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Biomedical subjects

D Barnes

Publications and source records attributed to D Barnes.

At least 55 records · Page 3Linked to original sources
PubMed1999

Simian virus 40 large T antigen J domain and Rb-binding motif are sufficient to block apoptosis induced by growth factor withdrawal in a neural stem cell line.

Serum-free mouse embryo (SFME) cells are a neural stem cell line that is dependent upon epidermal growth factor (EGF) for survival. Removal of EGF results in the G1 arrest and apoptosis of SFME cells. We have shown that the expression of simian virus 40 large T antigen in SFME cells blocks apoptosis and allows cell survival and division in the absence of EGF. Therefore the presence of T antigen abrogates the EGF requirement. The steady-state levels of p53, p21, and mdm-2 do not increase as SFME cells undergo apoptosis upon EGF withdrawal. Furthermore, the amino-terminal 136 amino acids (N136) of T antigen are sufficient to block death and to promote proliferation in the absence of EGF, while the carboxy-terminal fragment (C251-708), which contains the p53 binding site, is unable to block death. Taken together, these data suggest that SFME cells deprived of EGF undergo p53-independent apoptosis. Mutations that disrupt either the J domain or Rb family binding abolish the ability of T antigen to block SFME cell apoptosis and to promote cell growth. We conclude that T antigen must act on one or more members of the Rb family to inhibit SFME cell apoptosis.

Animals↗
PubMed1999

Assessment of reliability of lung function screening programs or longitudinal studies.

The aim was to determine reliability of lung function measurements performed according to recommendations of the American Thoracic Society (ATS) at a screening program in a large South African gold mine and to determine the usefulness of the reliability coefficient G for monitoring the reliability of lung function measurements in a mass screening program. The reliability coefficient G estimates the amount of random error of measurement, relative to the total variation in a measurement. The coefficient G was calculated as a correlation coefficient between two consecutive lung function tests performed within 6 mo, over a period of 43 mo on 3,378 miners. There was significant temporal variability in the reliability. For FEV(1), the coefficient G showed increased variability over the first 5 mo and stabilized at a value of 0.93 for the next 23 mo, after which it systematically declined over the next 15 mo. We estimated that in a large screening program, an optimal sample size of around 900 miners, examined randomly throughout the year, on a yearly basis, would provide a sufficient sample to examine monthly or quarterly fluctuation in the reliability. The value of the reliability coefficient G did not change when the time between two consecutive tests increased up to 15 mo. In conclusion, monitoring of lung function reliability in a screening program by the reliability coefficient G should improve data quality, and provide a measure on which the confidence in a decision-making process could be based when examining temporal changes in lung function for individual subjects.

Adult↗
PubMed1999

Serum vitellogenin levels and reproductive impairment of male Japanese Medaka (Oryzias latipes) exposed to 4-tert-octylphenol.

The induction of synthesis of the "female" yolk precursor protein vitellogenin (VTG) in male fish by estrogenic chemicals in the environment has been demonstrated in many recent reports. However, little is known about the organismal and biological significance of this phenomenon. To examine the relationship between VTG production in male fish and reproductive impairment, adult male medaka were exposed to 4-tert-octylphenol (OP), a known environmental estrogen, in concentrations ranging from 20 to 230 ppb for 21 days, under flow-through conditions. Following exposure, male fish were mated, in the absence of OP, with unexposed females. Breeding groups composed of exposed males and control females produced about 50% fewer eggs than control groups. VTG levels in serum of male fish increased with increasing OP exposure concentration and decreased after OP exposure was discontinued. Nevertheless, significant correlations (p<0.01) were observed between VTG levels in exposed male fish and 1) OP exposure concentrations, 2) percent of fertilized eggs, and 3) survival of embryos. OP-induced VTG synthesis and reproductive impairment appear to be closely linked phenomena. Histological examination indicated spermatogenesis in OP-exposed fish was inhibited, and some exposed fish had oocytes in their testes. Finally, OP caused a significant increase in the number of abnormally developing embryos, suggesting that OP may be genotoxic as well as estrogenic.

Animals↗
PubMed1999

Migraine in a specialist menopause clinic.

OBJECTIVES: Epidemiological studies suggest that migraine and headache worsen during the climacteric. The authors noted that women attending a specialist hospital-based menopause clinic frequently reported vasomotor and other common climacteric symptoms but few spontaneously reported headache or migraine. The aim of this study was to assess the prevalence of migraine and headache in women attending this clinic. METHODS: Seventy-four women consecutively attending the menopause clinic at St. Bartholomew's Hospital were questioned about headache. Those with a positive response were further interviewed to obtain a headache diagnosis. RESULTS: Headache was found to be a common symptom affecting 57% of women in the 3 months before attending a specialist menopause clinic. Migraine affected 29% of patients in the preceding 3 months. This condition was associated with significant disability: 80% of women reported that attacks were more frequent than once a month; 75% reported that the attacks were severe; 50% reported that the duration of treated attacks was longer than 1 day. DISCUSSION: The high prevalence of headache and migraine in this group suggests that perimenopausal women should routinely be asked about headache and offered appropriate advice. This should include optimal attack therapy and strategies for preventing attacks, which may include hormone replacement therapy (HRT). Further studies are warranted to evaluate the relationship between climacteric symptoms, headaches, migraine and HRT.

Adolescent↗
PubMed1998

Use of a clinical model for safe management of patients with suspected pulmonary embolism.

BACKGROUND: The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. OBJECTIVE: To determine the safety of a clinical model for patients with suspected pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Five tertiary care hospitals. PATIENTS: 1239 inpatients and outpatients with suspected pulmonary embolism. INTERVENTIONS: A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. MEASUREMENTS: Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. RESULTS: Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). CONCLUSION: Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.

Algorithms↗
PubMed1998

Structural and kinetic evidence for strain in biological catalysis.

A classic hypothesis for enzyme catalysis is the induction of strain in the substrate. This notion was first expressed by Haldane with the lock and key analogy-"the key does not fit the lock perfectly but exercises a certain strain on it" (1). This mechanism has often been invoked to explain the catalytic efficiency of enzymes but has been difficult to establish conclusively (2-7). Here we describe X-ray crystallographic and mutational studies of an antibody metal chelatase which strongly support the notion that this antibody catalyzes metal ion insertion into the porphyrin ring by inducing strain. Analysis of the germline precursor suggests that this strain mechanism arose during the process of affinity maturation in response to a conformationally distorted N-alkylmesoporphyrin.

Amino Acid Sequence↗
PubMed1998

A microsatellite within the MUC1 locus at 1q21 is altered in the neoplastic cells of breast cancer patients.

Paired DNA samples from the neoplastic and nonneoplastic cells of 118 patients with the sporadic, nonfamilial form of breast cancer were analyzed for evidence of genetic alteration at a polymorphic microsatellite mapped to intron 6 within the MUC1 gene at 1q21. Two other microsatellite loci, D1S104 and APO-A2, which also map to 1q21, were analyzed as well. The frequency of alteration at the microsatellite within the MUC1 locus was significantly higher than D1S104 or APO-A2 (P < 0.001). Analysis by Southern blotting of the VNTR region of the MUC1 gene revealed an amplification of one allele in 34 of 54 informative cases (63%). There was no significant association between these alterations and alterations of the microsatellite within the same locus, suggesting independent mechanisms were responsible for the genetic changes. Microsatellite loci D17S579 at 17q21, the site of the BRCA1 gene, and D18S34 at 18q21-qter, the deleted in colorectal cancer locus, were also analyzed by PCR. Alterations at D17S579 and D18S34 were detected in 18.8% and 6.2% of patients, respectively (P < 0.001, and P < 0.1 relative to the frequency of alteration at D1S104 or APO-A2). A previously described polymorphism of hMSH2 was altered in 16.4% of cases.

Breast Neoplasms↗
PubMed1998

Schizosaccharomyces pombe isp4 encodes a transporter representing a novel family of oligopeptide transporters.

We have recently cloned an oligopeptide transport gene from Candida albicans denoted OPT1. This gene showed significant sequence similarity to three open reading frames (ORFs) with no previously established function: isp4 from Schizosaccharomyces pombe and Saccharomyces cerevisiae YJL212C and YPR194C, identified during the genome project. The S. pombe gene isp4 was originally identified by Sato et al. as a gene that was upregulated through nitrogen starvation induction of meiosis. However, an isp4delta strain exhibited a wild-type phenotype with respect to sexual differentiation. We have found that the same isp4delta strain is deficient in tetrapeptide transport activity as measured by its resistance to toxic tetrapeptides, by its inability to accumulate a radiolabelled tetrapeptide and by the inability to use tetrapeptides as a sole source of an amino acid to satisfy an auxotrophic requirement. Similarly, we found that the ORF YPR194C from S. cerevisiae encodes an oligopeptide transporter. Sequence analyses as well as physiological evidence has led us to propose that the proteins encoded by isp4 and the genes identified from S. cerevisiae and C. albicans comprise a new group of transporters specific for small oligopeptides, which we have named the OPT family.

Amino Acid Sequence↗
PubMed1998

PTR3, a novel gene mediating amino acid-inducible regulation of peptide transport in Saccharomyces cerevisiae.

We have isolated and characterized the Saccharomyces cerevisiae PTR3 gene by functional complementation of a mutant deficient for amino acid-inducible peptide transport. PTR3 is predicted to encode a protein of 678 amino acids that exhibits no similarity to any other protein in the database. Deletion of the PTR3 open reading frame pleiotropically reduced the sensitivity to toxic peptides and amino acid analogues. Initial rates of radiolabelled dipeptide uptake demonstrated that elimination of PTR3 resulted in the loss of amino acid-induced levels of peptide transport. PTR3 was required for amino acid-induced expression of PTR2, the gene encoding the dipeptide/tripeptide transport protein, but was not necessary for nitrogen catabolite repression of peptide import or PTR2 expression. It was determined that PTR3 also modulates expression of BAP2, the gene encoding the branched-amino acid permease. Furthermore, we present genetic evidence that suggests that PTR3 functions within a novel regulatory pathway that facilitates amino acid induction of the PTR system.

Amino Acid Transport Systems↗
PubMed1998

Stromelysin 3: an independent prognostic factor for relapse-free survival in node-positive breast cancer and demonstration of novel breast carcinoma cell expression.

Stromelysin 3 (ST3) is a matrix metalloproteinase implicated in mammary carcinoma progression. To date, localization of ST3 expression in breast cancer by in situ hybridization and immunocytochemistry has shown that the expression of the enzyme is limited to only the stromal fibroblasts surrounding the cancer cells. We have immunostained a large group of ductal carcinoma in situ and invasive breast carcinomas using a monoclonal antibody (5ST-4A9) raised against the hemopexin-like domain of human ST3. We show that invasive lobular carcinomas express significantly less ST3 than invasive ductal carcinomas (IDCs) (P = 0.002). We also show, for the first time, that certain breast carcinoma cells that have undergone a degree of epithelial-to-mesenchymal transition, the so-called metaplastic carcinomas, can express ST3 mRNA and protein, which may in part explain the increased metastatic propensity seen in a number of these tumors. In addition, patients with IDC who had moderate to strong ST3 levels had significantly shorter disease-free survival than those with negative or weak ST3 levels (P = 0.02). Furthermore, in node-positive IDC patients, multivariate analysis revealed that ST3 level was a strong, independent prognostic parameter for disease-free survival (P = 0.005).

Adult↗
PubMed1998

Identification of missense and truncating mutations in the BRCA1 gene in sporadic and familial breast and ovarian cancer.

The cloning of the breast and ovarian cancer susceptibility gene, BRCA1, allows direct estimation of the proportion of these cancers in the general population which can be attributed to germline mutations in this gene. We have used a combination of SSCP, heteroduplex analysis, and chemical cleavage of mismatch to screen the BRCA1 gene for mutations in the germline of 42 patients with breast or ovarian cancer who either have a moderate family history of these cancers, or have no family history of malignancy but a very early onset of the disease. A total of 30 sequence variants were observed, eight of which have not been described previously. Three sequence changes detected by chemical cleavage or heteroduplex analysis were missed by SSCP. The variants included 13 missense mutations, which were assessed for their pathogenic implications. Two of these (M18T and A1708E) are nonconservative substitutions which are located in evolutionarily conserved regions of the gene: M18T lies just upstream of the RING finger motif, and A1708E abolishes the transcriptional transactivation activity of the carboxy-terminal region of BRCA1. Mutations were observed in eight patients overall (19.0%), and protein-truncating mutations occurred in five of 27 (18.5%) families with 1-3 cases of breast or ovarian cancer. The data suggest that a significant proportion of patients with a modest or no family history of these cancers may carry germline mutations in BRCA1.

Adult↗
PubMed1998

Medical readiness training exercise in El Salvador, Central America, 1996.

Medical Readiness Training Exercises (MEDRETEs) can be a valuable training tool for U.S. Army personnel in remote areas of deployment. We report our experience of the MEDRETE in El Salvador in 1996. Working with foreign physicians of the host country was a positive experience in which we learned local customs and mutual cooperation. Evaluation and treatment of nearly 6,000 patients increased goodwill in the community and provided an opportunity for teamwork for Army Reserve medical units, including increased discussions of public health issues. We also report on the field applicability of the advanced laboratory and pharmacy equipment we included in our training.

Adolescent↗
PubMed1997

Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis.

BACKGROUND: An intravenous rather than oral course of methylprednisolone is often prescribed for treating acute relapses in multiple sclerosis (MS) despite the lack of evidence to support this route of administration. Our double-blind placebo-controlled randomised trial was designed to compare the efficacy of commonly used intravenous and oral steroid regimens in promoting recovery from acute relapses in MS. METHODS: 42 patients with clinically definite relapse in MS received oral, and 38 intravenous, methylprednisolone. Clinical measurements at entry and at 1 week, 4 weeks, 12 weeks, and 24 weeks included Kurtzke's expanded disability status scale (EDSS), Hauser's Ambulatory Index, and an arm-function index. The primary outcome criterion was a difference between the two treatment groups of one or more EDSS grades at 4 weeks. FINDINGS: There were no significant differences between the two groups at any stage of the study in any measurement taken: the mean difference in EDSS at 4 weeks (adjusted for baseline level) was 0.07 grades more in those taking oral steroids (95% CI -0.46 to 0.60). The most optimistic outcome for intravenous therapy is an average benefit of less than half a grade improvement on EDSS over oral treatment. INTERPRETATION: Since our study did not show any clear advantage of the intravenous regime we conclude that it is preferable to prescribe oral rather than intravenous steroids for acute relapses in MS for reasons of patient convenience, safety, and cost.

Administration, Oral↗
PubMed1997

A randomized clinical trial of ursodeoxycholic acid as adjuvant treatment to prevent liver transplant rejection.

Acute rejection following orthotopic liver transplantation is a common problem despite current immunosuppressive regimens. Ursodeoxycholic acid (UDCA) has been shown in small, open-labeled studies to prevent rejection episodes, although its effects on complications such as infections, length of hospital stay, and survival have not been evaluated. We conducted a randomized, placebo-controlled, double-blind trial to determine if UDCA (10-15 mg/kg/d) added to a cyclosporine-based immunosuppressive regimen was associated with a decrease in the incidence of at least one episode of acute cellular rejection. Secondary end-points included determining differences in the total number of rejection episodes, the use of muromonab-CD3, the incidence of infections, length of hospital stay, and survival at 90 days and 1 year. Fifty-two patients were randomized, 28 to the treatment group and 24 to the placebo group. During the 3 months of the trial, there was no difference between the placebo and UDCA groups in the number of patients who were rejection-free; however, there were significantly fewer patients in the treatment group who had multiple episodes of acute rejection (0 vs. 6; P = .007). Patients in the treatment group experienced a significantly lower incidence of bacterial infections (4% vs. 29%; P = .02), shorter hospital stay (25 days vs. 34 days; P = .03), and better 90-day survival (100% vs. 83%; P = .04) and 1-year survival (93% vs. 79%). The addition of UDCA to a cyclosporine-based immunosuppressive regimen results in significantly fewer patients experiencing multiple episodes of rejection and improved survival at 90 days and at 1 year. The use of UDCA as adjuvant therapy for patients undergoing liver transplantation who are treated with a cyclosporine-based immunosuppressive regimen should be considered.

Adult↗