between ages 10 and 17 years. Each patient reported exertional myalgia, and had had at least two episodes of myoglobinuria following exertion or infection. Interictal neurological examinations, CK values, and routine muscle histology were normal. CPT II activities ranged from 3.8 to 9.7 pmol/min/mg protein (normal+/-SD=162.9+/-51.0 pmol/min/mg protein). Genetic analysis showed that one patient was homozygous and two were heterozygous for S113L, the common mutation in CPT II deficiency.</AbstractText>CPT II deficiency should be suspected in patients with persistent exertional myalgia who have one or more episodes of myoglobinuria. The diagnosis is confirmed using a combination of enzyme assay and genetic testing.</AbstractText>
|
2,337,975 |
Impact of direct-to-consumer advertising for hereditary breast cancer testing on genetic services at a managed care organization: a naturally-occurring experiment.
|
To describe the impact of Myriad Genetics, Inc.'s direct-to-consumer advertising (DTC-ad) campaign on cancer genetic services within two Managed Care Organizations, Kaiser Permanente Colorado (KPCO), Denver, Colorado, where the ad campaign occurred, and Henry Ford Health System (HFHS), Detroit, Michigan, where there were no advertisements.</AbstractText>The main outcome measures were the changes in number and pretest mutation probability of referrals approved for cancer genetic services at KPCO and HFHS during the campaign versus the year prior, and mutation probability of those undergoing testing.</AbstractText>At KPCO, referrals increased 244% during the DTC-ad compared to the same time period a year earlier (P value<0.001). The proportion of referrals at high pretest probability of a mutation (10% or greater) dropped from 69% the previous year to 48% during the campaign (P value<0.001). There was no significant change in pretest mutation probability among women who underwent testing between the two time periods. HFHS reported no significant change between the two time periods for numbers or mutation probability of referrals, or for mutation probability of women tested.</AbstractText>The DTC-ad caused significant increase in demand for cancer genetic services. In the face of potential future DTC-ad for inherited cancer risk, providers and payers need to consider the delivery of genetic services and genetic education for persons of all risk levels.</AbstractText>
|
2,337,976 |
Mutation analysis of autosomal dominant polycystic kidney disease genes in Han Chinese.
|
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in two genes, PKD1 and PKD2. The complexity of these genes, particularly PKD1, has complicated genetic screening, though recent advances have provided new opportunities for amplifying these genes. In the Han Chinese population, no complete mutational analysis has previously been conducted across the entire span of PKD1 and PKD2. Here, we used single-strand conformation polymorphism (SSCP) analysis to screen the entire coding sequence of PKD1 and PKD2 in 85 healthy controls and 72 Han Chinese from 24 ADPKD pedigrees. In addition to 11 normal variants, we identified 17 mutations (12 in PKD1 and 5 in PKD2), 15 of which were novel ones (11 for PKD1 and 4 for PKD2). We did not identify any seeming mutational hot spots in PKD1 and PKD2. Notably, we found several disease-associated C-T or G-A mutations that led to charge or hydrophobicity changes in the corresponding amino acids. This suggests that the mutations cause conformational alterations in the PKD1 and PKD2 protein products that may impact the normal protein functions. Our study is the first report of screenable mutations in the full-length PKD1 and PKD2 genes of the Han Chinese, and also offers a benchmark for comparisons between Caucasian and Han ADPKD pedigrees and patients.
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2,337,977 |
Molecular analysis of the CYP21 gene and prenatal diagnosis in families with 21-hydroxylase deficiency in northeastern Iran.
|
A rapid and convenient approach for the detection of the most common CYP21 gene mutations in patients with congenital adrenal hyperplasia (CAH) with classical forms of 21-hydroxylase deficiency was used. In addition, a new semiquantitative strategy for the detection of del8-bp was designed. These procedures were used for prenatal diagnosis and genotype-phenotype correlation in northeastern Iran.</AbstractText>Molecular analysis of the CYP21 gene for the detection of the 9 most common mutations (CYP21gene deletion, P30L, i2g, del-8bp, I172N, E6 cluster, V281L, Q318X and R356W) was performed on 30 CAH patients and for prenatal diagnosis in 2 cases.</AbstractText>Restriction fragment length polymorphism, amplification-created restriction sites, allele-specific polymerase chain reaction (PCR) and semiquantitative PCR were performed.</AbstractText>We characterized 90% of the CAH chromosomes. The most frequent mutations in the CYP21 gene were del-CYP21 (25%), I172N (22%) and i2g (15%). Unlike in other ethnic groups, there was no R356W mutation, however, a higher rate of del-8bp (10%) was found in our population. Wealso found 6 complex alleles in our patients. For 2 families prenatal CYP21 gene analysis resulted in the diagnosis of healthy fetuses and termination of dexamethasone treatment in the 15th week of gestation. Genotype-phenotype correlation was observed. The rate of homozygosity (50%) was greater than the predicted values due to the higher rate of parental consanguinity in our population.</AbstractText>These molecular procedures proved to be sensitive and rapid for the detection of the most common mutations of the CYP21 gene and prenatal diagnosis. Increased 17-hydroxyprogesterone, found in neonatal CAH screening, can be confirmed by these mutation analyses.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,337,978 |
Psychological impact of genetic testing for hereditary nonpolyposis colorectal cancer.
|
This study examines the impact of hereditary nonpolyposis colorectal cancer (HNPCC) genetic test results on psychological outcomes among cancer-affected and -unaffected participants up to 1 year after results disclosure.</AbstractText>A total of 155 persons completed study measures before HNPCC genetic testing, and at 2 weeks and 6 and 12 months after disclosure of test results.</AbstractText>Mean scores on all outcome measures remained stable and within normal limits for cancer-affected participants, regardless of mutation status. Among unaffected carriers of HNPCC-predisposing mutations, mean depression, state anxiety, and cancer worries scores increased from baseline to 2 weeks postdisclosure and decreased from 2 weeks to 6 months postdisclosure. Among unaffected noncarriers, mean depression and anxiety scores did not differ, but cancer worries scores decreased during the same time period. Affected and unaffected carriers had higher mean test-specific distress scores at 2 weeks postdisclosure compared with noncarriers in their respective groups; scores decreased for affected carriers and all unaffected participants from 2 weeks to 12 months postdisclosure. Classification of participants into high- versus low-distress clusters using mean scores on baseline psychological measures predicted significantly higher or lower follow-up scores, respectively, on depression, state anxiety, quality of life, and test-specific distress measures, regardless of mutation status.</AbstractText>Although HNPCC genetic testing does not result in long-term adverse psychological outcomes, unaffected mutation carriers may experience increased distress during the immediate postdisclosure time period. Furthermore, those with higher levels of baseline mood disturbance, lower quality of life, and lower social support may be at risk for both short- and long-term increased distress.</AbstractText>
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2,337,979 |
'The edge effect': an exploratory study of some factors affecting referrals to cancer genetic services in rural Wales.
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This exploratory study examines the role of rurality in referrals from primary care to the Cancer Genetics Service for Wales (CGSW) through a case study of referrals from Montgomeryshire, a predominantly rural area in mid-Wales located adjacent to the English border. Awareness of CGSW amongst practitioners is low. We found that rurality plays a role in referral behaviour as distance, time travelling and accessibility by car and public transport are all perceived to have an impact on the patient's decision to attend a clinic appointment. Some patients are being referred outside Wales as ease of access to services is considered more important than distance.
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2,337,980 |
[Muscular dystrophy].
|
The muscular dystrophies are a genetically heterogeneous group of progressive disorders that lead to the breakdown of the integrity of skeletal muscle. Numerous recent advances made in research into the molecular genetics of muscular dystrophy have highlighted the diversity of this family of disorders. Muscle biopsy allows the immunohistochemical analysis of various muscle specific proteins, and can provide important data enabling definitive diagnosis. Muscle biopsy is not always necessary, such as in the case of Duchenne or Fukuyama type dystrophies, which are relatively easy to diagnose by genetic testing; in such cases, however, consideration must given to the ethical implications of testing. The future promises the development of new therapeutic approaches and clinical applications based on genetic diagnostic data.
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2,337,981 |
[Gene diagnosis of antithrombin deficiency and factor VII deficiency].
|
Since 1996 we have performed gene diagnosis of hereditary antithrombin deficiency and factor VII deficiency. We studied twenty-three patients with antithrombin deficiency and identified eighteen distinct gene mutations including single nucleotide substitutions, small nucleotide deletions, a small nucleotide insertion, and whole gene deletions. In two patients, however, we couldn't find out any mutations. We studied three patients with factor VII deficiency and identified three missense mutations. Two patients were homozygous for the mutation, respectively. Unexpectedly one patient was heterozygous for a missense mutation in the EGF domain though her plasma level of factor VII was reduced to 7% of normal. These results revealed that the genetic backgrounds and molecular mechanisms of antithrombin deficiency and factor VII deficiency were highly heterogeneous.
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2,337,982 |
[Genetic medicine in Japan].
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Present status of genetic medicine in Japan is reviewed. More than five hundred medical doctors have now been qualified as Japanese board of clinical genetics. Training courses for genetic counselors have started in several colleges. Thirty-six hospitals organized by University or National Centers have independent units of clinical genetics. Two major Japanese homepages concerning about clinical genetics are available. Ethical guidelines for gene testing and prenatal diagnosis are published by Japanese Society for Human Genetics and other Japanese medical societies. Infrastructure for clinical genetics are now rapidly organized in Japan, however lots of problems are still waiting to be solved.
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2,337,983 |
[Ethical guidelines on genetic testing and gene therapy].
|
According to the recent and rapid advances in molecular genetics research, genetic testing and gene therapy have a potential of giving unexpected influence to the human beings. To prevent and to solve various ethical, legal and social implementations (ELSI) of genetic testing and gene therapy, several guidelines have been established. In Japan, all researchers and all clinicians have to know and keep the following three guidelines on genetic testing and a guideline on gene therapy: 1) "Guidelines for Researches on Human Genome and Gene (2001)" by the three Ministries (Education, Health and Economy), 2) "Guidelines for Genetic Testing (2001)" by the Genetic--medicine--related 10 societies, 3) "Ethical Principles on Entrusted Genetic Testing (2001)" by the Japan Registered Clinical Laboratories Association, and 4) "Guidelines for Clinical Research on Gene Therapy (2002)" by the two Ministries (Health and Education).
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2,337,984 |
[Genetic testing].
|
Mechanisms of human diseases have been elucidated along with the progress of the Human Genome Project, which has enabled accurate genetic testing towards personalized medicine. Besides the examination of an individual gene, RNA profiling, epigenetic test and molecular karyotyping have been applied to analyze clinical specimens. Current status of genetic testing technologies are briefly summarized, together with future perspectives.
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2,337,985 |
Primary hyperoxaluria type 1: is genotyping clinically helpful?
|
There is some controversy about the value of mutation analysis in the management of primary hyperoxaluria type 1 (PH1). About 50 different mutations of the AGXT gene encoding the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) are currently known. The three most common mutations in the Western population account for less than half of the mutant alleles, and no simple screening test is available. Does the genotype help in diagnosis, prognosis and therapy? Definitive diagnosis is indispensable if liver transplantation is considered and can under certain circumstances be established by mutation analysis, but a liver biopsy is still necessary to determine AGT activity in a number of cases. Prognosis is difficult to assess due to a large clinical variation, despite identical mutations. Although the homozygous 508G>A (Gly170Arg) mutation appears to be associated with a better (and 33insC with a worse) prognosis, there are too many exceptions for precise prediction. Pyridoxine responsiveness can be anticipated in some genotypes (508G>A (Gly170Arg) and 454T>A (Phe153Ile)), but it should still be tested for in all patients. Genetic testing is thus clinically helpful but has clear limitations.
|
2,337,986 |
A nonparametric approach to the analysis of longitudinal data via a set of level crossing problems with application to the analysis of microarray time course experiments.
|
Here we develop a completely nonparametric method for comparing two groups on a set of longitudinal measurements. No assumptions are made about the form of the mean response function, the covariance structure or the distributional form of disturbances around the mean response function. The solution proposed here is based on the realization that every longitudinal data set can also be thought of as a collection of survival data sets where the events of interest are level crossings. The method for testing for differences in the longitudinal measurements then is as follows: for an arbitrarily large set of levels, for each subject determine the first time the subject has an upcrossing and a downcrossing for each level. For each level one then computes the log rank statistic and uses the maximum in absolute value of all these statistics as the test statistic. By permuting group labels we obtain a permutation test of the hypothesis that the joint distribution of the measurements over time does not depend on group membership. Simulations are performed to investigate the power and it is applied to the area that motivated the method-the analysis of microarrays. In this area small sample sizes, few time points and far too many genes to consider genuine gene level longitudinal modeling have created a need for a simple, model free test to screen for interesting features in the data.
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2,337,987 |
Linkage analysis reveals two independent loci for ocular disorders in a local Japanese Black cattle population.
|
A vision-impairing ocular disorder was observed in a local Japanese Black cattle population, and assumed to be an autosomal recessive disease based on the presence of a founder cow. A genome scan using seven affected half-sib pairs revealed a linkage to BTA5 (Z(max) = 7.0, LOD(max) = 2.0), designated the bovine ocular disorder 1 (bod1) locus. Of the seven animals, three were heterozygous at the bod1 locus. Analysis in these three animals revealed linkage to markers on BTA18, and this locus was designated bod2. Detailed haplotype inspection of 16 affected animals indicated linkage to BTA5 in 12 animals, BTA18 in three animals, and linkage to both BTA5 and BTA18 in one animal. The bod1 locus was mapped to a 25 cM interval between DIK5237 and DIK5210 on BTA5 (Z(max) = 17.0, LOD(max) = 11.8), and bod2 was mapped to a 7 cM interval between DIK5411 and INRA038 on BTA18 (Z(max) = 13.0, LOD(max) = 4.0). This study demonstrated that the independent involvement of loss of function mutations in two loci is likely responsible for this genetic heterogeneity.
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2,337,988 |
Genetic testing and surgeon decision.
|
Colorectal cancer is a highly treatable and often curable disease when localized to the bowel. Traditional pathological staging systems have been useful in predicting the outcome of colorectal cancer, but is now evident that colorectal cancer is heterogeneous and its natural story strongly correlates with genetic alterations that occur during progression from adenoma to carcinoma to metastatic disease. The goal of many studies is to define a marker, or set of markers, on which therapeutic decisions could be made with greater precision for given individuals. In investigations in which at least 100 patients with locally advanced colon cancer have been studied, those in which monoclonal antibodies to p53 (PAB 1801/DO-7/D0-1) were used have generally demonstrated that mutant or overexpression of p53 is associated with a worse clinical outcome.
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2,337,989 |
[The role of genetic factors in human radioresistance].
|
The role of genetic factors in the development of chronic radiation disease (CRD), mostly caused by occupational external gamma-exposure, was evaluated. The data of molecular genetic survey of a cohort of 985 workers at the nuclear power plant, the Mayak PA, were analyzed. Among the genetic markers tested, an association between the haptoglobin (Hp) genetic system and the development of CRD was established. It was demonstrated that the contribution of genetic factors to the CRD onset was realized not within the whole, but in a relatively narrow dose interval (70 to 400 cGy), i.e., was relative. Furthermore, at equal irradiation doses, relatively higher risk of CRD was observed among the Hp 2-2 phenotype carriers (1.96) compared to lower risk among the Hp 1-1 and Hp 2-1 phenotype carriers (0.64). It was shown that with the increase of the irradiation dose, genotypic differences in the CRD frequency decreased to the point of their complete disappearance. Comparison of the roles of the genetic factors in the onset of such deterministic irradiation effect as CRD, with their roles in the onset of lung cancer in tobacco smokers revealed similar patterns. A scheme of the relationships between the effector intensity and the differences in the genetically determined radioresistance is presented. The data obtained do not support the idea that the survivals of the atomic bombing of Hiroshima and Nagasaki were the most radioresistant individuals, who are not representative for evaluating the radiation risk.
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2,337,990 |
Acute and genetic toxicity of essential oil extracted from Litsea cubeba (Lour.) Pers.
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Litsea cubeba oil is an aromatic essential oil extracted from the fresh fruits of Litsea cubeba (Lour.) Pers. It is used as a flavor enhancer in foods, cosmetics, and cigarettes; as a raw material in the manufacture of citral, vitamins A, E, and K, ionone, methyl ionone, and perfumes; and as an antimicrobial and insecticide. Based on the widespread use of L. cubeba oil, its insolubility in water, resulting in its partition in soil sediment, and its volatility when exposed to the atmosphere, risk of injury due to consumption and occupational exposure may be significant. In the present study, we studied the toxicity of L. cubeba oil with a battery of acute and genetic toxicity tests in Institute of Cancer Research mice and Sprague-Dawley rats. The oral, dermal, and inhalation 50% lethal dose and concentration (LD50 and LC50) of L. cubeba oil were determined. Results indicated that the oral LD50, the dermal LD50, and the inhalation LC50 are approximately 4,000 mg/kg of body weight, in excess of 5,000 mg/kg, and approximatively 12,500 ppm, respectively. We therefore conclude that L. cubeba oil is slightly toxic. In addition, the genetic toxicity of L. cubeba oil was assessed with Salmonella Typhimurium, by determination of the induction of micronuclei in bone marrow cells, and also by testing for chromosome aberration in spermatocyte cells of Institute of Cancer Research mice. The results of genetic toxicity testing of L. cubeba oil in vitro and in vivo were negative.
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2,337,991 |
[Genetic control of the fluorescent sounding indices testing gluten quality].<Pagination><StartPage>30</StartPage><EndPage>34</EndPage><MedlinePgn>30-4</MedlinePgn></Pagination><Abstract><AbstractText>The interactions of genes on 10 indices defined by fluorescent sound probe in the system of half-diallele crossings were studied. The indexes of hydrophobic interactions are controlled by additive-dominant system of genes. The epistatic interactions take place as well. Genetic properties of 10 cultivars and breeding forms of spring wheat were studied. The carriers of recessive alleles of breeding value were revealed.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kibkalo</LastName><ForeName>I A</ForeName><Initials>IA</Initials></Author><Author ValidYN="Y"><LastName>Bebiakin</LastName><ForeName>V M</ForeName><Initials>VM</Initials></Author><Author ValidYN="Y"><LastName>Kulagina</LastName><ForeName>T V</ForeName><Initials>TV</Initials></Author></AuthorList><Language>rus</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><VernacularTitle>Geneticheskiĭ kontrol' pokazateleĭ fliuorestsentnogo zondirovaniia, testiruiushchikh kachestvo kleĭkoviny.</VernacularTitle></Article><MedlineJournalInfo><Country>Ukraine</Country><MedlineTA>Tsitol Genet</MedlineTA><NlmUniqueID>0101671</NlmUniqueID><ISSNLinking>0564-3783</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005456">Fluorescent Dyes</NameOfSubstance></Chemical><Chemical><RegistryNumber>8002-80-0</RegistryNumber><NameOfSubstance UI="D005983">Glutens</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000483" MajorTopicYN="N">Alleles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003433" MajorTopicYN="N">Crosses, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004843" MajorTopicYN="Y">Epistasis, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005456" MajorTopicYN="N">Fluorescent Dyes</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005799" MajorTopicYN="N">Genes, Dominant</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017343" MajorTopicYN="N">Genes, Plant</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005808" MajorTopicYN="N">Genes, Recessive</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005838" MajorTopicYN="N">Genotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005983" MajorTopicYN="N">Glutens</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="Y">analysis</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008957" MajorTopicYN="N">Models, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014908" MajorTopicYN="N">Triticum</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000254" MajorTopicYN="N">growth & development</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>18</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>5</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>18</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15771087</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15771064</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>22</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>18</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1019-5297</ISSN><JournalIssue CitedMedium="Print"><Issue>8</Issue><PubDate><Year>2004</Year><Month>Dec</Month></PubDate></JournalIssue><Title>Likars'ka sprava</Title><ISOAbbreviation>Lik Sprava</ISOAbbreviation></Journal>[Analysis of hereditary predisposition factors to the development of polygenic diseases of viscera].
|
The interactions of genes on 10 indices defined by fluorescent sound probe in the system of half-diallele crossings were studied. The indexes of hydrophobic interactions are controlled by additive-dominant system of genes. The epistatic interactions take place as well. Genetic properties of 10 cultivars and breeding forms of spring wheat were studied. The carriers of recessive alleles of breeding value were revealed.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kibkalo</LastName><ForeName>I A</ForeName><Initials>IA</Initials></Author><Author ValidYN="Y"><LastName>Bebiakin</LastName><ForeName>V M</ForeName><Initials>VM</Initials></Author><Author ValidYN="Y"><LastName>Kulagina</LastName><ForeName>T V</ForeName><Initials>TV</Initials></Author></AuthorList><Language>rus</Language><PublicationTypeList><PublicationType UI="D004740">English Abstract</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><VernacularTitle>Geneticheskiĭ kontrol' pokazateleĭ fliuorestsentnogo zondirovaniia, testiruiushchikh kachestvo kleĭkoviny.</VernacularTitle></Article><MedlineJournalInfo><Country>Ukraine</Country><MedlineTA>Tsitol Genet</MedlineTA><NlmUniqueID>0101671</NlmUniqueID><ISSNLinking>0564-3783</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D005456">Fluorescent Dyes</NameOfSubstance></Chemical><Chemical><RegistryNumber>8002-80-0</RegistryNumber><NameOfSubstance UI="D005983">Glutens</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000483" MajorTopicYN="N">Alleles</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003433" MajorTopicYN="N">Crosses, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004843" MajorTopicYN="Y">Epistasis, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005456" MajorTopicYN="N">Fluorescent Dyes</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005799" MajorTopicYN="N">Genes, Dominant</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017343" MajorTopicYN="N">Genes, Plant</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005808" MajorTopicYN="N">Genes, Recessive</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005838" MajorTopicYN="N">Genotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005983" MajorTopicYN="N">Glutens</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="Y">analysis</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008957" MajorTopicYN="N">Models, Genetic</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014908" MajorTopicYN="N">Triticum</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000254" MajorTopicYN="N">growth & development</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>3</Month><Day>18</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>5</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>3</Month><Day>18</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15771087</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15771064</PMID><DateCompleted><Year>2005</Year><Month>04</Month><Day>22</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>18</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1019-5297</ISSN><JournalIssue CitedMedium="Print"><Issue>8</Issue><PubDate><Year>2004</Year><Month>Dec</Month></PubDate></JournalIssue><Title>Likars'ka sprava</Title><ISOAbbreviation>Lik Sprava</ISOAbbreviation></Journal><ArticleTitle>[Analysis of hereditary predisposition factors to the development of polygenic diseases of viscera].</ArticleTitle><Pagination><StartPage>21</StartPage><EndPage>23</EndPage><MedlinePgn>21-3</MedlinePgn></Pagination><Abstract>The article presents an analysis of hereditary factors and their role in predisposition to obstructive broncho-pulmonary diseases and duodenal ulcer in workers of metal manufacture. Morphological and phonotypical signs of systems of erythrocytic and blood plasma proteins were marked out, which enable to determine predisposition or resistance to the development of obstructive broncho-pulmonary diseases and duodenal ulcer.
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2,337,992 |
[Congenital muscular dystrophies: muscle-eye-brain disease].
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Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. We report on two brothers with MEB. The clinical and radiological characteristics are demonstrated.
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2,337,993 |
Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10,000 SNPs on DNA chips.
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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with a complex genetic background. Here, we present a genome screen for association in small scale, employing 11,555 single nucleotide polymorphisms (SNPs) on DNA chips for genotyping 100 MS patients stratified for HLA-DR2+ and 100 controls. More than 500 SNPs revealed significant differences between cases and controls before Bonferroni correction. A fraction of these SNPs was reanalysed in two additional cohorts of patients and controls, using high-throughput genotyping methods. A marker on chromosome 6p21.32 (rs2395182) yielded the highest significance level, validating the established HLA-DR association.
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2,337,994 |
Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort.
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The phenotype of Bardet-Biedl syndrome (BBS) is defined by the association of retinitis pigmentosa, obesity, polydactyly, hypogenitalism, renal disease and cognitive impairement. The significant genetic heterogeneity of this condition is supported by the identification, to date, of eight genes (BBS1-8) implied with cilia assembly or function. Triallelic inheritance has recently been suggested on the basis of the identification of three mutated alleles in two different genes for the same patient. In a cohort of 27 families, six BBS genes (namely BBS1, BBS2, BBS4, BBS6, BBS7 and BBS8) have been studied. Mutations were identified in 14 families. Two mutations within the same gene have been identified in seven families. BBS1 is most frequently implied with the common M390R substitution at the homozygous state (n=2), or associated with another mutation at BBS1 (n=3). Compound heterozygous mutations have been found in BBS2 (one family) and BBS6 (one family). In seven other families, only one heterozygous mutation has been identified (once in BBS1, twice for BBS2 and three times in BBS6). Although our study did not reveal any families with bona fide mutations in two BBS genes, consistent with a triallelic hypothesis, we have found an excess of heterozygous single mutations. This study underlines the genetic heterogeneity of the BBS and the involvement of possibly unidentified genes.
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2,337,995 |
Fine mapping of a QTL region with large effects on growth and fatness on mouse chromosome 2.
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We combined the use of a congenic line and recombinant progeny testing (RPT) to characterize and fine map a previously identified region of distal mouse chromosome 2 (MMU2) harboring quantitative trait loci (QTL) with large effects on growth and fatness. The congenic line [M16i.B6-(D2Mit306-D2Mit52); MB2] was created using an inbred line (M16i) derived from a line that had undergone long-term selection for rapid weight gain (M16) as the recipient for an approximately 38-cM region on MMU2 from the inbred line C57BL/6J. A large F2 cohort (1,200 mice) originating from a cross between MB2 and M16i was created, and 40 F2 males with defined recombinations within the QTL region were used to produce 665 segregating progeny. Linkage analysis of the F2 population detected QTL with very large effects on body weight, body fat, lean tissue mass, bone mineral density, and liver weight. Confidence intervals of the QTL were narrowed to regions of 1.5-4.5 cM. Analysis of progeny of the recombinant F2 males confirmed the existence of the QTL and further contributed to localization of their map positions. These efforts confirmed the presence of QTL with major effect on MMU2, narrowed the estimated region harboring the QTL from 38 to 12 cM, and further characterized phenotypic effects of the QTL, effectively culminating in a significantly decreased pool of positional candidate genes potentially representing these genes controlling predisposition to growth and fatness.
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2,337,996 |
Molecular basis of Hb H disease in southwest Iran.
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Although alpha0-thalassemia (thal) defects are not very frequent in the Iranian population, Hb H disease does occur in the country. We have analyzed the alpha gene cluster of 13 patients showing the presence of Hb H to establish the molecular background of this disease in southwest Iran (Shiraz and Hormozgan provinces). Using gap-polymerase chain reaction (gap-PCR) and direct DNA sequencing we have found the --MED-I deletion, the polyadenylation signal (poly A) mutations alphaT-Saudi alpha and alphaT-Turkish alpha and Hb Constant Spring (Hb CS) in association with the common -alpha3.7 deletion. This study has revealed that: 1) at least six genotypes are responsible for Hb H disease in the area: .-alpha3.7/ --MED-I; -alpha3.7/alphaT-Saudi alpha; alphaT-Saudi alpha/alphaT-Saudi alpha; alphaCSalpha/--MED-I; --MED-I/alphaT-Turkish alpha; and the atypical forms of Hb H disease -alpha3.7/alphaCSalpha. 2) The molecular background of Hb H disease in the southwest area of Iran is more similar to the Mediterranean type than to the Southeast Asian. 3) Hb Bart's hydrops fetalis syndrome and mild, intermediate or severe postnatal Hb H disease conditions can be expected, but at a relatively low incidence. 4) The diagnostic flowchart for patients with microcytic hypochromic anemia should include iron deficiency, beta-thal, alpha+- and alpha0-thal analyses.
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2,337,997 |
Campaign to control genetic blood diseases in Bahrain.
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Genetic blood diseases are frequent in Bahrain as in all Middle Eastern countries. Previous neonatal screening in 1984-1985 showed that the birth prevalence of sickle cell disease (SCD) was 2.1%, of sickle cell trait 11% and of glucose-6-phosphate dehydrogenase (G6PD) deficiency 25%. The Ministry of Health recognized the importance of controlling these diseases. In 1984, the first genetic clinic was established, which started the educational campaigns. Information booklets were prepared and distributed widely in schools and clubs in an attempt to increase awareness about these diseases among students and the public. In 1991, the Bahrain Hereditary Anemia Society was formed. In 1992, the Minister of Health formed a national committee for the prevention of genetic diseases in Bahrain. Screening of all pregnant women began, followed by newborn testing if the mother was found to be a carrier. In 1993, a premarital counseling (PMC) service was organized and in 1998, a student-screening project began. At this stage, we want to update the national birth prevalence figure by screening Bahraini newborns for these genetic diseases. This will help to design prevention programs and to measure the effect of health education on the previous birth prevalence figure.</AbstractText>A newborn screening study was conducted to determine the effects of this long-term campaign (16-18 years). Cord blood samples from 2,000 Bahraini newborns were tested for hemoglobinopathies and G6PD deficiency using HPLC.</AbstractText>18 newborns were found to have SCD. The new birth prevalence figure for SCD in Bahrain is 0.9%, which indicates a 60% decline in the birth prevalence rate.</AbstractText>With the continuation of education, awareness campaigns, screening of carriers and PMC, we expect the number of affected children born to be reduced tremendously over the next few years.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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2,337,998 |
Recently available techniques applicable to genetic problems in the Middle East.
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In this paper, we address the preventive health aspects of genetic problems in the Middle East and provide guidelines to prioritize preventive strategies. Applications of various novel genetic techniques such as comprehensive neonatal screening, high throughput heterozygote detection, preimplantation genetic diagnosis, Affymetrix systems, the NanoChip system and a new way of sensitive karyotyping for single-cell chromosome abnormalities are discussed. In conclusion, from the various genetic techniques available, each country should adopt strategies most suitable to its genetic needs and should prioritize the programs to be used in prevention.
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2,337,999 |
DNA diagnosis of single gene disorders in patients of non-European origin: experience from Kuwait.
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The aim of this study was to establish genetic DNA-diagnostic service in Kuwait.</AbstractText>Polymerase chain reaction, restriction fragment length polymorphisms, heteroduplex analysis and DNA sequencing were applied.</AbstractText>Direct testing for common mutations had variable success in Kuwaiti patients with different genetic disorders, and additional mutation analysis was required in many cases. Genetic heterogeneity, mutations of Mediterranean, African and Arabic/Middle Eastern origin, and homozygosity by descent are characteristic of patients from Kuwait.</AbstractText>More efforts aimed at the identification of mutations underlying genetic disorders in Kuwait as well as in other Gulf countries are warranted. This can be achieved by focusing genetic research in the academic institutions of Gulf countries towards this goal.</AbstractText>Copyright 2005 S. Karger AG, Basel.</CopyrightInformation>
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