Biomedical subjects

M J Brown

Publications and source records attributed to M J Brown.

At least 91 records · Page 5Linked to original sources

PubMed1999

Quantitative association between a newly identified molecular variant in the endothelin-2 gene and human essential hypertension.

BACKGROUND: Essential hypertension is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has incriminated endothelin-2 (ET2) as a candidate gene for human essential hypertension. This study sought to (i) determine the existence of any molecular variants in the ET2 gene; (ii) undertake an allelic-association study of any such variants found in a large group of well characterized hypertensive and control populations; and (iii) assess any quantitative relationship between the molecular variant and pretreatment blood presure. METHODS: The ET2 gene was subjected to single strand conformation polymorphism (SSCP) analysis in order to identify novel molecular variants. Well-characterized subjects recruited from our local population were used in our association study. Two hundred and forty-four hypertensive patients with pre-treatment blood pressure (range 139/94-237/133 mmHg) were well matched with 228 controls from our local population of 30000 healthy subjects (range 96/62-160/85 mmHg). All subjects were Caucasian. RESULTS: Polymerase chain reaction-SSCP identified a single A985G base change in 3'-UTR of the ET2 gene which was confirmed by direct sequencing. A restriction site for the enzyme BsmA1 was either created (+) or removed (-) with this polymorphism. Analysis of variance showed that the ET2 genotype was an independent predictor of pre-treatment diastolic blood pressure (DBP) in the hypertensive (P< 0.001) but not normotensive group with higher pressures tracking with the (-) allele. Other covariates such as age, sex, alcohol, cigarette smoking, body mass index and cholesterol showed no significant relationship with this genotype. The genotype frequencies for the hypertensive and control population were (-/-: -/+: +/+) 178 :58:8 and 168:55: 5, respectively (not significant). Subjects from the top and tail quartiles of measurement of blood pressure in both groups were selected for genotype and allele frequency comparison. Both genotype and allele differences were highly significant between the two extreme groups for DBP (genotype P< 0.001, alleles P< 0.01) distribution. A search for potential functional variants in linkage disequilibrium with A985G found one further variant in the 5'-UTR, C44T. Conditional haplotype probabilities in 214 chromosomes show that this polymorphism is not in linkage disequilibrium with the 3'-UTR. No other variants were found on a molecular screen of the transcribed portion of the ET2 gene. CONCLUSION: This newly identified polymorphism of the ET2 gene tracked significantly in hypertensives when blood pressure was assessed as a quantitative trait. The difference in genotype and allele frequencies between the extremes of blood pressure suggest that the ET2 locus influences the severity rather than the initial development of hypertension.

3' Untranslated Regions↗

PubMed1999

Calcium-channel blockade can mask the diagnosis of Conn's syndrome.

A 30-year-old woman presented with hypertension and hypokalaemia, and was found to have primary aldosteronism due to a Conn's adenoma, whose removal cured the hypertension. Before surgery, the characteristic biochemical changes which enabled the diagnosis were completely masked by administration of a calcium-channel blocker, amlodipine. It is likely that widespread use of this class of drugs contributes to under-diagnosis of Conn's syndrome as a curable cause of hypertension.

Adult↗

PubMed1999

Association of the G(s)alpha gene with essential hypertension and response to beta-blockade.

We examined whether the GNAS1 locus, encoding the G(s) protein alpha-subunit (G(s)alpha), is implicated in the genetic causes of essential hypertension. A common silent polymorphism (ATT-->ATC, Ile(131)) was identified in exon 5 of the G(s)alpha gene by single-strand conformation polymorphism analysis and DNA sequencing. This polymorphism consists of the presence (+) or absence (-) of a restriction site for FokI. Only 1 other rare allele was found in the coding region; the high GC content of the 5' noncoding sequence prevented mutation scanning of the promoter region of the gene. There was a significant difference in frequency of the FokI alleles between 268 white hypertensives (FokI+:FokI-, 51%:49%) and a matched group of 231 control subjects (FokI+:FokI-, 58%:42%) (P=0.02). Multiple regression analysis showed that the FokI genotype was independently related to the level of untreated systolic blood pressure in 294 well-characterized white hypertensives (P=0.01) but not in normotensives. The influence of the FokI allele on blood pressure (BP) response to beta-blockade was examined in 114 of the patients randomly assigned to this class of drug. Significant differences in frequency of the FokI allele were observed in the good responders (FokI+:FokI-, 62.5%:37.5%, n=36) versus the poor responders (FokI+:FokI-, 41.7%:58.3%, n=30) after beta-blocker therapy (P=0.02). In a multiple regression analysis, the G(s)alpha genotype was the only independent predictor of BP response. These results suggest that the GNAS1 locus might carry a functional variant that influences BP variation and response to beta-blockade in essential hypertension.

Adrenergic beta-Antagonists↗

PubMed1999

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Abatacept↗

PubMed1999

Syntaxin 11 is associated with SNAP-23 on late endosomes and the trans-Golgi network.

SNARE proteins are known to play a role in regulating intracellular protein transport between donor and target membranes. This docking and fusion process involves the interaction of specific vesicle-SNAREs (e.g. VAMP) with specific cognate target-SNAREs (e.g. syntaxin and SNAP-23). Using human SNAP-23 as the bait in a yeast two-hybrid screen of a human B-lymphocyte cDNA library, we have identified the 287-amino-acid SNARE protein syntaxin 11. Like other syntaxin family members, syntaxin 11 binds to the SNARE proteins VAMP and SNAP-23 in vitro and also exists in a complex with SNAP-23 in transfected HeLa cells and in native human B lymphocytes. Unlike other syntaxin family members, no obvious transmembrane domain is present in syntaxin 11. Nevertheless, syntaxin 11 is predominantly membrane-associated and colocalizes with the mannose 6-phosphate receptor on late endosomes and the trans-Golgi network. These data suggest that syntaxin 11 is a SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network in mammalian cells.

Alternative Splicing↗

PubMed1998

Characterization of isoleucyl-tRNA synthetase from Staphylococcus aureus. I: Kinetic mechanism of the substrate activation reaction studied by transient and steady-state techniques.

The kinetic mechanism for the amino acid activation reaction of Staphylococcus aureus isoleucyl-tRNA synthetase (IleRS; E) has been determined from stopped-flow measurements of the tryptophan fluorescence associated with the formation of the enzyme-bound aminoacyl adenylate (E.Ile-AMP; Scheme 1). Isoleucine (Ile) binds to the E.ATP complex (K4 = 1.7 +/- 0.9 microM) approximately 35-fold more tightly than to E (K1 = 50-100 microM), primarily due to a reduction in the Ile dissociation rate constant (k-1 approximately 100-150 s-1, cf. k-4 = 3 +/- 1.5 s-1). Similarly, ATP binds more tightly to E.Ile (K3 = approximately 70 microM) than to E (K2 = approximately 2.5 mM). The formation of the E.isoleucyl adenylate intermediate, E.Ile-AMP, resulted in a further increase in fluorescence allowing the catalytic step to be monitored (k+5 = approximately 60 s-1) and the reverse rate constant (k-5 = approximately 150-200 s-1) to be determined from pyrophosphorolysis of a pre-formed E.Ile-AMP complex (K6 = approximately 0.25 mM). Scheme 1 was able to globally predict all of the observed transient kinetic and steady-state PPi/ATP exchange properties of IleRS by simulation. A modification of Scheme 1 could also provide an adequate description of the kinetics of tRNA aminoacylation (kcat,tr = approximately 0.35 s-1) thus providing a framework for understanding the kinetic mechanism of aminoacylation in the presence of tRNA and of inhibitor binding to IleRS.

Adenosine Triphosphate↗

PubMed1998

Characterization of isoleucyl-tRNA synthetase from Staphylococcus aureus. II. Mechanism of inhibition by reaction intermediate and pseudomonic acid analogues studied using transient and steady-state kinetics.

The interactions of isoleucyl-tRNA synthetase (IleRS, E) from Staphylococcus aureus with both intermediate analogues and pseudomonic acid (PS-A) have been investigated using transient and steady-state techniques. Non-hydrolyzable analogues of isoleucyl-AMP (I) were simple competitive inhibitors (Ile-ol-AMP, Ki = 50 nM and Ile-NHSO2-AMP, Ki = 1 nM;). PS-A (J) inhibits IleRS via a slow-tight binding competitive mechanism where E.J (Kj = approximately 2 nM), undergoes an isomerization to form a stabilized E*.J complex (K*j = 50 pM). To overcome tight-binding artifacts when K*j << [E], K*j values were estimated from PPi/ATP exchange where [S] >> Km, thus raising K*j,app well above [E]. Using [3H]PS-A, it was confirmed that binding occurs with 1:1 stoichiometry and is reversible. Formation of inhibitor complexes was monitored directly through changes in enzyme tryptophan fluorescence. For Ile-ol-AMP and Ile-NHSO2-AMP, the fluorescence intensity of E.I was identical to that when E.Ile-AMP forms catalytically. Binding of PS-A induced only a small change in IleRS fluorescence that was characterized using transient kinetic competition. SB-205952, a PS-A analogue, produced a 37% quenching of IleRS fluorescence upon binding as a result of radiationless energy transfer. Inhibitor reversal rates were obtained by measuring relaxation between spectroscopically different complexes. Together, these data represent a comprehensive solution to the kinetics of inhibition by these compounds.

Anti-Bacterial Agents↗

PubMed1998

Structure of human endothelin-2 gene and demonstration of common expression in human right atrial tissue.

The endothelins (ET) are a group of three vasoactive peptides also known to be involved in vascular remodeling. ET1 is the most extensively studied, but recent evidence has highlighted the role of the little investigated ET2 gene as a potential candidate gene in regulating blood pressure. To allow the future role of this gene to be studied the structure of human ET2 was characterized and intron/exon boundaries were determined. With this structural information and using reverse-transcriptase PCR technology we show that the ET2 gene is commonly expressed in human right atrial tissue. This work will allow a more detailed assessment of the role of this physiologically important gene in human essential hypertension.

Base Sequence↗

PubMed1998

Invasive aspergillosis in the immunocompromised host: utility of computed tomography and bronchoalveolar lavage.

OBJECTIVE: Bronchoalveolar lavage is performed almost routinely in immunocompromised patients with suspected pneumonia, but it has a low yield in the diagnosis of pulmonary aspergillosis. The aim of this study was to determine whether computed tomography (CT) is helpful in determining the likelihood of a positive bronchoalveolar lavage by allowing distinction of patients with angioinvasive aspergillosis from those with Aspergillus bronchopneumonia. METHODS AND RESULTS: A retrospective study was performed including consecutive immunocompromised patients with suspected pneumonia who underwent CT scanning of the chest and bronchoalveolar lavage and who had definite diagnosis of pulmonary aspergillosis. The CT scans were reviewed by two chest radiologists and classified as showing features consistent with angioinvasive or airway invasive aspergillosis. Twenty-one patients met the inclusion criteria. Bronchoalveolar lavage was positive for fungi in two of 11 patients with CT findings consistent with angioinvasive aspergillosis and eight of 10 patients with CT scans consistent with Aspergillus bronchopneumonia (P < 0.01, chi-squared test). CT findings of angioinvasive aspergillosis included nodules measuring 1-3.5 cm in diameter in six, segmental consolidation in three, and both nodules and segmental consolidation in two patients. CT findings of Aspergillus bronchopneumonia including peribronchial consolidation in five, small centrilobular micronodules in one, and both in four patients. CONCLUSIONS: Chest CT is helpful in determining the likelihood of successful diagnosis of pulmonary aspergillosis by bronchoalveolar lavage.

Adolescent↗

PubMed1998

Technical report: Cystic air spaces in the lung: change in size on expiratory high-resolution CT in 23 patients.

PURPOSE: To determine the presence of change in size of air-filled cysts in the lung on expiration by comparison between inspiratory and expiratory high-resolution computed tomography (CT) scans. MATERIALS AND METHODS: Inspiratory and expiratory high-resolution (1-mm collimation) CT scans were obtained in 23 patients with lung cysts due to a variety of lung diseases. The 23 patients had a total of 27 types of cystic lesions including bullae (n=7), honeycomb cysts due to fibrosing alveolitis (n=11), lymphangioleiomyomatosis (LAM, n=2), cystic adenomatoid malformation (n=1), and bronchiectasis (n=6). An adequate expiratory effort, with at least 5% decrease in the anteroposterior or transverse thoracic diameter, was required for inclusion in the study. Inspiratory and expiratory scans at corresponding anatomic levels were compared to determine any change in size of the cysts on expiration. RESULTS: Cystic lesions due to bronchiectasis, LAM and fibrosing alveolitis decreased in size on expiratory CT. In six of seven cases bullae decreased in size, and in one patient with a single bulla it remained unchanged. In one case a single cyst due to cystic adenomatoid malformation increased in size on expiration. CONCLUSION: The majority of lung cysts decrease in size on expiration suggesting that they communicate with the airways.

Adult↗

PubMed1998

Who manages hypertensive patients? The primary care-hospital interface.

The term hypertension is used loosely to cover the right-hand skew of the blood pressure frequency distribution. It embraces almost 20% of the population, of which the major part will fare as well with or without treatment, and a much smaller group of true patients in whom underlying causes are or will be found, the causes being mainly genetic. The role of the primary care physicians is in the initial detection of patients in both groups, and in the reduction of attributable risk by collectively pushing the blood pressure distribution to the left. The role of the specialists is effective diagnosis, prognosis, and management of the more narrowly defined hypertensive patients, to reverse their high relative risk of complications, ideally at a stage before they become at high absolute risk.

Humans↗

PubMed1998

Gamma-aminobutyric acidA receptor function is desensitised in rat cultured cerebellar granule cells following chronic flunitrazepam treatment.

This study examined gamma-aminobutyric acidA (GABA(A)) receptor function in cultured rat cerebellar granule cells by using microphysiometry following chronic flunitrazepam exposure, and correlated the findings with the alpha1 and beta2/3 subunit protein expression and [3H]muscimol binding after the same treatment paradigm. Flunitrazepam treatment reduced (p < 0.05) the maximal GABA-stimulated increase in extracellular acidification rate (Emax) (16.5 +/- 1.2% and 11.3 +/- 1.0%, 2-day control and treated cells, respectively; 17.4 +/- 1.0% and 9.9 +/- 0.7%, 7-day control and treated cells, respectively; best-fit Emax +/- SEM, n = 7), without affecting the GABA concentration required to elicit 50% of maximal response (EC50) (1.2 +/- 1.7 and 2.3 +/- 1.8 microM, 2-day control and treated cells, respectively; 1.7 +/- 1.5 and 1.5 +/- 1.5 microM, 7-day control and treated cells, respectively; best-fit EC50 +/- SEM, n = 7). Flunitrazepam exposure also abolished the flunitrazepam potentiation of the GABA response, caused a transient reduction of the GABA(A) receptor alpha1 and beta2/3 subunit proteins over the initial 2 days, but did not alter [3H]muscimol binding compared with vehicle-treated cells. The results suggest that changes in GABA(A) receptor subunit protein expression, rather than loss of [3H]muscimol binding sites, underlie the chronic flunitrazepam-mediated desensitisation of GABA(A) receptor function.

Acids↗

PubMed1998

Positive association of tyrosine hydroxylase microsatellite marker to essential hypertension.

Despite advances in the understanding of monogenic hypertensive disorders, the genetic contribution to essential hypertension has yet to be elucidated. The position of tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis renders it a candidate gene for the etiology of hypertension. The TH gene contains an internal, informative microsatellite marker (TCAT)9. We undertook (1) an association study in a group of well-characterized hypertensive subjects (HT) and control subjects (NT) and (2) an affected sibling pair (ASP) study using sibships from our local family practices. Two hundred twenty-seven hypertensive patients (pretreatment systolic/diastolic blood pressure [BP] range, 139/94 to 237/133 mm Hg; age range [SD], 30 to 71 [8.5] years) were age- and gender-matched with 206 control subjects (BP range, 96/62 to 153/86 mm Hg; age range, 40 to 70 [7.6] years). One hundred thirty-six affected sibling pairs were recruited for our linkage study; 73 young borderline hypertensive subjects (YHT) (pretreatment BP range, 123/76 to 197/107 mm Hg; age range, 20 to 51 [9.4] years) were also recruited in whom recent pretreatment norepinephrine and epinephrine levels were available. All subjects were white. The TH short tandem repeat (STR) was amplified using specific polymerase chain reaction cycling conditions in all subjects, and products were run on an ABI 373A sequencer. TH alleles were assigned using Genescan and Genotyper software. Five TH alleles were present and designated A through E. Allele frequencies in the NT population (A, B, C, D, and E: 0.24, 0.17, 0.13, 0.20, and 0.26, respectively) were significantly different from the HT cohort (A, B, C, D, and E: 0.24, 0.19, 0.11, 0.11, and 0.35, respectively), P<0. 0005 (Pearson's test chi2=19.94; 4 df). The E allele appears overrepresented in the HT group, whereas the D allele appears to be overrepresented in the NT group. TH genotype frequencies were also significantly different between cases and controls (P<0.001; chi2=36. 57; 14 df). Both groups were in Hardy-Weinberg proportion. There was a trend (NS) for the D allele to be associated with a lower BP when BP was analyzed as a quantitative trait. ASP linkage data was analyzed using Splink, a nonparametric program. Expected values for sharing 0, 1, and 2 alleles (Z0, Z1, and Z2, respectively) may be expected to be 25%, 50%, and 25%, respectively, by chance (assuming identity by descent). These probabilities were calculated by Splink as 34, 68, and 34, respectively, and compared with observed values of 36.8, 67.9, and 31.3, respectively; thus, there was no excess sharing of TH alleles among affected sibling pairs (P=0.59; logarithm of odds ratio score, 0.0). TH allele frequencies in our YHT group (A, B, C, D, and E: 0.24, 0.20, 0.12, 0.15, and 0.29, respectively) were similar to those of our NT cohort (P>0.05). There was a trend for lower pretreatment plasma norepinephrine levels with the D allele in this YHT cohort. A common and potentially functional variant at codon 81(Val-->Met) within exon 2 of the TH gene (which we show to be in linkage disequilibrium with TH-STR) was also typed in our YHT but did not associate with catecholamine levels and is therefore unlikely to account for our findings with D and E TH-STR. In conclusion, the TH locus strongly associates with essential hypertension in a case-control model using well-characterized hypertensive and control groups. An ASP linkage model was negative, presumably because of lack of power. This study suggests that the TH gene, or a nearby gene, may be involved in the etiology of essential hypertension.

Adult↗

PubMed1998

Disseminated intravascular coagulation and status epilepticus.

Status epilepticus has been associated with disseminated intravascular coagulation (DIC), but little is known regarding the pathogenesis of this uncommon association. We describe a 41-year-old woman with status epilepticus resulting in death in whom laboratory data demonstrated profound activation of the coagulation and fibrinolytic systems; autopsy findings were consistent with DIC. The occurrence of DIC in status epilepticus may be related to widespread endothelial damage secondary to seizure-induced hyperpyrexia. Body temperature should be closely monitored in patients with prolonged seizures.

Adult↗

PubMed1998

Catamenial mononeuropathy and radiculopathy: a treatable neuropathic disorder.

OBJECT: The aim of this study was to investigate the indications and treatment options in patients with lower-extremity neuropathies and radiculopathies caused by endometriosis. METHODS: The authors identified five patients whose symptoms included catamenial pain, weakness, and sensory loss involving the sciatic and femoral nerves and multiple lumbosacral nerve roots. Radiographic studies supported the diagnosis of catamenial neuropathy or radiculopathy, but definitive diagnosis depended on surgical and pathological examination. Treatment of symptoms, including physical therapy and a course of antiinflammatory or analgesic medication, was not helpful. Patients responded favorably to hormonal therapy. Laparoscopy or open exploration for extrapelvic lesions was performed for diagnosis or for treatment when hormone therapy failed. Pain and sensory symptoms responded well to therapy. Weakness improved, but never recovered completely. CONCLUSIONS: Catamenial neuropathy or radiculopathy should be considered when evaluating reproductive-age women with recurring focal neuropathic leg pain, weakness, and sensory loss.

Adult↗

PubMed1998

Abdominal ascites in electric eels (Electrophorus electricus) associated with hepatic hemosiderosis and elevated water pH.

Six electric eels (Electrophorus electricus) from various centers that house aquatic organisms presented clinically with abdominal distension following prolonged exposure to elevated environmental pH. Postmortem examination revealed marked ascites. Culture of the abdominal fluid from three of the eels yielded either Aeromonas hydrophila or Citrobacter freundii, which were most likely secondary invaders. Histopathology showed marked iron accumulation in both hepatocytes and hepatic macrophage aggregates.

Animals↗

PubMed1998

Point-of-service teams: a leadership opportunity.

To welcome the transitions in management and leadership roles, a leader may consider developing the skills necessary to promote the success of interdisciplinary point-of-service teams. The author discusses factors that contribute to success in leading a point-of-service team. Key strategies and leader behaviors are addressed. A case study describing one point-of-service team for patient care redesign is presented and analyzed. The experience was viewed very positively by the leaders of the team; opportunities for further improvement are offered.

Hospital Restructuring↗

PubMed1998

The effect of dietary intervention on changes in total cholesterol, blood pressure and weight in a Cambridge study.

The study examined the impact of dietary advice on cholesterol reduction, to see whether diet was more effective when preceded by a cholesterol estimation. A total of 635 healthy individuals aged between 40 and 60 years attended a general practice cardiovascular risk screening in 1990. All subjects had their blood pressure, body mass index and smoking history recorded, and 50% were randomised to cholesterol measurement. Two years later, all individuals were invited to participate in a follow-up screening and 356 individuals took part (158 men, 198 women). All the above estimations were undertaken in 100% of attendees. The mean total cholesterol levels and weight declined in the subjects who were given dietary advice and had their cholesterol measured, while the mean cholesterol level increased slightly in subjects who did not receive dietary advice but had their cholesterol measured. The was a significant increase in diastolic blood pressure in all patients. The figures for reported smokers decreased from 22.4% to 19.4% in men and 19.4% to 8.4% in women. The results suggest that dietary advice can achieve a sustained reduction in cholesterol levels, but may require the stimulus of a prior cholesterol estimation.

Adult↗