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Biomedical subjects

M J Brown

Publications and source records attributed to M J Brown.

At least 145 records · Page 8Linked to original sources
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

Polyketide synthesis in vitro on a modular polyketide synthase.

BACKGROUND: The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, contains some 30 active sites distributed between three multienzyme polypeptides (designated DEBS1-3). This complexity has hitherto frustrated mechanistic analysis of such enzymes. We previously produced a mutant strain of S. erythraea in which the chain-terminating cyclase domain (TE) is fused to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension in S. erythraea. This mutant strain produces triketide lactone in vivo. We set out to purify the chimaeric enzyme and to determine its activity in vitro. RESULTS: The purified DEBS1-TE multienzyme catalyzes synthesis of triketide lactones in vitro. The synthase specifically uses the (2S)-isomer of methylmalonyl-CoA, as previously proposed, but has a more relaxed specificity for the starter unit than in vivo. CONCLUSIONS: We have obtained a purified polyketide synthase system, derived from DEBS, which retains catalytic activity. This approach opens the way for mechanistic and structural analyses of active multienzymes derived from any modular polyketide synthase.

Cell-Free System↗
PubMed1995

Messenger RNAs encoding the natriuretic peptides and their receptors are expressed in the eye.

The rates of secretion and removal of aqueous humour are major determinants of intraocular pressure (IOP). The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) are vasodilators with variable effects on electrolyte and water transport at sites such as the nephron. There is some evidence that they may also affect fluid balance in the eye. As a first step in understanding the function of these peptides in the eye, we have used the technique of cDNA amplification with the polymerase chain reaction to demonstrate the presence of mRNA transcripts encoding the three natriuretic peptide receptors (NPR-A, NPR-B and NPR-C) in the retina, choroid and ciliary process of the rat and rabbit eye. In addition we have observed a differential distribution of ANP, BNP and CNP mRNAs in ocular tissues suggesting that at least part of the natriuretic peptide immunoreactivity detected in the eye arises from local synthesis of peptide. Thus, the eye appears to be able to synthesize all the components of the natriuretic peptide system necessary to modulate IOP independently of changes in the plasma concentrations of these peptides.

Animals↗
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

Differences in transcription and translation of long and short Gs alpha, the stimulatory G-protein, in human atrium.

1. We have previously reported the relative mRNA and protein level of the long and short splice variants of Gs alpha (Gs alpha L and Gs alpha S) in human atrium. We have now measured the relative proportions of the serine+ and serine- variants of Gs alpha L and Gs alpha S in human atrium, and assessed, indirectly, whether their differential expression may (i) regulate Gs alpha phosphorylation, and (ii) be regulated by atrial cyclic AMP levels. 2. The serine+ and serine- variants of Gs alpha L and Gs alpha S were estimated by single nucleotide primer extension in 36 right atrial strips of which half were from beta-adrenoceptor-blocked patients. The ratio of serine+ to serine- variants was 0.06 +/- 0.12 for Gs alpha L, compared with 8.04 +/- 12.16 for Gs alpha S (P < 0.001). 3. Isoelectric points of Gs alpha and Gs alpha S in the atria of four beta-adrenoceptor-blocked and four non-beta-adrenoceptor-blocked patients were estimated by two-dimensional gel electrophoresis. Two-dimensional gel analysis gave a consistent pattern with several spots for both Gs alpha L and Gs alpha S; however, the isoelectric points of Gs alpha S were more acid (5.18 +/- 0.24) than those of Gs alpha L (5.87 +/- 0.17, P < 0.001). 4. No significant difference in either the serine variants or isoelectric point value was observed between beta-adrenoceptor-blocked and non-beta-adrenoceptor-blocked patients. 5. In conclusion, all four Gs alpha variants were expressed in human atrium, but Gs alpha L is almost entirely of the serine- form. Gs alpha S has a more acidic isoelectric point than Gs alpha L, indicating a possible post-translational modification. The lack of difference in our results between beta-adrenoceptor-blocked and non-beta-adrenoceptor-blocked patients suggests indirectly that cyclic AMP is an unlikely candidate for regulating splicing or post-translational modification of Gs alpha in vivo.

Adrenergic beta-Antagonists↗
PubMed1995

Calcitonin gene-related peptide as an endogenous vasodilator: immunoblockade studies in vivo with an anti-calcitonin gene-related peptide monoclonal antibody and its Fab' fragment.

1. Calcitonin gene-related peptide (CGRP) is localized in perivascular sensory neurons and is a potent vasodilator. We investigated the utility of immunoblockade as an in vivo technique for probing the role of CGRP as an endogenous vasodilator. 2. The effects of an anti-CGRP monoclonal antibody (MAb; coded C4.19) and its Fab' fragment on CGRP-induced changes in blood pressure and skin blood flow were studied in pentobarbitone-anaesthetized rats. Antidromic skin vasodilatation in the rat hind paw was measured by laser Doppler fluxmetry. 3. The dose-response relationship for the hypotensive effect of intravenous rat alpha CGRP (r alpha CGRP) was similarly shifted rightward by MAb C4.19 IgG (1 mg/rat; intravenously) and Fab' fragment (2 mg/rat; intravenously). The C-terminal fragment of human alpha CGRP (h alpha CGRP8-37) also blocked the hypotensive effect of r alpha CGRP. 4. MAb C4.19 Fab' fragment (2 mg/rat; intravenously) and h alpha CGRP8-37 (100 nmol/kg; intravenously), but not MAb C4.19 IgG (up to 3 mg/rat; intravenously) or normal mouse Fab' fragment (2 mg/rat; intravenously), blocked the increased skin blood flow response to antidromic stimulation of the saphenous nerve. 5. The mean percentage changes in skin blood flow parameters due to MAb C4.19 Fab' fragment were significantly different from those due to normal mouse Fab' fragment (unpaired t-test; P < 0.05) but not from those due to h alpha CGRP8-37. 6. The results demonstrate the pharmacokinetic advantage of Fab' fragment over IgG for immunoblockade studies in vivo and support the role of CGRP in mediating skin vasodilatation.

Animals↗
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

A comparison of the contractile effects of 5-hydroxytryptamine, sumatriptan and MK-462 on human coronary artery in vitro.

1. MK-462 (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H- indol-3-yl]ethylamine) is a novel selective 5-HT1D-receptor agonist which in clinical trials has been shown to be an effective antimigraine agent. As angiographic studies have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction in patients, we compared the effects of MK-462 with those of 5-HT and those of sumatriptan, on isolated segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients (n = 22, 2 females, 20 males, aged 21-60 years) undergoing cardiac transplantation. Endothelium-denuded ring segments of coronary artery, 2mm long were mounted in organbaths for isometric tension recording. For each arterial ring segment, a cumulative concentration-effect curve to either 5-HT, sumatriptan or MK-462 was determined. After maximal response to each agonist had been obtained, ketanserin (a 5-HT2 receptor antagonist) 0.6 microM was added to the tissue bath, followed by methiotepin (0.6 microM) and the reduction in tension produced by the addition of each antagonist was determined. 3. Out of 22 coronary arteries studied, only 10 showed any response (contraction) to 5-HT. Not all arteries which responded to 5-HT contracted in response to both sumatriptan and MK-462 (one ring from each artery being exposed to a single agonist in each case).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Vessels↗
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↗
PubMed1995

Hutchinson's sign and its importance in rhinology.

Herpes zoster ophthalmicus usually has a typical appearance. However, if the disease is limited to the nasociliary branch of the trigeminal nerve, the ocular appearance may be confusing. Hutchinson in 1865 first noted that involvement of the external nasal branch of the fifth cranial nerve was associated with an increased incidence of ocular zoster. A case of herpes zoster ophthalmicus is presented that clinically resembled an ocular complication of sinus disease. The presence of a localized vesicular rash at the nasal tip assisted in an early diagnosis. Although this sign is known amongst ophthalmologists, its importance in rhinology is stressed. An anatomical explanation of Hutchinson's sign is given and the treatment of herpes zoster ophthalmicus is briefly discussed.

Acyclovir↗
PubMed1995

Management of hypertension in general practice: agreements with and variations from the British Hypertension Society guidelines.

A random sample of 200 East Anglian general practitioners was surveyed to establish current trends in the management of hypertension, including measurement of blood pressure (BP), patient investigation, treatment and follow-up. A total of 125 (62.5%) completed questionnaires was returned. Responses were used to assess the range of self-reported management practice and the extent of conformity with the British Hypertension Society guidelines. Although there was a broad spectrum of reported practice, many respondents adhered closely to the guidelines in relation to BP measurement, use of non-pharmacological treatment, treatment goals, choice of drug and patient investigation. Not surprisingly, the greatest disparity between reported and recommended practice occurred in areas where guidelines have only recently become available: treatment of isolated systolic hypertension and of the elderly hypertensive. Here, the survey provides a useful baseline against which to monitor future changes in management.

Aged↗
PubMed1995

Genetic variability of the ET-1 and the ETA receptor genes in essential hypertension.

Because evidence suggests that endothelin-1 (ET-1) plays a role in the pathogenesis of hypertension, we examined the variability within the ET-1 and the ET(A) receptor genes in patients with essential hypertension (EH). Genomic DNA was used for amplification of both genes by PCR. Polymorphisms within these genes were identified by single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing. Single-base insertions (C at position 121; A at position 138) were identified in the untranslated region of exon 1 of the ET-1 gene. The C insertion was invariant, whereas the A insertion, which abolished a BsiY1 restriction site, occurred only in samples that showed altered mobility profiles on SSCP analysis. This strategy also identified a silent polymorphism in codon 323 (CAC-->CAT) of the ET(A) receptor gene, which created an AflII restriction site. The frequency distribution of these polymorphisms was compared in an EH population [diastolic blood pressure (DBP) > or = 95 mm Hg; n = 100] and a matched normotensive (NT) group (BP < or = 140/85 mm Hg). No significant differences in AflII genotype distribution were found between the EH and NT groups. However, chi 2 analysis suggested a significant difference between the BsiY1+/+, BsiY1-/+, and BsiY1-/- genotype frequencies in the two groups (EH 58:38:4%; NT 47:44:9% (p = 0.045)). In addition, two-way analysis showed a strong correlation between DBP and the BsiY1-/- polymorphism. These results suggest that these polymorphisms act as markers for the level of DBP.

Adult↗
PubMed1995

Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition.

OBJECTIVES: To investigate the relationship between polymorphisms in the angiotensin converting enzyme (ACE), angiotensinogen (AGT) and type 1 angiotensin-II (AT1R) genes and (1) quantitative variations in blood pressure and (2) the blood pressure response to ACE inhibition in a hypertensive cohort. DESIGN AND METHODS: We administered monotherapy with ACE inhibitors to 125 previously untreated essential hypertensives. Genotypes for ACE insertion and deletion, AGT M235T and AT1R A1166-->C polymorphisms were determined in DNA extracted from peripheral blood leucocytes. The influence of genotype on pretreatment blood pressure and the ACE inhibitor-induced decrease in blood pressure was tested by analysis of variance and multiple regression analysis, adjusting for age, sex, body mass index, alcohol intake and, where appropriate, pretreatment blood pressure. RESULTS: ACE and AT1R genotypes were independent predictors of pretreatment systolic and diastolic blood pressure, with an apparent interaction between these two gene loci. Although it did not influence pretreatment blood pressure in this population, AGT genotype was an independent predictor of the blood pressure response to ACE inhibition. CONCLUSIONS: The ACE and AT1R gene loci (chromosomes 17q and 3q, respectively) may carry alleles influencing blood pressure variation in this hypertensive population, with a possible epistatic interaction between the two loci. The AGT T235 allele does not appear to be a marker for blood pressure variation in this group, but variants on chromosome 1q lying in or near the AGT gene may contribute to individual differences in the blood pressure response to ACE inhibition. Among essential hypertensives, differences in the ACE inhibitor response appear, in part, to be genetically determined.

Adolescent↗
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↗