PubMed Health⌕ Search

Biomedical subjects

M J Brown

Publications and source records attributed to M J Brown.

At least 19 recordsLinked to original sources
PubMed1995

A simple molecular assay for the C1166 variant of the angiotensin II type 1 receptor gene.

Studies of human polygenic diseases require the genotyping of polymorphic markers from large numbers of subjects. The rapid detection of the insertion (I)/deletion(D) polymorphism of the angiotensin converting enzyme (ACE) gene by the polymerase chain reaction (PCR) has facilitated the study of this locus in a a number of cardiovascular diseases, but not all gene polymorphisms are as easily detected. We describe a rapid mismatch-PCR/restriction fragment length polymorphism (RFLP) assay for the C1166 variant of the angiotensin II type 1 receptor gene, a mutation which may interact with the ACE polymorphism in the determining of risk of myocardial infarction. This rapid assay, which requires no special equipment or expertise, will be useful in confirming the interaction between these two gene loci. The principles utilised can be applied more generally to the detection of any polymorphic single base substitution.

Base Sequence↗
PubMed1995

Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage.

Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis. The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, has been modified by repositioning of a chain-terminating cyclase domain to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension. The resulting mutant markedly accelerates formation of the predicted triketide lactone, compared to a control in which the repositioned domain is inactive. Repositioning of the cyclase should be generally useful for redirecting polyketide synthesis to obtain polyketides of specified chain lengths.

Base Sequence↗
PubMed1995

Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group.

BACKGROUND: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. METHODS: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, < or = 0.30 x 10(9)/L [300/microL]), or asymptomatic HIV (CD4 cell count, < or = 0.20 x 10(9)/L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. RESULTS: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). CONCLUSIONS: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.

AIDS-Related Opportunistic Infections↗
PubMed1995

Palatal myoclonus affected by neck position.

Palatal myoclonus is defined as a continuous, rhythmic contraction of the palatal musculature. Reverberant neuronal activity in a region of the brain stem known as the Guillain-Mollaret triangle is believed to underlie this condition. We present a case of palatal myoclonus which could be abolished by anterior neck flexion. The pathology and management of this condition is briefly discussed.

Female↗
PubMed1995

Expression of the alpha- and beta-subunits of the stimulatory and inhibitory G-proteins in beta 1-adrenoceptor-blocked and non-beta-adrenoceptor-blocked human atrium.

1. Chronic beta 1-adrenoceptor blocker therapy induces hyperresponsiveness of the beta 2-adrenoceptor in human atrium. To investigate whether the beta 2-adrenoceptor sensitization induced by beta 1-adrenoceptor blockade is associated with altered gene expression of G-proteins, which couple the receptors to adenylate cyclase, we determined the mRNA expression of the alpha- and beta-subunits of the stimulatory G-protein, Gs, and inhibitory G-protein, Gi, in human right atrial appendage by polymerase chain reaction and by enhanced chemiluminescence Northern blot analysis. 2. The polymerase chain reaction revealed bands of predicted size of Gs alpha, both short form and long form, all three Gi alpha subtypes and three G beta subtypes. In Northern blots, the digoxigenin-labelled antisense cRNA probe specific for Gi alpha 2 hybridized to a predominant band at 2.3 kb, whereas the Gi alpha 3 cRNA probe detected a message of 1.8 kb in total RNA extracted from human atrium. The cRNA probe encoding Gs alpha revealed one major band at 1.9 kb and one minor band at 1.7 kb. The G beta cRNA probes detected messages of 3.4 kb for G beta 1, 1.8 kb for G beta 2 and 1.9 kb for G beta 3 in human atrium. 3. The mRNA levels of Gs alpha in beta 1-adrenoceptor-blocked atria (n = 12) were not significantly different from those in non-beta-adrenoceptor-blocked atria (n = 12), nor were there any significant differences in the Gi alpha 2 mRNA levels between atria from patients treated with beta 1-adrenoceptor blockers and untreated patients. The ratios of 1.9-kb Gs alpha mRNA to 1.7-kb Gs alpha mRNA and of 1.9-kb Gs alpha mRNA to 2.3-kb Gi alpha 2 mRNA in beta 1-adrenoceptor-blocked patients were almost identical to those in non-beta-adrenoceptor-blocked patients. Neither G beta 1 mRNA nor G beta 2 mRNA expression in beta 1-adrenoceptor-blocked atria differed significantly from that in non-beta-adrenoceptor-blocked atria. 4. We conclude that the previously observed sensitization following beta 1-adrenoceptor-blockade of beta 2-adrenoceptors in human atria is unlikely to be mediated by altered gene expression of the alpha- and beta-subunits of G-proteins.

Adrenergic beta-1 Receptor Antagonists↗
PubMed1995

Alpha-blockade and calcium antagonism: an effective and well-tolerated combination for the treatment of resistant hypertension.

OBJECTIVE: To test whether the combination of calcium antagonism is additive with the other newer antihypertensives, namely alpha-blockers and angiotensin converting enzyme (ACE) inhibitors. DESIGN: Three-way double-blind, Latin-square crossover studies in two groups of 12 patients with essential hypertension. The three treatment periods were amlodipine, doxazosin (study A) or enalapril (study B), and the combination of amlodipine with the second drug. METHODS: Each treatment was taken for 1 month, preceded by a 2-week single-blind run-in period, in which the patients received a low dose of doxazosin (study A) or enalapril (study B) to enable recruitment of patients with moderate or severe hypertension. Blood pressure, foot volume and plasma noradrenaline concentration were measured at the end of each run-in and treatment period. RESULTS: The combination of alpha-blockade and calcium antagonism caused a fall in supine and erect blood pressures. These falls were significantly greater than on either drug alone, and greater than the sum of the falls when taking the individual drugs. The combination of amlodipine and the ACE inhibitor was also additive. Both combinations with amlodipine were tolerated well by all patients. CONCLUSIONS: The combination of alpha-blockade and calcium antagonism has not previously been studied and should be useful for resistant hypertensives who have not tolerated beta-blockade or ACE inhibitors. The combination of ACE inhibition and calcium antagonism has previously been shown to be additive; its use as a positive control in the present studies suggests that the use of an active drug for a run-in period may be a useful design for permitting the study of patients from whom all treatment cannot safely be withdrawn.

Adrenergic alpha-Antagonists↗
PubMed1995

Beta-adrenoceptor subtypes in human coronary artery: desensitization of beta 2-adrenergic vasorelaxation by chronic beta 1-adrenergic stimulation in vitro.

We previously demonstrated that right atrial strips from patients treated with beta 1-selective antagonists exhibit sensitization of beta 2-adrenergic responses in vitro. We also showed that cardiac beta 2-adrenergic sensitization can be induced in normal subjects prospectively by beta 1-blocker treatment. To determine whether such cross-talk could be induced in vitro, we studied beta-adrenoceptor-mediated vasorelaxation in deendothelialized rings of human coronary artery from patients undergoing cardiac transplantation. After incubation with 10 microM phenoxybenzamine for 1 h, concentration-effect curves were determined to norepinephrine (NE) and epinephrine (EPI), with or without 300 nM CGP 20712A (a beta 1-selective antagonist), 50 nM ICI 118551 (a beta 2-selective antagonist), or both antagonists. Both beta 1- and beta 2-adrenergic components to vasorelaxation were detected. Other rings were incubated for 16 h with either 1 microM NE (a selective beta 1-adrenoceptor agonist) or 300 nM CGP 20712A, or both. After washout, concentration-effect curves were determined to EPI in the presence of 300 nM CGP 20712A (beta 2-adrenergic responses). No differences in beta 2-adrenergic vasorelaxation were noted after prolonged incubation with either CGP 20712A or the combination of CGP 20712A and NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1995

Childhood lead poisoning in Massachusetts communities: its association with sociodemographic and housing characteristics.

OBJECTIVES: The purpose of the study was to examine the relationship between communities' sociodemographic and housing characteristics and incidence of lead poisoning. METHODS: This was a population-based correlational study of 238,275 Massachusetts children from birth through 4 years of age who were screened for lead poisoning in 1991-1992. A logistic regression model was developed with the community as the unit of analysis, the case identification rate for lead poisoning (newly identified children with venous blood lead > or = 25 micrograms/dL per 1000 children) as the dependent variable, and US census variables as independent variables. RESULTS: A significant independent relationship with the community case identification rate of lead poisoning was found for seven variables: median per capita income, percentage of housing built before 1950, percentage of the population who were Black, percentage of children screened, and a "poverty index." Rates of iron deficiency and percentage of Hispanics were not associated with the case identification rate of lead poisoning. CONCLUSIONS: Massachusetts communities' incidence of lead poisoning is correlated with sociodemographic and housing characteristics. In states similar to Massachusetts and without screening data, this model may help target screening programs.

Black or African American↗
PubMed1994

Bovril and moclobemide: a novel therapeutic strategy for central autonomic failure.

The consumption of tyramine-containing foods is contraindicated in patients on classic monoamine oxidase (MAO) inhibitors. We report successful therapeutic use of moclobemide (a MAO-A selective inhibitor) plus controlled amounts of Bovril (a tyramine-rich yeast-extract available as a food) in a patient with pure central autonomic failure who was rendered bed-bound by severe postural hypotension. Standing blood pressure is now at least 90/45 mm Hg. The selectivity of moclobemide allows about a tenth of ingested tyramine to reach nerve endings and thus the modest hypertensive effect of this combination re-established day-to-day function by restoring normotension.

Activities of Daily Living↗
PubMed1994

Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.

OBJECTIVE: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING: Outpatient clinics at 19 tertiary care medical centers. PATIENTS: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

AIDS-Related Complex↗
PubMed1994

The effects of hedges on spray deposition and on the biological impact of pesticide spray drift.

Two series of drift deposition measurements were carried out at different wind speeds using sodium fluorescein as a tracer dye sprayed over a grass field 6 m upwind of a hedge. Efficient receptors were placed below and above hedge height (1.6 m) between 1 and 20 m downwind from the sprayed area. Receptors below hedge height reflected a sudden decrease in deposition immediately behind the hedge, followed by a gradual increase again up to 15 m, i.e., nine times the height of the hedge. The sheltering effect of a hedge from the biological impact of spray drift was studied by bioassays using tomato and Lychnis flos-cuculi plants for the herbicide MCPA and young Pieris brassicae larvae for the insecticide cypermethrin. These demonstrated that the protection afforded to sensitive species in strong winds may be quite limited, and severe damage may be inflicted over considerable distances. In intermediate cases, a protected zone is followed by a zone of further significant damage before drift depositions cease to have further effect. In some cases, the sheltered zone may extend to a distance where drift deposition, even in the absence of a hedge, has minimal effect.

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1994

Poisoned landscapes: the epidemiology of environmental lead exposure in Massachusetts children 1990-1991.

This research models the geographic variation in lead poisoning among children living in Massachusetts between 1990 and 1991. Elevated levels of blood lead, which reduce educational performance, arise because children are exposed to unnaturally concentrated sources of lead in the built environment. A Poisson regression model indicates that a large number of children with lead poisoning may be detected in towns with a high proportion of older housing, female headed households, African-Americans, and an industrial heritage. Our results suggest links between the processes of urbanization and industrialization in Massachusetts and today's lead poisoned landscapes.

Child, Preschool↗
PubMed1994

Electric field-directed fibroblast locomotion involves cell surface molecular reorganization and is calcium independent.

Directional cellular locomotion is thought to involve localized intracellular calcium changes and the lateral transport of cell surface molecules. We have examined the roles of both calcium and cell surface glycoprotein redistribution in the directional migration of two murine fibroblastic cell lines, NIH 3T3 and SV101. These cell types exhibit persistent, cathode directed motility when exposed to direct current electric fields. Using time lapse phase contrast microscopy and image analysis, we have determined that electric field-directed locomotion in each cell type is a calcium independent process. Both exhibit cathode directed motility in the absence of extracellular calcium, and electric fields cause no detectable elevations or gradients of cytosolic free calcium. We find evidence suggesting that galvanotaxis in these cells involves the lateral redistribution of plasma membrane glycoproteins. Electric fields cause the lateral migration of plasma membrane concanavalin A receptors toward the cathode in both NIH 3T3 and SV101 fibroblasts. Exposure of directionally migrating cells to Con A inhibits the normal change of cell direction following a reversal of electric field polarity. Additionally, when cells are plated on Con A-coated substrata so that Con A receptors mediate cell-substratum adhesion, cathode-directed locomotion and a cathodal accumulation of Con A receptors are observed. Immunofluorescent labeling of the fibronectin receptor in NIH 3T3 fibroblasts suggests the recruitment of integrins from large clusters to form a more diffuse distribution toward the cathode in field-treated cells. Our results indicate that the mechanism of electric field directed locomotion in NIH 3T3 and SV101 fibroblasts involves the lateral redistribution of plasma membrane glycoproteins involved in cell-substratum adhesion.

Animals↗