Altered proton extrusion in cells adapted to growth at low extracellular pH

Coronary vasodilator and hemodynamic profiles of JTV-506, a newly synthesized 2,2-bis-methoxymethyl benzopyran-derivative potassium channel opener, were evaluated in conscious dogs. JTV-506 (2.5-10 microg/kg, i.v.) elicited dose-dependent increases in coronary blood flow (CBF) and heart rate (HR) but only slight changes in mean blood pressure (MBP). Other vasodilators such as levcromakalim, nicorandil, diltiazem, and nitroglycerin, when administered intravenously, elicited increases in CBF and HR and a decrease in MBP. When dosed orally JTV-506 (0.01-0.1 mg/kg), levcromakalim (0.01-0.1 mg/kg), nicorandil (1-10 mg/kg), and nifedipine (3-30 mg/kg) also elicited increases in CBF and HR and a decrease in MBP. JTV-506 caused a marked increase in CBF with slight changes in HR and MBP. In contrast to JTV-506, however, the changes caused by levcromakalim, nicorandil, and nifedipine were accompanied by a marked increase in HR and a marked decrease in MBP. These results suggest that the action of JTV-506 on hemodynamics is different from that of other vasodilators, including reference potassium channel openers, and that the profile of cardiovascular action of JTV-506 may be useful in the treatment of angina pectoris.     

Accelerated lung function decline in swine confinement workers

We conducted a longitudinal study to determine the annual rate decline in pulmonary function measurements in male swine confinement workers. For comparison, a grain farming group and a nonfarming rural-dwelling control group were also chosen for the longitudinal study. Two hundred seventeen swine confinement workers, 218 grain farmers, and 179 nonfarming control subjects had valid pulmonary function measurements at the baseline observation conducted in 1990 to 1991 and at the second observation conducted in 1994 to 1995. The swine confinement workers were younger (mean age=38.3+/-11.7 [SD] years) than the nonfarming control subjects (42.6+/-10.4 years) and the grain farmers (44.5+/-11.9 years). When stratified by age, nonfarming control subjects had the lowest mean annual rate decline in FEV1 and FVC in all age categories. The swine confinement workers had the largest annual rate decline in FEV1 and FVC, and this was most obvious in the middle age categories. After controlling for age, height, smoking, and baseline pulmonary function, swine confinement workers had excess annual decline of 26.1 mL in FEV1 (p=0.0005), 33.5 mL in FVC (p=0.0002), and 42.0 mL/s in forced expiratory flow between 25% and 75% of FVC (FEF[25-75%]) (p=0.02) over nonfarming control subjects. Grain farmers had excess annual decline of 16.4 mL in FEV1 (p=0.03), 26.7 mL in FVC (p=0.002), and 11.2 mL/s in FEF(25-75%) (p=0.38) over control subjects. These findings suggest that workers engaged in the swine industry and grain farmers appear prone to accelerated yearly losses in lung function and may therefore be at risk for the future development of chronic airflow limitation.     

Role of metabolism in ethyl carbamate-induced suppression of antibody response to sheep erythrocytes in female Balb/C mice

A possible role of metabolism by cytochrome P450 (P450) in ethyl carbamate-induced suppression of the antibody response to a T-cell-dependent antigen, sheep erythrocytes (SRBCs), was investigated in female Balb/C mice. When mice were treated with ethyl carbamate intraperitoneally for 14 consecutive days at 25, 50, 100, 200 and 400 mg/kg, the antibody response was significantly suppressed from 200 mg/kg. These doses also caused a decrease in thymus weight. An acute dosing of ethyl carbamate at 1 g/kg also caused not only a significant suppression of the antibody response, but also a decrease in thymus weight. The antibody response was most likely to be the IgM antibody response, which was demonstrated in a haemagglutination study. When mice were pretreated with phenobarbital (80 mg/kg) for 3 days to induce P450 enzymes, followed by administration of ethyl carbamate intraperitoneally for 7 consecutive days, the antibody response was more suppressed than in saline-pretreated controls. Moreover, a study using aminoacetonitrile, a P450 inhibitor, showed that the antibody response suppressed by ethyl carbamate was completely recovered by the inhibitor. The present results suggest that metabolism of ethyl carbamate by P450 may be the critical pathway to produce metabolites capable of suppressing the antibody response.     

Efficacy of taxol in the orpk mouse model of polycystic kidney disease

Studies on conscious Sprague-Dawley rats using intracerebral dialysis in live animals combined with high-performance liquid chromatography with electrochemical detection showed that administration of apomorphine into the nucleus accumbens decreased the levels of dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in the extracellular space of the dorsal striatum throughout the observation period and produced a transient reduction in the level of homovanillic acid in the dialysate from this structure. The studies demonstrated that reversible exclusion of the nucleus accumbens with procaine produced a transient increase in the levels of dopamine metabolites, without an increase in serotonin metabolites, in the extracellular space of the dorsal striatum. These results demonstrate that the nucleus accumbens affects dopamine metabolism in the striatum, this being mediated by the dopamine-reactive system in the nucleus accumbens.     

Increased levels of plasma cholesteryl ester hydroperoxides in patients with subarachnoid hemorrhage

The pathophysiology of subarachnoid hemorrhage (SAH) may involve free radical production and lipid peroxidation. We examined plasma levels of cholesteryl ester hydroperoxides (CEOOH) and antioxidants in 25 patients with SAH, and 10 neurologic controls with lacunar stroke. Patients with SAH had significantly increased plasma levels of CEOOH, which peaked on day 5 after the ictus. Concentrations of CEOOH were significantly increased, and ascorbic acid concentrations were significantly decreased in patients who developed vasospasm compared with patients without vasospasm. Increased levels of CEOOH were associated with increased mortality and correlated with clinical outcome scales. These results implicate oxidative stress in the pathogenesis of SAH and suggest that measurements of CEOOH in plasma may be useful both prognostically as well as in monitoring therapeutic interventions.     

Obesity, eating disorders and restrained eating: is leptin the missing link?

Prior to the general availability of Haemophilus influenzae type b vaccine in the Republic of Ireland, a two-year study of the epidemiology of invasive Haemophilus influenzae disease was carried out. Of 137 invasive strains of Haemophilus influenzae examined in a central laboratory, 94.2% were serotype b and 90.5% were biotype I. Seventeen percent of serotype b strains produced beta-lactamase, and 2.3% were resistant to both ampicillin and chloramphenicol. The majority of serotype b strains were electrophoretic types of the electrophoretic 12 clone family, principally 12.5. Meningitis was the most common infection caused by serotype b. The study data extend the current knowledge of strains of Haemophilus influenzae causing invasive disease in the Republic of Ireland.