PubMed Health⌕ Search

Biomedical subjects

R M Martin

Publications and source records attributed to R M Martin.

At least 19 recordsLinked to original sources
PubMed2000

Local production of anti-CD4 antibody by transgenic allogeneic grafts affords partial protection.

BACKGROUND: Immunosuppressive drugs and anti-lymphocyte antibody are used clinically to suppress cellular rejection responses. However, these systemic regimens often led to general immunodeficiency and thus increased susceptibility to opportunistic infection and neoplasia. Immunosuppressive molecules delivered locally may be a way of inhibiting rejection responses, whereas systemic immunity is preserved. To achieve protective local immunosuppression, we produced a graft secreting its own immunomodulator, by deriving transgenic mice expressing a chimeric anti-CD4 antibody (GK2c) in the pancreas. METHODS AND RESULTS: Transgenic mice in bml genetic background expressing a modified anti-mouse CD4 antibody (GK2c) under two promoters have been produced. Tissue expression of GK2c was detected by immunoperoxidase staining. Under the cytomegalovirus promoter, there was abundant GK2c expression in pancreatic exocrine tissue. Under the rat preproinsulin II promoter, there was abundant GK2c expression in pancreatic endocrine tissue only. High-expression transgenic lines had 10-100 microg/ml GK2c in blood plasma. By flow cytometry, these transgenic mice were devoid of CD4+ cells in their peripheral lymphoid organs. To test transgenic mice as donors, fetal pancreata from transgenic mice were grafted into fully allogeneic CBA mice under the kidney capsule, transgenic grafts had prolonged survival compared with control non-transgenic grafts. Furthermore, GK2c transgenic grafts had reduced infiltration with an absence of CD4+ cells at the graft site without any effect on the cell composition in lymphatic tissues. CONCLUSION: Transgenic grafts that secrete anti-CD4 antibody can afford some protection against graft rejection, while only affecting the CD4 population at the graft site.

Animals↗
PubMed2000

SPAK, a STE20/SPS1-related kinase that activates the p38 pathway.

We have cloned a member of the STE20/SPS1 protein kinase family from a transformed rat pancreatic beta cell line. SPAK (STE20/SPS1-related, proline alanine-rich kinase) belongs to the SPS1 subfamily of STE20 kinases and is highly conserved between species. SPAK is expressed ubiquitously, although preferentially in brain and pancreas. Biochemical characterization of SPAK catalytic activity demonstrates that is a serine/threonine kinase that can phosphorylate itself and an exogenous substrate in vitro. SPAK is immunoprecipitated from transfected mammalian cells as a complex with another, as yet uncharacterized, serine/threonine kinase which is capable of phosphorylating catalytically-inactive SPAK and myelin basic protein in an in vitro kinase assay. SPAK specifically activates the p38 pathway in cotransfection assays. Like MST1 and MST2, SPAK contains a putative caspase cleavage site at the junction of the catalytic domain and the C-terminal region. Full-length SPAK is expressed in the cytoplasm in transfected cells, while a mutant corresponding to caspase-cleaved SPAK is expressed predominantly in the nucleus. The similarity of SPAK to other SPS1 family members, its ability to activate the p38 pathway, in addition to its putative caspase cleavage site, provide evidence that SPAK may act as a novel mediator of stress-activated signals. Oncogene (2000) 19, 4290 - 4297

Amino Acid Sequence↗
PubMed2000

Metallization of molecular hydrogen: predictions from exact-exchange calculations.

We study metallization of molecular hydrogen under pressure using exact-exchange (EXX) Kohn-Sham density-functional theory in order to avoid well-known underestimates of band gaps associated with standard local-density or generalized-gradient approximations. Compared with the standard methods, the EXX approach leads to considerably (1-2 eV) higher gaps and significant changes in the relative energies of different structures. Metallization is predicted to occur at a density of greater, approximately greater than 0.6 mol/cm(3) (corresponding to a pressure of greater, approximately greater than 400 GPa), consistent with all previous measurements.

Journal Article↗
PubMed2000

Local secretion of a chimeric anti-CD4 antibody protects against graft rejection in the NOD mouse.

BACKGROUND: Engineering a graft to secrete its own immunosuppressive antibodies may minimize the risks associated with current high dose systemic immunosuppression. METHODS AND RESULTS: A beta cell insulinoma cell line (NIT-1) was transfected with genes encoding a chimeric anti-CD4 antibody. The NIT-1 cells secreted functional chimeric anti-CD4 antibody that bound to the CD4 molecule on mouse thymocytes and inhibited in vitro proliferation of CD4+ve T cells. Both test and control transfected cell lines grew at a similar rate in immunodeficient mice. In immunocompetent NOD mice, NIT-1 cells are normally rejected by a cellular immune response against the SV40 T antigen. Although control transfected NIT-1 cells were rapidly rejected by NOD mice, anti-CD4 secreting NIT-1 cells grew significantly better and were able to form tumors at the site of injection. CONCLUSIONS: The local secretion of chimeric anti-CD4 antibody from transfected cells can contribute to graft survival in our transplantation model.

Animals↗
PubMed2000

The incidence of adverse events and risk factors for upper gastrointestinal disorders associated with meloxicam use amongst 19,087 patients in general practice in England: cohort study.

AIMS: Meloxicam is a novel nonsteroidal anti-inflammatory drug (NSAID) which may be associated with fewer adverse upper gastrointestinal events than other NSAIDs because it preferentially inhibits the inducible enzyme cyclo-oxygenase-2 relative to the constitutive isoform, cyclo-oxygenase-1. The aims of the study were to: determine the rate of adverse events associated with meloxicam in general practice, stratify these rates by selected risk factors, and to identify signals of previously unsuspected adverse events associated with meloxicam. METHODS: As part of the national prescription-event monitoring pharmacovigilance system for newly launched drugs in general practice, all patients prescribed meloxicam in England between December 1996 and March 1997 were identified by the central Prescription Pricing Authority. We sent short questionnaires to all prescribers asking about adverse events experienced within 6 months of the first prescription. RESULTS: There were 19 087 patients in the study. The rate of dyspepsia during the first month of exposure was 28.3 per 1000 patient-months. There were 33 reports of upper gastrointestinal haemorrhage during treatment (rate: 0.4 per 1000 months). A history of gastrointestinal disorder in the previous year was associated with an increased rate of dyspepsia (rate ratio: 3.0; 95% confidence interval: 2.6, 3.4), abdominal pain (2.1; 1.6, 2.6), and peptic ulcer (4.0; 1.4, 13.2). Prior NSAID use was associated with a 20-30% decrease in the rate of dyspepsia and abdominal pain in patients starting meloxicam, while patients prescribed concomitant gastroprotective agents had a two to three-fold increased rate of dyspepsia, abdominal pain and peptic ulceration. Other rare events were thrombocytopenia (n = 2); interstitial nephritis (n = 1) and idiosyncratic liver abnormalities (n = 1). CONCLUSIONS: In the absence of gastro-intestinal risk factors the incidence of gastro-intestinal disturbance was low. Such risk factors should be carefully reviewed prior to prescribing meloxicam.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies.

AIMS: To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. METHODS: In prescription-event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. RESULTS: The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0. 18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0. 17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age-response relationship. CONCLUSIONS: Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management.

Ten male pseudohermaphrodites with 17 beta-hydroxysteroid dehydrogenase 3 (17 beta-HSD3) deficiency were evaluated in 1 clinic with an average follow-up of 10.1 years. The diagnoses were made by demonstrating low to normal serum testosterone levels, high androstenedione levels, and high ratios of serum androstenedione to testosterone in the basal state or after treatment with human chorionic gonadotropin. The molecular features of the underlying mutations were identified in all 7 families. Two additional males in the same families are believed to be affected on the basis of history obtained from family members. All of the 46,XY individuals in these families were registered at birth and raised as females (despite the presence of ambiguous genitalia in all or most), and all virilized after the time of expected puberty due to a rise in serum testosterone to or toward the normal male range. The age at diagnosis varied from 4 to 37 years. Ten individuals were studied by the same psychologist, and change of gender role (social sex) from female to male occurred in 3 subjects and in the 2 presumed affected subjects not studied. The individual with the highest serum testosterone level maintained female sexual identity, and in 2 families some of the affected males changed gender role and others did not. Thus, while androgen action plays a role in the process, additional undefined psychological, social, and/or biologic factors must be determinants of gender identity/role behavior. Management of the 7 individuals who chose to maintain female sex roles included castration, clitoroplasty, vaginal enlargement procedures when appropriate, treatment of hirsutism, cricoid cartilage reduction, and estrogen replacement. Three of the 7 are married (2 twice), 1 is involved in a long-term heterosexual relationship, 1 is engaged to be married, and the other 2 are not married and not believed to be sexually active. The 3 subjects who changed gender role behavior to male underwent hypospadias repair, and 1 was given supplemental testosterone therapy. One of these men is divorced, and the other 2 (aged 29 and 35 years) are unmarried. The diagnosis in 8 of these subjects was made after the time of expected puberty; it is unclear whether the functional and social outcomes would have been different if the diagnosis had been made and therapy begun earlier in life.

17-Hydroxysteroid Dehydrogenases↗
PubMed2000

Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients.

Myelin basic protein (MBP), a candidate autoantigen in multiple sclerosis (MS), exists in different isoforms and charge isomers generated by differential splicing of exons and by a combination of posttranslational modifications, respectively. These various isoforms and charge isomers of MBP vary in abundance and most likely serve different functions during myelinogenesis and remyelination. The least cationic among the charge isomers of MBP is citrullinated and is referred to as MBP-C8. MBP-C8 is relatively increased in the population of MBP isomers in more developmentally immature myelin and in MS brain tissue. In a previous study, we found that MBP-C8-reactive T cells could be detected in CD4+ T cell lines (TCL) generated with MBP from both MS patients and normal controls. Here, we examined the frequency and peptide specificity of MBP-C8-specific TCL generated with MBP-C8 in MS patients and controls. Ten subjects grouped in five sets, each an MS patient and a control, were studied. In all cases, the MS patient had either a higher overall number of MBP-C8-responding lines, responded with greater sensitivity to the MBP-C8 antigen or both. Few lines responded to the MBP-C8 peptides but, if they did, they appeared to be specific to the carboxyl-half of the MBP-C8 molecule. Given the large amounts of citrullinated MBP in MS brain tissue, a preferential T cell response to MBP-C8 may be involved in the induction and perpetuation of this disease. Multiple Sclerosis (2000) 6 220 - 225

Adult↗
PubMed2000

Origin of an ovarian steroid cell tumor causing isosexual pseudoprecocious puberty demonstrated by the expression of adrenal steroidogenic enzymes and adrenocorticotropin receptor.

Ovarian steroid cell tumors are rare neoplasms composed of typical steroid hormone-secreting cells. Most ovarian steroid cell tumors, however, cannot be appropriately classified on a morphological basis, because the neoplastic cells closely resemble adrenal cortical cells. Nevertheless, the true adrenal origin of such tumors has been difficult to demonstrate. Here we report a 3-yr-old girl with isosexual pseudoprecocious puberty due to an ovarian steroid tumor whose adrenal cell origin was determined by the presence of messenger ribonucleic acid (mRNA) of adrenal-specific steroidogenic P450 enzymes (P450c11 and P450c21) and ACTH receptor (ACTHR). Her height was +2.3 SD, and she had Tanner stage III breast development, Tanner stage II pubic hair, and a normal clitoris. Bone age was 5 yr. Basal gonadotropin levels were undetectable (<0.6 U/L for LH and <1.0 U/L for FSH) and remained undetectable after stimulation with 100 microg GnRH, i.v. Basal serum testosterone and 17-hydroxyprogesterone levels were slightly elevated, whereas basal serum androstenedione, estradiol, and dehydroepiandrosterone sulfate levels were clearly elevated. Pelvic ultrasound disclosed an enlarged uterus and an adnexal multicystic mass in the right ovary, and pathological studies disclosed an ovarian steroid cell tumor. To establish the cellular origin of the tumor we determined the presence of mRNA for P450c11, P450c21, and ACTHR in tumor tissue and normal adrenal and ovarian tissue. Detection of ACTHR, P450c21, and P450c11 mRNAs isoforms was achieved in tumoral and adrenal control tissue, but not in the ovary control tissue. The RT-PCR products of P450c11 from adrenal control tissue were composed by both BglI-sensitive and -resistant complementary DNAs, indicating the presence of both P450c11AS and P450c11beta, whereas RT-PCR product from the tumor was resistant to BglI digestion, indicating only the presence of P450c11beta. We conclude that the histological origin of so-called adrenal rest tumor could be reliably determined by assessing the expression of specific genes in the tumor as P450c11beta and P450c21. The use ofthese molecular tools will allow a more precise classification of an important subset of the ovarian steroid cell tumors and can help to identify ectopic adrenal tissue in ovary and testis.

Adrenal Glands↗
PubMed1999

Newer antidepressants: a comparison of tolerability in general practice.

BACKGROUND: An increasing number of antidepressants have been released on the United Kingdom market in recent years, and these are being prescribed more frequently in general practice. Clinical trials suggest that such agents have similar efficacy and the choice of drug is probably based on tolerability, toxicity in overdose, and cost. AIM: To compare the tolerability and safety profile of six, newly marketed antidepressants used in general practice. METHOD: Studies have been conducted for six antidepressants: fluoxetine, sertraline, paroxetine, moclobemide, venlafaxine, and nefazodone, using the technique of prescription-event monitoring. Patients were identified using incident dispensed prescription data. Questionnaires were sent to patients' general practitioners six months after the date of first prescription. Questionnaires asked for date of birth, sex, indication for prescribing each drug, and all events entered in the patients' records after the date of first prescription. RESULTS: Each cohort exceeded 10,000 patients. Nausea/vomiting was the most frequently reported event for all drugs. The difference in incidence rates for drowsiness/sedation, male sexual dysfunction, and hypertension is shown. Mortality data are also reported. CONCLUSION: Frequently reported events were similar for all six drugs but there were clinically and statistically significant differences for less frequently reported events. The adjusted mortality rate was identical between the six drugs. This study provides valuable comparative data for six, widely used antidepressants in general practice.

Adult↗
PubMed1998

The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice.

Isotyping and quantitation of murine IgG2a antibodies are widely performed with commercial monoclonal and polyclonal antisera raised against BALB/c IgG2a myeloma proteins. Recently it became evident that inbred mouse strains with the Igh1-b allele do not have the gene for IgG2a and instead express the IgG2c isotype. We show that commercial anti-IgG2a sera cross-react inadequately against IgG2c in immunoblot and ELISA and hence, are not suitable to detect and measure this subclass in mouse strains such as C57BL/6, C57BL/10 and NOD. We have used DNA immunization to generate polyclonal anti-IgG2c serum and demonstrated that it is essential to use IgG2c-specific antiserum to quantify accurately isotypic responses in mouse strains with the Igh1-b allele.

Alleles↗
PubMed1998

Trends in prescribing H2-receptor antagonists and proton pump inhibitors in primary care.

BACKGROUND: H2-receptor antagonists and proton pump inhibitors account for approximately 15% of primary care prescribing costs in the UK. AIM: To examine the use of antisecretory drugs in primary care between October 1991 and September 1996. METHOD: Analysis of prescribing data from an ongoing postal survey performed every 3 months on a rolling quota of 250 UK general practitioners (GPs), identified from a representative sampling frame of 1000 GPs. RESULTS: There were 8811 new courses of proton pump inhibitors and 11,948 new courses of H2-receptor antagonists during this study. The number of new prescriptions for proton pump inhibitors increased by 174.5%, but decreased for H2-receptor antagonists by 12.5%. Proton pump inhibitors were mostly prescribed for reflux disease (52.7%) and H2-receptor antagonists for non-specific dyspepsia (43.6%). Proton pump inhibitors (14.1%) were less likely to be stopped than H2-receptor antagonists (35.3%) overall, and they were less likely to be stopped because of perceived ineffectiveness (5.3%) than H2-receptor antagonists (23.8%). The rate of stopping treatment because of side-effects was about 3% for both classes of drug. CONCLUSIONS: Prescribing of proton pump inhibitors has increased sharply each year since 1991. One reason may be that GPs perceive proton pump inhibitors to be more effective than H2-receptor antagonists.

Anti-Ulcer Agents↗
PubMed1998

Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies.

AIMS: Little is known about the frequency with which suspected adverse drug reactions are seen by general practitioners after the prescription of newly marketed drugs. We investigated age and sex specific incidence rates of suspected adverse drug reactions recorded by general practitioners in England after the prescription of selected newly marketed drugs. METHODS: Information was collected from 48 national cohort studies of newly marketed drugs studied by prescription-event monitoring. Questionnaires were sent to prescribers asking for details of events and suspected adverse drug reactions recorded in the patients' notes occurring after the drugs were prescribed. RESULTS: During the 48 cohort studies, a total of 513608 patients were investigated, of which 221781 (43.2%) were males and 285862 (55.7%) were females. The overall incidence of suspected adverse drug reactions in males was 12.9 per 10000 patient-months of exposure (95% confidence limits 12.3 to 13.5), and in females was 20.6 per 10000 patient-months of exposure (95% confidence limits 19.9 to 21.3). The overall age-standardised relative risk of an adverse drug reaction in females compared with males was 1.6 (1.5-1.7). This sex difference was significant in all age groups above 19 years of age, and was relatively consistent across all age groups (chi2 test for heterogeneity = 9.2, P=0.3). The highest rate of recording in males was in the 50-59 year age group, and in females was in the 30-39 year age group. CONCLUSIONS: In general practice in England, suspected adverse drug reactions to newly marketed drugs are recorded more often in adults aged between 30 and 59 years of age and are 60% more common in women than in men. The sex difference occurs in all age groups over 19 years of age.

Adult↗
PubMed1998

The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England.

OBJECTIVE: To determine the proportion and nature of congenital anomalies in babies born to women exposed to newly marketed drugs during the first trimester. DESIGN: Non-interventional observational cohort studies. METHODS: The women were identified in confidence by the Prescription Pricing Authority. The doctor was sent a questionnaire to determine clinical events, including pregnancy, occurring after the drug was dispensed. A supplementary questionnaire determined the outcome of each reported pregnancy. SETTING: General medical practice in England. POPULATION: Women exposed to newly marketed drugs in whom pregnancy was recorded. MAIN OUTCOME MEASURES: Outcomes of pregnancies, the proportion and nature of congenital anomalies in the babies born. RESULTS: 2511 pregnancies were reported. In 831 of these pregnancies a newly marketed drug had been taken during the first trimester and in 74 during the second/third trimester. The outcome was ascertained for 780 (94%) of these 831 pregnancies: 547 (66%) births; 10 (1%) ectopic pregnancies; 94 (11%) spontaneous miscarriages; 5 (< 1%) missed abortions; 120 (14%) legal abortions; and 4 (< 1%) intrauterine deaths. 557 infants were born, of whom 14 (2.5%) had congenital anomalies. CONCLUSIONS: The proportion of live infants with a congenital abnormality born to mothers exposed to newly marketed drugs in the first trimester was similar to the percentage of congenital anomalies estimated by the Office for National Statistics. These data add valuable information to the safety database of these drugs.

Abnormalities, Drug-Induced↗