Impact of gender on the metabolism of apolipoprotein A-I in HDL subclasses LpAI and LpAI:AII in older subjects

The behavior of apolipoprotein (apo) A-I in lipoprotein (Lp) AI and LpAI:AII was studied in 11 postmenopausal females and 11 males matched for plasma triglyceride and total cholesterol levels. Subjects consumed a baseline diet [35% fat (14% saturated, 15% monounsaturated, and 7% polyunsaturated), 15% protein, 49% carbohydrate, and 147 mg cholesterol/1000 kcal] for 6 weeks before the start of the kinetic study. At the end of the diet period, using a primed-constant infusion of [5,5,5-2H3]leucine, residence times (RT) and secretion rates (SR) of apoA-I were determined in 2 subpopulations of high-density lipoprotein (HDL) particles, LpAI and LpAI:AII. Plasma total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations were similar in males and females. The mean plasma HDL cholesterol concentration in males (1.14 +/- 0.23 mmol/L; mean +/- SD) was lower than in females (1.42 +/- 0.18 mmol/L; P =. 0034). Similarly, the mean plasma concentration of apoA-I in males (130 +/- 21 mg/dL) was lower than that in females (150 +/- 19 mg/dL; P = .0421). The RT of apoA-I in either LpAI or LpAI:AII was similar between men and women. Despite the higher plasma apo A-I levels in female compared with male subjects, total apoA-I and apoA-I in LpAI and LpAI:AII pool sizes were similar between the two groups, attributable to the lower body weight of the female subjects. The mean SR of total apoA-I in males (8.5 +/- 2.7 mg.kg-1.d-1) was 22% lower than in females (10.9 +/- 2.3 mg.kg-1.d-1; P = .0389). The SR of both apoA-I in LpAI and LpAI:AII was lower in males than females, although the differences did not reach statistical significance. These data suggest that the difference observed in HDL cholesterol concentration between males and females is attributable to SR of apoA-I and not the catabolic rate.     

Alpha-tubulin missense mutations correlate with antimicrotubule drug resistance in Eleusine indica

The primary leaves of young barley seedlings contain two major, extracellular, acid-soluble proteins of ca. 22 and 23 kDa apparent molecular mass. These proteins disappeared from the intercellular washing fluid upon stress treatments that enhanced H2O2 levels and that induced resistance to subsequent challenge by the powdery mildew fungus Erysiphe graminis f. sp. hordei. A partial peptide sequence of the 22 kDa protein was determined, and a cDNA clone was isolated. The 22 kDa protein belongs the the group of germin-like proteins (GLPs) and was designated HvGLP1. Despite its similarity to germin, i.e. oxalate oxidase, no oxalate oxidase activity of HvGLP1 could be detected. The RNA and soluble protein of HvGLP1 was highly abundant in young leaves, less abundant in older leaves and absent in roots. HvGLP1 RNA oscillated with a circadian rhythm, the minimum and maximum of RNA abundance being at the end of the dark and light periods, respectively. Heat and H2O2 treatment as well as pathogen infection caused disappearance of HvGLP1 protein from the fraction of soluble proteins of the intercellular space. HvGLP1 protein could be re-solubilized from cell walls of heat- or H2O2-treated leaves by boiling in SDS suggesting non-covalent cross linking. Although a physiological role of HvGLP1 insolubilization is still open, the protein may serve as marker for oxidative stress in cereals.     

Angiotensin converting enzyme inhibition, AT1 receptor inhibition, and combination therapy with pacing induced heart failure: effects on left ventricular performance and regional blood flow patterns

BACKGROUND: AT1 receptor activation has been demonstrated to cause increased vascular resistance properties which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of ACE inhibition (ACEI) alone, AT1 receptor blockade alone and combined ACEI and AT1 receptor blockade on LV pump function, systemic hemodynamics and regional blood flow patterns in the normal state and with the development of pacing induced CHF, both at rest and with treadmill induced exercise. METHODS AND RESULTS: Pigs (25 kg) were instrumented in order to measure cardiac output (CO), systemic (SVR) and pulmonary vascular (PVR) resistance, neurohormonal system activity, and myocardial blood flow distribution in the conscious state and assigned to one of 4 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 7); (2) ACEI (benazeprilat, 3.75 mg/day) and pacing (n = 7); (3) AT1 receptor blockade (valsartan, 60 mg/day) and rapid pacing (n = 7); and (4) ACEI and AT1 receptor blockade (benazeprilat/valsartan, 1/60 mg/day, respectively) and pacing (n = 7). Measurements were obtained at rest and with treadmill exercise (15 degrees, 3 miles/h; 10 min) in the normal control state and after the completion of the treatment protocols. With rapid pacing, CO was reduced at rest and with exercise compared to controls. ACEI or AT1 blockade normalized CO at rest, but remained lower than control values with exercise. Combination therapy normalized CO both at rest and with exercise. Resting SVR in the CHF group was higher than controls and SVR fell to a similar degree with exercise; all treatment groups reduced resting SVR. With exercise, SVR was reduced from rapid pacing values in the ACEI and combination therapy groups. PVR increased by over 4-fold in the rapid pacing group both at rest and with exercise, and was reduced in all treatment groups. In the combination therapy group, PVR was similar to control values with exercise. Plasma catecholamines and endothelin levels were increased by over 3-fold with chronic rapid pacing, and were reduced in all treatment groups. In the combination therapy group, the relative increase in catecholamines and endothelin with exercise were significantly blunted when compared to rapid pacing only values. LV myocardial blood flow at rest was reduced in the rapid pacing only and monotherapy groups, but was normalized with combination therapy. CONCLUSION: These findings suggest that with developing CHF, combined ACE inhibition and AT1 receptor blockade improved vascular resistive properties and regional blood flow distribution to a greater degree than that of either treatment alone. Thus, combined ACEI and AT1 receptor blockade may provide unique benefits in the setting of CHF.     

Effect of computer-based alerts on the treatment and outcomes of hospitalized patients

BACKGROUND: Hospital computing systems play an important part in the communication of clinical information to physicians. We sought to determine whether computer-based alerts for hospitalized patients can affect physicians' behavior and improve patients' outcomes. METHODS: We performed a prospective time-series study to determine whether computerized alerts to physicians about rising creatinine levels in hospitalized patients receiving nephrotoxic or renally excreted medications led to more rapid adjustment or discontinuation of those medications, and to determine whether such alerts protected renal function. RESULTS: Laboratory data were observed for 20,228 hospitalizations, with documentation of 1573 events (instances of rising creatinine levels during treatment with a nephrotoxic or renally excreted drug). During the intervention period, doses were adjusted or medications discontinued an average of 21.6 hours sooner after such an event (P < .0001). For patients receiving nephrotoxic medications during the intervention period, the relative risk of serious renal impairment was 0.45 (95% confidence interval, 0.22 to 0.94) as compared with the control period, and the mean serum creatinine level was 14.1 mumol/L (0.16 mg/dL) lower on day 3 (P < .01) and 25.6 mumol/L (0.29 mg/dL) lower on day 7 (P < .05) after an event. Forty-four percent of physicians who responded to a questionnaire said that the alerts had been helpful in the care of their patients, whereas 28% found them annoying. Sixty-five percent wished to continue receiving alerts. CONCLUSIONS: Computer-based alerts regarding patients with rising creatinine levels affect physician behavior, prevent serious renal impairment, preserve renal function, and are accepted by clinicians.     

Cloning and functional expression analysis of the alpha subunit of mouse ATP synthase

The alpha subunit of the mitochondrial ATP synthase is part of the F1 enzymatic complex known to bind ADP, phosphate and ATP and is at the heart of the mitochondrial energy-producing mechanism. The mouse embryonal carcinoma variant of the alpha subunit cDNA was cloned and the complete nucleotide sequences of two different lengths of clones were determined. Two distinct polyadenylation sites in the cDNA sequence were detected and two sizes of mRNAs were confirmed by Northern blot hybridization. Two putative ATP-binding motifs - A and B, have been hypothesized for this enzyme based on previous NMR work on another ATP-binding enzyme, adenylate kinase. We have constructed four deletion mutants of the alpha subunit of the mouse F1-ATP synthase to examine the putative role of these domains. The resulting recombinant proteins were expressed and purified. Functional studies with the immobilized mutants proved the significance of both sites for ATP binding.     

Presentation of the intrasubject coefficient of variation for sample size planning in bioequivalence studies

Bioequivalence studies are generally performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. Unfortunately, this information is usually not presented in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. Thus, the essential information for sample size planning of future studies is not made available to other researchers. In order to overcome such shortcomings, the presentation of results from bioequivalence studies should routinely include the intrasubject coefficient of variation. For the relevant coefficients of variation, theoretical background together with modes of calculation and presentation are given in this communication with particular emphasis on the multiplicative model.