Tryptase mediates hyperresponsiveness in isolated guinea pig bronchi

Hyperresponsiveness of airway smooth muscle to allergens and environmental factors has long been associated with the pathophysiology of asthma. Tryptase, a serine protease of lung mast cells, has been implicated as one of the mediators involved in the induction of hyperresponsiveness. As a consequence, tryptase inhibitors have become the subject of study as potential novel therapeutic agents for asthma. Secretory leukocyte protease inhibitor (SLPI) is a naturally occurring protein of human airways which exhibits anti-tryptase activity. To assess the potential therapeutic utility of SLPI in asthma, its effects were evaluated using in vitro and ex vivo models of airway hyperresponsiveness and compared with the effects of the small molecule tryptase inhibitor APC-366. Our results demonstrate that SLPI inhibits tryptase-mediated hyperresponsiveness in vitro and attenuates the hyperresponsiveness observed in airway smooth muscle from antigen-sensitized animals subjected to antigen exposure. The small molecule tryptase inhibitor APC-366 has a similar inhibitory effect. Thus, tryptase appears to be a significant contributor to the development of hyperresponsiveness in these models. To the extent that tryptase contributes to the development and progression of asthma, SLPI may possess therapeutic potential in this disease setting.     

Polarization of Th-cell responses: a phylogenetic consequence of nonspecific immune defence?

CD4+ T helper (Th)-cell responses are polarized into Th1 and Th2 types. Here, Paul Garside and Allan McI. Mowat propose that this is an evolutionary consequence of the relationship between specific adaptive immunity, individual components of the nonspecific inflammatory response and different types of infection. This concept has important implications both for understanding protective immunity and for vaccine design and delivery.     

Peripheral benzodiazepine receptor expression on leukocytes and neutrophil function during anticonvulsant monotherapy

AIM: To gain a full understanding of the concept of equity and means of promoting and monitoring a more equitable healthservice. BACKGROUND: With previous policy decisions having sidelined equity, a new government is likely to wish to reverse this trend. ORIGINS OF INFORMATION: Government and expert opinion. DATA ANALYSIS: A critical approach to previous literature. KEY ISSUES: Equity is not a unitary concept and so it is explored and dissected using the framework of: Distribution of Resources, Access and Uptake of Healthcare, Standards and Outcomes of Healthcare, Health Status. Means of improving and monitoring equity in these four areas are suggested. CONCLUSIONS: There are a number of ways of considering the concept of equity and for any fruitful discussion to occur there needs to be an agreed working definition. Specific topics are discussed where equity is lacking and a plan of action is suggested which is likely to improve equity in the areas identified.     

ATP-diphosphophydrolase activity in rat heart tissue

Extracellular nucleotides interact with specific receptors on the cell surface and are locally metabolized by ecto-nucleotidases. Biochemical characterization of the ATPase and ADPase activities detected in rat heart sarcolemma, under conditions where mitochondrial ATPase and adenylate kinase were blocked, supports our proposal that both activities correspond to a single enzyme, known as ATP-diphosphohydrolase or apyrase. The physiological function of this enzyme could be dephosphorylation of the nucleotides present in the interstitial heart compartment acting together with 5'-nucleotidase. Both hydrolytic activities have similarities in: sarcolemma localization, bivalent metal ion dependence, optimum pH, effect of several amino acid residue modifiers, competitive inhibition of nucleotide analogs, and broad nucleoside di-and triphosphate specificity. The ATPase activity could not be separated from the ADPase either through isoelectrofocusing or electrophoresis under acid conditions.     

Susceptibility to atrial fibrillation: a study in an ovine model of pacing-induced early heart failure

INTRODUCTION: The development of susceptibility to atrial fibrillation (AF) is a common consequence of many forms of cardiovascular disease, especially heart failure. In this study we used a sheep model of pacing-induced stable early heart failure to describe, quantify, and relate the level of susceptibility to AF to changes in structural and electrophysiologic parameters. METHODS AND RESULTS: Epicardial electrodes were implanted on the atria and right ventricles of nine sheep. The AF threshold, atrial vulnerability period, atrial effective refractory period (ERP), and interatrial conduction time were examined during control and over a 6-week period of ventricular pacing at 190 beats/min. Left atrial (LA) area and left ventricular (LV) fractional shortening were monitored using echocardiography. There were significant increases in LA susceptibility to AF (P < 0.0003), LA area (P < 0.0002), and LA ERP400 (P < 0.0002). Rate of increase in LA area was related positively to AF susceptibility (P = 0.02) and inversely to LA ERP400 (P = 0.002). LV fractional shortening decreased to approximately 50% of control value (P < 0.00001). No changes were observed in right atrial electrophysiology. CONCLUSION: In this study, susceptibility (the ability of an extrastimulus to induce AF) was rigorously measured within a predetermined format. Significant relationships were found to exist between susceptibility, certain of the observed changes in atrial electrophysiology and structure.     

Effects of clorazepate, diazepam, and oxazepam on a laboratory measurement of aggression in men

The liver S9 head space vial equilibration technique is an in vitro alternative that holds promises for a satisfactory in vivo extrapolation of liver metabolism of volatile organic chemicals. The aim of this study was to investigate the suitability of this methodology for the extrapolation of in vitro metabolic data from rodent to man by allometry with the two highly metabolized organic solvents toluene and n-hexane as model substances. The calculated hepatic clearance of toluene in man from rodent liver S9 in this study was equal to the reported total body clearance of toluene in man, suggesting insignificant extrahepatic clearance of toluene in humans. The calculated hepatic clearance of n-hexane was less than the reported values of total body clearance of n-hexane in man, indicating an about 80% extrahepatic clearance of n-hexane in humans. Both results are in line with our present knowledge of the metabolism of the two organic solvents in man. Allometric scaling from rodent liver S9 head space incubations to in vivo metabolism of toluene and n-hexane in man thus seems promising and could be a method of choice for scaling of organic solvent metabolism in general.