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M J Brown

Publications and source records attributed to M J Brown.

At least 73 records · Page 4Linked to original sources
PubMed2000

A genome-wide search for susceptibility loci to human essential hypertension.

We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (n=263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with P<0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (P<0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.

Aged↗
PubMed2000

Pathoaetiology, epidemiology and diagnosis of hypertension.

Hypertension is currently defined in terms of levels of blood pressure associated with increased cardiovascular risk. A cut-off of 140/90 mm Hg is accepted as a threshold level above which treatment should at least be considered. This would give a prevalence of hypertension of about 20% of the adult population in most developed countries. Hypertension is associated with increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. Hypertension results from the complex interaction of genetic factors and environmental influences. Many of the genetic factors remain to be discovered, but environmental influences such as salt intake, diet and alcohol form the basis of nonpharmacological methods of blood pressure reduction. Investigation of the individual hypertensive patient aims to identify possible secondary causes of hypertension and also to assess the individual's overall cardiovascular risk, which determines the need for prompt and aggressive therapy. Cardiovascular risk can be determined from (i) target organ damage to the eyes, heart and kidneys; (ii) other medical conditions associated with increased risk; and (iii) lifestyle factors such as obesity and smoking. Secondary causes of hypertension are individually rare. Screening tests should be initially simple, with more expensive and invasive tests reserved for those in whom a secondary cause is suspected or who have atypical features to their presentation. The main determinants of blood pressure are cardiac output and peripheral resistance. The typical haemodynamic finding in patients with established hypertension is of normal cardiac output and increased peripheral resistance. Treatment of hypertension should initially use nonpharmacological methods. Selection of initial drug therapy should be based upon the strength of evidence for reduction of cardiovascular mortality in controlled clinical trials, and should also take into account coexisting medical conditions that favour or limit the usefulness of any given drug. Given this approach, it would be reasonable to use a thiazide diuretic and/or a beta-blocker as first-line therapy unless there are indications to the contrary. Individual response to given drug classes is highly variable and is related to the underlying variability in the abnormal pathophysiology. There are data to suggest that the renin-angiotensin system is more important in young patients. The targeting of this system in patients under the age of 50 years with a beta-blocker (or ACE inhibitor), and the use of a thiazide diuretic (or calcium antagonist) in patients over 50 years, may enable blood pressure to be controlled more quickly.

Adult↗
PubMed2000

The gain-of-function G389R variant of the beta1-adrenoceptor does not influence blood pressure or heart rate response to beta-blockade in hypertensive subjects.

Mutation scanning of the beta1-adrenoceptor gene has identified a polymorphism, G389R, that markedly affects G-protein coupling of the receptor and resulting cAMP production. We have investigated the effect of this functionally active polymorphism on clinical response to beta-adrenoceptor blockade. Two cohorts of untreated hypertensive patients randomly assigned to a beta1-selective beta-blocker at the start of antihypertensive therapy were studied retrospectively to see if the G389R polymorphism influenced the response in terms of blood pressure and heart rate. The blood pressure and heart rate responses to treatment were assessed 4 weeks later and compared with the G389R genotype, ascertained by PCR/restriction fragment length polymorphism. The falls in blood pressure and heart rate for the first group (n = 92) by genotype were: GG, 20.1 +/- 3.5/13.9 +/- 2.7 mmHg (systolic/diastolic blood pressure), 18.4 +/- 2.2 beats/min; GR, 20.0 +/- 2.2/15.0 +/- 1.3 mmHg, 16.5 +/- 1.5 beats/min; RR, 20.8 +/- 2.3/13.4 +/- 1.1 mmHg, 16.0 +/- 1.4 beats/min. For the second group (n = 55) the corresponding falls were: GG, 17.0 +/- 4.3/11.2 +/- 3.4 mmHg, 12.0 +/- 3.5 beats/min; GR, 16.6 +/- 1.8/14.4 +/- 1.1 mmHg, 13.1 +/- 2.1 beats/min; RR, 18.0 +/- 1.6/13.0 +/- 1.4 mmHg, 14.4 +/- 1.4 beats/min. The G389R genotype also failed to have a significant effect on pretreatment blood pressure or heart rate in either group. These data suggest that, despite clear functional differences between the G389R receptor variants expressed in vitro, the polymorphism does not affect the haemodynamic response of hypertensive subjects to chronic beta1-adrenoceptor blockade.

Adrenergic beta-Antagonists↗
PubMed1999

A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK.

BACKGROUND: Endothelium-derived nitric oxide (NO) is synthesised from L-arginine by endothelial nitric oxide synthase (eNOS) encoded by the NOS 3 gene on chromosome 7. Because reduced NO synthesis has been implicated in the development of coronary atherosclerosis, which has a heritable component, we hypothesised that polymorphisms of NOS 3 might be associated with increased susceptibility to this disorder. METHODS AND RESULTS: Single-strand conformation polymorphism analysis of NOS 3 identified a G-->T polymorphism in exon 7 of the gene which encodes a Glu-->Asp amino acid substitution at residue 298 of eNOS. We investigated the relationship between this Glu(298)-->Asp variant and atherosclerotic coronary artery disease (CAD) using 2 independent case-controlled studies. In the first study (CHAOS), cases consisted of 298 unrelated patients with positive coronary angiograms and controls were 138 unrelated healthy individuals ascertained through a population health screen. In the second study (CHAOS II), the cases were 249 patients with recent myocardial infarction (MI), and a further 183 unrelated controls. There was an excess of homozygotes for the Asp298 variant among patients with angiographic CAD, and among patients with recent MI when compared with their respective controls (35.9% versus 10.2%, P<0.0001 in CHAOS, and 18.1% versus 8.7%, P<0.02 in CHAOS II). In comparison to Glu(298) homozygotes, homozygosity for Asp(298) was associated with an odds ratio of 4.2 (95% CI, 2.3 to 7.9) for angiographic CAD and 2.5 (95% CI, 1.3 to 4.2) for MI. CONCLUSIONS: Homozygosity for a common NOS 3 polymorphism (894 G-->T) which encodes a Glu298-->Asp amino acid substitution in eNOS is a risk factor for angiographic CAD and recent MI in this population.

Aged↗
PubMed1999

Optimisation of antihypertensive treatment by crossover rotation of four major classes.

BACKGROUND: Most comparisons of antihypertensive drugs are undertaken in parallel groups. We undertook a crossover rotation of the four main classes of antihypertensive drugs, in untreated young hypertensive patients, to assess the response rate with monotherapy achieved by a systematic rotation. METHODS: 56 patients, mean blood pressure 161/98 mm Hg, entered the rotation, of whom 36 received all four monthly cycles of treatment with an angiotensin-converting-enzyme (ACE) inhibitor (A), beta-blocker (B), calcium-channel blocker (C), and diuretic (D). Each patient's best drug was then repeated to assess repeatability. Two measures of individual variability in response were used. First, the value of rotation was measured by the increased proportion of patients reaching target blood pressure on their best drug versus their first drug. Second, we assessed whether the responses to each drug were correlated with each other. FINDINGS: Significant variability in response was found. 20 of the 41 patients reaching target blood pressure (< or =140/90 mm Hg) failed to achieve this target on their first drug. Rotation increased from 22/56 (39%) to 41/56 (73%) the success of monotherapy (p=0.0001); in half the patients, blood-pressure on the best treatment was 135/85 mm Hg or less. There were significant correlations between the blood pressure responses to A and B (r=0.5, p<0.01), and C and D (r=0.6, p<0.001), but not between the other four pairings of treatments. The responses to the AB pair were, on average, at least 50% higher than those to the CD pair; this difference was highly significant by multivariate repeated-measures ANOVA. INTERPRETATION: There is a marked variability in hypertensive patients' response to different antihypertensive drugs. The basis may be underlying variability in types of essential hypertension. Optimisation of treatment requires systematic rotation through several therapies; however, an "AB/CD" rule is proposed in which one of each of the two pairs of treatments is initially selected to abbreviate the rotation in routine practice.

Adrenergic beta-Antagonists↗
PubMed1999

Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes.

Dendritic cells (DCs) emigrate to regional lymph nodes (LNs) during immune responses via afferent lymphatic channels. Secondary lymphoid-tissue chemokine (SLC), a CC chemokine, is expressed in secondary lymphoid organs and mediates the chemotaxis of lymphocytes and DCs via its receptor, CC chemokine receptor 7 (CCR7). By dual-label fluorescence confocal microscopy, we showed MHC class II-positive cells within SLC-staining lymphatic channels in the mouse dermis. SLC was a potent in vitro chemoattractant for cultured, migratory skin DCs, and it enhanced the emigration of MHC class II-positive DCs from mouse skin explants by an average of 2.5-fold. Mature or cytokine-activated, but not resting, Langerhans cells expressed CCR7 mRNA by RT-PCR. Anti-SLC Abs, but not control or anti-eotaxin Abs, blocked the in vivo migration of 51Cr-labeled, skin-derived DCs from footpads to draining LNs by 50% (n = 9, p < 0. 005). Thus, we provide direct evidence that SLC and CCR7 participate in the emigration of DCs from peripheral tissue to LNs via lymphatics.

Animals↗
PubMed1999

T-cell activation: interplay at the interface.

Recent studies have shown that, when a T cell interacts with a cognate antigen-presenting cell, an organized adhesive contact is formed between the two cells by a process which involves the dynamic, three-dimensional redistribution of entire signaling assemblies.

Antigen-Presenting Cells↗
PubMed1999

Polyethylene glycol-mediated infection of non-permissive mammalian cells with semliki forest virus: application to signal transduction studies.

Semliki Forest Virus (SFV) vectors allow the subcloning of a gene of interest directly in the expression vector, thus avoiding the need to select and purify viral recombinants, making this viral expression system attractive over many others for mammalian protein expression. We now describe a novel and generally applicable method for infection of non-permissive mammalian cells with SFV, that greatly enhances the utility of this expression system. We demonstrate that the hygroscopic polymer poly (ethylene glycol), PEG, promotes the infectivity of cells by SFV under conditions that did not promote cell-cell fusion. We also found that the PEG-induced infection and expression of an exogenous protein (green fluorescent protein, GFP) did not elevate the basal tyrosine kinase activity, induce a stress-activated responses, or result in aberrant cell responses. Expression of GFP tagged-Vav, an activator of stress-activated protein kinase (SAPK/JNK), resulted in the expected induction of JNK activity and in the normal redistribution of Vav in response to engagement of the high affinity receptor for IgE (FcepsilonRI). Thus, our findings that PEG allows the infection of non-permissive cells by SFV makes this system extremely attractive for expression of proteins in mammalian cells, and studies on signal transduction and cellular localization in immune and non-immune cells.

3T3 Cells↗
PubMed1999

An unusual presentation of an encephalocele to the otolaryngologist.

An unusual case of encephalocele causing obstruction of the upper airway in a neonate is described. The patient presented with a large mass in the neck, which extended from the base of the skull to the level of the larynx. Although there was no evidence of a defect of the skull base, subsequent excision and histological examination confirmed an encephalocele.

Airway Obstruction↗
PubMed1999

Selective beta1-adrenoceptor blockade enhances the activity of the stimulatory G-protein in human atrial myocardium.

1. Chronic selective beta1-adrenoceptor (beta1AR) blocker treatment enhances the sensitivity of beta2-adrenoceptor (beta2AR) in human heart (Hall et al., 1990; 1991). To clarify the mechanism of the cross-sensitization between beta1AR and beta2AR, we determined whether the stimulatory G-protein (G(s)alpha) function is increased in atria from beta1AR-blocker treated patients compared with non-beta-blocked patients, and investigated whether this change is caused by an alteration of post-translational modification of Gsalpha protein. 2. G(s)alpha function was determined by reconstitution of human atrial G(s)alpha into S49 cyc- cell membranes. In the reconstitution system, GTPgammaS stimulated cyclic AMP generation in a dose-dependent manner. Upon 10(-4) M GTPgammaS stimulation, G(s)alpha activity in the beta1AR-blocker, atenolol, treated group (78.2+/-10. 3 pmol cyclic AMP mg(-1) min(-1) 10(-3)) was 65% higher than that in non-beta-blocked patients (47.3+/-6.3 pmol cyclic AMP mg(-1) min(-1) 10(-3), n=15, P=0.02). 3. Isoelectric point (pI) valu G(s)alpha were measured by two dimensional gel electrophoresis (2D-E) and the amount of each isoform quantified by image analysis of a Western blot of the gel using specific antibody. Multiple isoforms of G(s)alpha were detected by 2D-E with different pI values. There were no significant differences between the groups of patients in either pI values or the proportions of the acidic isoforms of G(s)alpha to the main basic form (n=12, P>0.05). 4. The results suggest that chronic beta1AR-blockade enhances Gsalpha function in human atrium, and this may account in part for the hypersensitivity of beta2AR and other Gs-coupled receptors during beta1AR-blockade. The increased G(s)alpha function is unlikely to be caused directly by blockade of protein kinase A phosphorylation of G(s)alpha protein.

Adenylyl Cyclases↗
PubMed1999

Characterization of E-cadherin-containing junctions involving skin-derived dendritic cells.

Adherens junctions are sites of contact between epithelial cells in which adhesion is mediated by homophilic interactions of classical cadherins that are linked to the cytoskeleton via catenins. E-cadherin constitutes the major adhesion molecule in adherens junctions of keratinocytes (KC) and mediates the binding of Langerhans cells to KC in vitro. To characterize structures responsible for E-cadherin-mediated binding of Langerhans cells, we utilized Langerhans cells-like fetal skin-derived dendritic cells (FSDDC) capable of E-cadherin-mediated adhesion. Confocal microscopy of FSDDC aggregates demonstrated colocalization of E-cadherin and catenins to areas of cell-cell contact. Immunoprecipitation confirmed a physical association of E-cadherin with intracellular catenins (alpha-, beta-, gamma-catenin/plakoglobin and p120CAs). Transmission electron microscopy of FSDDC aggregates revealed structures with features of adherens junctions in areas of cell-cell contact, and post-embedding immunoelectron microscopy localized beta-catenin to these regions. To characterize junctions that accounted for the adhesion of Langerhans cells-like dendritic cells and KC, disaggregated FSDDC were cocultured with primary murine KC. Transmission electron microscopy analysis of cocultures demonstrated FSDDC-KC contacts that were analogous to those seen in FSDDC aggregates. Confocal microscopy demonstrated focal accumulations of E-cadherin and colocalization of beta-catenin in areas of contact between KC and immature (Langerhans cell-like) dendritic cells, but not in areas of contact between KC and mature (lymph node dendritic cell-like) dendritic cells. E-cadherin in Langerhans cells appears to be localized in structures that resemble adherens junctions formed by nonpolarized epithelial cells. Loss of ability to form or maintain these structures after the induction of Langerhans cells activation/ maturation likely results in the attenuation of Langerhans cells-KC adhesion that precedes Langerhans cells emigration from the epidermis.

Animals↗
PubMed1999

Similarities and differences between augmentation index and pulse wave velocity in the assessment of arterial stiffness.

We investigated whether there was a correlation between the simultaneous assessments of augmentation index (AI) and pulse wave velocity (PWV), undertaken by the SphygmoCor system, and what were the principal factors responsible for differences in these two putative assessments of arterial stiffness, in 105 offspring (41 men, 64 women) aged 19-71 years, of patients with familial hypertension. Arterial stiffness was measured using the SphygmoCor pulse wave analysis system. AI and PWV correlated significantly and positively (r = 0.29, p < 0.005) and the strength of the correlation was greater when each gender was examined separately. This led us to observe several-fold higher AI in women (22.04 +/- 12) than in men (8.59 +/- 13) (p < 0.001); the difference could be explained only in part by an inverse regression correlation between AI and height (r = -0.45; p < 0.001), but not PWV. AI was also more influenced than PWV by heart rate and blood pressure. AI is strongly correlated with a previously validated estimate of arterial stiffness, PWV. It is probable that separate normal ranges should be established for men and women, while further studies determine what parameters other than height are responsible for the gender difference.

Adult↗