Confirmation of a role for the 389R>G beta-1 adrenoceptor polymorphism on exercise capacity in heart failure.
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Analysis of Variance↗
Biomedical subjects
M J Brown
Publications and source records attributed to M J Brown.
Differential expression of adenylyl cyclase subtypes in human cardiovascular system.
In human myocardium, beta1-adrenoceptor stimulation achieves maximal inotropic response but less than 50% of maximal adenylyl cyclase activation, whereas the reverse is true of the beta2-adrenoceptor. Four types of adenylyl cyclase, type IV-VII, have been described in mammalian heart, but their expression and relative distribution in human heart and blood vessels is not known. We found that type IV, V, VI and VII adenylyl cyclases were all expressed in cardiomyocytes. Whereas types IV and VII RNA were more abundant in extra-cardiac than cardiac tissues, both absolute and relative expression of type VI was greatest in heart, and lower in tissues lacking a beta1-adrenoceptor. Type V expression was virtually confined to atrium. In situ mRNA hybridisation showed that the beta1-adrenoceptor co-localised with type VI adenylyl cyclase but not other subtypes in juxtoglomerular cells of human kidney. The tissue specific expression of these adenylyl cyclase subtypes may favour its coupling to corresponding receptors expressed in the given tissue type.
Adenylyl Cyclases↗
N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals.
The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (VO2 peak) and then to fatigue at 92% VO2 peak. NAC was intravenously infused at 125 mg.kg(-1).h(-1) for 15 min and then at 25 mg.kg(-1).h(-1) for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% VO2 peak was reproducible in preliminary trials (coefficient of variation 5.6 +/- 0.6%) and with NAC was enhanced by 26.3 +/- 9.1% (NAC 6.4 +/- 0.6 min vs. Con 5.3 +/- 0.7 min; P <0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue (P <0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC (P <0.001). Muscle TGSH (P <0.05) declined and muscle GSH tended to decline (P=0.06) during exercise. Both were greater with NAC (P <0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise (P <0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained individuals, with enhanced muscle cysteine and GSH availability a likely mechanism.
Acetylcysteine↗
Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV.
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Algorithms↗
Use of an enzyme-linked immunosorbent assay to diagnose avian tuberculosis in a captive collection of wildfowl.
The current study assessed the diagnostic accuracy of an enzyme-linked immunosorbent assay (ELISA) and evaluated it as a diagnostic screening aid for avian tuberculosis (TB) in a wildfowl collection at the Wildfowl and Wetlands Trust Centre at Llanelli, Wales, U.K.. Four hundred and eighteen birds of the collection, including geese, ducks, and swans, were screened for mycobacterial antibody levels. Of those birds tested, 40 died during the period of this study and gross post mortem examinations were performed. The ELISA showed a sensitivity of 76.9% and a specificity of 55.6% using post-mortem findings as the 'gold standard'. Thirteen of the examined birds showed evidence of avian TB at necropsy. In addition, liver and spleen biopsies of 19 birds were examined histopathologically. There was minimal agreement between gross post mortem and histopathological findings. PCR performed on 13 of the specimens prepared for histopathology did not identify the presence of mycobacterial DNA. The findings reveal a need for further research to improve the sensitivity and specificity of this ELISA and the accurate diagnosis of avian TB.
Animals↗
Greater inotropic and cyclic AMP responses evoked by noradrenaline through Arg389 beta 1-adrenoceptors versus Gly389 beta 1-adrenoceptors in isolated human atrial myocardium.
1. We studied the biochemical and contractile responses of isolated human myocardial tissue expressing native receptor variants of the 389G>R beta(1)-adrenoceptor polymorphism. 2. Right atrial appendage was obtained from homozygous RR patients (n=37) and homozygous GG patients (n=17) undergoing elective cardiac surgery. The positive inotropic effect of noradrenaline in these tissues, mediated through beta(1)-adrenoceptors, was studied using electrically stimulated (1 Hz) atrial strips, as well as the effects of noradrenaline on cyclic AMP levels and cyclic AMP-dependent protein kinase. 3. Tissue from RR homozygotes (n=14) showed significantly increased inotropic potency to noradrenaline (-log EC(50), M=6.92+/-0.12) compared to GG homozygotes (n=8, -log EC(50), M=6.36+/-0.11, P<0.005). This difference was not dependent on tissue basal force. 4. Tissue cyclic AMP levels (pmol mg(-1)) were also greater in RR homozygotes (basal 34.8+/-3.7 n=12, 300 nM noradrenaline 41.4+/-7.6 n=9, 30 micro M noradrenaline 45.2+/-3.2 n=22, 0.2 mM isoprenaline 48.3+/-4.2 n=16) compared to GG homozygotes (basal 30.7+/-4.4 n=5, 300 nM noradrenaline 32.6+/-6.92 n=5, 30 micro M noradrenaline 38.1+/-3.1 n=8, 0.2 mM isoprenaline 42.6+/-5.2 n=6, P=0.007). There were no differences between the variants in terms of cyclic AMP-dependent protein kinase activity. 5. These data provide the first evidence that enhanced G-protein coupling of the R389 beta(1)-adrenoceptor variant reported in rodent fibroblast expression systems is also present in native human receptors. The functional consequence of this is to significantly alter the inotropic potency of beta(1)-adrenoceptor activation depending on its genotype at the 389 position.
Adrenergic beta-1 Receptor Agonists↗
Better blood pressure control: how to combine drugs.
Prospective comparisons of different drug classes have shown that differences in blood pressure control, rather than differences between drug classes, have the over-riding influence on overall outcome. The same studies have also reinforced the need, in the majority of patients, to use combinations of drugs in order to achieve the target of <140/85 mmHg. By contrast, most patients in routine practice receive single agents and consequently fail to achieve target blood pressure. This failure reflects in part the emphasis in individual studies and subsequent guidelines on comparison of individual drugs. In this article we show how the consistency of both theory and a broad range of evidence permits a didactic approach to combination therapy. Our advice is based on the growing recognition that essential hypertension and its treatment fall into two main categories. Younger Caucasians usually have renin-dependent hypertension that responds well to angiotensin-converting-enzyme inhibition or angiotensin receptor blockade (A) or ss blockade (B). Most other patients have low-renin hypertension that responds better to calcium channel blockade (C) or diuretics (D). These latter drugs activate the renin system rendering patients responsive to the addition of renin suppressive therapy. Coincidence of the initials of these main drug classes with the first four letters of the alphabet permits an AB/CD rule, according to which recommended combinations are one drug from each of the "AB" and "CD" categories of drugs. However, the diabetogenic potential of the older "B" and "D" classes leads us to advise against combining "B" and "D" in older patients, and to recommend "A" + "C" + "D" as standard triple therapy for resistant hypertension.
Antihypertensive Agents↗
The methylerythritol phosphate pathway and its significance as a novel drug target.
Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are the precursors for all isoprenoid compounds. Two pathways are found in Nature for their biosynthesis. The mevalonate (MVA) pathway is found in eukaryotes, algae, archae and some gram-positive bacteria. Gram-negative bacteria, plants and some gram-positive bacteria utilize the methyl erythritol phosphate (MEP) pathway. The distribution and the orthogonal nature of the pathways make the MEP pathway an attractive new target for antibiotics and herbicides. The MEP pathway is essential for bacterial viability. Inhibitors to the MEP pathway represent a "dual-use technology" because potential targets include potential biological warfare agents in addition to common human pathogens. The CDC has three categories designated for Biological Diseases/Agents. Three of the six entities designated as the highest priority (Category A) are organisms that utilize, or appear to utilize, the MEP pathway. Among the 12 second highest priority agents (Category B) listed, 8 are organisms that appear to utilize the MEP pathway. Common human pathogens that can be targeted include the organisms responsible for peptic ulcers, tuberculosis, malaria, food safety threats, and sexually transmitted diseases. There is so far only one inhibitor reported that specifically blocks the MEP pathway and is being investigated clinically. This compound, fosmidomycin, has been shown to be somewhat effective in treating Plasmodium falciparum, the parasite responsible for malaria. We foresee that new MEP pathway inhibitors will open up an entirely new class of antibiotics. An MEP pathway intermediate has also been shown to be the most potent gammadelta T cell activator.
Animals↗
N-acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans.
Infusion of the antioxidant N-acetylcysteine (NAC) reduces fatigability in electrically evoked human muscle contraction, but due to reported adverse reactions, no studies have investigated NAC infusion effects during voluntary exercise in humans. We investigated whether a modified NAC-infusion protocol (125 mg. kg(-1). h(-1) for 15 min, then 25 mg. kg(-1). h(-1)) altered blood redox status and enhanced performance during intense, intermittent exercise. Eight untrained men participated in a counterbalanced, double-blind, crossover study in which they received NAC or saline (control) before and during cycling exercise, which comprised three 45-s bouts and a fourth bout that continued to fatigue, at 130% peak oxygen consumption. Arterialized venous blood was analyzed for glutathione status, hematology, and plasma electrolytes. NAC infusion induced no severe adverse reactions. Exercise decreased the reduced glutathione (P < 0.005) and increased oxidized glutathione concentrations (P < 0.005); NAC attenuated both effects (P < 0.05). NAC increased the rise in plasma K(+) concentration-to-work ratio (P < 0.05), indicating impaired K(+) regulation, although time to fatigue was unchanged (NAC 102 +/- 45 s; saline 107 +/- 53 s). Thus NAC infusion altered blood redox status during intense, intermittent exercise but did not attenuate fatigue.
Acetylcysteine↗
MRC/BHF Heart Protection Study.
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Antioxidants↗
Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study.
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Adrenergic beta-Antagonists↗
Evaluation of land use/land cover datasets for urban watershed modeling.
Land use/land cover (LULC) data are a vital component for nonpoint source pollution modeling. Most watershed hydrology and pollutant loading models use, in some capacity, LULC information to generate runoff and pollutant loading estimates. Simple equation methods predict runoff and pollutant loads using runoff coefficients or pollutant export coefficients that are often correlated to LULC type. Complex models use input variables and parameters to represent watershed characteristics and pollutant buildup and washoff rates as a function of LULC type. Whether using simple or complex models an accurate LULC dataset with an appropriate spatial resolution and level of detail is paramount for reliable predictions. The study presented in this paper compared and evaluated several LULC dataset sources for application in urban environmental modeling. The commonly used USGS LULC datasets have coarser spatial resolution and lower levels of classification than other LULC datasets. In addition, the USGS datasets do not accurately represent the land use in areas that have undergone significant land use change during the past two decades. We performed a watershed modeling analysis of three urban catchments in Los Angeles, California, USA to investigate the relative difference in average annual runoff volumes and total suspended solids (TSS) loads when using the USGS LULC dataset versus using a more detailed and current LULC dataset. When the two LULC datasets were aggregated to the same land use categories, the relative differences in predicted average annual runoff volumes and TSS loads from the three catchments were 8 to 14% and 13 to 40%, respectively. The relative differences did not have a predictable relationship with catchment size.
Cities↗
Noise exposure and hearing loss among student employees working in university entertainment venues.
OBJECTIVES: Most studies to date on sound levels in entertainment establishments have concentrated on exposure levels for the attending public, rather than employees who may be at greater risk of hearing loss. Of particular concern are young employees. The aim of this pilot study was to (i) estimate typical sound levels in different areas where amplified music was played, (ii) measure temporary threshold shift (TTS) and (iii) estimate the dependence of hearing threshold shifts on measured noise levels. METHODS: This study focused on students working part-time (up to 16 h/week) in music bars and discotheques in a university entertainment venue. All 28 staff were invited to participate in the study. Pre- and post-exposure audiometry was used to determine hearing threshold at both high and low frequencies. Personal dosemeters and static measurements were made to assess noise levels and frequency characteristics. A questionnaire was used to determine patterns of noise exposure and attitudes to noise levels and hearing loss. RESULTS: Of the 28 student employees working in the three areas, 14 (50%) agreed to take part in the study, giving 21 pre- and post-shift audiograms. The mean personal exposure levels for security staff were higher than those of bar staff, with both groups exceeding 90 dB(A). The maximum peak pressure reading for security staff was 124 dB. Although TTS values were moderate, they were found to be highly significant at both low and high frequencies and for both ears. Twenty-nine per cent of subjects showed permanent hearing loss of more than 30 dB at either low or high frequencies. The correlation between TTS and personal exposure was higher at 4 kHz than the low and high frequencies. CONCLUSIONS: Contemporary music may be an important yet little considered contributor to total personal noise exposure, especially amongst young employees. Employees need to be better informed of risks of hearing loss and the need to report changes in hearing acuity. Suggestions are made on strategies for improving the assessment of noise exposure in entertainment venues.
Adult↗
GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity.
Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK-3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competitive GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and beta-catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK-3 activity towards Tau and beta-catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and beta-catenin.
Adaptor Proteins, Signal Transducing↗
Meteorological simulations of boundary-layer structure during the 1996 Paso del Norte Ozone Study.
Meteorological simulations centered around the border cities of El Paso and Ciudad Juárez have been performed during an ozone episode that occurred on August 13, 1996 during the 1996 Paso del Norte Ozone Study field campaign. Simulations were performed using the HOTMAC boundary-layer meteorological model using a 1, 2, 4 and 8-km horizontal grid size nested mesh system. Investigation of the vertical structure and evolution of the atmospheric boundary layer for the August 12-14 time period is emphasized in this paper due to its suspected importance in precipitating the ozone episode [Sci Total Environ (2001)]. This period was characterized by a slowly-evolving high pressure system over the region, a persistent upper-level jet at 2500-3500 m above ground level (agl), deep daytime mixed layer heights of 3500 m depth and unusually deep nighttime stable layers extending up to 2500 m above the ground. The fact that the boundary-layer growth stalled on the morning of August 13 relative to that on August 12 has been suggested as a possible reason for the ozone episode on the 13th. In addition, relatively weak surface-level winds were measured on August 13. Using both model results and experimental data we hypothesize explanations for the slower mixed-layer growth on the morning of the 13th and the stronger surface-level winds found on the 12th and 14th.
Air Movements↗
Males of social insects can prevent queens from multiple mating.
During copulation, males of Bombus terrestris fill the queen's sexual tract with a mating plug after transferring their sperm. The sticky secretion is produced by the male's accessory glands and disappears within a couple of days. Experiments now show that the primary function of the plug is to reduce the subsequent mating probability of the queen. The plug is not efficient in preventing sperm migration into the spermatheca. Due to its low energetic value, the plug is also unlikely to serve as a nuptial gift. This type of male interference with female mating propensity has so far not been found in social insects. This finding could, at least tentatively, explain why females of B. terrestris may not be able to take advantage of the demonstrated benefits of multiple mating. Furthermore, such male interference could be a more general phenomenon in social insects, with obvious ramifications for the evolution of polyandry in this group.
Animals↗
Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin.
Chemokine-induced polarization of lymphocytes involves the rapid collapse of vimentin intermediate filaments (IFs) into an aggregate within the uropod. Little is known about the interactions of lymphocyte vimentin with other cytoskeletal elements. We demonstrate that human peripheral blood T lymphocytes express plectin, an IF-binding, cytoskeletal cross-linking protein. Plectin associates with a complex of structural proteins including vimentin, actin, fodrin, moesin, and lamin B in resting peripheral blood T lymphocytes. During chemokine-induced polarization, plectin redistributes to the uropod associated with vimentin and fodrin; their spatial distribution indicates that this vimentin-plectin-fodrin complex provides a continuous linkage from the nucleus (lamin B) to the cortical cytoskeleton. Overexpression of the plectin IF-binding domain in the T cell line Jurkat induces the perinuclear aggregation of vimentin IFs. Plectin is therefore likely to serve as an important organizer of the lymphocyte cytoskeleton and may regulate changes of lymphocyte cytoarchitecture during polarization and extravasation.
Actins↗