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Biomedical subjects

M J Brown

Publications and source records attributed to M J Brown.

At least 127 records · Page 7Linked to original sources
PubMed1996

The causes of essential hypertension.

1. Confusion between the criteria for defining and diagnosing hypertension may have misled the search for the causes of hypertension. 2. The systematic approach of molecular genetics appears to offer the best chance of explaining hypertension, but the attractions are partly offset by the large numbers required, and unproven record of the genetic techniques in finding functional mutations in complex human disorders. 3. Part of the evidence for the polygenic nature of essential hypertension derives from the variable response to a large number of different anti-hypertensive agents. Systematic investigation of this variability may provide a basis for dividing patients into genetically more homogeneous sub-groups, within which smaller numbers will be required to detect the genes responsible for the susceptibility to hypertension. 4. The proportion of hypertensive patients with affected siblings has been studied in 6000 patients from Addenbrookes Hospital and local general practices. A recurrence risk for hypertension of approximately 3.5 was found. 5. Approximately two-thirds of patients have no known affected siblings. The next largest group, about one third, is patients whose siblings are all hypertensive. In a small group, < 10% of all patients, half the siblings are hypertensive. 6. We conclude from these surprising findings that hypertension is not a continuous, multifactorial part of the normal blood pressure distribution. They suggest that several more single-gene disorders causing hypertension will be found. The sibships where all members are hypertensive are inconsistent with the segregation of Mendelian genetics and suggest the selection of some genes linked to hypertension at the time of gamete maturation.

Genetic Predisposition to Disease↗
PubMed1996

(--)-Timolol is a more potent antagonist of the positive inotropic effects of (--)-adrenaline than of those of (--)-noradrenaline in human atrium.

1. The affinity of (--)-timolol for beta 1- and beta 2-adrenoceptors was determined on isolated atrial preparations from patients undergoing open heart surgery. The times for onset and offset of antagonism of the positive inotropic effects of (--)-adrenaline and (--)-noradrenaline by (--)-timolol were measured. 2. The antagonism of the positive inotropic effects of (--)-adrenaline and (--)-noradrenaline by (--)-timolol (0.1-100 nM) was simple competitive in human atrium tissue. The slope of Schild-plots was not significantly different from 1.0 [0.93 +/- 0.09 for (--)-adrenaline, 0.97 +/- 0.09 for (--)-noradrenaline]. 3. The inotropic effects of (--)-adrenaline were antagonized significantly more by each concentration of (--)-timolol than those of (--)-noradrenaline. KB-values (-log M) were 10.10 +/- 0.09 against (--)-adrenaline and 9.43 +/- 0.07 against (--)-noradrenaline (P < 0.001). 4. Blocking kinetics of (--)-timolol for the beta-adrenoceptor were relatively slow. Half-times for the onset of blockade by 10 times KB of (--)-timolol were approximately 30 min for both (--)-adrenaline and (--)-noradrenaline; offset times were similar. 5. It is concluded that (--)-timolol has a higher affinity for the beta 2-adrenoceptor than for the beta 1-adrenoceptor in human atrium. This property may be beneficial clinically in protecting against the beta 2-adrenoceptor hypersensitivity induced by cardiac beta 1-adrenoceptor blockade, but also explain why severe asthma can occur after administration of very low intra-ocular doses of the drug.

Adrenergic beta-Agonists↗
PubMed1996

Molecular mechanisms of benzodiazepine-induced down-regulation of GABAA receptor alpha 1 subunit protein in rat cerebellar granule cells.

1. Chronic benzodiazepine treatment of rat cerebellar granule cells induced a transient down-regulation of the gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit protein, that was dose-dependent (1 nM-1 microM) and prevented by the benzodiazepine antagonist flumazenil (1 microM). After 2 days of treatment with 1 microM flunitrazepam the alpha 1 subunit protein was reduced by 41% compared to untreated cells, which returned to, and remained at, control cell levels from 4-12 days of treatment. Chronic flunitrazepam treatment did not significantly alter the GABAA receptor alpha 6 subunit protein over the 2-12 day period. 2. GABA treatment for 2 days down-regulates the alpha 1 subunit protein in a dose-dependent (10 microM-1 mM) manner that was prevented by the selective GABAA receptor antagonist bicuculline (10 microM). At 10 microM and 1 mM GABA the reduction in alpha 1 subunit expression compared to controls was 31% and 66%, respectively. 3. The flunitrazepam-induced decrease in alpha 1 subunit protein is independent of GABA, which suggests that it involves a mechanism distinct from the GABA-dependent action of benzodiazepines on GABAA receptor channel activity. 4. Simultaneous treatment with flunitrazepam and GABA did not produce an additive down-regulation of alpha 1 subunit protein, but produced an effect of the same magnitude as that of flunitrazepam alone. This down-regulation induced by the combination of flunitrazepam and GABA was inhibited by flumazenil (78%), but unaffected by bicuculline. 5. The flunitrazepam-induced down-regulation of alpha 1 subunit protein at 2 days was completely reversed by the protein kinase inhibitor staurosporine (0.3 microM). 6. This study has shown that both flunitrazepam and GABA treatment, via their respective binding sites, caused a reduction in the expression of the GABAA receptor alpha 1 subunit protein; an effect mediated through the same neurochemical mechanism. The results also imply that the benzodiazepine effect is independent of GABA, and that the benzodiazepine and GABA sites may not be equally coupled to the down-regulation process, with the benzodiazepine site being the more dominant. The biochemical mechanism underlying the benzodiazepine-mediated down-regulation of the alpha 1 subunit protein seems to involve the activity of staurosporine-sensitive protein kinases.

Animals↗
PubMed1996

Blood pressure and the M235T polymorphism of the angiotensinogen gene.

The angiotensinogen gene locus (1q42-43) has been linked to hypertension in affected relative-pair studies (including a previous UK study), but the role of the Met-->Thr polymorphism at position 235 remains controversial. Using this marker, we investigated the relationship between angiotensinogen genotype and blood pressure in two data sets from the East Anglia region of the United Kingdom. Two hundred twenty-three untreated hypertensive and 187 normotensive control subjects were recruited through local general practices. Blood pressure (including pretreatment measurements in the hypertensive group), age, sex, body mass index, alcohol consumption, cholesterol level, and angiotensinogen genotype were recorded for all subjects. The influence of angiotensinogen genotype on blood pressure was assessed with a general linear model ANOVA with adjustment for age, sex, body mass index, and alcohol consumption. There was no evidence for an association between angiotensinogen genotype and blood pressure level in either the hypertensive or normotensive data set. Angiotensinogen genotype did not influence blood pressure in subjects aged < 50 years, women, or those with a body mass index < 26 kg/m2. We conclude that the angiotensinogen Met-->Thr polymorphism is not a marker for blood pressure level in these East Anglian subjects. Further studies are required to confirm the involvement of the 1q locus in the development of hypertension in UK subjects and to delineate the functional variant(s) in this chromosomal region that influences blood pressure.

Angiotensinogen↗
PubMed1996

Chronic inflammatory demyelinating polyneuropathy associated with malignant melanoma.

We report three patients who developed chronic inflammatory demyelinating polyneuropathy (CIDP) in association with malignant melanoma. In two cases, melanoma was discovered during the initial evaluation for neuropathy. Two patients also had vitiligo, an antibody-mediated disorder that may complicate melanoma. Melanoma cells and Schwann cells are both of neuroectodermal cell origin, with shared surface antigens. Shared immunoreactivity may account for the association between melanoma and CIDP, as with vitiligo.

Adult↗
PubMed1996

Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus (HNA) is an autosomal dominant disorder associated with recurrent, episodic, painful brachial neuropathies. Mildly dysmorphic facial features, including hypotelorism, long nasal bridge, and upslanting palpebral fissures, are present in affected persons in some pedigrees with HNA. To determine the chromosomal location of the HNA gene, we carried out genetic linkage studies with polymerase chain reaction-based DNA markers in two large pedigrees. Linkage to markers from the distal long arm of chromosome 17 was established.

Adult↗
PubMed1996

Functional heterogeneity of human term cytotrophoblasts revealed by differential sensitivity to extracellular Ca2+ and nucleotides.

We have prepared purified cytotrophoblasts from human term placentas and examined the sensitivity of fura-2 loaded cells to the nucleotides ATP and UTP and to changes in extracellular Ca2+ concentration ([Ca2+]o). Purified cytotrophoblasts were obtained by collagenase digestion and separation according to density using self-generated Percoll gradients. The cytotrophoblast fraction was free of red cell and largely free of white cell contamination (as assessed by uniformly negative staining for vimentin and the failure of > 90% of fura-2 loaded cells to respond to the chemotactic peptide fMet-Leu-Phe). Purified cells secreted progesterone in a linear fashion over several hours in the presence of 25-hydroxycholesterol. The cells ranged in size from approximately 7.5 to 50 microns in diameter as described previously for purified cytotrophoblasts, and an analysis of cells for sensitivity to [Ca2+]o or nucleotides suggested functional heterogeneity within the cytotrophoblast population. Small cells (7.5-10 microns) were negative for cytokeratin-8 and, after loading with fura-2, were insensitive to extracellular nucleotides but sensitive to elevations in [Ca2+]o. Medium-sized cells (12-20 microns) were largely cytokeratin-positive (70% of cells) and sensitive to both ATP and UTP but largely insensitive to [Ca2+]o. Large cells (25-50 microns) were uniformly cytokeratin-positive (100% of cells) and, after fura-2 loading, sensitive to both [Ca2+]o and extracellular ATP or UTP. We examined the likely origin of small, medium and large cytotrophoblasts using an immunomagnetic cell sorting procedure that separates villous cytotrophoblasts (which do not express major histocompatibility class I antigens) from extravillous cytotrophoblasts. This procedure resulted in the selective sedimentation of almost all medium and large cells, leading to the conclusion that the small cells were villous cytotrophoblasts whereas medium and large cells were predominantly extravillous in origin. The data suggest that small, medium and large cytotrophoblasts have distinct roles in the function of the term placenta.

Adenosine Triphosphate↗
PubMed1996

Iron deficiency in Massachusetts communities: Socioeconomic and demographic risk factors among children.

OBJECTIVES: This study examined the association between community rates of iron deficiency in children and sociodemographic characteristics of Massachusetts communities. METHODS: Between April 1990 and March 1991, 238 273 Mssachusetts children 6 through 59 months of age were screened; iron deficiency was defined as an erythrocyte protopophyrin concentration of 0.62 micromol/L or higher and a blood lead level of less than 1.2 micromol/L. Sociodemographic data were obtained from the 1990 US Census. RESULTS: Five percent of communities had iron deficiency rates greater than 13.9 per 100 children screened. Iron deficiency rate was positively associated with proportion of Southeast Asians (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.08, 1.12), proportion of Hispanics (OR = 1.008, 95% CI = 1.002, 1.013), and high school incompletion (OR = 1.028, 95% CI = 1.020, 1.035). Similarly, an examination of three Massachusetts cities indicated that the iron deficiency rate was higher for children with Southeast Asian (relative risk [RR] = 3.6, 95% CI = 3.3, 3.8) and Hispanic (RR = 1.6, 95% CI = 1.5, 1.8) surnames than for all other children. CONCLUSIONS: Wide variation exists in iron deficiency rates for children in Massachusetts communities. Community iron deficiency was associated with low socioeconomic status and high proportions of Southeast Asians and Hispanics.

Anemia, Iron-Deficiency↗
PubMed1996

INSIGHT: international nifedipine GITS study intervention as a goal in hypertension treatment.

The objective of the study is to compare fatal and nonfatal cardiovascular endpoints in hypertensive patients randomised to the calcium-channel blocker, nifedipine GITS or a thiazide diuretic, co-amilozide. A total of 6592 patients from nine countries (UK, France, Israel, Spain, Italy, The Netherlands, Sweden, Denmark and Norway) will be recruited, aged 55-80 and with a blood pressure (BP) > or = 150/95 or > or = 160 mm Hg (systolic). All patients will have at least one other major cardiovascular risk factor. Patients will be minimised by country and risk factors and randomised to double-blind treatment with either nifedipine GITS or diuretic. After a single dose titration, additional treatment will be atenolol or enalapril (where beta-blockade is contra-indicated). After achieving a target BP of 140/90 mm Hg patients will be followed for a total of 3 years. Primary endpoints are myocardial infarction, stroke, subarachnoid haemorrhage, heart failure and sudden cardiac death. The study has a power of 80% at 5% significance to detect a difference between 8% event rate over 3 years in diuretic-treated patients and 6% in those receiving nifedipine.

Aged↗
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↗