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Biomedical subjects

L Brown

Publications and source records attributed to L Brown.

At least 145 records · Page 8Linked to original sources
PubMed1996

Cardiac and vascular responses of isolated rat tissues treated with diterpenes from Sinularia flexibilis (coelenterata: octocorallia).

The marine environment is a rich source of compounds with cardiovascular activity. This study characterizes the cardiac and vascular responses in isolated rat tissues of flexibilide, dihydroflexibilide and sinulariolide, three diterpenes isolated from the soft coral Sinularia flexibilis. On rat left ventricular papillary muscles, dihydroflexibilide and flexibilide showed similar potencies (-log EC50 = 4.69 +/- 0.05 and 4.66 +/- 0.06, respectively); the maximal response to dihydroflexibilide of 1.4 +/- 0.2 mN was 35 +/- 7% that of calcium chloride in the same muscles. All diterpenes relaxed rat thoracic aortic rings precontracted with KC1 (100 mM) with similar potencies (flexibilide, -log EC50 = 4.17 +/- 0.06). Flexibilide was further characterized and shown to increase force in isolated rat left atria by 0.8 +/- 0.5 mN at 1 x 10(-4) M, to increase rate of contraction in isolated rat right atria by 18 +/- 5 beta/min at 3 x 10(-5) M and to completely relax endothelium-denuded rat thoracic aortic rings (-log EC50 = 4.14 +/- 0.05). Toxicity as indicated by the occurrence of ectopic beats was not observed with the diterpenes at concentrations which produced complete relaxation of blood vessels, maximal positive inotropic activity and minor positive chronotropic responses. Thus, these compounds may be useful lead compounds in the search for improved treatment of cardiovascular disease, especially heart failure.

Animals↗
PubMed1996

Lifestyle, environmental pollution and lung cancer in cities of Liaoning in northeastern China.

Several studies were conducted in cities of Liaoning Province, one of the areas of China with heavy concentrations of industry, to investigate the effects of life-style factors and environmental pollutants on lung cancer causation. A case-control study involving 1249 lung cancer patients and 1345 population-based controls was conducted in 1985-1988 in Shenyang, the capital of Liaoning. Cigarette smoking was found to be the principal cause of lung cancer in this population, accounting for 55% of the disease in males and 37% in females. There was also a significant increase in lung cancer risk associated with an overall index of indoor air pollution due to coal-burning emission. The population attributable risk (PAR) for indoor air pollution was 13% for males and 17% for females. Risks were significantly increased for workers in the non-ferrous smelter (odds ratio (OR) = 2.6, 95% CI, 1.3-5.1), chemical and drug manufacturing (OR = 3.0, 95% CI, 1.0-8.0), and the glass and pottery industry (OR = 1.6, 95% CI, 1.0-2.5). Studies in the Anshan Iron-Steel Complex showed a significant excess of lung cancer for workers exposed to a variety of dusts. A standardized proportional mortality ratio (SPMR) study of 8887 deaths during 1980-1989 among male workers of the complex indicated a 37% excess risk of lung cancer compared to residents of the city. A nested case-control study was then conducted in that complex. A total of 610 cases of lung cancer diagnosed during 1987-1993 and 959 randomly selected controls from 196 993 active and retired employees of the complex were interviewed. Historical monitoring records for dust and benzo(a)pyrene (B(a)P) were collected from 1956-1992 to calculate cumulative exposure for each person. Results suggested that risks were increased for all occupations in which there was exposure to dusts, with the highest risks seen among coke oven workers (OR = 3.5, 95% CI, 2.0-6.4) and fire-resistant brick makers (OR = 2.9, 95% CI, 1.9-4.4). Significant dose-response patterns between cumulative total dust, cumulative total B(a)P and lung cancer risk were observed. The findings suggest that smoking and environmental pollution combine to account for elevated rates of lung cancer in cities of northeastern China.

Adenocarcinoma↗
PubMed1996

Decision rules for predicting future lipid values in screening for a cholesterol reduction clinical trial.

Recent large clinical trials have required screened patients to have serial measurements of an entry criteria variable, eliminating patients form further consideration if the average value is not in the eligibility range specified by the trial protocol. The increasing costs of large clinical trials required that they be executed efficiently. One way to improve efficiency would be to reduce the number of required screening measurements for a patient likely to be ineligible. A procedure is proposed that predicts the value of an average based on n measurements serially obtained on a patient during the screening phase when only m < n measurements are available. The employment of this procedure in a large clinical trial that uses low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglycerides as entry criteria during the screening process is described. As a second example, this procedure is applied to population screening for lipid levels above a treatment threshold. The National Cholesterol Education Program recommends that the average of two LDL cholesterol measurements be used to determine whether LDL cholesterol is above 130 mg/dl, the threshold for treating patients with coronary heart disease. However, data from a sample of patients from a postinfarction population suggest that, if a single LDL cholesterol is above 146 mg/dl, the probability is greater than 95% that the average of the two LDL cholesterol measurements will be above 130 mg/dl.

Adult↗
PubMed1996

Bacteremia and sepsis.

Recent evolution in the thinking of sepsis syndrome has provided a framework on which new clinical and basic research can be built. The separation of the inciting event and the cascade of subsequent physiologic changes has profound effects on how sepsis is thought of and ultimately how it will be treated. Early identification and treatment of infections and identifying patients at risk, to prevent SIRS, is the current role of Eps. Resuscitation of severe sepsis is more complex than other forms of shock and may require extensive resources if rapid admission or transfer to an intensive care unit is not available. As in many instances, the EP must be knowledgeable and skilled in the early identification and initial management of these patients until the definitive care can be provided. Modulation of the inflammatory response appears to be a prime prospect, but its practicality remains to be proved. Research and future roles of EPs include defining the population of ED patients at risk for SIRS and use of mediators of the inflammatory response. Emergency medicine is positioned in a critical point in the care of these patients.

Bacteremia↗
PubMed1996

Unravelling the familial tendency to aneurysmal disease: popliteal aneurysm, hypertension and fibrillin genotype.

PURPOSE: To screen patients with abdominal aortic aneurysm for popliteal aneurysm and investigate cardiovascular and genetic risk factors associated with aneurysmal disease at more than one site (generalised aneurysmal disease). SUBJECTS, DESIGN AND SETTING: All patients referred to the Regional Vascular Surgical Service at Charing Cross Hospital with unruptured abdominal aortic aneurysm between 1989 and 1993 were screened for popliteal aneurysms, using ultrasonography. MAIN OUTCOME MEASURES: Palpation of a popliteal aneurysm or ultrasonographic detection of popliteal dilatation, where the ratio maximum popliteal fossa diameter/suprageniculate popliteal diameter was > or = 1.5, in relation to cardiovascular and genetic risk factors. RESULTS: Clinical examination detected popliteal aneurysms in only 11/232 patients (5%), but ultrasonography demonstrated the presence of popliteal aneurysm in a further 13 patients, 24/232 in total (10%). Multivariate regression identified four independent factors associated with popliteal dilatation disease: age (p = 0.046), height (p = 0.006), systolic hypertension (p = 0.037) and triglyceride concentration (p = 0.009). Generalised aneurysmal disease and systolic blood pressure were associated with polymorphic variation in the fibrillin-1 gene, but not with variations in the apolipoprotein B and type III collagen genes. CONCLUSIONS: Few patients with abdominal aortic aneurysm (10%) also have popliteal aneurysms: the risk of popliteal dilatation increases with age, height, systolic blood pressure, triglyceride concentration and fibrillin genotype. The strong interaction between fibrillin genotype and blood pressure may contribute to the familial tendency to aortic aneurysm.

Age Factors↗
PubMed1996

Unstable carotid plaques: preoperative identification and association with intraoperative embolisation detected by transcranial Doppler.

OBJECTIVES: To investigate whether unstable carotid plaque characteristics, as determined by preoperative colour Duplex ultrasonography (CDU) and postoperative histological examination, were associated with particulate embolisation, detected by transcranial Doppler (TCD), during the initial dissection of the carotid bifurcation during carotid endarterectomy(CEA). DESIGN: A prospective, consecutive study was undertaken of 50 patients undergoing carotid endarterectomy(CEA). SETTING: Leicester Royal Infirmary, Leicester, U.K. MATERIALS: Carotid plaques were assessed preoperatively using CDU. Intraoperative TCD monitoring of the ipsilateral middle cerebral artery was performed using a Scimed 2MHz TCD. Carotid plaques removed at operation were processed histologically and multiple sections assessed microscopically. CHIEF OUTCOME MEASURES: Plaque composition was classified ultrasonically and histologically according to the Gray-Weale classification and plaque surface characteristics were graded according to a five point classification. TCD detected emboli were identified and counted during the initial dissection of the artery. MAIN RESULTS: Particulate embolisation occurred in nine patients. Histologically, embolisation was associated with ulcerated plaque in three cases and ulcerated plaque with associated thrombus in six cases (p = 0.0005). However, the ability of CDU to positively predict embolisation based on the correct identification of an unstable plaque surface was only 25%. CONCLUSIONS: Embolisation during dissection is strongly associated with ulcerated plaque with associated thrombus. CDU is unable to reliably identify these characteristics preoperatively. Intraoperative TCD monitoring can detect potentially harmful embolisation during this stage enabling surgical technique to be modified appropriately.

Arteriosclerosis↗
PubMed1996

Quantification of insulin release from implantable polymer-based delivery systems and augmentation of therapeutic effect with simultaneous release of somatostatin.

Insulin injections control diabetes mellitus but do not reproduce physiologic regulation. Polymer-based controlled-release technology has enabled us to demonstrate: that the controlled release of insulin from polymer matrices can indeed be used to control diabetes mellitus but does so at the expense of hyperinsulinemia and hypoglycemia; and that somatostatin can be delivered in similar fashion, so as to provide glucose homeostasis in a more physiologic range, at lower insulin levels and at somatostatin doses below those used in intermittent infusion studies; and, that microgram quantities of a drug can be delivered successfully in vivo with intact biological function and in a manner that can be monitored continuously. In the present study the simultaneous polymer-matrix-controlled release of insulin with somatostatin extended glycemic control in diabetic rats. Eleven rats received subcutaneous polymer matrix implants containing insulin alone and 11 rats received implants containing insulin and somatostatin. Plasma and urinary glucose control were improved in both groups. Glucose concentrations in the insulin alone group remained depressed for 5 days until insulin release from the matrices declined below 11.6 units/kg/day. When somatostatin was delivered at 0.75-1.1 micrograms/kg/day together with insulin, plasma glucose control persisted for 12 days until insulin release decreased below 3.6 units/kg/day. It is our hope that further experiments regarding the potential role of both controlled-release devices and somatostatin will be performed to provide continuing therapeutic alternatives to the insulin-dependent diabetic. This is also the first in vivo demonstration of the simultaneous release of two biologically active peptide hormones from polymer matrices. The use of the polymer matrix systems may not only have profound effects on the ambulatory care of diabetes but might also permit the investigation of the synergistic effects of other families of compounds.

Animals↗
PubMed1996

Defence against the immune barrage: helminth survival strategies.

Parasites have generated a range of countermeasures against the host immune system which allows their survival long enough for reproduction to occur. Parasite subsistence is enhanced by evasion of the immune response utilizing mechanisms such as antigenic variation of exposed immunogenic proteins, shedding of surface proteins which are the target of an immune response, and protease production to neutralise specific anti-parasite immune components. Recent advances in the fields of immunology and parasitology have highlighted a range of mechanisms by which the parasite actively modulates the immune response to allow survival. Parasite factors can directly suppress the function of certain subsets of immune cells as well as stimulating other cell populations which have suppressive activity. Strategies such as the skewing of the type 1-type 2 cytokine profile to that of a less appropriate response, and the mimicry of host immune regulatory proteins are becoming more widely acknowledged as means by which helminths enhance their survival. An illustration of the extent by which parasites can exploit host immune components is emphasized by the use of host cytokines as parasite growth factors. This review will examine some of the strategies developed by helminths which enables them not only to survive in the host, but also to prosper.

Animals↗
PubMed1996

Profile of postdischarge rehospitalizations and acute care visits for seven patient groups.

The study's purpose was to examine postdischarge rehospitalizations and acute care visits in seven high risk, high volume, high-cost patient groups. Subjects were drawn from an urban tertiary teaching hospital. The total sample (N = 764) consisted of seven patient groups (drawn from five randomized clinical trials): very low birthweight (VLBW) infants (n = 79); women post-unplanned cesarean birth (n = 122) and their infants (n = 123); pregnant women with diabetes (n = 55); women post-hysterectomy surgery (n = 109); and elderly with medical cardiac Diagnostic Related Groups (DRGs) (n = 142) and elderly with surgical cardiac DRGs (n = 134). The VLBW infant and pregnant diabetic groups were predominantly African American, the elderly and hysterectomy groups predominantly Caucasian, and the cesarean group almost equally distributed. The lowest rate of rehospitalization (2%) occurred in the cesarean group, the highest (35%) in the pregnant diabetics. In four groups (cesarean and infants, hysterectomy and surgical elderly), 60%-100% of the rehospitalizations occurred within 4 weeks of discharge. Subjects requiring acute care visits ranged from 13% (hysterectomy) to 82% (VLBW infants). Acute care visits demonstrated greater distribution throughout the follow-up periods but also tended to concentrate in the first 4 weeks postdischarge.

Acute Disease↗
PubMed1996

Efficient translation of the RpoS sigma factor in Salmonella typhimurium requires host factor I, an RNA-binding protein encoded by the hfq gene.

The RpoS transcription factor (also called sigma Sor sigma 38) is required for the expression of a number of stationary-phase and osmotically inducible genes in Escherichia coli. RpoS is also a virulence factor for several pathogenic bacteria, including Salmonella typhimurium. The activity of RpoS is regulated in response to several different signals, at the transcriptional and translational levels as well as by proteolysis. Here we report that host factor I (HF-I), the product of the hfq gene, is required for efficient expression of rpoS in S. typhimurium. HF-I is a small, heat-stable, site-specific RNA-binding protein originally characterized for its role in replication of the RNA bacteriophage Q beta of E. coli. Its role in the uninfected bacterial cell has previously been unknown. Assays of Beta-galactosidase in strains with rpoS-lac fusions, Western blot (immunoblot) analysis, and pulse-labeling and immunoprecipitation of both fusion proteins and native RpoS show that an S. typhimurium hfq mutant has a four- to sevenfold reduction in expression of rpoS that is attributable primarily to a defect in translation. These results add a new level of complexity to the regulation of RpoS activity.

Amino Acid Sequence↗
PubMed1996

Clinical case management: what works, what doesn't.

Often, what works best depends less on a specific model, and more on choosing the right people. Two nurses were selected to role model critical path and case management principles. These clinical care coordinators focused on all involved disciplines, cost containment and quality outcomes.

Case Management↗
PubMed1995

Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators.

Although elevated plasma cholesterol levels represent a well-established and significant risk for developing atherosclerosis, there is a wide spectrum of cholesterol levels in patients with coronary artery disease (CAD). Most secondary prevention studies have generated convincing evidence that cholesterol reduction in patients with high cholesterol levels is associated with improved clinical outcome by reducing risk of further cardiovascular events. However, other risk factors may play a prominent role in the pathogenesis of coronary disease in the majority of patients with near-normal cholesterol values. The Cholesterol and Recurrent Events (CARE) study was designed to address whether the pharmacologic reduction of cholesterol levels with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, pravastatin, would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who have survived an MI yet have a total cholesterol value < 240 mg/dl (< 6.2 mmol/liter). The other inclusion criteria for this study were age 21-75 years, low density lipoprotein (LDL) cholesterol levels of 115-174 mg/dl (3.0-4.5 mmol/liter), and fasting serum triglyceride levels < 350 mg/dl (< 4.0 mmol/liter). A total of 4,159 eligible consenting patients without other study exclusions were then randomly assigned to receive either pravastatin 40 mg daily or matching placebo in addition to their individualized conventional therapy. The trial was designed to have a median follow-up of 5 years. Study endpoints will be evaluated with respect to predefined subgroups according to baseline lipid values, age, gender, prior cardiovascular risk factors, and history.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Development of a cleavage-site-specific monoclonal antibody for detecting metalloproteinase-derived aggrecan fragments: detection of fragments in human synovial fluids.

We have developed a monoclonal antibody AF-28 that specifically recognizes a neo-epitope on polypeptides with N-terminal FFGVG ... sequences. This sequence is found at the N-terminus of aggrecan fragments that have been digested with matrix metalloproteinases (MMPs). By immunoblotting, monoclonal antibody AF-28 specifically detected G2 fragments derived from an aggrecan G1-G2 substrate digested with stromelysin, collagenase, gelatinase and matrilysin, but failed to detect G2 fragments obtained from elastase, trypsin or cathepsin B digests. Undigested G1-G2 was not detected. In addition, AF-28 antibody detected fragments derived from whole aggrecan and this detection did not require prior treatment with chondroitinase or keratanase. Competition experiments confirmed that peptides containing internal ... FFGVG ... sequences were not detected by the antibody, while native MMP-digested aggrecan fragments and a synthetic 32-mer peptide with FFGVG ... N-termini were equally competitive on a molar basis. An FFGVG 5-mer, and an FGVGGEEDI9-mer which lacked the N-terminal phenylalanine residue, were 50 times and 230 times respectively less competitive than the FFGVG ... 32-mer. Two fragments from the interglobular domain, F342-F373 and F342-D441, that are predicted products of G1-G2 digestion by neutrophil collagenase but have not previously been detected, could be detected with AF-28. The epitope recognized by AF-28 was also detected in human synovial fluids by Western blot analysis. A broad band of 100-200 kDa was detected in some patients and a dominant band of 40-60 kDa was found in two patients. The size of this small fragment corresponds with that seen for the porcine F342-E373 product and may represent the natural physiological product of aggrecan cleaved in vivo at both the MMP site (... DIPEN341 decreases F342FGVG ...) and the aggrecanase site (... ITEGE373 decreases A374RGSVI ...).

Aggrecans↗
PubMed1995

Vaginal symptoms and insulin dependent diabetes mellitus.

AIMS: To assess the incidence of vaginal symptoms in younger women with insulin dependent diabetes, and also to assess the relationship between symptoms and other clinical risk factors for candidiasis. METHOD: A population-based questionnaire was administered to women aged 18-40 years with insulin dependent diabetes. Subjects were asked about symptoms of "vaginal thrush" as a surrogate question for symptoms suggestive of vaginal infection. Glycaemic control was assessed by measurement of glycated haemoglobin. (Non-diabetic reference range of 30-50 mmol/mol haem). RESULTS: One hundred and twenty-four out of 144 eligible women completed the questionnaire, a participation rate of 86%. Of the women interviewed, 60% had experienced one or more episodes attributed to "vaginal thrush", in the previous year. All seven subjects with a glycated haemoglobin of 100 mmol/mol haem or greater, experienced vaginal symptoms in the previous year. The relationship between frequency of vaginal symptoms and glycated haemoglobin was however weak. CONCLUSIONS: Vaginal symptoms are common in younger women with insulin dependent diabetes and are not confined to subjects with poor diabetes control. We recommend that health professionals caring for these women enquire about symptoms of vaginitis so that appropriate diagnosis and treatment can be initiated.

Adolescent↗
PubMed1995

The relationship of patients' cognitive status and therapists' ratings of psychological distress among psychoactive substance users in long-term residential treatment.

Patients in a long-term residential substance abuse treatment program (N = 168) were asked to complete the Symptom Checklist-90-Revised (SCL-90-R), a brief inventory that measures psychological distress in nine symptom areas. Using the Symptom Checklist-90 Analogue (SCL-90 Analogue), which allows raters to assess patients along the same dimensions measured by the SCL-90-R, therapists also estimated the degree of psychological distress they observed in their patients. Significantly larger discrepancies were found between therapists' ratings of their patients and patients' ratings of themselves when patients were cognitively impaired (N = 57) than when patients did not display these decrements (N = 111). Furthermore, these patient-therapist assessment differences were negatively related to measures of patients' participation in treatment and length of stay in the program. Clinical and research implications of these findings are discussed.

Adaptation, Psychological↗
PubMed1995

Apoptosis and the cell cycle.

Apoptosis is an evolutionarily conserved 'suicide' programme present in all metazoan cells. Despite its highly conserved nature, it is only recently that any of the molecular mechanisms underlying apoptosis have been identified. Several lines of reasoning indicate that apoptosis and cell proliferation coincide to some degree: many oncogenes that promote cell cycle progression also induce apoptosis; damage to the cell cycle or to DNA integrity is a potent trigger of apoptosis; and the key tumour suppressor proteins, p105rb and p53, exert direct effects both on cell viability and on cell cycle progression. There is less evidence, however, to indicate that apoptosis and the cell cycle share common molecular mechanisms. Moreover, the interleukin-1 beta converting enzyme (ICE) family of cysteine proteases is now known to play a key role in apoptosis but has no discernible role in the cell cycle, arguing that the two processes are discrete.

Animals↗
PubMed1995

Seroreactivity of analogous antigenic epitopes in glycoprotein 120 expressed in HIV-1 subtypes A, B, C, and D.

This article describes the impact of sequence variation on the distribution and seroreactivity of linear antigenic epitopes in gp120 encoded in new Ugandan HIV-1 clones from subtypes A, C, and D, and in North American clones from the B subtype. A region of the env gene encoding the C2 to V5 domains was PCR amplified from the lysates of peripheral blood leukocytes or from short-term cultured isolates. Computer-assisted analyses were conducted on the amino acid sequences to determine the distribution of surface structures in gp120. Despite marked sequence diversity, eight analogous epitopes were predicted for all clades of the virus analyzed. Synthetic peptides comprising the putative principal neutralizing determinant E2[V3], and other B cell epitopes E3[V3-V4], E4[V3-V4], E7[C3], and E8[V5], from a seroprevalent Ugandan isolate, AUG06c, were tested in ELISA for antigenicity with sera from Uganda, New York, and Thailand. Variable magnitudes of seroreactivity were observed for all of the peptides tested. However, a significantly higher degree of serum cross-reactivity was detected with the V3 loop peptide. ELISA reactivities of the same serum panel indicated that V3 loop peptides containing the apical residues GPGR (clones AUG06c and BRT3) or GPGQ (CUG045 and DUG044) were more antigenic and display extensive cross-reactivity as compared to analogous peptides comprising GLGQ (DUG23c), GQGQ (DUG042), or GPWG (BRT1). BETATURN analysis of the divergent V3 loop apical residues showed a good correlation of probable beta-turn occurrence with strong seroreactivity. These findings suggest that the major antigenic specificities in the divergent clades of HIV-1 are well conserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗