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PubMed1995

The gene for a human microfibril-associated glycoprotein is commonly deleted in Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable multiple congenital anomaly/mental retardation syndrome associated with deletion of chromosome 17p11.2. Here we report the identification of a novel gene encoding a human microfibril-associated glycoprotein (MFAP4), which has been mapped to the SMS region. A full-length cDNA corresponding to this gene has been sequenced, and reveals a coding region of 255 amino acids. MFAP4 has a fibrinogen-like domain and shares a high level of sequence homology to a fragment of a bovine 36 kDa microfibril-associated glycoprotein. The N-terminus of the protein bears an Arg-Gly-Asp sequence that serves as the ligand motif for cell surface receptor integrin. These structural features of MFAP4 suggest that it is an extracellular matrix protein involved in cell adhesion or intercellular interactions. Deletion analysis has been conducted on 31 SMS patients by polymerase chain reaction and Southern analysis of somatic cell hybrids retaining the del(17)(p11.2) chromosome or by fluorescence in situ hybridization. The MFAP4 locus is deleted in 30 of 31 SMS patients. Thus, the function of this gene must be considered in the pathogenesis of SMS. Given our previous hypothesis that SMS is a contiguous gene syndrome, complete and exhaustive definition of the critical deletion interval and a thorough phenotype-genotype correlation is required to demonstrate the role and importance of the MFAP4 gene in SMS.

Abnormalities, Multiple↗

PubMed1999

Aging and recognition memory: changes in regional cerebral blood flow associated with components of reaction time distributions.

We used H(2)15O positron emission tomography (PET) to measure age-related changes in regional cerebral blood flow (rCBF) during a verbal recognition memory task. Twelve young adults (20 to 29 years) and 12 older adults (62 to 79 years) participated. Separate PET scans were conducted during Encoding, Baseline, and Retrieval conditions. Each of the conditions involved viewing a series of 64 words and making a two-choice response manually. The complete reaction time (RT) distributions in each task condition were characterized in terms of an ex-Gaussian model (convolution of exponential and Gaussian functions). Parameter estimates were obtained for the mean of the exponential component (tau), representing a task-specific decision process and the mean of the Gaussian component (mu) representing residual sensory coding and response processes. Independently of age group, both tau and mu were higher in the Encoding and Retrieval conditions than in the Baseline condition, and tau was higher during Retrieval than during Encoding. Age-related slowing in task performance was evident primarily in mu. For young adults, rCBF activation in the right prefrontal cortex, in the Retrieval condition, was correlated positively with mu but not with tau. For older adults, rCBF changes (both increases and decreases) in several cortical regions were correlated with both mu and tau. The data suggest that the attentional demands of this task are relatively greater for older adults and consequently lead to the recruitment of additional neural systems during task performance.

Adult↗

PubMed2002

Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.

BACKGROUND AND OBJECTIVE: Alexander disease is a slowly progressive CNS disorder that most commonly occurs in children. Until recently, the diagnosis could only be established by the histologic finding of Rosenthal fibers in brain specimens. Mutations in the glial fibrillary acidic protein (GFAP) gene have now been shown in a number of biopsy- or autopsy-proven patients with Alexander disease. A prospective study on patients suspected to have Alexander disease was conducted to determine the extent to which clinical and MRI criteria could accurately diagnose affected individuals, using GFAP gene sequencing as the confirmatory assay. METHODS: Patients who showed MRI white matter abnormalities consistent with Alexander disease, unremarkable family history, normal karyotype, and normal metabolic screening were included in this study. Genomic DNA from patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the GFAP gene. RESULTS: Twelve of 13 patients (approximately 90%) were found to have mutations in GFAP. Seven of those 12 patients presented in infancy with seizures and megalencephaly. Five were juvenile-onset patients with more variable symptoms. Two patients in the latter group were asymptomatic or minimally affected at the time of their initial MRI scan. The mutations were distributed throughout the gene, and all involved sporadic single amino acid heterozygous changes that changed the charge of the mutant protein. Four of the nine changes were novel mutations. CONCLUSIONS: In symptomatic and asymptomatic patients with a predominantly frontal leukoencephalopathy by MRI, GFAP gene mutation analysis should be included in the initial diagnostic evaluation process for Alexander disease.

Adolescent↗

PubMed2005

Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene.

AIMS: Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM. METHODS AND RESULTS: A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04). CONCLUSION: We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (approximately 10%), and mutation carriers present with delayed onset, in contrast to TNNT2.

Adult↗

PubMed2004

Polymorphisms in ADAM33 are associated with allergic rhinitis due to Japanese cedar pollen.

BACKGROUND: A recent report provided evidence that a disintegrin and metalloprotease domain 33 (ADAM33), a member of the ADAM family, is a novel susceptibility gene in asthma linked to bronchial hyper-responsiveness. However, there has been no investigation of the genetic role of ADAM33 variants in nasal allergy. OBJECTIVE: The purpose of this study was to test the association between ADAM33 polymorphisms and Japanese cedar pollinosis (JCPsis), a most common seasonal allergic rhinitis in Japan. METHODS: We conducted a case-control association study among a Japanese population, involving 95 adult individuals with JCPsis and 95 normal healthy controls. A total of 22 single-nucleotide polymorphisms (SNPs) in ADAM33 were genotyped using PCR-based molecular methods. RESULTS: Six SNPs of ADAM33 gene, three in introns (7575G/A, 9073G/A and 12540C/T) and three in the coding region (10918G/C, 12433T/C and 12462C/T), were strongly associated with JCPsis (P = 0.0002-0.022 for absolute allele frequencies) and most of the SNPs were in linkage disequilibrium with each other. A higher frequency of the common alleles of these SNPs was noted for the subjects with JCPsis in comparison with healthy controls. We also identified a haplotype associated with the disease susceptibility. In addition, associations were found between ADAM33 polymorphisms and various cedar pollinosis phenotypes including clinical severity, eosinophil counts in nasal secretion and allergen-specific IgE levels in sera, but not total serum IgE levels. CONCLUSION: These results indicate that polymorphisms in the ADAM33 gene are associated with susceptibility to allergic rhinitis due to Japanese cedar pollen, but the functional relationship still needs clarification.

ADAM Proteins↗

PubMed2002

Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages.

The human malaria parasite Plasmodium falciparum poses an increasing threat to human health in the tropical regions of the world, and the validation and assessment of possible drug targets is required for the development of new antimalarials. It has been shown that the erythrocytic stages of the parasites, which are responsible for the pathology of the disease in humans, are under enhanced oxidative stress and are particularly vulnerable to exogenous challenges by reactive oxygen species. Therefore it is postulated that the disruption of the antioxidant and/or redox systems of the parasite is a feasible way to interfere with their development during erythrocytic schizogony. In order to test this suggestion thioredoxin reductase (TrxR), an enzyme heavily involved in maintenance of redox homeostasis and antioxidant defense, was knocked out in P. falciparum. It was impossible to generate parasites with a disrupted trxR gene suggesting that TrxR is essential for P. falciparum erythrocytic stages. Technical problems were excluded by transfecting a 3' replacement construct, which recombined correctly and transfectants did not show any phenotypic alterations. In order to prove that the trxR knockout was responsible for the lethal phenotype of the null mutants, a co-transfection with both the knockout construct and a construct containing the trxR coding region under the control of the calmodulin promoter was conducted. Despite the disruption of the trxR gene, parasites were viable. In a Southern blot analysis a complicated restriction pattern was obtained, but it was shown by pulse field gel electrophoresis and field inverse gel electrophoreses that only the trxR gene locus on chromosome 9 was targeted by the constructs. It was found that the co-transfected constructs form concatemeric structures prior to integration into the trxR gene locus, which is further supported by plasmid rescue followed by restriction analyses of the plasmids. Northern and Western blot analyses proved that the co-transfectants highly overexpress TrxR from the introduced gene. Our results demonstrate that TrxR is essential for the survival of the erythrocytic stages of P. falciparum.

Animals↗

PubMedDate not supplied

Expression of the tumor suppressor gene PTEN is not altered in the progression of ovarian carcinomas and does not correlate with p27Kip1 expression.

This study was designed to investigate the role of PTEN in the progression of ovarian cancer. We performed mutation analysis and determined PTEN gene expression in tissue from both primary and relapsed cancers and in the corresponding occult metastases. Furthermore, p27Kip1 staining was conducted in order to explore a putative functional link. The study group comprised 112 tumor tissue specimens from 37 ovarian cancer patients. Expression of both PTEN and p27Kip1 was determined by immunohistochemistry. The PTEN mutational spectrum was determined by PCR-based sequence analysis. Fifty-six per cent of the tumors were positive for PTEN expression and 75% were p27Kip1 positive. For both markers, tumor cells ranged from 0 to 90% positivity. In 55% (20/37) of the cases, PTEN expression in the primary tumor was consistent and in the corresponding advanced cancer tissues, whereas the remainder showed considerable variation. p27Kip1 was consistently expressed in 16 out of 37 cases (43%). No mutations were observed in the coding region of the PTEN gene. No correlation was observed between PTEN and p27Kip1 expression. Our data indicate that expression of PTEN, but not p27Kip1 (one of the major mediators of PTEN function) is unchanged during the progression of ovarian cancer. This study suggests that in ovarian cancer PTEN does not play a major role in disease progression and is not involved in the alteration of p27Kip1 expression.

Adult↗

PubMed1994

A national profile of the use of intensive care by Medicare patients with cancer.

BACKGROUND: The broad picture of intensive care unit (ICU) outcomes and expenditures cannot be discerned from previous studies that were conducted at single hospitals and focused on narrow subsets of patients. METHODS: This study provides a comprehensive national profile of ICU used by Medicare patients with cancer. The data source was the Medicare Provider Analysis and Review file for fiscal year 1990, representing 100% of all hospital admissions that occurred within 723 ICD-9-CM codes and organized into 11 code groups. Using screening criteria, admissions were categorized as surgical (both major and minor procedures) or nonsurgical (no procedures) and with and without involvement of the ICU. The categories were compared using the following outcome variables: total hospital charges, ICU charges, ancillary charges, average length of stay, and in-hospital mortality. RESULTS: This study population accounted for nearly 800,000 admissions, of which 143,458 (18.1%) involved the use of the ICU. Actual ICU charges represented 4.9% of the $9.3 billion in total hospital charges. Intensive care unit use is associated positively with service intensity, and 73% of all the admissions involving the ICU were for major procedures. Only 2% involved no procedures. Admissions involving use of the ICU generate higher charges and longer lengths of stay than non-ICU admissions, although the differences decrease with declining treatment intensity and resource use. In-hospital mortality rates, for those cases that used the ICU, were 9.8% for major procedures, 21.2% for minor procedures, and 37.6% for cases involving no procedures. CONCLUSIONS: Contrary to the conclusions drawn from previous research, these findings suggest that patients who receive less intense service and use fewer hospital resources are more likely to die in the hospital than those who receive more care, with or without a stay in the ICU during the hospitalization. A global view of ICU use does not support the conclusion that a disproportionate share of special care resources is expended on futile care of the terminally ill or excessive monitoring of low risk patients, although these problems undoubtedly exist. Analysis of comprehensive national data regarding the use of intensive care provides a perspective that challenges some of the conclusions based on more limited studies that were conducted in single hospitals and focused on nonsurvivors or subsets of patients narrowly defined in other ways.

Critical Care↗

PubMedDate not supplied

Improvements in breast cancer pathology practices among medicare patients undergoing unilateral extended simple mastectomy.

The information contained in pathology reports of breast cancer specimens is of critical importance to treating physicians for selection of local regional treatment, adjuvant therapy, evaluation of therapy, estimation of prognosis, and analysis of outcomes. This information is also of great importance to patients and their families. In 2000, a Breast Cancer Pathology Advisory Group was formed to advise on the design of a project to assess the quality of pathology reports on unilateral extended simple mastectomy (ICD-9-CM procedure code 85.43) specimens from Medicare patients in New York State. This group comprised clinical pathologists, breast surgeons, medical oncologists, clinical breast cancer specialists, and a radiation oncologist. The group suggested that the reports be examined for several elements (quality indicators) that are relevant to patient care and prognosis. Baseline random sample data assessing these elements were established from a random sample of all cases for the calendar year 1999. A random sample of 748 cases (43.5%) of unilateral extended simple mastectomy was chosen from among 1718 cases for the calendar year 1999. Of these, 555 (74.2%) were suitable for review. The remaining 193 (25.8%) cases did not satisfy the inclusion criteria. Aggregate performance on 7 quality indicators (presence of carcinoma, laterality of specimen, number of lymph nodes present, number of positive nodes, documentation of lymph nodes, histologic type, and largest dimension of the tumor) was 83.7% or better, whereas performance was 69.4% or less on 10 others (resection margin status, verification of tumor size, gross observation of the lesion, histologic grade, angiolymphatic invasion, nuclear grade, location of the tumor, mitotic rate, extent of tubule formation, and perineural invasion). The last, perineural invasion, was used as a control element and was not considered an evaluative quality indicator. Performance levels for New York State were significantly lower for histologic grade, resection margin status, and angiolymphatic invasion than in similar studies elsewhere. In addition, there were significant interhospital disparities in the performance levels for these quality indicators. Whereas some hospitals always recorded certain indicators, others never did. This in part reflects differing degrees of adoption of recommended specialty society protocols. The second phase of the project consisted of an educational feedback program involving the directors of pathology laboratories in New York State. The aggregate findings of the baseline study were shared with all the pathologists. In addition, each hospital that performed unilateral extended simple mastectomies during the study period received its own specific data so that it could compare its performance with the aggregate performance. The results of the baseline study also were shared with the New York Pathological Society and the New York State Society of Pathologists. The latter described the results in its newsletter. A postintervention review of the medical charts of a sample of 297 Medicare patients discharged from New York State acute care hospitals with an ICD-9-CM procedure code of 85.43 (unilateral extended simple mastectomy) was conducted for the 6-month period from December 1, 2001, through May 31, 2002. The 8 quality indicators, performance for which was below 84% in the baseline, were chosen for this remeasurement. Statistically significant improvements (P < .0001) occurred in all the 8 quality indicators, ranging from 12.6% to 19.9%. The results of this study indicate that the issues identified by breast cancer pathology reports are amenable to improvement. Such improvement can serve both the patients and the treating physicians better in making adjuvant treatment decisions, estimating prognosis, and evaluating outcomes. It also will be of help to patients and their families in making other life decisions.

Aged↗

PubMed2002

Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD. METHODS AND RESULTS: To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; P<0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, P= 0.001). CONCLUSION: The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.

Adult↗

PubMed2006

Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.

The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F, and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel, we conducted a prospective pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d. We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*1/*1) homozygotes, while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2 (*1/*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 muM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% +/- 14.9% on day 7 (P < .001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% +/- 14.6% on day 7, P = .22 vs baseline, and P < .003 vs *1/*1 subjects). Similar results were found with VASP phosphorylation. The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.

Adolescent↗

PubMed2005

Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation.

OBJECTIVE: To evaluate clinical, genetic, and electrophysiologic features of patients with Andersen-Tawil syndrome (ATS) in the United Kingdom. METHODS: Clinical and neurophysiologic evaluation was conducted of 11 families suspected to have ATS. Molecular genetic analysis of each proband was performed by direct DNA sequencing of the entire coding region of KCNJ2. Control samples were screened by direct DNA sequencing. The electrophysiologic consequences of several new mutations were studied in an oocyte expression system. RESULTS: All 11 ATS families harbored pathogenic mutations in KCNJ2 with six mutations not previously reported. Some unusual clinical features including renal tubular defect, CNS involvement, and dental and phonation abnormalities were observed. Five mutations (T75M, D78G, R82Q, L217P, and G300D) were expressed, all of which resulted in nonfunctional channels when expressed alone, and co-expression with wild-type (WT) KCNJ2 demonstrated a dominant negative effect. CONCLUSION: Six new disease-causing mutations in KCNJ2 were identified, one of which was in a PIP2 binding site. Molecular expression studies indicated that five of the mutations exerted a dominant negative effect on the wild-type allele. KCNJ2 mutations are an important cause of ATS in the UK.

Adolescent↗

PubMed1999

Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1.

Small and intermediate conductance Ca2+-activated K+ channels play a crucial role in hyperpolarizing the membrane potential of excitable and nonexcitable cells. These channels are exquisitely sensitive to cytoplasmic Ca2+, yet their protein-coding regions do not contain consensus Ca2+-binding motifs. We investigated the involvement of an accessory protein in the Ca2+-dependent gating of hIKCa1, a human intermediate conductance channel expressed in peripheral tissues. Cal- modulin was found to interact strongly with the cytoplasmic carboxyl (C)-tail of hIKCa1 in a yeast two-hybrid system. Deletion analyses defined a requirement for the first 62 amino acids of the C-tail, and the binding of calmodulin to this region did not require Ca2+. The C-tail of hSKCa3, a human neuronal small conductance channel, also bound calmodulin, whereas that of a voltage-gated K+ channel, mKv1.3, did not. Calmodulin co-precipitated with the channel in cell lines transfected with hIKCa1, but not with mKv1. 3-transfected lines. A mutant calmodulin, defective in Ca2+ sensing but retaining binding to the channel, dramatically reduced current amplitudes when co-expressed with hIKCa1 in mammalian cells. Co-expression with varying amounts of wild-type and mutant calmodulin resulted in a dominant-negative suppression of current, consistent with four calmodulin molecules being associated with the channel. Taken together, our results suggest that Ca2+-calmodulin-induced conformational changes in all four subunits are necessary for the channel to open.

Amino Acid Sequence↗

PubMed2026

Identification of rare maternal copy number variants by genome-wide analysis of noninvasive prenatal screening data in 113,017 pregnant women.

OBJECTIVES: Knowledge of copy number variants (CNVs) is relevant to maternal and fetal health and can be obtained from noninvasive prenatal screening (NIPS) of pregnancy. However, genome-wide analysis of maternal CNVs using NIPS data has not been conducted in large populations. METHODS: For CNV analysis, the human genome was segmented into 10 kilobase pairs (Kb) bins, and the relative sequencing depth of each bin was calculated. The circular binary segmentation algorithm was used to estimate CNVs. Detected CNVs from two pregnancies of the same participant were compared to validate the reproducibility. All CNVs were merged into CNV regions (CNVRs) to evaluate their frequency, distributions, and relationship with disease-related genes and regions. RESULTS: In this study, 113,017 pregnant women were recruited. A total of 363,886 CNVs larger than 50 Kb were detected in 101,779 individuals and merged into 43,005 CNVRs. For evaluating the reproducibility of CNVs, 90.18% of deletions and 88.07% of duplications were consistent. In general, 78.13% of individuals carried CNVRs that overlapped protein-coding genes, while 14.76% overlapped OMIM genes. We detected 246 novel CNVRs, 134 (54.47%) involving protein-coding genes. For the perspective of maternal-fetal health, we identified 4,984 (4.41%) individuals as carriers of 5,243 CNVs containing known pathogenic or likely pathogenic regions, including 22q11.2 region and DMD gene.. CONCLUSIONS: NIPS sequencing data is a reliable source for maternal CNV detection. These CNVs constitute an integrate component in maternal-fetal health management.

Humans↗

PubMed2001

Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome.

BACKGROUND: The voltage-gated, rapid-delayed rectifier current (I(Kr)) is important for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the alpha-subunit HERG and KCNE2 for the beta-subunit MiRP1, cause acquired and congenital long Q-T syndrome (LQTS) and other cardiac arrhythmias. METHODS: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The method was used to screen 40 unrelated LQTS patients. RESULTS: Eleven mutations, of which six were novel, were found in KCNH2. Interestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing the need to examine the entire gene when screening for mutations. No mutations were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. CONCLUSIONS: The potential role of rare polymorphisms in the HERG/MiRP1 K+-channel should be clarified with respect to drug interactions and susceptibility to arrhythmia and sudden death.

Cation Transport Proteins↗

PubMed2003

Women's perspectives on intimate partner violence services: the hope in Pandora's box.

OBJECTIVE: To explore women's perspectives about how to enhance services for those who experience intimate partner violence (IPV) and how to improve the links between such services and the health care setting. METHODS: We conducted 6 focus groups involving 67 women in both rural and urban settings in North Carolina. A standardized interview guide was used to investigate the women's perspectives on the study objectives. Coding and theme analyses were conducted to assess new ideas and/or common themes among the groups. RESULTS: Participants identified currently available services for women experiencing IPV, including health care providers, police and the legal system, domestic violence shelters, and churches. Participants discussed existing barriers to addressing violence within the health care system, including cost of medical services, risk of having social services remove their children, violence being too personal to discuss, and doctors' inability to provide what they thought victims really needed. Participants agreed that the most important role for providers would be referrals to useful services (advocacy, job training, and financial support). Participants also emphasized the need for community-based prevention efforts. CONCLUSION: We found a striking lack of support among women participants in our study for using the health care setting as part of the service response to IPV. Participants believed that the health care system is not set up to allow providers to provide the level of individual assistance that they thought would be most useful. Participants did have hope that women's risk of future IPV would decrease if they were provided with useful community-based services and if community-wide prevention efforts were implemented.

Adult↗

PubMed1999

Locus specificity of polymorphic alleles and evolution by a birth-and-death process in mammalian MHC genes.

We have conducted an extensive phylogenetic analysis of polymorphic alleles from human and mouse major histocompatibility complex (MHC) class I and class II genes. The phylogenetic tree obtained for 212 complete human class I allele sequences (HLA-A, -B, and -C) has shown that all alleles from the same locus form a single cluster, which is highly supported by bootstrap values, except for one HLA-B allele (HLA-B*7301). Mouse MHC class I loci did not show locus-specific clusters of polymorphic alleles. This was considered to be because of either interlocus genetic exchange or the confusing designation of loci in different haplotypes at the present time. The locus specificity of polymorphic alleles was also observed in human and mouse MHC class II loci. It was therefore concluded that interlocus recombination or gene conversion is not very important for generating MHC diversity, with a possible exception of mouse class I loci. According to the phylogenetic trees of complete coding sequences, we classified human MHC class I (HLA-A, -B, and -C) and class II (DRB1) alleles into three to five major allelic lineages (groups), which were monophyletic with high bootstrap values. Most of these allelic groups remained unchanged even in phylogenetic trees based on individual exons, though this does not exclude the possibility of intralocus recombination involving short DNA segments. These results, together with the previous observation that MHC loci are subject to frequent duplication and deletion, as well as to balancing selection, indicate that MHC evolution in mammals is in agreement with the birth-and-death model of evolution, rather than with the model of concerted evolution.

Alleles↗

PubMed1993

Functional sites in the 5' region of human immunodeficiency virus type 1 RNA form defined structural domains.

The 5' region of HIV-1 RNA contains functional elements involved in key steps of the retroviral cycle, such as genomic RNA transcription, splicing, translation, dimerization or initiation of reverse transcription. In the present work, we investigated the conformation of the first 500 nucleotides covering the RNA leader and the 5' gag coding sequences of HIV-MAL, using chemical probing. We provide detailed information on almost each nucleotide at one of their Watson-Crick positions and on position N-7 of purines. Experiments were conducted on two in vitro transcribed RNA fragments (1 to 707 and 1 to 311). A secondary structure model was derived by combining the experimental data, computer predictions and sequence comparison. Under conditions favoring dimerization (high salt concentration), HIV-1 RNA folds into independent structural domains that can be related to defined functional regions. The first domain corresponds to TAR forming a stable stem-loop. Intrinsic structural features are found to stabilize the TAR hairpin loop. The second domain (nucleotides 56 to 299) contains the PBS sequence, which is located in a stable subdomain constrained by a four stem junction (nucleotides 139 to 218). Although the MAL isolate has an insertion near the PBS, probably resulting from the duplication of a 23-nucleotide sequence, the structural organization of this subdomain is conserved in all other HIV-1 isolates. The third domain (nucleotides 300 to 404) contains the splice donor site, packaging and dimerization elements and the AUG initiation codon of gag. A major result is the structural versatility of this region. Two mutually exclusive structures, both equally in agreement with probing data, could modulate the different functions involving this domain. The reduced accessibility of the gag translational initiation site possibly accounts for the low efficiency of the in vitro translation of the dimer. Finally, the 5' gag coding sequences form a metastable domain.

Animals↗