Unnamed: 0
int64 0
2.34M
| titles
stringlengths 5
21.5M
| abst
stringlengths 1
21.5M
|
|---|---|---|
2,339,200 | Rapid combined genotyping assay for four achondroplasia and hypochondroplasia mutations by real-time PCR with multiple detection probes. | Achondroplasia (ACH) and hypochondroplasia (HYCH) are the most prevalent genetic short-stature syndromes. Whereas the diagnosis of ACH can be established on clinical and radiologic grounds alone in the majority of cases, HYCH is more difficult to confirm. Molecular genetic analysis of both skeletal dysplasias can be especially helpful for the purpose of prenatal diagnosis, in early childhood to differentiate definitively between the largely overlapping phenotypes, and in atypical presentations. The two most prevalent mutations for each syndrome cause substitution of a single respective nucleotide. These mutations can be identified by a variety of molecular methods, including PCR with restriction enzyme digestion or direct DNA sequencing. We have developed a single-step, real-time PCR assay in which two detection probes are applied in combination with a single anchor probe at each mutation position. Because the two most prevalent mutations for each syndrome cause substitution of a single respective nucleotide, this approach guarantees optimal differentiation during probe dissociation analysis after amplification. This assay, which is performed on the LightCycler thermocycler, enables the rapid and reliable detection of the two most common FGFR3 mutations associated with ACH (1138G --> A and 1138G --> C; G380R) and HYCH (1620C --> A and 1620 C --> G; N540K) in a single test. |
2,339,201 | GJB2 and GJB6 mutations in 165 Danish patients showing non-syndromic hearing impairment. | Thirty-two genes causing non-syndromic hearing impairment (NSHI) have been cloned, including GJB2 and GJB6 encoding the gap junction subunits connexin 26 and connexin 30, respectively. One mutation in GJB2, 35delG, accounts for a large percentage of GJB2 hearing impairment in Southern Europe whereas a considerably lower frequency has been reported from Northern European populations. Recently, a 342-kb deletion implicating GJB6 was found in 22 out of 44 NSHI patients of Spanish origin with only one mutated allele of GJB2. We report the first study of GJB2 and GJB6 mutations in Danish patients with NSHI. We tested 165 individuals and found GJB2 mutations in 16 individuals. The deletion implicating GJB6 was found in two individuals out of 9 heterozygous for GJB2 mutation. Furthermore, we screened 509 unselected samples from the Danish newborn population for the 35delG mutation in GJB2. We found 9 samples heterozygous for 35delG and 11 samples heterozygous for mutations leading to amino acid variants in GJB2 protein. In conclusion, our data are in accordance with results from other Northern European populations. Furthermore, our data on the GJB6 deletion suggest that routine screening for this deletion could help to explain hearing impairment in some Northern European NSHI patients heterozygous for a mutation in GJB2. |
2,339,202 | Heterozygosity for Tay-Sachs and Sandhoff diseases in non-Jewish Americans with ancestry from Ireland, Great Britain, or Italy. | Previous reports have found that non-Jewish Americans with ancestry from Ireland have an increased frequency of heterozygosity for Tay-Sachs disease (TSD), although frequency estimates are substantially different. Our goal in this study was to determine the frequency of heterozygosity for TSD and Sandhoff diseases (SD) among Irish Americans, as well as in persons of English, Scottish, and/or Welsh ancestry and in individuals with Italian heritage, who were referred for determination of their heterozygosity status and who had no known family history of TSD or SD or of heterozygosity for these conditions. Of 610 nonpregnant subjects with Irish background, 24 TSD heterozygotes were identified by biochemical testing, corresponding to a heterozygote frequency of 1 in 25 (4%; 95% CI, 1/39-1/17). In comparison, of 322 nonpregnant individuals with ancestry from England, Scotland, or Wales, two TSD heterozygotes were identified (1 in 161 or 0.62%; 95% CI, 1/328-1/45), and three TSD heterozygotes were ascertained from 436 nonpregnant individuals with Italian heritage (1 in 145 or 0.69%; 95% CI, 1/714-1/50). Samples from 21 Irish heterozygotes were analyzed for HEXA gene mutations. Two (9.5%) Irish heterozygotes had the lethal + 1 IVS-9 G --> A mutation, whereas 9 (42.8%) had a benign pseudodeficiency mutation. No mutation was found in 10 (47.6%) heterozygotes. These data allow for a frequency estimate of deleterious alleles for TSD among Irish Americans of 1 in 305 (95% CI, 1/2517-1/85) to 1 in 41 (95% CI, 1/72-1/35), depending on whether one, respectively, excludes or includes enzyme-defined heterozygotes lacking a defined deleterious mutation. Pseudodeficiency mutations were identified in both of the heterozygotes with ancestry from other countries in the British Isles, suggesting that individuals with ancestry from these countries do not have an increased rate of TSD heterozygosity. Four SD heterozygotes were found among individuals of Italian descent, a frequency of 1 in 109 (0.92%; 95% CI, 1/400-1/43). This frequency was higher than those for other populations, including those with Irish (1 in 305 or 0.33%; 95% CI, 1/252-1/85), English, Scottish, or Welsh (1 in 161 or 0.62%; 95% CI, 1/1328-1/45), or Ashkenazi Jewish (1 in 281 or 0.36%; 95% CI, 1/1361-1/96) ancestry. Individuals of Irish or Italian heritage might benefit from genetic counseling for TSD and SD, respectively. |
2,339,203 | Attitude toward genetic testing for cancer risk in Istanbul. | To identify attitudes toward genetic testing, and the effects of this information on decisions regarding issues such as pregnancy, abortion, and prophylactic surgery, several subsets of the Turkish population were surveyed in hospital settings. Individuals (n = 179) chosen arbitrarily from four different subsets of a Turkish population were asked to participate in a confidential 23-question survey. Survey participants were familiar with the concept of cancer being a familial disease (85.5%), and 84.7% of them expressed interest in genetic testing to determine cancer risk, 83.9% would have their fetuses tested for such cancer risk, 65.1% would terminate their pregnancies, 92.2% would have their children tested if they were determined to have an increased cancer risk, 71.9% would agree to undergo prophylactic oophorectomy or orchiectomy and 67.6% would have mastectomy/prostatectomy should there be an increased cancer risk to these organs. It appears that at least the sampled segment of a Turkish population is willing to undergo genetic testing to determine if they are at increased risk for cancer. The feasibility and acceptance of genetic testing and the influence of education and genetic counseling in the Turkish people should further be evaluated with a larger stratified sample of the population. |
2,339,204 | Description of the first two seemingly unrelated Greek Cypriot families with a common C618R RET proto-oncogene mutation. | Germ-line mutations of the RET proto-oncogene cause three different cancer syndromes: multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma (FMTC). The objective of the present study was the clinical and molecular characterization of the first two Greek Cypriot families diagnosed with MEN2A and FMTC. The clinical diagnosis of the probands was based on clinical presentation and supported with laboratory findings (calcitonin and carcinoembryonic antigen tumor marker levels). We screened the RET gene by direct DNA sequencing of exons 10, 11, and 16 using genomic DNA as templates. After identification of the mutation, we also developed the amplification refractory mutation system (ARMS) as an alternative method to direct sequencing for genetic diagnosis of 22 additional individuals from both families. We identified the germ-line missense mutation T --> C of codon 618 of exon 10 (C618R) in the probands of both families. By using ARMS, two members of the MEN2A family and five members of the FMTC family were also found positive for the C618R mutation. These are the first seemingly unrelated families in Cyprus investigated clinically and molecularly in detail and shown to transmit this common RET proto-oncogene mutation. |
2,339,205 | Mutation analysis of hMSH2 and hMLH1 in colorectal cancer patients in India. | The aim of this work was to study the mutation profile in hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients in India. On the basis of the Bethesda criteria, 31 colorectal cancer patients were studied first for microsatellite instability, using the five markers recommended by the Bethesda guidelines. Twelve of 31 tumor samples were found to be MSI-H, 9 of 31 were MSI-L, and the rest were MSS. The 12 patients with MSI-H were analyzed for mutations in hMSH2 and hMLH1 genes using PCR-denaturing high-performance liquid chromatography (dHPLC), followed by sequencing of samples showing abnormal peaks. Of the five mutations detected, three were found to be deleterious mutations (hMSH2-R680X, hMLH1-E671X, and a splice junction mutation IVS16-2A --> G); one had a mutation of probable significance (hMLH1-C680G) and one was of unknown significance (hMSH2-R171K). This study has also shown that most of the early-onset colon (4/7) and early-onset rectal (15/21) cancers are MSS or MSI-L. This is the first study to describe the mutation in hMSH2 and hMLH1 in Indian patients, a low incidence region for colorectal cancer. A two-stage procedure using MSI testing followed by PCR-dHPLC was found to be an efficient method in studying the mutation profile in high-risk patients. |
2,339,206 | High-risk premenopausal women's experiences of undergoing prophylactic oophorectomy: a descriptive study. | Women who are at increased risk of developing ovarian cancer because of their family history may need to make decisions about the medical management of their cancer risk--whether to have ovarian screening or undergo prophylactic surgery. This qualitative study explores the perceived physical and emotional implications of undergoing preventative surgery using data collected during interviews with 23 high-risk premenopausal women who had undergone prophylactic oophorectomy because of their family history of cancer. Despite the fact that all of these women regarded their decision to undergo surgery extremely positively, 20 women also described what they regarded as the costs of undergoing surgery. These included post-operative complications, the onset of menopausal symptoms, side effects of hormone replacement therapy, and negative effects on body image and gender identity. The perceived benefits of surgery were described as risk reduction, enabling one to fulfil family obligations, removing the need for gynecological screening, cessation of menstruation, and positive side effects of hormone replacement therapy. This study suggests there is a need to inform women about potential physical and emotional sequelae of oophorectomy prior to undergoing this procedure. |
2,339,207 | Subjective and objective risk of breast cancer in Ashkenazi Jewish individuals at risk for BRCA1/2 mutations. | The aims of the study were to (1) examine the differences between subjective and objective estimates of the risk of breast cancer in those being tested for BRCA1/2 mutations, (2) explore new ways to conceptualize risk, and (3) examine the change in subjective risk of developing breast cancer throughout the process of genetic counseling and testing. Participants were 86 Ashkenazi Jewish women with a family or personal history indicating risk for BRCA1/2 mutations. Surveys to assess subjective risk of breast cancer (percentage risk, projected age of onset, and survival time) were administered before counseling, after counseling, and after receipt of test results. Subjective percentage risk of breast cancer was compared to estimated objective risk to determine accuracy. Those with no personal history of cancer receiving positive results became more accurate from post-counseling to post-result. Those receiving positive results increased their estimate of their percentage risk, and those receiving uninformative negative results decreased their estimate of their percentage risk from post-counseling to post-result. Those without a personal history of cancer decreased in perceived risk from post-counseling to post-result. No change in projected age of onset of breast cancer or survival time with breast cancer was seen from pre- to post-counseling or from post-counseling to post-result, and no change in accuracy or in percentage risk of breast cancer was seen from pre- to post-counseling. Individuals use information from genetic counseling to form estimates of percentage risk following receipt of test results; however, projected age of onset and survival time with breast cancer, areas not targeted by genetic counseling that may be more closely linked to health behavior, do not change. |
2,339,208 | Characterization of two novel BRCA1 germ-line mutations involving splice donor sites. | Deleterious BRCA1 mutations have significant clinical implications for the patients that carry them. Point mutations in critical functional domains and frameshift mutations that lead to early termination of protein translation are associated with a 60-80% risk of breast cancer and a 20-40% risk of ovarian cancer. In contrast, the significance of mutations located in intronic regions of BRCA1, even in the setting of a family history of breast and ovarian cancer, is not always clear. Some of these mutations occur in splice donor/acceptor consensus sites. These mutations can affect heteronuclear RNA (hnRNA) processing, leading to the loss of functional BRCA1 protein and thus may be disease-associated. However, it is important to verify the effect of these mutations, because splicing alterations cannot be predicted from genomic sequence alone. We report here the characterization of two novel BRCA1 mutations identified in families seen in our cancer risk evaluation clinic that alter splice donor sites of BRCA1. We show that both mutations alter transcript splicing and result in truncated BRCA1. IVS17 + 1G --> T leads to inclusion of part of intron 17 after the coding sequence of exon 17, resulting in early termination of BRCA1 protein following codon 1692. 252del5insT abolishes the splice donor site in exon 3, leading to the skipping of exon 5 and BRCA1 protein truncation following codon 45. Thus, both mutations result in loss of BRCA1 function, and carriers of these mutations should be counseled in the same manner as carriers of other truncating BRCA1 mutations. |
2,339,209 | BRCA1 mutations in a population-based study of breast cancer in Stockholm County. | The mutation frequency of BRCA1 and BRCA2 in women with breast cancer varies according to family history, age at diagnosis and ethnicity. The contribution of BRCA1 and BRCA2 mutations in breast cancer populations, unselected for age and family history, has been examined in several studies reporting mutation frequencies between 1% and 12% by screening methods, population sizes, and to what extent the gene/s were screened differed in the studies. We wanted to clarify the proportion of breast cancer attributable to mutations in BRCA1 in an unselected breast cancer population from the Stockholm region. All incident breast cancer patients treated surgically in a 19-month period were eligible for the study and 70% (489/696) participated. Exon 11 of BRCA1 was screened for mutations using the protein truncation test, and the mutation frequency was estimated from that. In previous studies on high-risk families from Stockholm, more than 70% of the mutations were detected in exon 11. Two mutations were found, both in patients with a family history or their own medical history of ovarian cancer, giving a mutation frequency in exon 11 of 0.4% and an estimated BRCA1 mutation frequency of <1%. Mutations in BRCA1 in unselected breast cancer cases in our region are rare and likely to be found only in high-risk families. Our BRCA1 prevalence is the lowest of all studies on unselected breast cancer patients, probably reflecting the comparatively low rates detected also in high-risk breast cancer families from the region. |
2,339,210 | Prevalence of major depression one year after predictive testing for Huntington's disease. | Psychiatric hospitalizations, completed suicides, and suicide attempts are rare after predictive testing for Huntington's disease (HD). Case studies have shown that major depression can be a consequence of being tested, although no studies have shown how common this is. The present study evaluated the prevalence of major depression during the first year after disclosure. We conducted retrospective data and chart reviews of 153 persons (50 testing positive, 103 testing negative) evaluated every 3 months for depression. There was no significant baseline difference in the percentage of "positives" and "negatives" who had pre-testing major depressive episodes (14% vs. 12%, respectively). A senior psychiatrist reviewed data from the Schedule for Affective Disorders and Schizophrenia-Change Version, from the Beck Depression Inventory, and from clinical notes for every follow-up contact completed. The 1-year prevalence of major depression among positives was 6.0%, compared to 3.0% among negatives (p = 0.30), and an estimated 3% population prevalence. One-year prevalence of clinically significant depressive symptoms, whether or not major depression was diagnosed, was 20.0% in positives and 12.6% in negatives (p = 0.17). Although not statistically significant, depressive symptoms and major depression occurred more frequently among those who tested positive. Despite some evidence to the contrary, including our own studies, a positive predictive test for HD is not psychologically benign. Clinical testing programs should assess patients for depressive symptoms after testing, and patients with clinically significant complaints should be referred to a mental health professional. |
2,339,211 | Informing carriers of beta-thalassemia: giving the good news. | This study explored the value of informing beta-thalassaemia carriers of the advantages, as well as the disadvantages of carrier status. Twenty-eight carriers of beta-thalassaemia were interviewed immediately after counselling, and again 2 weeks later. Both interviews included administration of a psychological scale (previously used for cystic fibrosis). Immediately after the first interview the intervention group (n = 18) were informed of the protective effect of the beta-thalassaemia trait against malaria and coronary heart disease. The control group (n = 10) was given the same information after the second interview. The effect of giving the positive information was assessed by comparing participants' scores at the first and second interview. Knowledge of carrier status aroused several negative feelings, including shock, sadness, and anger, but little feeling of stigmatization. Two weeks later, negative feelings were unchanged in the control group, but they were reduced in all members of the intervention group. All members of the intervention group considered it important to inform carriers of the positive aspects as well as the risks associated with carrier status. Carriers of recessive disorders with a known heterozygote advantage should be informed of the advantage. This information has now been incorporated into the comprehensive information system for hemoglobin disorders available at http://www.chime.ucl.ac.uk/ApoGI/. |
2,339,212 | Rapid detection of common southeast Asian beta-thalassemia mutations by nonisotopic multiplex PCR-SSCP analysis. | This report describes the detection of seven beta-thalassemia mutations common in Southeast Asia by amplifying three short PCR fragments in two separate tubes, followed by single-strand conformation polymorphism (SSCP) analysis in single lanes. These mutations are -28 A --> G, codon 17 A --> T, IVS1 + 5 G --> C, codon 41/42 -CTTT, codon 43 G --> T, codon 71/72 + A, and IVS2 + 654 C --> T, and account for 70% to over 95% of the cases in this region. This rapid nonisotopic method was also found capable of detecting other mutations within the amplified fragments. It is simple, rapid, and cheap, and thus suitable for carrier screening and prenatal diagnosis in Southeast Asia. |
2,339,213 | Hereditary hemochromatosis genetic testing of at-risk children: what is the appropriate age? | The objective of this study was to consider the objective evidence and ethical arguments for the appropriate age to test children at risk of developing hereditary hemochromatosis. A literature search for information on iron overload in children, onset of disease expression for hemochromatosis, and recommendations for age of cascade screening was undertaken. We examined the objective evidence and arguments for testing in early childhood and those for delaying testing until later teenage years. Cascade testing of offspring of people with hemochromatosis is widely advocated because it is an easily preventable disease. The ideal age to test those offspring is a matter of debate. Some authorities advocate testing at a very young age whereas others recommend delaying testing until late teenage years. To date there has been no published overview of the objective evidence and arguments central to this debate. In children who are C282Y homozygous, iron overload is rare in the first two decades of life and associated morbidity has only been documented in 1 patient. In the cascade setting, genetic testing for hemochromatosis need not be offered until late teenage years. |
2,339,214 | Attitudes about and psychosocial outcomes of HFE genotyping for hemochromatosis. | We examined attitudes regarding genetic testing and psychosocial outcomes of HFE genotyping for hemochromatosis. A total of 87 persons with hemochromatosis (patients) (39 women, 48 men), who underwent HFE genotyping, and 50 persons with hypertension (controls) (22 women, 28 men), who had not undergone HFE genotyping, completed a structured interview in which they reported attitudes about benefits and disadvantages of genetic testing and their understanding of genetics and hemochromatosis. Among patients, adherence to treatment for hemochromatosis was assessed. Controls estimated the likelihood of experiencing several potential positive and negative psychosocial outcomes after a positive genetic test. Patients reported their experience pertinent to these outcomes. Patients received information about hemochromatosis when they were diagnosed, and controls read a brief description of hemochromatosis before answering questions. Patients correctly answered 65% of knowledge questions and controls correctly answered 59%. Most participants believed genetic testing is beneficial and described few negative aspects of testing. Controls expected to experience more anxiety, depression, and anger related to a positive genetic test than was reported by patients (p < 0.001). One patient reported discrimination related to the HFE genotype. Most patients were compliant with the iron depletion and maintenance phases of treatment for hemochromatosis. Race, sex, marital status, income, education, barriers to treatment, and knowledge were not significantly associated with adherence to maintenance phlebotomy. We conclude that HFE genotyping appears to be viewed positively and would be generally accepted were it offered as part of a screening program for hemochromatosis. Persons who have not undergone genetic testing may overestimate their emotional responses to a positive test result. In the present hemochromatosis patients, few reported that HFE genotyping was accompanied by negative psychosocial outcomes. |
2,339,215 | Preconceptional cystic fibrosis carrier screening: attitudes and intentions of the target population. | The aim of this study was to assess the attitudes and intentions of individuals planning a pregnancy with regard to preconceptional cystic fibrosis (CF) carrier screening and to determine factors associated with a positive and negative/neutral intention to have the test. A survey, based on a questionnaire, was conducted among a stratified random sample of 303 recently married couples (606 individuals). Of the eligible individuals, 70% (n = 380) participated. Of the respondents, 73% had a positive attitude toward a routine offer of preconceptional CF carrier screening, and 56% had the intention to participate in a screening program. A positive intention to have the test was associated with high perceived anticipation of regret, intended preconceptional behavior, high perceived pressure from experts, high perceived consequences of the test results, low perceived barriers, and low perceived negative consequences for family members. These results suggest that the offer of routine preconceptional CF carrier screening would lead to substantial acceptance among couples planning a pregnancy. Several variables related with intention were identified. |
2,339,216 | Breast Cancer in Canadian Women. | HEALTH ISSUE: Although lung cancer is the leading cause of cancer deaths for Canadian women, breast cancer is the most frequently diagnosed. About 5400 women are expected to die from this disease in 2003. In 1998, a woman's lifetime risk of breast cancer was about one in nine. KEY FINDINGS: A number of risk factors for breast cancer have been identified. These include advancing age, hormonal factors (eg. early menarche, late menopause and late age at first full-term pregnancy), familial risk, BRCA-1 and BRCA-2 gene mutations, diet and postmenopausal obesity.Several interventions have been introduced to assist women at high risk for breast cancer, including genetic counseling and testing for women who have strong family histories of breast cancer; selective estrogen receptor modifiers, such as tamoxifen, that has been shown to reduce breast cancer rates; prophylactic mastectomy and screening. DATA GAPS AND RECOMMENDATIONS: Guidelines are unclear in several areas, particularly in screening. Where clinical guidelines are available, health services research or ongoing monitoring (by provincial/territorial cancer agencies) is needed to assess compliance with the guidelines and to ensure equity of access within the provinces/territories.Key components of organized screening programs need to be established, in part to ensure that screening is carried out in high-quality, co-ordinated programs. There is also a need to develop ways to involve women fully in informed decision-making and to address several policy issues to prevent disparities in access to high-quality services. Patenting issues associated with genetic tests also need to be clarified. |
2,339,217 | State-dependency in C. elegans. | Memory and the expression of learned behaviors by an organism are often triggered by contextual cues that resemble those that were present when the initial learning occurred. In state-dependent learning, the cue eliciting a learned behavior is a neuroactive drug; behaviors initially learned during exposure to centrally acting compounds such as ethanol are subsequently recalled better if the drug stimulus is again present during testing. Although state-dependent learning is well documented in many vertebrate systems, the molecular mechanisms underlying state-dependent learning and other forms of contextual learning are not understood. Here we demonstrate and present a genetic analysis of state- dependent adaptation in Caenorhabditis elegans. C. elegans normally exhibits adaptation, or reduced behavioral response, to an olfactory stimulus after prior exposure to the stimulus. If the adaptation to the olfactory stimulus is acquired during ethanol administration, the adaptation is subsequently displayed only if the ethanol stimulus is again present. cat-1 and cat-2 mutant animals are defective in dopaminergic neuron signaling and are impaired in state dependency, indicating that dopamine functions in state-dependent adaptation in C. elegans. |
2,339,218 | Prenatal diagnosis in Li-Fraumeni syndrome. | The hallmark of Li-Fraumeni syndrome (LFS), a familial cancer syndrome, is constitutional TP53 mutation. The authors addressed the complex question of predictive prenatal genetic testing for cancer risk associated with inheritance of TP53 mutation.</AbstractText>A classic LFS family including the proband (a 20-month-old boy with rhabdomyosarcoma), his 36-year-old father with osteosarcoma, and his 40-year-old paternal aunt with bilateral breast cancer were identified as carriers of a TP53 germline mutation, a novel 1 base pair deletion in exon 5. A few years later, the mother became pregnant twice, and the parents requested prenatal diagnosis on each occasion. Genetic counseling, psychological evaluation, and support were provided by a multidisciplinary team including a pediatric oncologist, a geneticist, a psychosocial worker, a prenatal care provider, and an ethical representative. After providing overall information on LFS, including the high risk of developing secondary multiple neoplasms in LFS survivors, the committee approved prenatal diagnosis at the request of the family.</AbstractText>In the two pregnancies, the two fetuses were found to be carriers of the same mutation. Nine years from diagnosis of the first tumor, the proband, and a month later his father, developed second tumors, multifocal osteosarcoma and leiomyosarcoma, respectively.</AbstractText>Children with primary tumors belonging to LFS should be considered for screening for germline mutations and genetic counseling by a multidisciplinary team. Whether family members are found to be positive or negative as carriers, such measures may provide, by reducing uncertainty, psychological benefit to high-risk families.</AbstractText> |
2,339,219 | Exposure of hematopoietic stem cells to benzene or 1,4-benzoquinone induces gender-specific gene expression. | Chronic exposure to benzene results in progressive decline of hematopoietic function and may lead to the onset of various disorders, including aplastic anemia, myelodysplastic syndrome, and leukemia. Damage to macromolecules resulting from benzene metabolites and misrepair of DNA lesions may lead to changes in hematopoietic stem cells (HSCs) that give rise to leukemic clones. We have shown previously that male mice exposed to benzene by inhalation were significantly more susceptible to benzene-induced toxicities than females. Because HSCs are targets for benzene-induced cytotoxicity and genotoxicity, we investigated DNA damage responses in HSC from both genders of 129/SvJ mice after exposure to 1,4-benzoquinone (BQ) in vitro or benzene in vivo. 1,4-BQ is a highly reactive metabolite of benzene that can cause cellular damage by forming protein and DNA adducts and producing reactive oxygen species. HSCs cultured in the presence of 1,4-BQ for 24 hours showed a gender-independent, dose-dependent cytotoxic response. RNA isolated from 1,4-BQ-treated HSCs and HSCs from mice exposed to 100 ppm benzene by inhalation showed altered expression of apoptosis, DNA repair, cell cycle, and growth control genes compared with unexposed HSCs. Rad51, xpc, and mdm-2 transcript levels were increased in male but not female HSCs exposed to 1,4-BQ. Males exposed to benzene exhibited higher mRNA levels for xpc, ku80, ccng, and wig1. These gene expression differences may partially explain the gender disparity in benzene susceptibility. HSC culture systems such as the one used here will be useful for testing the hematotoxicity of various substances, including other benzene metabolites. |
2,339,220 | Prenatal screening and diagnosis for pediatricians. | The pediatrician who cares for a child with a birth defect or genetic disorder may be in the best position to alert the family to the possibility of a recurrence of the same or similar problems in future offspring. The family may wish to know about and may benefit from methods that convert probability statements about recurrence risks into more precise knowledge about a specific abnormality in the fetus. The pediatrician also may be called on to discuss abnormal prenatal test results as a way of understanding the risks and complications that the newborn infant may face. Along with the increase in knowledge brought about by the sequencing of the human genome, there has been an increase in the technical capabilities for diagnosing many chromosome abnormalities, genetic disorders, and isolated birth defects in the prenatal period. The purpose of this report is to update the pediatrician about indications for prenatal diagnosis, current techniques used for prenatal diagnosis, and the status of maternal screenings for detection of fetal abnormalities. |
2,339,221 | BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. | According to the international criteria for hereditary non-polyposis colorectal cancer (HNPCC) diagnostics, cancer patients with a family history or early onset of colorectal tumours showing high microsatellite instability (MSI-H) should receive genetic counselling and be offered testing for germline mutations in DNA repair genes, mainly MLH1 and MSH2. Recently, an oncogenic V600E hotspot mutation within BRAF, a kinase encoding gene from the RAS/RAF/MAPK pathway, has been found to be associated with sporadic MSI-H colon cancer, but its association with HNPCC remains to be further clarified.</AbstractText>BRAF-V600E mutations were analysed by automatic sequencing in colorectal cancers from 206 sporadic cases with MSI-H and 111 HNPCC cases with known germline mutations in MLH1 and MSH2. In addition, 45 HNPCC cases showing abnormal immunostaining for MSH2 were also analysed.</AbstractText>The BRAF-V600E hotspot mutation was found in 40% (82/206) of the sporadic MSI-H tumours analysed but in none of the 111 tested HNPCC tumours or in the 45 cases showing abnormal MSH2 immunostaining.</AbstractText>Detection of the V600E mutation in a colorectal MSI-H tumour argues against the presence of a germline mutation in either the MLH1 or MSH2 gene. Therefore, screening of these mismatch repair (MMR) genes can be avoided in cases positive for V600E if no other significant evidence, such as fulfilment of the strict Amsterdam criteria, suggests MMR associated HNPCC. In this context, mutation analysis of the BRAF hotspot is a reliable, fast, and low cost strategy which simplifies genetic testing for HNPCC.</AbstractText> |
2,339,222 | CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma. | Primary open-angle glaucoma (POAG) is a leading cause of visual impairment worldwide and a complex genetic disorder that affects mostly adults. Mutations in the MYOCILIN (MYOC) and OPTINEURIN genes account for rare forms with a Mendelian inheritance and for <5% of all POAG cases. The CYP1B1 gene, a member of the cytochrome P450 gene family, is a major cause of primary congenital glaucoma (PCG), a rare and severely blinding disease with recessive inheritance. However, CYP1B1 mutations have also been associated with cases of juvenile-onset glaucoma in some PCG families or shown to modify the age of onset of glaucoma linked to a MYOC mutation in a large family.</AbstractText>To investigate the role of CYP1B1 mutations in POAG predisposition, irrespective of the presence of a MYOC mutation.</AbstractText>CYP1B1 coding region variation was characterised by denaturing high performance liquid chromatography (DHPLC) and sequencing in 236 unrelated French Caucasian POAG patients and 47 population-matched controls.</AbstractText>Eleven (4.6%) patients carried one or two mutated CYP1B1 gene(s) and no MYOC mutation. They showed juvenile or middle-age onset of disease (median age at diagnosis, 40 years, range 13-52), significantly earlier than in non-carrier patients. Apart from one, all mutations detected in POAG patients were previously associated with PCG.</AbstractText>CYP1B1 mutations might pose a significant risk for early-onset POAG and might also modify glaucoma phenotype in patients who do not carry a MYOC mutation.</AbstractText> |
2,339,223 | BRCAPAP: feasibility of clinical BRCA testing on liquid-based cervical cytology: implications for biomarker development. | The study was designed to test the feasibility that lower genital tract cytology is a compatible medium for robust germ line genetic analyses.</AbstractText>BRCA1 and/or BRCA2 gene mutational analysis was done on DNA isolated from liquid-based cervical or vaginal cytology taken from 17 consenting women (age 29-65 years) who previously had genetic counseling followed by BRACAnalysis (Myriad Genetics, Salt Lake City, UT) blood analyses. Eleven women had known mutations in either BRCA1 or BRCA2 (cases) and six had no identified mutations (controls) on entry into the study. Anonymized cytology samples were sent to Myriad Genetics with a request for testing that was limited to the degree of genomic testing previously done on the blood samples.</AbstractText>One cervicovaginal specimen from a test-positive woman had inadequate cellular content that precluded gene sequencing and therefore was excluded from this analysis. For the 16 women with adequate cytologic specimens, there was 100% concordance for BRCA mutation test results between blood and genital tract cytology (kappa = 1.0; 95% confidence interval, 0.51-1.0).</AbstractText>We have shown the feasibility of using liquid-based genital tract cytology as an alternative biospecimen to blood for germ line genetic analysis using a clinical approved assay. It needs to be emphasized that any type of testing for BRCA1 or BRCA2 mutation genotype should only be done in the setting of pretest and posttest counseling.</AbstractText> |
2,339,224 | Glutathione S-transferases M1, T1, and P1 and breast cancer: a pooled analysis. | The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the genes GSTM1 and GSTT1 and a base transition polymorphism at codon 105 (Ile-->Val) in GSTP1 were investigated in relation to breast cancer risk. Tobacco smoking and reproductive factors were examined as potential effect modifiers. Individual data from seven case-control studies were pooled within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens. To measure the effect of GSTs on breast cancer risk, odds ratios and 95% confidence intervals were computed adjusting for study center and age. The modifying effect was investigated by stratification on variables of smoking habits and reproductive history. A total of 2,048 cases with breast cancer and 1,969 controls were analyzed. The relative odds ratio (95% confidence interval) of breast cancer was 0.98 (0.86-1.12) with the GSTM1 null, 1.11 (0.87-1.41) with the GSTT1 null, 1.01 (0.79-1.28) with GSTP1 heterozygous mutants, and 0.93 (0.62-1.38) with GSTP1 homozygous mutants. Stratification by smoking or reproductive factors did not reveal a modifying effect of these variables, nor was there any association between GSTM1 and age at diagnosis of breast cancer. This is the largest study investigating susceptibility to breast cancer due to polymorphisms in the GST genes. The results conclusively show that single gene GST polymorphisms do not confer a substantial risk of breast cancer to its carriers. Furthermore, GSTs did not interact with smoking or reproductive history to modify cancer risk. |
2,339,225 | Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivo. | Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects.</AbstractText>The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 +/- 0.6 ng/mL) compared with wild-types (8.8 +/- 0.4 ng/mL) and heterozygotes (9.1 +/- 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 +/- 1.1 micromol/L) compared with homozygous subjects (10.9 +/- 0.4 micromol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 +/- 6.3 ng/mL) compared with wild-types (112.2 +/- 5.2 ng/mL) and heterozygous individuals (125.1 +/- 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants.</AbstractText>Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.</AbstractText> |
2,339,226 | Strategies for prevention of colorectal cancer: pharmaceutical and nutritional interventions. | Interventions designed to delay or prevent the development of invasive colorectal adenocarcinoma might result in a profound impact on the incidence of and mortality from colorectal cancer. Current developmental efforts focus in two major directions: identification and testing of combination-targeted signal transduction pathway modulators and development of nutriceuticals. Both approaches recognize the heterogeneity of the carcinogenesis process. Combinations of agents (eg, aspirin or sulindac with DFMO, calcium with fiber), which have complementary or synergistic mechanisms or agents with broad spectrum anti-carcinogenic effects can potentially improve upon the effects of single agents and account for redundant signal transduction pathways involved in uncontrolled growth of clonal cells. Preliminary data in rodent systems suggest nutriceuticals or standardized foodstuffs, which contain multiple components, many of which are not identified have synergistic anticarcinogenesis effects. Diet modulation or supplementation with known standardized foodstuffs may be ideal in individuals at risk for colorectal cancer. Current clinical models for colorectal cancer prevention focus upon a pathologic-surrogate endpoint (reducing the recurrence or emergence of adenomas). This surrogate, generally accepted at a regulatory level, might not represent the true malignant progression from normal colonic mucosa to the malignant phenotype. Could the intervention simply prevent the emergence of adenomas that would not have progressed to invasive neoplasia in any event? Despite this major weakness, the adenoma remains the regulatory endpoint for efficacy because the cancer event remains rare, even among individuals selected as high-risk epidemiology but without known, highly pressured genetic-based stress. Over the next decade, the emergence of molecular and proteomic profiling tools have the potential of selecting adenomas that will progress to adenocarcinomas and will allow for investigation to be focused on individuals at increased risk. |
2,339,227 | [Hereditary blistering disorders]. | Epidermolysis bullosa (EB) is a group of genetic skin disorders whose common feature is the formation of blisters following minor trauma. They present with a wide clinical spectrum of manifestations because of a variety of molecular defects. In patients with mild phenotypes, only skin is affected. The most severe EB forms are multiorgan disorders with a poor prognosis. EB arises from abnormalities in proteins of the dermal-epidermal junction. These specialized protein components aggregate to form anchoring complexes, which attach the epidermis to the dermis. Three major EB-forms can be distinguished on the basis of ultrastructural blistering level: EB simplex--epidermolytic, junctional EB--in the lamina lucida and dystrophic EB--dermolytic. To establish a provisional diagnosis for an EB patient, clinical data, family history and morphologic examination of the skin, e.g. by antigen-mapping, are needed. Complete knowledge of the genetic defect provides the basis to a rational genetic counseling and prenatal testing. Treatment of EB is based on wound care; multidisciplinary management of cases with severe course is required. |
2,339,228 | [Inherited metabolic disorders with cutaneous manifestations]. | Over the last years, the genetic basis of several monogenic inherited metabolic diseases has been elucidated. Interestingly, some of these disorders manifest with characteristic cutaneous symptoms that are often crucial for diagnosis. In most cases, however, besides the skin other organs are affected. Therefore, an interdisciplinary supervision of these patients is highly important. In this review we will discuss diseases that constitute a challenge not only for dermatologists but also for physicians from other specialties. A particular emphasis is put on genetic and clinical features of these disorders as well as current therapeutic concepts. |
2,339,229 | [Antigenic and genetic characterizations of group A influenza viruses H3N2 circulated in men in China during 2000-2002]. | To understand the antigenic and genetic characteristics of influenza A H3N2 viruses circulated in man in China from 2000 to 2002.</AbstractText>Embryonated chicken eggs inoculated with virus for amplification of viral yield. The harvesting egg allantoic fluids with influenza viruses were provided for testing antigen and RNA extraction. Virion RNA was transcribed into cDNA by reverse transcriptase, cDNA amplified by PCR, and the product of PCR was purified. Afterward RNA sequence analysis was performed by the dideoxynucleotide chain termination method using synthetic oligodeoxynucleotide primers. Finally the phylogenetic tree was analyzed with MegAlign software.</AbstractText>The H3N2 viruses isolated during 2000-2002 were different in amino acid sequences on HA1 domain protein molecule from those of A/Wuhan359/1995 H3N2 as well as those of A/Sydney/7/1997 H3N2 strains. There were four different positions of amino acid sequence on HA1 domain protein molecule among the H3N2 viruses isolated in 2000 and during 2001-2002. They located at 83, 186, 202, 222 and 225 position, respectively. Of them 83 and 186 were in antigenic determinant E and B, respectively. The others located at left wall of the receptor binding site (RBS).</AbstractText>From the end of 2001 to the beginning of 2002, the influenza epidemic in Northern China caused by H3N2 virus was due to occurrence of antigenic and genetic changes of influenza A(H3N2) virus.</AbstractText> |
2,339,230 | [Construction of replication-deficient recombinant adenovirus expressing gag-polDelta and gp140TM genes of human immunodeficiency virus in mice]. | Construction of replication-deficient recombinant adenovirus expressing gag-pol and env genes of human immunodeficiency virus (HIV) in mice.</AbstractText>gag-polDelta and gp140TM genes were cloned into shuttle vector pAdTrack-CMV respectively, and then the plasmids containing gag-polDelta or gp140TM gene were cotransformed with the backbone of adenovirus into E.coli BJ5183. Transfections of the recombinants were performed to obtain recombinant adenoviruses. Its immunogenicity was evaluated by testing antibody levels of mice primed with DNA vaccines and boosted with recombinant adenoviruses.</AbstractText>The replication-deficient recombinant adenovirus could express Gp140TM, Gag P55 and P24 proteins correctly. The mice primed with DNA vaccines and boosted with recombinant adenoviruses elicited high titer of HIV-1-specific antibody compared with that inoculated with DNA vaccines only.</AbstractText>Replication-deficient recombinant adenovirus expressing gag-polDelta and gp140TM can elicit high titer HIV-1-specific antibodies.</AbstractText> |
2,339,231 | [Construction and immune potency of recombinant adenovirus containing codon-modified HIV-1 gp120]. | To construct replication-deficient recombinant adenovirus expressing wild and codon-modified HIV-1 gp120.</AbstractText>The viral codons were changed to the codon usage of highly expressed mammal gene, the resulting modified gp120 gene was synthesized. The wild and modified gp120 genes were cloned into shuttle vector pShuttle-CMV respectively, and then the constructed plasmids containing gp120 gene was cotransformed with the backbone vector pADeasy-1 into E.coli BJ5183. Transfection of the recombinant AdEasy plasmid into 293 cells was performed to obtain recombinant adenoviruses. The mice were immunized with the recombinant adenoviruses. Their immunogenicity was evaluated by testing antibody and CTL levels of immunized mice.</AbstractText>Two strains of recombinant adenovirus expressing wild and codon-modified HIV-1 gp120 were obtained. The protein expressing level of the recombinant adenoviruses containing modified genes was much higher than that containing wild genes. The mice immunized with recombinant adenoviruses elicited HIV-1 specific antibody and CTL response. The rAd-mod gp120 group was better than the rAd-wt gp120 group.</AbstractText>Replication-deficient recombinant adenovirus expressing HIV-1 gp120 can elicit HIV-1 specific humoral and cellular response, the codon-modified recombinant virus was more efficient than the native.</AbstractText> |
2,339,232 | Monitoring and modeling horizontal gene transfer. | Monitoring efforts have failed to identify horizontal gene transfer (HGT) events occurring from transgenic plants into bacterial communities in soil or intestinal environments. The lack of such observations is frequently cited in biosafety literature and by regulatory risk assessment. Our analysis of the sensitivity of current monitoring efforts shows that studies to date have examined potential HGT events occurring in less than 2 g of sample material, when combined. Moreover, a population genetic model predicts that rare bacterial transformants acquiring transgenes require years of growth to out-compete wild-type bacteria. Time of sampling is there-fore crucial to the useful implementation of monitoring. A population genetic approach is advocated for elucidating the necessary sample sizes and times of sampling for monitoring HGT into large bacterial populations. Major changes in current monitoring approaches are needed, including explicit consideration of the population size of exposed bacteria, the bacterial generation time, the strength of selection acting on the transgene-carrying bacteria, and the sample size necessary to verify or falsify the HGT hypotheses tested. |
2,339,233 | Problems in monitoring horizontal gene transfer in field trials of transgenic plants. | Transgenic crops are approved for release in some countries, while many more countries are wrestling with the issue of how to conduct risk assessments. Controls on field trials often include monitoring of horizontal gene transfer (HGT) from crops to surrounding soil microorganisms. Our analysis of antibiotic-resistant bacteria and of the sensitivity of current techniques for monitoring HGT from transgenic plants to soil microorganisms has two major implications for field trial assessments of transgenic crops: first, HGT from transgenic plants to microbes could still have an environmental impact at a frequency approximately a trillion times lower than the current risk assessment literature estimates the frequency to be; and second, current methods of environmental sampling to capture genes or traits in a recombinant are too insensitive for monitoring evolution by HGT. A model for HGT involving iterative short-patch events explains how HGT can occur at high frequencies but be detected at extremely low frequencies. |
2,339,234 | Combining the transmission disequilibrium test and case-control methodology using generalized logistic regression. | To study the role of genetic factors in the etiology, susceptibility, or severity of disease, several methods are available. In a transmission disequilibrium test, genotypes of cases are compared to those of their parents to explore whether a specific allele, or marker, at a locus of interest appears to be transmitted in excess of what is expected on the basis of Mendelian inheritance. Such apparent excess transmission indicates that cases are being selected for that allele, thereby providing evidence that this allele is a risk factor for disease. In case-control studies, genotypes of cases are compared to those of controls from the same population to identify whether a specific allele is associated with disease. If so, either the allele at this locus or one in linkage disequilibrium with it may be causally related to the etiology of the disease. Here, we discuss the problem of combining a transmission disequilibrium test and a case-control comparison, in order to integrate all available information, and thereby increase statistical power. As the same cases are used in both approaches, the two results are not independent. However, parents of cases can be independently compared to controls. Both the issue of testing for a genetic effect and the estimation of relative risks under the multiplicative model using generalized logistic regression are discussed. |
2,339,235 | Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. | Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence. |
2,339,236 | Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44. | Using restriction fragment length polymorphism and pyrosequencing methods, we genotyped two TNFA gene promoter SNPs (-G308A, -G238A) and analyzed the haplotype structure in 24 Canadian families of primarily Celtic origin. Our results demonstrate that after correction for multiple testing based on simulations of 10 000 replicates of unlinked/unassociated data, there is evidence for association (P=0.026) of a specific haplotype (-308A, -238G) with schizophrenia and schizophrenia spectrum disorders with a family-based trimmed haplotype linkage disequilibrium test (Trimhap). Stratifying the 22 families with genome scan data by TNFA promoter haplotypes followed by reanalysis of linkage to schizophrenia throughout the genome, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 (D1S1609) demonstrated a significant increase (P=0.025) in LOD score from 0.15 to 3.01 with a broad definition of the schizophrenia phenotype and a dominant mode of inheritance. This result replicates a previously reported positive result of linkage of schizophrenia spectrum disorders to this area of the genome. We also illustrated that simulation studies are pivotal in evaluating the significance of results obtained with newer statistical methods, when multiple, but not independent, tests are performed, and when sample stratification is utilized to reduce the impact of heterogeneity or assess the interaction between loci. |
2,339,237 | Impact of a cancer registry-based genealogy service to support clinical genetics services. | In collaboration with the network of genetics clinics in Scotland, a brief questionnaire was designed to gather data prospectively about the impact of information arising from pedigree research provided by Scottish Cancer Registry personnel. Pedigree research in Scotland is facilitated by access to public records of births, deaths, marriages, and historic census returns up to 1901, and enables the construction of accurate and extensive family pedigrees encompassing generations beyond the detailed knowledge of the proband. Subject to existing confidentiality guidelines, linkage of these pedigrees to cancer registration records results in a more comprehensive family history including the age at diagnosis of any cancer, multiple primary cancers, and cancers unreported from death certificates. Of 454 requests for pedigree research completed between 1 April 2002 and 31 March 2003, questionnaires were returned for 425 (94%). The information fed back to genetics clinics led to changes in family history, risk categorisation, and management in 41%, 30%, and 23% of cases, respectively. Management advice altered in both directions, that is, to institute active follow-up and surveillance of clinic attendees and their relatives where none was previously envisaged, and viceversa. The interests of current and future generations of patients concerned about their familial risk of cancer will be served by measures which enable cancer registries to collect data that are as accurate and complete as possible. |
2,339,238 | Correlations between phenotype and microsatellite instability in HNPCC: implications for genetic testing. | Hereditary nonpolyposis colorectal cancer (HNPCC) is widely considered to be a syndrome of defective mismatch repair (MMR). A major concern with genetic diagnosis of HNPCC is the variable, often low, percentage of pathogenic germline mutations that can be detected in MMR genes using common screening methods. The variable percentage of mutation detected is in part related to the sensitivity of conventional screening methods and may also depend on the heterogeneous genetics of HNPCC. Thus, identification of phenotypic criteria predictive of germline mutations in MMR genes may be helpful in efficient HNPCC genetic testing. Clinical diagnostic criteria, initially developed for HNPCC (e.g., Amsterdam I and II, or Bethesda criteria), can be used to clinically select patient candidates that carry germline mutations in MMR genes. More useful criteria were previously developed by analyzing families with germline MMR mutations. Using a complementary approach based on tumor microsatellite instability analysis, we confirm that the Amsterdam criteria are significantly better than the Bethesda criteria in predicting families with MSI-H tumors (P = 0.0227). Our results also suggest that a cutoff at < 50 years' mean age at diagnosis of HNPCC-related cancers (especially colorectal and endometrial cancer) may be an additional tool for the identification of families with defective MMR. Recent advances in MMR mutation screening are expected to improve detection of pathogenic MMR mutations in these families. Conversely, the high proportion of MSS tumors observed in our series of families with advanced age at cancer diagnosis is consistent with the low percentage of MMR mutations detected by previous studies in families with this phenotype. These families probably carry mutations in other genes that may or may not be related to MMR. Additional studies are necessary to clarify the molecular basis for HNPCC in families with MSS tumors. |
2,339,239 | Evaluation of psychosocial effects of pre-symptomatic testing for breast/ovarian and colon cancer pre-disposing genes: a 12-month follow-up. | A prospective study of psychosocial consequences following predictive testing for inherited mutations in breast/ovarian and colon cancer susceptibility genes BRCA1, BRCA2, MLH1, and MSH2 was performed. Eighty-seven healthy women were tested for known family mutations and self-assessment scales were used to evaluate anxiety, depression and quality of life. Extensive pre- and post-test information was given. Questionnaires were responded before testing and four times after during the following year. A statistically significant decrease in anxiety mean scores over time was observed among the studied participants. The levels of depression in cancer genes carriers decreased over time while, surprisingly the levels in non-carriers increased. Compared to a normative Swedish sample all women tested showed similar levels of anxiety but women tested for breast cancer genes showed statistically lower levels of depression. Vitality dropped initially after disclosure of the testing of colon cancer genes carriers, followed by increasing levels. No change in vitality or in other quality of life parameters was seen in the other groups and the levels were similar to Swedish norm data. Most tested individuals were satisfied with the testing procedure including genetic counselling and testing and all of them but one would redo the testing. Healthy self-referred women going through predictive breast/ovarian or colon cancer gene testing, including extensive pre- and post-test information and support, in general, will not experience adverse psychological consequences. |
2,339,240 | Proendocrine genes coordinate the pancreatic islet differentiation program in vitro. | In the developing pancreas, the basic helix-loop-helix (bHLH) protein Neurogenin3 (Ngn3) specifies which precursor cells ultimately will become endocrine cells and initiates the islet differentiation program. NeuroD1, a closely related bHLH protein and a downstream target of Ngn3, maintains the differentiation program initiated by Ngn3. We have developed an in vitro model of Ngn3-dependent differentiation by infecting pancreatic duct cell lines with an Ngn3-expressing adenovirus. We found that both Ngn3 and its downstream target NeuroD1 activated the islet differentiation program in these cells by inducing the expression of genes with early roles in the differentiation cascade, as well as genes characteristic of fully differentiated islet cells. Induction of these genes, as exemplified by the insulin1 gene, involved alteration of the local chromatin structure. Interestingly, the subsets of genes activated by Ngn3 and NeuroD1 were not completely overlapping, indicating that these two bHLH proteins serve specific functions in the development of the endocrine pancreas. In addition, microarray gene expression analysis identified a previously uncharacterized group of Ngn3-induced genes with potentially important roles in islet development and function. These studies demonstrate how Ngn3 initiates islet differentiation and provide us with a model for testing methods for producing islet cells for people with diabetes. |
2,339,241 | Tests for establishing compatibility of an observed genotype distribution with Hardy-Weinberg equilibrium in the case of a biallelic locus. | The classical chi(2)-procedure for the assessment of genetic equilibrium is tailored for establishing lack rather than goodness of fit of an observed genotype distribution to a model satisfying the Hardy-Weinberg law, and the same is true for the exact competitors to the large-sample procedure, which have been proposed in the biostatistical literature since the late 1930s. In this contribution, the methodology of statistical equivalence testing is adopted for the construction of tests for problems in which the assumption of approximate compatibility of the genotype distribution actually sampled with Hardy-Weinberg equilibrium (HWE) plays the role of the alternative hypothesis one aims to establish. The result of such a construction highly depends on the choice of a measure of distance to be used for defining an indifference zone containing those genotype distributions whose degree of disequilibrium shall be considered irrelevant. The first such measure proposed here is the Euclidean distance of the true parameter vector from that of a genotype distribution with identical allele frequencies being in strict HWE. The second measure is based on the (scalar) parameter of the distribution first introduced into the present context by Stevens (1938, Annals of Eugenics 8, 377-383). The first approach leads to a nonconditional test (which nevertheless can be carried out in a numerically exact way), the second to an exact conditional test shown to be uniformly most powerful unbiased (UMPU) for the associated pair of hypotheses. Both tests are compared in terms of the exact power attained against the class of those specific alternatives under which HWE is strictly satisfied. |
2,339,242 | Components of feed efficiency in broiler breeding stock: influence of water intake and gastrointestinal contents. | An experiment was conducted with 3 lines of broilers to evaluate the potential roles of water intake and fill of the gastrointestinal (GI) tract on feed conversion ratio (FCR) as measured in a 1-wk FCR test. Birds were reared to juvenile selection age (41 d) and subsequently selected, with the best 18 to 29% of male chicks placed into cages for FCR testing. Feed and water intake were highly correlated in all lines, with each in turn highly correlated with weight gain on test. Although filling of the GI tract differed between the top and bottom halves of the FCR distribution, FCR as measured and corrected for weight of GI tract contents were highly correlated (r = 0.59 to 0.93). Differences between FCR classes were striking for weight gain, but differences between FCR class groups were subtle for starting weight and feed intake. These subtle differences are difficult to detect in a single generation, but may add up through generations of selection. Based on the results of the current and previous studies, it appears that selection for improved FCR works at multiple levels to improve efficiency of feed conversion in broiler breeding stock. |
2,339,243 | Phenotypic and genotypic characterization of invasive Streptococcus pneumoniae clinical isolates. | The emergence of infection caused by invasive penicillinnonsusceptible (PNS) and multidrug-resistant strains of Streptococcus pneumoniae has become a worldwide concern, necessitating the epidemiologic surveillance of such strains.</AbstractText>One aim of this study was to identify clones of invasive PNS S pneumoniae among isolates in Riyadh, Saudi Arabia. The second aim was to compare these clones with international clones to track their spread in Saudi Arabia.</AbstractText>The phenotypes of invasive isolates characterized as S pneumoniae were determined using susceptibility testing and serotyping (capsular test and E-test). The genotypes of PNS isolates were determined using random amplified polymorphic DNA analysis. The genetic relatedness of these local strains to the international widespread clones was investigated.</AbstractText>Of 296 S pneumoniae isolates identified using biochemical and culture characteristics, 89 (30.1%) were invasive. Susceptibility testing using the E-test revealed that 17 of the 89 invasive isolates (19.1%) were PNS. Most of the 89 isolates (89.9%) were resistant to sulfamethoxazole-trimethoprim; 32.6% and 23.6% of isolates were resistant to chloramphenicol and tetracycline, respectively. All of the isolates (100.0%) were fully susceptible to ceftriaxone and vancomycin. Capsular serotyping of the 89 isolates showed that 19A (18.0%), 613 (14.6%), 23F (13.5%), 9V (11.2%), 14 (6.7%), 19F (5.6%), and 18C (4.5%) were the most predominant serogroups/serotypes. The 17 PNS strains were confirmed on polymerase chain reaction to have penicillin resistance genes. Of these 17 strains, international clone 19A-a was the most predominant (41.2%), followed by 6B-a (17.6%), and 23F-a and 9V-a (each, 11.8%).</AbstractText>The present study identified the spread of the 4 most commonPNS S pneumoniae isolates (clones)-19A, 613, 23F, and 9V-to Riyadh, but identified no new clones among patients having invasive infection with S pneumoniae in Riyadh. This study emphasizes that international PNS clones have contributed to the prevalence and spread of PNS pneumococci among the clinical isolates in Saudi Arabia.</AbstractText> |
2,339,244 | Interleukin-1 gene cluster polymorphisms and risk of Alzheimer's disease in Chinese Han population. | Interleukin-1 (IL-1) has been implicated as a key cytokine in Alzheimer's disease (AD) pathogenesis. IL-1 gene polymorphisms, especially IL-1A C((-)889)T polymorphism, have been suggested to be associated with AD risk and onset age. To determine if IL-1 polymorphisms are genetic risk factors for developing AD in Chinese Mainland population, we analyzed IL-1A ((-)889), IL-1B ((-)511) and IL-1RN variable number of tandem repeat (VNTR) polymorphisms in a sample of 145 sporadic AD patients and 181 healthy controls. Our data revealed that the three polymorphisms in IL-1 gene cluster might not play a key role in AD pathogenesis in Chinese Mainland Han population. |
2,339,245 | Mitochondrial genotype and risk for Alzheimer's disease: cross-sectional data from the Vienna-Transdanube-Aging "VITA" study. | The Vienna Transdanube Aging (VITA) study searches for early markers of Alzheimer's disease (AD) by examining the mental status in a community-based cohort of 606, 75-years old volunteers that are then related to various clinical and genetic analyses. To determine whether mutations in mtDNA are involved in expression of AD, the mtDNA of 79 "control" participants is screened for alterations by sequencing of "hot-spot-regions". This study on mtDNA mutations has eliminated the influence of aging on the occurrence of mtDNA alterations by sequencing samples from persons at the age of exactly 75 years. Thus, our cohort reveals a snap-shot of mitochondrial sequences of elderly persons. So far, a high percentage (56%) of persons with known or unknown mutations in the fragments analyzed were found. These data will be compared in due time to a cohort of participants with proven late-onset AD. |
2,339,246 | Identification of a 98-kb DNA segment containing the rice Eui gene controlling uppermost internode elongation, and construction of a TAC transgene sublibrary. | The recessive 'tall rice' phenotype associated with the mutation eui (elongated upper-most internode) is an important agronomic trait that has been introduced into hybrid rice to eliminate panicle enclosure in all types of male-sterile lines and produce good-quality seeds in high yield and at low cost. Based on our previous Eui mapping data, we conducted fine-structure mapping and positional cloning of the gene using an F2 population comprising more than 5000 individuals derived from a cross of the near-isogenic lines 307T (eui/eui) with the recurrent parent Zhenshan 97 (Eui/Eui). In total 45 CAPS (cleaved amplified polymorphic sequences) markers located within an interval of 14.5 cM were analyzed in the subpopulation of 1298 homozygous recessive plants. The resulting high-resolution map defined a 98-kb interval containing the Eui locus flanked by the markers M0387 and M01, and three markers were found to co-segregate with Eui. In order to facilitate the identification of the Eui gene, we used a transformation-competent artificial chromosome (TAC) vector to construct a set of contiguous TAC clones from the Nipponbare BACs (obtained from the Clemson University Genome Institute; CUGI) spanning this region. These clones can be used to streamline complementation testing. The markers tightly linked to the Eui locus can also be used in breeding male-sterile lines with the elongated uppermost internode. |
2,339,247 | Low prevalence of MYOC mutations in UK primary open-angle glaucoma patients limits the utility of genetic testing. | Primary open angle glaucoma (POAG) affects 1% of people over age 40. Early detection and treatment can prevent blindness, but the disease is often asymptomatic until a late stage. Positive family history is an important risk factor and previous studies indicate that approximately 5% of POAG results from mutations in the myocilin ( MYOC) gene, raising the possibility of identifying individuals genetically predisposed to glaucoma. We collected DNA samples from 426 unselected UK POAG patients and analyzed them for MYOC mutations. The Q368X mutation was found in six patients (1.4%). No other mutations were identified, suggesting that amongst patients unselected for family history, the prevalence of MYOC mutations in the UK is lower than in other populations. Genetic and glaucoma screening was offered to first-degree relatives of these six probands (group 1) and of age/sex-matched mutation-negative controls (group 2). Of 11 group-1 relatives, three carried Q368X, one of whom already had glaucoma. Notably, of the 13 relatives in both groups who were mutation negative, one was already being treated for ocular hypertension. We therefore caution against changing glaucoma surveillance regimens in such individuals and suggest that routine untargeted genetic testing for MYOC mutations in patients with POAG would be of limited value until additional significant genetic risk factors are identified. |
2,339,248 | Genetic disorders and the optic nerve: a clinical survey. | Genetic disorders can cause a broad range of optic nerve pathology. Clinical symptoms and examination findings of optic nerve dysfunction may provide early clues to the presence of inherited genetic disease. For many disorders, molecular genetic testing is available for the diagnosis of affected individuals and the identification of unaffected carriers. This article surveys a broad array of systemic genetic disorders affecting the optic nerve, reviewing their ocular manifestations, systemic findings, and clinical genetics. |
2,339,249 | Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols. | We compare the long-term benefits and side effects of deflazacort using two treatment protocols from Naples (N) and Toronto (T). Boys with Duchenne muscular dystrophy between the ages of 8 and 15 years and who had four or more years of deflazacort treatment were reviewed. Diagnostic criteria included males with proximal muscle weakness evident before 5 years, increased serum creatine kinase and genetic testing and/or a muscle biopsy consistent with Duchenne muscular dystrophy. Thirty-seven boys were treated with protocol-N using deflazacort at a dose of 0.6 mg/kg per day for the first 20 days of the month and no deflazacort for the remainder of the month. Boys with osteoporosis received daily vitamin D and calcium. Deflazacort treatment started between 4 and 8 years of age. Thirty-two were treated with protocol-T using deflazacort at a dose of 0.9 mg/kg per day, plus daily vitamin D and calcium. Treatment started between 6 and 8 years of age. All boys were monitored every 4-6 months. The results were compared with age-matched controls in the two groups (19 for protocol-N and 30 for protocol-T). For the boys treated with protocol-N, 97% were ambulatory at 9 years (control, 22%), 35% at 12 years (control, 0%), 25% at 15 years (control, 0%). For the 32 boys treated with protocol-T, 100% were ambulatory at 9 years (control, 48%), 83% at 12 years (control, 0%) and 77% at 15 years (control, 0%). No aids or leg braces were used for ambulation. In boys 13 years and older, a scoliosis of >20 degrees developed in 30% of the boys on protocol-N, 16% on protocol-T and 90% of controls. For protocol-N, no cataracts were observed while in protocol-T, 30% of boys had asymptomatic cataracts that required no treatment. Fractures occurred in 19% (control 16%) of boys on protocol-N and 16% (control, 20%) of boys on protocol-T. This report illustrates: (a) the importance of collaborative studies in developing treatment protocols in Duchenne muscular dystrophy and (b) the long-term beneficial effects of deflazacort treatment in both protocols. However, the protocol-T seems to be more effective and frequently is associated with asymptomatic cataracts. |
2,339,250 | Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1). | Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy. |
2,339,251 | Rapid assessment of anti-HIV siRNA efficacy using PCR-derived Pol III shRNA cassettes. | Identification of sequences within a target mRNA that are susceptible to potent siRNA knockdown often requires testing several independent siRNAs or shRNA expression cassettes. Using RNAi against HIV RNAs is further complicated by the length of the viral genome, the complexity of splicing patterns, and the propensity for genetic heterogeneity; consequently, it is most important to identify a number of siRNA targets that potently block viral replication. We previously described a facile PCR-based strategy for rapid synthesis of si/shRNA expression units and their testing in mammalian cells. Using this approach, which is rapid and inexpensive, it is possible to screen a number of potential RNAi targets in HIV to identify those that are most susceptible to RNAi. We report that shRNA expression cassettes constructed by PCR and cotransfected directly into mammalian cells with HIV proviral DNA express shRNAs that are inhibitory to HIV-1 replication. Our results also demonstrate that there is a wide range of efficacies among shRNAs targeting different sites throughout the HIV genome. By screening several different targets we were able to identify a sequence in a common tat/rev exon that is exquisitely sensitive to RNAi. Furthermore we relate the efficacies of our PCR product expressed shRNAs to the relative stabilities of the siRNA duplexes and the accessibilities of the target sites to antisense base pairing in cell extracts. |
2,339,252 | Frontotemporal dementia: genetics and genetic counseling dilemmas. | Frontotemporal dementia (FTD) is a neurodegenerative disease with early symptoms of personality change and/or language disorder. Approximately 40% of individuals with FTD have a family history of dementia; however, in our experience, less than 10% have clear autosomal dominant inheritance. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases, but are unusual except in families with more than 3 individuals with FTD. The genetics of FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnoses, and lost family histories. The objective of this paper is to enable physicians to recognize hereditary patterns and genetic concerns of FTD families and to understand genetic counseling strategies.</AbstractText>The complexity of FTD genetics and genetic counseling are illustrated using 4 case histories. Case 1 demonstrates the difficulty obtaining a reliable FTD family history. Case 2 illustrates how psychiatric phenocopies can make family linkage studies difficult. The lack of genotype and phenotype correlation and issues of predictive genetic testing within FTD families are the subject of case 3, and case 4 shows how normal aging language difficulties and cognitive changes can be misinterpreted when a family history of dementia is present.</AbstractText>Physicians seeing patients with possible FTD should be aware of the risk of a genetic etiology. A 3-generation family history should be obtained with attention to neurologic, psychiatric, and behavioral symptoms. Variable expression and phenocopies are confounding factors when assessing a possible genetic etiology. Referral of the patient and family for genetic counseling is recommended.</AbstractText> |
2,339,253 | Iconix Pharmaceuticals, Inc.--removing barriers to efficient drug discovery through chemogenomics. | Iconix Pharmaceuticals, Inc. is pioneering the new field of chemogenomics--the integration of chemistry and genomics to profile, optimize and monitor clinical candidates and drug treatment. Iconix's chemogenomic capabilities enable pharmaceutical companies to increase the odds of advancing the right compounds to the clinic and managing the development of those compounds in human testing, thus reducing attrition rates and the costs of drug discovery. |
2,339,254 | Toward individualized pharmaceutical care of East Asians: the value of genetic testing for polymorphisms in drug-metabolizing genes. | Research into the relationship between genetics and drug response has focused on polymorphisms in genes that encode drug-metabolizing enzymes, particularly the genes of cytochrome P450 superfamily 2, which affect the clearance of the anticoagulant warfarin, proton pump inhibitors, tricyclic antidepressants, and many other clinically relevant drugs. Much of this work has targeted East Asians, a genetically distinguishable and populous group. Researchers have identified polymorphisms that inactivate gene function, compared polymorphism frequencies in East-Asian and Caucasian populations, and determined the effects on the pharmacokinetic parameters of drugs. Detection in an individual of polymorphisms known to inactivate a drug-metabolizing enzyme is predictive of poor metabolism of drugs processed by that pathway, which itself may be predictive of an atypical drug response. Genetic tests can be used to screen for individuals with poor metabolizer phenotypes, with the ultimate goal of predicting the clinical effects of drugs. |
2,339,255 | Pharmacogenetics of antiretroviral therapy: genetic variation of response and toxicity. | The application of a pharmacogenetic approach to antiretroviral drug therapy represents a significant challenge, as treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host, as well as drug-drug, interactions. However, despite this inherent complexity, considerable gains have been made in understanding how genetic factors influence the efficacy and toxicity of HIV therapy. In this review the available evidence regarding genetic variation in drug disposition will be examined, including the potential for relatively polymorphic drug-metabolizing enzymes (e.g., cytochrome P450 isoforms) and drug transporters (e.g., P-glycoprotein) to influence the disposition of HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. In addition, the role of genetic variation in determining the immune response to drug-specific antigens will be considered as a potentially significant determinant of susceptibility to idiosyncratic drug reactions (e.g., major histocompatibility complex alleles associated with abacavir hypersensitivity). The current and potential clinical utility of pharmacogenetic testing in HIV management will also be emphasized. |
2,339,256 | A step-wise diagnosis of fragile X syndrome in Taiwan. | Fragile X syndrome (FXS), an X-linked dominant disorder, is one of the common forms of inherited mental retardation. This project aimed at identifying fragile X syndrome patients in schools by a two-step diagnosis with questionnaire and photography followed by molecular analysis. A total of 734 children with mental retardation were enrolled from kindergartens, primary schools, junior high schools, and schools for the mentally retarded. School teachers or nurses administered the questionnaires and took pictures of the faces and hands for of the patients. After viewing of the questionnaire and photos by a geneticist, 145 cases were selected for molecular study and 11 cases were identified as having full mutations in the FMRI gene. The detection rate was 1.5% (11 in 734) in all enrolled cases, and was 7.6% (11 in 145) in those who underwent molecular test. Those affected by FXS were more likely to have simian crease (p<0.001) and a head circumference larger than the 50th percentile (p=0.0295), and those who were not affected by FXS were lower in gestational age (p=0.0243). This screening method is useful for the detection of fragile X syndrome. |
2,339,257 | Hybrid pancreatic tissue substitute consisting of recombinant insulin-secreting cells and glucose-responsive material. | Insulin-dependent diabetes is a serious pathological condition, currently treated by blood glucose monitoring and daily insulin injections, which, however, do not prevent long-term complications. A tissue-engineered pancreatic substitute has the potential to provide a more physiologic, less invasive, and potentially less costly treatment of the disease. A major issue in developing such a substitute is the cells being used. Nonpancreatic cells, retrieved from the same patient and genetically engineered to secrete insulin constitutively or with some glucose responsiveness, offer the significant advantages of being immune-acceptable and relaxing the tissue availability limitations, which exist with islets from cadaveric donors. These cells, however, do not have insulin secretion dynamics appropriate for restoration of euglycemia in higher animals and, eventually, humans. In this study, we present the concept of a hybrid pancreatic substitute consisting of such cells sequestered in a material exhibiting glucose-dependent changes of its permeability to insulin. A Concanavalin A-glycogen material sandwiched between two polycarbonate membranes and exhibiting glucose-dependent sol-gel transformations was used. Rates of insulin transport through this material in gel and sol forms were characterized for both FITC-labeled insulin in solution and insulin secreted by betaTC3 mouse insulinoma cells. Effective diffusivities through sol were found to be up to 3.5-fold higher than through the gel state of the material. A mathematical model of a hybrid construct was formulated and analyzed to simulate the secretory behavior in response to step ups and downs in the surrounding glucose concentration. The experimental and modeling studies indicate that a hybrid pancreatic substitute consisting of constitutively secreting cells and glucose-responsive material has the potential to provide a more physiologic regulation of insulin release than the cells by themselves or in an inert material. |
2,339,258 | Ethics of PGD: thoughts on the consequences of typing HLA in embryos. | As with so many fields of study associated with assisted human reproduction, many ethical issues are raised by the practice of preimplantation diagnosis of inherited disease (PGD). Some are part and parcel of assisted conception, e.g.the rights of human embryos in vitro and of embryologists to establish them, carry out research and discard them. Others unique to clinical PGD were discussed at an earlier meeting on PGD (Edwards et al., 2003). Recent developments in PGD are discussed briefly in this Commentary, especially the ethics of designer babies. |
2,339,259 | Preimplantation genetic diagnosis with HLA matching. | Preimplantation genetic diagnosis (PGD) has recently been offered in combination with HLA typing, which allowed a successful haematopoietic reconstitution in affected siblings with Fanconi anaemia by transplantation of stem cells obtained from the HLA-matched offspring resulting from PGD. This study presents the results of the first PGD practical experience performed in a group of couples at risk for producing children with genetic disorders. These parents also requested preimplantation HLA typing for treating the affected children in the family, who required HLA-matched stem cell transplantation. Using a standard IVF procedure, oocytes or embryos were tested for causative gene mutations simultaneously with HLA alleles, selecting and transferring only those unaffected embryos, which were HLA matched to the affected siblings. The procedure was performed for patients with children affected by Fanconi anaemia (FANC) A and C, different thalassaemia mutations, Wiscott-Aldrich syndrome, X-linked adrenoleukodystrophy, X-linked hyperimmunoglobulin M syndrome and X-linked hypohidrotic ectodermal displasia with immune deficiency. Overall, 46 PGD cycles were performed for 26 couples, resulting in selection and transfer of 50 unaffected HLA-matched embryos in 33 cycles, yielding six HLA-matched clinical pregnancies and the birth of five unaffected HLA-matched children. Despite the controversy of PGD use for HLA typing, the data demonstrate the usefulness of this approach for at-risk couples, not only to avoid the birth of affected children with an inherited disease, but also for having unaffected children who may also be potential HLA-matched donors of stem cells for treatment of affected siblings. |
2,339,260 | Design and bioproduction of a recombinant multi(bio)functional elastin-like protein polymer containing cell adhesion sequences for tissue engineering purposes. | Genetic engineering techniques were used to design and biosynthesise an extracellular matrix (ECM) analogue. This was designed with a well-defined molecular architecture comprising different functional domains. The structural base is a elastin-derived repeating unit, which confers an adequate elastic characteristic. Some of these elastin domains have been modified to contain lysine; this amino acid can be used for crosslinking purposes. The polymer also contain periodically spaced fibronectin CS5 domains enclosing the well-known cell attachment sequence REDV. Finally, the polymer has target sequences for proteolitic action. These sequences are those found in the natural elastin and are introduced to help in the bioabsorption of the polymer. In addition, these proteolitic sequences were chosen in a way that, after proteolitic action, the released fragments will be bioactive. These fragments are expected to promote cell proliferation activity, angiogenesis and other bioactivities of interest for tissue growing, repairing and healing. After purification, the resulting polymers proved to be of high purity and correct sequence. Glutaraldehyde has shown to be a cross-linking agent for this polymer, yielding insoluble hydrogel matrices. This work is framed in a long term project aimed to exploit the power of genetic engineering for the design and bioproduction of complex ECM analogues showing the rich complexity and multi (bio)functionality of the natural matrix. |
2,339,261 | Women's experiences of undergoing BRCA1 and BRCA2 testing: organisation of the German Hereditary Breast and Ovarian Cancer Consortium Survey and Preliminary Data from Münster. | In order to promote safe and effective testing for BRCA1 and BRCA2 mutations in clinical practice, a network of expert centres in hereditary breast and ovarian cancer ('Verbundprojekt familiärer Brust- und Eierstockkrebs'; German Consortium on Hereditary Breast and Ovarian Cancer) has been established by the Deutsche Krebshilfe (German Cancer Aid). To improve practice, evaluations based upon the views of patients who have undergone testing concerning the impact of the genetic diagnosis and the quality of the services they receive and require are undertaken.</AbstractText>Herein, we first describe the protocols for interdisciplinary pre- and post-test counselling and for molecular diagnostics, then the feedback from the patients undergoing testing. Women and men who had obtained their test results at least 6 months earlier were interviewed using a questionnaire including open and standardised questions at 11 participating centres in 2002-2003. Reported here are the survey protocol and preliminary data from interviews with women conducted by the centre based at the University of Münster's Medical School in 2002 (n = 46).</AbstractText>Compared to international guidelines, the Consortium's protocols provide more specifically outlined indications based on the mutation frequencies observed in the German population for families that should be offered interdisciplinary counselling and genetic testing. The data from the Münster survey suggest that there is little regret regarding the decision to undergo testing and that the vast majority of women would undergo the test again. However, women with positive findings experienced more problems than women with negative results. They were less prone to recommend the test and to communicate the tests results in their family compared to women with negative test results. Communication of test results within the family was characterised by preferential information of female family members.</AbstractText>BRCA1/2 testing should be provided within a framework that ensures harmonisation and standardisation of services and that protects users. Women and men with positive test results may need special support from counsellors on how to handle test results in their families. Strategies need to be developed and evaluated on how to help stimulate and facilitate the dissemination of information within families without potentially 'overstraining' the 'messenger patient', at least when a mutation has been identified.</AbstractText>Copyright 2004 S. Karger AG, Basel</CopyrightInformation> |
2,339,262 | BRCA1/2 mutation carriers: living with susceptibility. | To examine whether being a BRCA1/2 mutation carrier affects a wide array of aspects of life, and if so, how.</AbstractText>Participants were grouped according to their carrier status (carrier and noncarrier status), health status (affected or unaffected by cancer), and their enrollment at the counseling service (probands and other family members). One hundred and sixty-five women completed a self-administered questionnaire following their genetic consultation session.</AbstractText>Probands/nonprobands and carriers/noncarriers did not differ with regard to demographic characteristics, health behaviors including medical checkups, the distress they experience or their resources (sense of coherence, social integration, religiosity). Individuals affected by cancer did differ on some of these aspects from participants without cancer.</AbstractText>From the results of this study, being a carrier could not be considered a psychosocial risk factor, nor does it seem to have an effect on carriers' resources and lifestyle.</AbstractText>Copyright 2004 S. Karger AG, Basel</CopyrightInformation> |
2,339,263 | Information-seeking behaviour and psycho-social interactions during the genetic testing process. | The first aim of this study was to investigate the information-seeking behaviour (ISB) of women attending cancer genetic consultations at which the possibility of BRCA testing is considered. We focused here specifically on ISB apart from the cancer genetic consultation, i.e. on what complementary sources of information about genetic testing were consulted and what factors were involved in this behaviour. The second aim was to study the role of the social network used by the patients to collect various opinions on which to base their decisions about being tested.</AbstractText>A prospective cohort study (2000-2002) was therefore carried out on all women attending a single cancer genetic clinic in France after a BRCA1/2 analysis had been proposed. Closed questionnaires were administered before and after the second cancer genetic consultation. The purpose of this consultation was to confirm the patient's decision to be tested.</AbstractText>Results were analysed in 108 subjects (mean age 47 years, SD 11 years; 74% affected by breast/ovarian cancer). Prior to the 2nd consultation, 35.2% of the women had actively looked for information about BRCA1/2 testing, as compared to 25.0% afterwards. After multivariate adjustment by logistic regression, the pre-consultation ISB was found to be associated with greater satisfaction with the information about the psycho-social consequences of genetic testing [adjusted odds ratio (ORadj) 1.03, 95% confidence interval (CI) 1.01-1.06] (scale from 0 to 100) and about the certainty of being a gene carrier (ORadj 3.04, 95% CI 1.16-7.98). Those who actively looked for complementary information were also more often accompanied at the consultation by a family member (ORadj 4.82, 95% CI 1.85-12.56). The other variables tested (depression, coping, socio-demographic and medical characteristics) were not significant (p > 0.05). The role of the social network in the decision making process was perceived as being less helpful when the persons consulted tended to have neutral or unfavourable opinions about genetic testing.</AbstractText>Few women actively sought complementary information about BRCA genetic testing in addition to the cancer genetic consultation. Those who did so differed from the others in terms of their social network and their satisfaction with the consultation. The cancer geneticist is the key actor in women's decision making about genetic testing.</AbstractText>Copyright 2004 S. Karger AG, Basel</CopyrightInformation> |
2,339,264 | The reactions of general practitioners, nurses and midwives in Flanders concerning breast cancer risks in a high-risk situation. | To investigate the reactions of general practitioners (GPs), nurses and midwives concerning the cancer risks in a high-risk family.</AbstractText>Questionnaires were sent to 356 GPs, 881 nurses and 119 midwives.</AbstractText>The response rate was 60% for GPs, 58% for midwives and 33% for nurses. The breast cancer risk of an unaffected patient from a high-risk family as well as the risk of her daughter were mostly (>80%) correctly evaluated as increased. The percentage answering 'increased risk' dropped to 40% for the daughters of the patient's brother. Half of the GPs and nurses/midwives explicitly mentioned that a predictive DNA test was available. Less than one third would recommend such a test for a young child. Reluctance was also observed regarding prophylactic mastectomy.</AbstractText>These results should be taken into account in genetic education initiatives for GPs, nurses and midwives.</AbstractText>Copyright 2004 S. Karger AG, Basel</CopyrightInformation> |
2,339,265 | Cancer genetics service provision: a comparison of seven European centres. | To conduct a survey in seven European cancer genetics centres to compare service provision, organisation and practices for familial breast and colon cancer consultations and testing. Information was obtained on aspects of services both nationally and locally.</AbstractText>A detailed survey questionnaire was adapted collaboratively to obtain the required information. Initial survey data were collected within each centre and interim results were discussed at two European Workshops. Where differences in practice existed, details were clarified to ensure accuracy and adequacy of information. Participating centres were Haifa (Israel), Hannover (Germany), Leiden (The Netherlands), Leuven (Belgium), Manchester (UK), Marseille (France) and Milan (Italy), representing countries with populations ranging from 6.5 to 80 million.</AbstractText>The European countries diverged in regard to the number of cancer genetics centres nationally (from 8 in Belgium to 37 in France), and the average population served by each centre (from 0.59 million in Israel to 3.32 million in Italy). All centres offered free care at the point of access, but referral to specialist care varied according to national health care provision. At a centre level, staff roles varied due to differences in training and health care provision. The annual number of counsellees seen in each participating centre ranged from 200 to over 1,700. Access to breast surveillance or bowel screening varied between countries, again reflecting differences in medical care pathways. These countries converged in regard to the wide availability of professional bodies and published guidelines promoting aspects of service provision. Similarities between centres included provision of a multidisciplinary team, with access to psychological support, albeit with varying degrees of integration. All services were dominated (70-90%) by referrals from families with an increased risk of breast cancer despite wide variation in referral patterns. Collection of pedigree data and risk assessment strategies were broadly similar, and centres used comparable genetic testing protocols. Average consultation times ranged between 45 and 90 min. All centres had access to a laboratory offering DNA testing for breast and bowel cancer-predisposing genes, although testing rates varied, reflecting the stage of service development and the type of population. Israel offered the highest number of genetic tests for breast cancer susceptibility because of the existence of specific founder mutations, in part explaining why the cancer genetics service in Haifa differed most from the other six.</AbstractText>Despite considerable differences in service organisation, there were broad similarities in the provision of cancer genetic services in the centres surveyed.</AbstractText>Copyright 2004 S. Karger AG, Basel</CopyrightInformation> |
2,339,266 | The evolving role of genomics in shaping care for persons with dementia. | Alzheimer's disease and other chronic dementing conditions remain formidable challenges for individuals, their families, and health care providers. In addition to the challenges inherent in the sheer numbers affected, the complex and relatively unpredictable progression of these disorders complicates the delivery of interventions for health care providers. Identifying genetic and environmental etiologic factors and understanding their relationship to the natural history of dementia brings health care providers closer to more effective pharmacologic treatments and perhaps cure. In the meantime, genomics research brings professional nurses closer to providing more specific, perhaps individualized, anticipatory guidance and to providing nonpharmacologic interventions in a genotype-directed way to patients with chronic dementing conditions. The emergence of a genomics-based health care environment presents an opportunity and a challenge for gerontological nurse clinicians, educators, and researchers--an opportunity to evolve practice toward a higher level of specificity and effectiveness and a challenge to do so in a equitable and sensitive manner that improves health and quality of life for all served. |
2,339,267 | Genetics for targeting disease prevention: diabetes. | This article provides an overview of current thinking regarding genetics and diabetes (type 1, type 2, and gestational diabetes mellitus),including a selective look at a few implicated gene variants. This article explores how this information might be applied in current and future clinical practice to (1) predict who is at risk for diabetes and its complications, (2) identify and intervene to prevent or delay the development of diabetes in persons at risk, (3) identify patients with diabetes in an early stage and intervene to prevent later complications,and (4) individualize therapy for patients with diabetes to improve outcomes. The article concludes with some general thoughts about genetics and diabetes prevention in the future. |
2,339,268 | Cancer genetics in primary care. | The cloning of two major breast cancer susceptibility genes, BRCA1 and BRCA2, in 1994 and 1995 and the subsequent development of commercial genetic testing has brought hereditary cancer genetics into the public eye. In addition to DNA-based genetic testing, new strategies and treatments have been developed to provide accurate assessment of cancer risk and to reduce the chances of cancer developing in the future. This increasing scientific and public attention has prompted some cancer patients and their families to find out whether they "have the cancer gene" and has placed more responsibility on primary care clinicians to identify people who should be referred for specialized services of hereditary cancer genetics. |
2,339,269 | The primary care physician's approach to congenital anomalies. | Children with congenital anomalies often represent a special diagnostic and management challenge. To provide optimal care for these children, one must employ a systematic approach to identify the likely pathogenic mechanism leading to the birth defects present. Determining how distinct anomalies relate to one another may lead to elucidation of a specific genetic etiology for the patient's condition. Genetic testing is increasingly available to allow for diagnostic confirmation. Using this systematic approach to a child with congenital anomalies permits accurate prognostic and recurrence risk counseling, informed management decisions, and the appropriate allocation of social support and medical resources. |
2,339,270 | What's new in prenatal screening and diagnosis? | This article provides clinicians with an overview of current methods for prenatal genetic screening and diagnosis. Topics include developments in prenatal screening procedures such as ethnicity-based carrier testing, maternal serum screening, and ultrasonography. Diagnostic alternatives to amniocentesis include chorionic villus sampling and preimplantation diagnosis. Future endeavors such as three-dimensional ultrasonography and fetal cell sorting are discussed. |
2,339,271 | Legacy of the American eugenics movement: implications for primary care. | One hundred years ago the first "genetic revolution" promised a boon to society through the rational application of scientific knowledge about heredity. Leading American physicians, psychologists,social workers, scientists, educators, and philanthropists advocated a eugenics agenda that called for the elimination of the "unfit." This legacy has affected profoundly the current nondirective model of genetic counseling. As primary care now prepares for the age of genomic medicine, the history of eugenics provides a perspective for the application of patient-centered care and shared decision-making models to the process of genetic testing. |
2,339,272 | Genetic counseling in primary care: longitudinal, psychosocial issues in genetic diagnosis and counseling. | Primary care clinicians have an essential role in genetic counseling.This role is distinct from the usual role of genetic counselors. First,primary care clinicans are often involved in the early stages of identifying who may benefit from genetic assessment, helping patients to decide when it is appropriate to pursue genetic information, and preparing them for consultation. Second, the styles of counseling and guidance common in generalist practice are different from the nondirective approach espoused in genetic counseling. Third, primary care clinicians often have a working knowledge of the patient's family, the context in which genetic information has its impact. They are likely to care for family members in addition to the identified patient,and may be well-positioned to adopt a family-based approach to managing genetic risk. Finally, primary care involves a longitudinal perspective, in which genetic information (the family history, for example) takes on new meaning and sometimes more urgency, as diseases progress, family members are newly diagnosed, and patients enter new phases of the life cycle. Patient continuity will play a pivotal role in the care and long-term management for individuals found to be at risk for genetic illness. |
2,339,273 | The family medical history. | In this era of genomic medicine it is easy to be dazzled by an array of diagnostic tools to aid in clinical diagnosis and presymptomatic risk assessment, yet a simple family medical history remains the single most cost-effective "genetic test." A family medical history can be compared with a genetic "biopsy." Learning the skills of obtaining and interpreting a family history is just as central for primary care clinicians as a basic proficiency in interpreting pathology or radiograph reports. In this article the essentials of recording a medical family history and basic inheritance patterns are reviewed. Suggestions for dealing with sensitive family information are also discussed. |
2,339,274 | Management of Portuguese patients with hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution for future guidelines based on a clinical study. | Hyperplastic polyposis (HP) is a rare condition characterized by the presence of multiple hyperplastic polyps in the colon, which has been associated to an increased risk of colorectal cancer (CRC). Guidelines for management of this disease remain, so far, undefined.</AbstractText>To evaluate, in symptomatic patients with HP, phenotypic characteristics as well as results of a screening program in their at-risk first-degree relatives.</AbstractText>Pedigree information and clinical and endoscopic data of 14 patients with HP was studied. SEVENTEEN AND METHODS: at-risk first-degree relatives from six families were also invited to perform screening colonoscopy.</AbstractText>Twelve of fourteen (86%) patients had fewer than 100 colorectal polyps. Polyps' sizes ranged from 2 to 25 mm and were uniformly distributed through the whole colon in 43% of the patients. Hyperplastic polyps predominated, but 11/14 (79%) patients also harbored serrated as well as classic adenomatous polyps. CRC was present in 6/14 (43%) of the patients at the time of diagnosis. Familial history of CRC/polyps was positive in 6/12 (50%) of cases. Colonoscopy in at-risk relatives disclosed polyps in 10/17 (59%) of cases with at least one additional patient having criteria for HP.</AbstractText>Although small, this series demonstrates that a high level of suspicion is needed to diagnose the HP syndrome, in which serrated adenomas seem to be the hallmark. Although an elevated percentage of CRC was observed in this series of symptomatic patients with HP, prospective studies in asymptomatic individuals are needed to clearly quantify the risk of CRC in patients with HP. Because familial aggregation of HP was present in 3/12 (25%) of kindreds, screening colonoscopy should be offered to first-degree relatives.</AbstractText> |
2,339,275 | Testing for HER2 in breast cancer. | HER2 is a paradigm of a molecular target whose appropriate assessment is pivotal in the targeting of novel therapies for breast cancer, notably including Herceptin/Trastuzumab. Determining the correct levels requires immunohistochemical and molecular biological skills that are reproducible and measurable, coupled with a knowledge of the appropriate morphological and pathobiological context. Attaining these goals is not easy and laboratories testing for HER2 should maintain a high level of throughput of tests and engage in a recognized external quality assurance scheme. Fluorescence in-situ hybridization testing remains a particular challenge and there is a range of testing strategies. This testing forms the model for the identification of other novel molecular targets. In the future rapid throughput techniques such as real-time quantitative polymerase chain reaction (rqPCR), tissue microarrays or both should bring significant economies of cost and scale. |
2,339,276 | Rapid carrier screening using short tandem repeats in the phenylalanine hydroxylase gene. | Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by defects in the phenylalanine hydroxylase (PAH) system. Our work aimed to screen the PAH locus for the presence of potentially useful short tandem repeats (STR) as markers for carrier detection in PKU families in Egypt, and to determine the level of PAH heterozygosity within the Egyptian population. The system contains at least eight independent alleles in the Egyptian population, transmitted in a Mendelian fashion. Variations in the number of STR in the 16 families studied gave rise to polymorphisms that proved to be suitable markers for PKU carrier detection and prenatal diagnosis. The most frequent allelic fragment size in PKU patients was 246 bp (35.7%), which together with a fragment of 254 bp accounted for 60.7% of the mutant chromosomes. |
2,339,277 | Red cell glucose-6-phosphate dehydrogenase phenotypes in Iraq. | We attempted to characterize biochemically glucose-6-phosphate dehydrogenase (G6PD) variants in Iraqi individuals. Thus 758 healthy Iraqi males aged 18-60 years were randomly selected and 46 (6.1%) were G6PD deficient. Although the predominant non-deficient G6PD phenotype was G6PD B (92.6%), G6PD A+ was found in polymorphic frequency (1.3%). In the deficient group, 31 cases were fully characterized, including 17 cases with features consistent with G6PD Mediterranean variant, while 12 had other biochemical features and were labelled as non-Mediterranean variant. The remaining two deficient cases were characterized as G6PD A- variant. The presence of a significant number of non-Mediterranean variant was unexpected and may be related to the more heterogeneous background of the Iraqi people. |
2,339,278 | Single nucleotide polymorphism detection in aldehyde dehydrogenase 2 (ALDH2) gene using bacterial magnetic particles based on dissociation curve analysis. | Single nucleotide polymorphism (SNP) detection for aldehyde dehydrogenase 2 (ALDH2) gene based on DNA thermal dissociation curve analysis was successfully demonstrated using an automated system with bacterial magnetic particles (BMPs) by developing a new method for avoiding light scattering caused by nanometer-size particles when using commercially available fluorescent dyes such as FITC, Cy3, and Cy5 as labeling chromophores. Biotin-labeled PCR products in ALDH2, two allele-specific probes (Cy3-labeled detection probe for ALDH2*1 and Cy5-labeled detection probe for ALDH2*2), streptavidin-immobilized BMPs (SA-BMPs) were simultaneously mixed. The mixture was denatured at 70 degrees C for 3 min, cooled slowly to 25 degrees C, and incubated for 10 min, allowing the DNA duplex to form between Cy3- or Cy5-labeled detection probes and biotin-labeled PCR products on SA-BMPs. Then duplex DNA-BMP complex was heated to 58 degrees C, a temperature determined by dissociation curve analysis and a dissociated single-base mismatched detection probe was removed at the same temperature under precise control. Furthermore, fluorescence signal from the detection probe was liberated into the supernatant from completely matched duplex DNA-BMP complex by heating to 80 degrees C and measured. In the homozygote target DNA (ALDH2*1/*1 and ALDH2*2/*2), the fluorescence signals from single-base mismatched were decreased to background level, indicating that mismatched hybridization was efficiently removed by the washing process. In the heterozygote target DNA (ALDH2*1/*2), each fluorescence signals was at a similar level. Therefore, three genotypes of SNP in ALDH2 gene were detected using the automated detection system with BMPs. |
2,339,279 | Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. | Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia--and, more recently, for bipolar disorder--on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P=.0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples. |
2,339,280 | Univerricht-Lundborg disease: underdiagnosed in the Netherlands. | Univerricht-Lundborg disease (ULD), with its major symptom of action myoclonus, is supposed to be very rare in the Netherlands and western Europe. We hypothesized that the syndrome may be underdiagnosed in patients with myoclonus epilepsy.</AbstractText>Mutation analysis of the cystatin B gene was performed in 21 cases with uncontrolled myoclonus.</AbstractText>Seven of the 21 evaluated cases carried mutations in the cystatin B gene. Diagnosis of ULD was made with a mean delay of 20 years from symptom onset.</AbstractText>This study from a country without previous reports of ULD suggests that underdiagnosis of the syndrome is likely. These findings also indicate that persons with juvenile-onset myoclonus epilepsy with action myoclonus should be analyzed for ULD.</AbstractText>Copyright 2004 International League Against Epilepsy</CopyrightInformation> |
2,339,281 | Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel. | Mutations in the genes that encode subunits of the M-type K+ channel (KCNQ2/KCNQ3) and nicotinic acetylcholine receptor (CHRNA4) cause epilepsy in humans. The purpose of this study was to examine the effects of the Szt1 mutation, which not only deletes most of the C-terminus of mouse Kcnq2, but also renders the Chnra4 and Arfgap-1 genes hemizygous, on seizure susceptibility and sensitivity to drugs that target the M-type K+ channel.</AbstractText>The proconvulsant effects of the M-channel blocker linopirdine (LPD) and anticonvulsant effects of the M-channel enhancer retigabine (RGB) were assessed by electroconvulsive threshold (ECT) testing in C57BL/6J-Szt1/+ (Szt1) and littermate control C57BL/6J+/+ (B6) mice. The effects of the Szt1 mutation on minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizures were evaluated by varying stimulation intensity and frequency.</AbstractText>Szt1 mouse seizure thresholds were significantly reduced relative to B6 littermates in the minimal clonic, minimal tonic hindlimb extension, and partial psychomotor seizure models. Mice were injected with LPD and RGB and subjected to ECT testing. In the minimal clonic seizure model, Szt1 mice were significantly more sensitive to LPD than were B6 mice [median effective dose (ED50) = 3.4 +/- 1.1 mg/kg and 7.6 +/- 1.0 mg/kg, respectively]; in the partial psychomotor seizure model, Szt1 mice were significantly less sensitive to RGB than were B6 mice (ED50 = 11.6 +/- 1.4 mg/kg and 3.4 +/- 1.3 mg/kg, respectively).</AbstractText>These results suggest that the Szt1 mutation alters baseline seizure susceptibility and pharmacosensitivity in a naturally occurring mouse model.</AbstractText>Copyright 2004 International League Against Epilepsy</CopyrightInformation> |
2,339,282 | Duration of herd participation in dairy herd improvement milk recording in the United States. | Participation in milk-recording programs that provide data for national genetic evaluations of dairy cattle in the United States is voluntary, but the effectiveness of the evaluation system increases with the number of herds that contribute data. To investigate patterns of herd participation in Dairy Herd Improvement (DHI) testing, periods of continuous testing were computed based on the year that a herd initiated or terminated testing and by geographical region. Continuous testing was defined as at least one test per 6-mo period. Some herds discontinued testing and then re-enrolled. Across all years (1960 through 2002), 65% of herds had one period of continuous testing (no testing lapse). The percentage of herds with testing lapses decreased as the number of lapses increased and as the initial test year became more recent; overall, only 1.5% of herds had more than 6 continuous testing periods. For herds that terminated DHI testing from 1960 through 2002, 64% were on continuous test for <3 yr. In general, herd frequencies decreased as continuous test period increased except for continuous testing of > or =20 yr, which increased to 13% for years 2000 to 2002. Herds with more recent termination dates had remained on continuous test longer, and one-third of herds that were still on test after June 2002 had been on test for at least 20 yr. The duration of herd participation was longest for the northeastern and mideastern United States and shortest for the southeastern United States. Multiple periods of testing with lapses of >6 mo between test periods represent a loss of data that could have enhanced the study and evaluation of genetic characteristics of US dairy cattle. |
2,339,283 | Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. | A definitive diagnosis of primary hyperoxaluria type 1 (PH1) and primary hyperoxaluria type 2 (PH2) requires the measurement of alanine:glyoxylate aminotransferase (AGT) and glyoxylate reductase (GR) activities, respectively, in a liver biopsy. We have evaluated a molecular genetic approach for the diagnosis of these autosomal-recessive diseases.</AbstractText>Polymerase chain reaction (PCR) was used to detect three common mutations in the AGXT gene (c.33_34insC, c.508G>A, and c.731T>C) and one, c.103delG, in the GRHPR gene in DNA samples from 365 unrelated individuals referred for diagnosis of PH1 and/or PH2 by liver enzyme analysis.</AbstractText>One or more of these mutations was found in 183 (68.8%) biopsy proven cases of PH1 and PH2 with a test negative predictive value of 62% and 2%, respectively. 102 (34.1%) patients were homozygous or compound heterozygous, making a molecular diagnosis possible. Age of onset and presenting features were similar in patients homozygous for any of the four mutations. Of the AGXT homozygotes, only the c.508G>A mutant was associated with significant AGT catalytic activity and in two of these activity was in the low normal range, possibly reflecting variation in mitochondrial content of the biopsy as this particular mutation is associated with mitochondrial mistargeting.</AbstractText>Limited mutation analysis can provide a useful first line test for PH1 and PH2 in patients in whom primary hyperoxaluria is suspected and in whom secondary causes have been excluded. Those patients in whom a single mutation, or no mutation, is found can then be selectively targeted for liver biopsy.</AbstractText> |
2,339,284 | Should we maintain the 95 percent reference intervals in the era of wellness testing? A concept paper. | The reference interval is probably the most widely used decision-making tool in clinical practice, with a modern use aiming at identifying wellness during health check and screening. Its use as a diagnostic tool is much less recognised and may be obsolete. The present study investigates the consequences of the new practice for the interpretation of prospective value, negative vs. positive, the probability of confirming wellness, and number of false results based on selected strategy for reference interval establishment. Calculations assumed normalised Gaussian-distributed reference intervals with analytical variation set to zero and absolute accuracy. Also assumed is the independency of tests. Probability for no values outside reference intervals in healthy subjects was calculated from the formula p(no) outside=(1 - p(single)) and according to the formula for repeated testing: p(one) outside =n x p(single) (1 - p(single))n-1 etc. Here n is the number of tests performed and p(single) is the probability of one result outside reference limits with the general formula p(i) outside n-i=k x p(single)i (1- p(single))n-i, with k being the binominal coefficient and i the number outside the reference intervals. Use of the 99.9 centile for health checks will increase the probability for no false from 60% to 99% for 10 tests, and from 46% to 98% for 15 tests. The probability for one false-positive result in 10 tests in a panel can be reduced from 32% to 1% if the 99.9% centile is substituted for the 95% centile. For two in 10 tests, the probability can be reduced from 8% to below 0.1%. In both cases, selection of the 99.9% centile improves the diagnostic accuracy. Reference intervals are needed as a "true" negative reference for absence of disease, and should cover the 99.9% centile of the reference distribution of an analyte to avoid false positives. For this new use, it is critical that reference persons are absolutely normal without clinical, genetic and biochemical signs of the condition being investigated. However, reference intervals cannot substitute clinical decision limits for diagnosis and medical intervention. |
2,339,285 | Transmission of ring chromosome 13 from a mother to daughter with both having a 46,XX, r(13)(p13q34) karyotype. | Ring chromosomes are thought to be the result of breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments. Another mechanism of ring formation is believed to be the simple fusion of chromosome ends with preservation of telomeric and subtelomeric sequences. Ring chromosome 13 was first described in 1968 and its incidence estimated at 1 in 58,000 live births. Severe phenotypes associated with large deletions of 13q have been described as "ring chromosome 13 syndrome." Features of the "ring chromosome 13 syndrome" include mental retardation (often severe), growth retardation, microcephaly, facial dysmorphism, and hand, foot or toe abnormalities. We report on a case of a mother and daughter with r(13) and mild phenotypes. Our patient, IA, had chromosome analysis performed at about 4(1/2) years of age due to some developmental delay. This revealed 46,XX, r(13)(p13q34) karyotype with no loss of any chromosomal band. Her mother, EA, was subsequently found to have the same ring 13. IA's maternal grandmother had a normal karyotype while her maternal grandfather was unavailable for testing. Fluorescence in situ hybridization (FISH) analysis showed loss of a specific subtelomeric 13q region in r(13) in the mother. Clinically, IA had macular hyperpigmentation on the chin and mild delay in speech and fine motor skills. EA, 22 years of age, had mild short stature and borderline mental retardation. To our knowledge, this is the first report of a case of familial transmission of r(13). We compare phenotypes of our cases with those from other reported cases of r(13) and discuss the possible mechanism of formation of this ring chromosome. |
2,339,286 | "You have shown me my end": attitudes toward presymptomatic testing for familial amyotrophic lateral sclerosis. | Amyotrophic lateral sclerosis (ALS) is a lethal degenerative motor neuron disease. Approximately, 5-10% of cases of ALS are familial (FALS), inherited primarily as an autosomal dominant trait. Recently, mutations in Cu/Zn superoxide dismutase (SOD1) have been identified; 15-20% of familial cases carry this mutation, providing a marker for diagnosis, carrier testing, and prenatal detection. We assessed understanding of genetics of FALS in relatives of patients cared for at the Forbes Norris MDA/ALS Research Center in San Francisco. A total of 25 participants completed a questionnaire and semistructured interview. Of these, 60% would have gene testing for themselves; 36% believed testing of children or adolescents was a good idea. Overall knowledge of genetics of FALS was limited. Also, 24% of respondents understood the inheritance pattern of FALS; 64% were aware that not all individuals who had the gene would show symptoms in their lifetime. Families were confused about whether they would receive results from linkage studies. We recommend that: (1) physicians refer relatives of newly diagnosed individuals for genetic counseling and possibly psychological counseling; (2) investigators ensure that participants comprehend the purpose of gene identification is for research, not disclosure of individual results; (3) families be helped to understand how to keep abreast of medical and genetic advances; (4) following the model of Huntington disease (HD), consensus guidelines for FALS genetic counseling and testing be developed. |
2,339,287 | Five years of molecular diagnosis of Fragile X syndrome (1997-2001): a collaborative study reporting 95% of the activity in France. | The Fragile X syndrome is the most common cause of inherited mental retardation. Clinical features are neither specific nor constant and molecular diagnosis is thus widely used since the characterization of the causal mutation in 1991. The aim of this project was to study the evolution of Fragile X diagnosis in France. A preliminary study of the efficiency of screening for the Fragile X mutation in mentally retarded probands with no previous familial diagnosis was done in the Strasbourg's laboratory with a comparison between data from 1991-1994 and 1997-2000. This study showed an improvement in the use of the Fragile X testing regarding the probands' age at diagnosis and the recruitment of sporadic and female cases. To avoid possible bias in clinical referrals and to evaluate the situation nation wide, this study was enlarged to 28 of the 30 laboratories involved in the Fragile X diagnosis in France from 1997 to 2001 (20,816 probands tested, data representative of 95% of the national screening activity). Median age at diagnosis decreased from 9.2 to 5.8 (average 16-11.6y) between the 1991-1994 and the 1997-2001 studies. Over this period, 477 new families were diagnosed with Fragile X, representing 2.8% of tested male probands (417/14,867) and 1.0% of tested female probands (60/5,949). Forty one percent of positive cases corresponded to probands with a familial history of mental retardation, compared to 66% in the initial (1991-1994) study. We also discuss issues concerning premutations discovered in affected individuals and in females with premature ovarian failure (POF). |
2,339,288 | Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. | The authors report mutation screening of the p150 subunit of dynactin (DCTN1) and the cytoplasmic dynein heavy chain (DNCHC1) genes in 250 patients with ALS and 150 unrelated control subjects. Heterozygous missense mutations of the DCTN1 gene were detected in one apparently sporadic case of ALS (T1249I), one individual with familial ALS (M571T), two patients with familial ALS, and two unaffected relatives in the same kindred (R785W). The allelic variants of the DCTN1 gene may represent a previously unknown genomic risk factor for ALS. |
2,339,289 | Enhanced retinal ganglion cell differentiation by ath5 and NSCL1 coexpression. | The molecular mechanism underlying retinal ganglion cell (RGC) differentiation is not fully understood. In this study, the role of the basic helix-loop-helix (bHLH) genes ath5 and NSCL1 in RGC differentiation was examined, by testing whether their coexpression would promote RGC differentiation to a greater extent than either gene alone.</AbstractText>The replication-competent avian RCAS retrovirus was used to coexpress ath5 and NSCL1 through an internal ribosomal entry site. The effect of the coexpression on RGC differentiation was assayed in vivo in the developing chick retina and in vitro in RPE cell cultures derived from day 6 chick embryos.</AbstractText>Coexpression of ath5 and NSCL1 in RPE cells cultured in the presence of bFGF promoted RPE transdifferentiation toward RGCs, and the degree of transdifferentiation was much higher than with either gene alone. Cells expressing RGC markers, including RA4, calretinin, and two neurofilament-associated proteins, displayed processes that were remarkably long and thin and often had numerous branches, characteristics of long-projecting RGCs. In the developing chick retina, retroviral expression of NSCL1 resulted in a moderate increase in the number of RGCs, results similar to retroviral expression of ath5. Coexpression of ath5 and NSCL1 yielded increases in RGCs greater than the sum of their increases when expressed separately.</AbstractText>Both in vitro and in vivo data indicate that the combination of ath5 and NSCL1 promotes RGC differentiation to a greater degree than either gene alone, suggesting a synergism between ath5 and NSCL1 in advancing RGC development.</AbstractText>Copyright Association for Research in Vision and Ophthalmology</CopyrightInformation> |
2,339,290 | Erythrocyte osmotic fragility test for screening of alpha-thalassemia-1 and beta-thalassemia trait in pregnancy. | To evaluate the sensitivity and specificity of osmotic fragility test (OFT) as a screening test in predicting the severe thalassemia trait (alpha-thalassemia-1 & beta-thalassemia).</AbstractText>A descriptive analysis and diagnostic test of non-anemic pregnant women attending antenatal care clinic, Maharaj Nakorn Chiang Mai, during April, and July 2002 was made. Blood samples were collected from 446 singleton pregnancies with no obvious medical complication such as iron deficiency anemia. OFT was performed in the same day, using 0.45% glycerin saline solution and the cut-off value of less than 60% was used for an abnormal test. Quantitative HbA2 test and PCR (SEA type) were done as a gold standard to confirm the diagnosis of beta-thalassemia trait and alpha-thalassemia-1 trait, respectively.</AbstractText>The main outcome measures were sensitivity, specificity, positive and negative predictive value of OFT. If the OFT cut-off value of less than 60% was considered positive, the test had a sensitivity, specificity, positive and negative predictive value of 97.6%, 72.9%, 33.6%, and 99.5%, respectively.</AbstractText>OFT has high sensitivity in detection of alpha-thalassemia-1 trait or beta-thalassemia trait and due to its simplicity with very low cost it may, therefore, be considered as a screening test in a wide population.</AbstractText>Copyright 2004 International Federation of Gynecology and Obstetrics</CopyrightInformation> |
2,339,291 | Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. | A screen of the entire coding region of the USH2A gene in 129 unrelated patients with Usher syndrome type II (USH2) and in 146 unrelated patients with non-syndromic autosomal recessive retinitis pigmentosa (ARRP) uncovered 54 different sequence variations, including 18 likely pathogenic mutations (13 frameshift, three nonsense, and two missense), 12 changes of uncertain pathogenicity (11 missense changes and one in-frame deletion), and 24 non-pathogenic rare variants or polymorphisms. Of the 18 likely pathogenic mutations, nine were novel. Among the USH2 patients, 50 (39%) had one or two likely pathogenic mutations. The most common mutant allele in USH2 patients was E767fs, which was found in 29 patients, including one homozygote. Among the ARRP patients, we found 17 (12%) with one or two likely pathogenic mutations. The most common mutant allele in ARRP patients was C759F and it was found in 10 patients. The C759F allele was also found in two USH2 patients; in neither of them was a change in the other allele found. The second most common mutant allele in both patient groups was L1447fs (found in 6/50 USH2 patients and 6/17 ARRP patients). Of the 50+17=67 patients with identified USH2A mutations, only one mutation in one allele was found in 41+12=53 (79%); the reason for the high proportion of patients with only one identified mutation is obscure. Our results indicate that USH2A mutations are found in about 7% of all cases of RP in North America, a frequency similar to the RPGR gene (8%) and the rhodopsin gene (10%). |
2,339,292 | Identification of insulin variants using Raman spectroscopy. | Drop coating deposition Raman (DCDR) spectroscopy is used to obtain high-quality normal Raman spectra from small volumes (10 microl) of dilute insulin solutions (3-400 microM) for spectral identification and chromatographic detection. The results are used to demonstrate the spectroscopic classification (identification) of three natural insulin variants-human, bovine, and porcine-that differ by between one and three amino acid residues. DCDR measurements were performed on solutions obtained from reverse phase high-performance liquid chromatography (RP-HPLC) eluent fractions, either before or after lyophilization. Classification is demonstrated using replicate DCDR measurements, followed by normalized Savitsky-Golay second derivative preprocessing and partial least squares training with either leave-one-out or batch-to-batch testing. |
2,339,293 | Over-representation of exonic splicing enhancers in human intronless genes suggests multiple functions in mRNA processing. | The human transcriptome is constituted of a great majority of intron-containing and a minority of intron-lacking mRNAs; given the different processing these transcripts undergo, they are expected to carry, intermingled with coding properties, very different editing information. Here we applied a computational approach to compare intronless and intron-containing coding sequences. Hexamer composition comparison allowed the definition of over- and under-represented motifs in intronless genes; surprisingly, experimental testing revealed that intron-lacking coding sequences are enriched rather than depleted in elements with splicing enhancement ability. Similarly, we show evidence that intronless transcripts display a significantly higher frequency of both shuttling and non-shuttling SR protein binding sites compared to intron-containing sequences. These observations suggest that SR proteins (and possibly other splicing factors) play a role in cellular processes distinct from splicing. |
2,339,294 | The allelic spectra of common diseases may resemble the allelic spectrum of the full genome. | Identification of the genes responsible for common human diseases promises to be one of the most significant advances in medical knowledge and treatment. To date, the numerous attempts to identify the genes responsible for complex and multi-factorial common diseases have met with only a handful of successes. The key to calculating the optimal effort and ideal approach to successful identifications lies with understanding the likely allelic spectrum of the target disease. The allelic spectrum describes the number of disease loci and the frequency of each disease allele. It has been implicitly assumed that disease spectra are biased towards either commonness or rareness relative to the allelic spectrum of the overall human genome. We present a hypothesis that the allelic spectra of common diseases are generally similar to the spectrum that characterizes the entire genome. This hypothesis is supported by the fact that only a few loci have major significance to familial disease risks and that there may be many disease loci which each make a minor contribution to a disease. Additionally, although relatively few alleles of the human genome have been examined for disease involvement, current estimates of the number of disease genes are very high. Because selection will have been operating only weakly and for a relatively short time on most of the alleles associated with complex diseases, spectra that are characteristic of near-neutral selection may well apply. We thus propose that the hitherto neglected hypothesis that puts the likely allelic spectra of common diseases in the middle ground between the prevailing hypotheses of spectral skew towards rareness or commonness is the most likely. By using this hypothesis as the null, research resources may be optimally allocated and greater success in identifying disease genes may be achieved. |
2,339,295 | Genetics and genetic counseling: recommendations for Alzheimer's disease, frontotemporal dementia, and Creutzfeldt-Jakob disease. | In this paper we discuss the clinical genetics of three neurodegenerative diseases (Alzheimer's disease, frontotemporal dementia, and Creutzfeldt-Jakob disease), the current application of genetic testing for these diseases, and the role of genetic counseling in familial dementia. We review the literature addressing the clinical application of these genetic findings, including susceptibility testing and predictive testing. In addition, we share our own experience working with families with familial neurodegenerative disease, the genetic counseling process, and the major issues that need attention in the genetic counseling setting. |
2,339,296 | Prospects of genetic research of mild cognitive impairment. | Mild cognitive impairment (MCI) is a common problem in the elderly. Genetic research may yield valuable clues to improve the diagnostic and prognostic tools for MCI. As the majority of patients progress into Alzheimer's disease (AD) and other forms of dementia, the genetics of MCI cannot be separated from the genetics of AD and dementia in general. Follow-up studies of carriers of mutations underlying AD may yield valuable clues for the development of new diagnostic tools for MCI. In particular, large-scale studies of carriers of the apolipoprotein E 4 allele may still be of interest. Our knowledge of the genes involved in MCI is still very limited. In addition, we need powerful and carefully designed candidate gene studies aiming to discover new genes involved in the risk and progression of MCI. Although the genetics of MCI will be difficult to disentangle, there is ample opportunity to improve research of the genes involved. |
2,339,297 | Family cancer histories predictive of a high risk of hereditary non-polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1. | Hereditary non-polyposis colorectal cancer (HNPCC) results from inactivating germline mutations in a set of DNA-mismatch-repair genes, of which the most clinically relevant are hMSH2 and hMLH1. Computer-assisted pedigree risk assessment tools are available to assist in the calculation of an individual's likelihood of bearing such a deleterious mutation. One such tool, cancergene version 3.4 (http://www3.utsouthwestern.edu/cancergene) was used to assess the risk of a deleterious mutation in the genes hMSH2 and/or hMLH1 in a series of probands selected from a panel of 67 South-western Ontario kindred previously identified as likely candidates for HNPCC by established clinical criteria. A DNA sample isolated from peripheral blood leukocytes obtained from each of these probands was examined for genomic rearrangement using the multiplex ligation-dependent probe amplification (MLPA) method. Of the individuals calculated to have a risk of >50% of a hMSH2 or hMLH1 gene mutation by the CancerGene risk assessment tool, 69% (9/13) were shown to have a genomic rearrangement resulting in the deletion of one or more exons of one of these two genes. Family cancer histories predictive of a high risk of HNPCC significantly associate with a genomic rearrangement in hMSH2 or hMLH1. |
2,339,298 | Genetic modification of T cells for cancer therapy. | The use of immune cells with restricted specificities for the treatment of cancer is a rapidly emerging area of clinical research. Chimeric receptors composed of the single-chain variable domain of murine antibodies and human signaling molecules are a promising tool to redirect the specificity of autologous or allogeneic immune cells. The success of this approach depends on the identification of target molecules expressed preferentially on cancer cells. Moreover, appropriate primary and secondary stimuli must be delivered to generate vigorous and durable immune responses. Since cancer cells often lack ligands for key co-stimulatory molecules, the addition of molecules such as CD28 or 4-1BB to the chimeric receptors can significantly improve their function. Studies in vitro and in animal models indicate that immune cells expressing chimeric receptors can have remarkable anti-cancer activity, while experimental and clinical data indicate that long-term persistence of adoptively transferred cells is feasible. Therefore, testing of this approach in clinical trials is warranted. We here review the principles and methodologies for designing chimeric receptors and delivering them into immune cells, as well as some of the potential complications associated with this form of cell therapy. |
2,339,299 | Ethics of genetic counseling--basic concepts and relevance to Islamic communities. | Scientific advances and technical developments in the field of laboratory diagnosis and their practical applications have raised ethical issues linked to religion, beliefs, lifestyle and traditions prevailing in different communities. Some of these are pertinent to genetic screening at various stages of life, prenatal diagnosis and the right of the genetically affected fetus to live--all aspects relevant to inbreeding marriages. Of relevance are medical and ethical principles based on professional responsibility. These ideological and social aspects encounter the challenges of science and its applications in the health field, which are linked, directly or indirectly, to scientific achievements and applications related to human genetics. Analysis of the human genome and identification of its sequence, and chemical components, and theories arising from connection of human genome components in health and disease conditions, have led to global requirements to outline legal aspects and ethical principles in relation to diagnosis, prevention and health care. This paper presents basic aspects of disseminating genetic information, guiding the individual, the couple, or the concerned family through genetically induced ill health and methods of control and prevention. The paper discusses the elements and manner and presents details of the application of genetic counseling in Islamic communities in light of scientific, religious, social and legal aspects in the Islamic arena. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.