Changes in plasma renin activity in cirrhosis: a reappraisal based on studies in 67 patients and "low-renin" cirrhosis.

The generally held views that plasma renin activity (PRA) is increased in cirrhosis and that this is secondary to reductions in the "effective" blood or extracellular fluid (ECF) volumes, consequent on the effects of portal hypertension, were re-examined in the present study. Measurements of PRA in 67 patients representing different clinical stages of cirrhosis showed that the mean value in 15 patients without ascites was significantly reduced. In 21 of 35 with ascites, PRA was either reduced or within the normal range. A low plasma renin substrate concentration was not the cause for the low PRA. These findings are not in keeping with the concepts of reduced "effective" blood or ECF volumes at least for the majority of patients at these stages of cirrhosis under the conditions of the present study. The only group showing a significantly increased PRA had evidence of renal impairment. In these 17 patients the underlying reduction in renal perfusion may have been the stimulus to the kidney that led to an increase to renin secretion.

The preclinical pharmacology of "Arimidex" (anastrozole; ZD1033)--a potent, selective aromatase inhibitor.

Anastrozole is a comparatively simple, achiral benzyltriazole derivative, 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-++ +methylpropiononitrile), that inhibits human placental aromatase with an IC50 of 15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and androstenedione-induced uterine hypertrophy) and monkeys (lowering of plasma oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose, does not affect plasma aldosterone levels or Na+/K+ excretion in rats, plasma K+ concentrations in dogs, or cause adrenal hypertrophy in rats or dogs. It therefore has no discernible effect on adrenocorticoid hormone synthesis in vivo at very large multiples of its maximally effective aromatase-inhibiting dose. At similar large multiples in rats it displays no oestrogenic, anti-oestrogenic, androgenic, anti-androgenic, progestogenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity. Anastrozole is thus a potent and highly selective aromatase inhibitor, with no intrinsic hormonal activities--a pharmacological profile particularly suitable for the treatment of breast cancer.

Passive protection of piglets by monoclonal antibodies against experimental infection with Actinobacillus pleuropneumoniae.

Mouse monoclonal antibodies 11C11 (an IgG) and 4A9 (an IgM), which combine with a superficial component of cells belonging, respectively, to serovars 1 or 3 of Actinobacillus pleuropneumoniae, were given intraperitoneally 24 hours before and intranasally one hour before two-week-old, colostrum-deprived piglets were exposed by the intranasal route to 10(9) viable cells of either strain Shope 4074 (serovar 1) or 2/10 (serovar 3). Compared with control piglets given phosphate buffered saline or the heterologous monoclonal antibody, this procedure conferred substantial protection against the development of peracute or acute pleuropneumonia. Protection against the experimental disease was somewhat less in other piglets to which monoclonal antibody 4A9 was given only by the intranasal route one hour before the organism was administered than in those given the antibody intraperitoneally 24 hours beforehand, although its effect was still significantly greater than in piglets given phosphate buffered saline only. These two monoclonal antibodies consequently offer means of investigating at the molecular level the pathogenesis of the disease associated with A pleuropneumoniae and the potential value of anti-idiotypes as immunising agents.

The effects on rat thyroid function of an hepatic microsomal enzyme inducer.

1. Following daily administration to male albino rats for 2 weeks, beta-naphthoflavone (25 and 60 mg kg-1, i.p.) and phenobarbitone (100 mg kg-1, p.o.) produced their characteristic patterns of induction of P450-related enzyme activities. beta-naphthoflavone also induced p-nitrophenol glucuronidation by 160% over controls, while phenobarbitone produced only a 45% induction of this conjugation activity. 2. beta-Naphthoflavone produced significant reductions in plasma thyroxine (T4) concentrations on days 4 and 16 and also decreased tri-iodothyronine (T3) on day 4. Thyroid-stimulating hormone (TSH) was significantly increased on day 16 by the higher dose of beta-naphthoflavone. Thyroid weight was significantly increased at both dose levels on day 16 and liver weight was significantly increased on both days 4 and 16. No histopathological changes were seen in the liver or pituitary, but 30% of the animals showed minimal to mild follicular epithelial hypertrophy of the thyroid gland. 3. Phenobarbitone had no effect on T4 concentrations, but significantly decreased T3 on day 4. TSH increased by 60% on day 16, but was not statistically significantly compared with controls. Thyroid weight was significantly increased on day 16 and liver weight was significantly increased on days 4 and 16. Mild to moderate thyroid follicular epithelial hypertrophy and moderate hepatocyte hypertrophy occurred in all animals. No histopathological changes were seen in the pituitary. 4. The early changes in T4 and/or T3 were probably due to increased hepatic clearance by induction of thyroxine glucuronidation with both compounds. Thyroid hypertrophy would be expected to follow as a result of activation of the hypothalamic-pituitary-thyroid axis.(ABSTRACT TRUNCATED AT 250 WORDS)

1H-NMR spectroscopy as a means of monitoring nephrotoxicity as exemplified by studies with cephaloridine.

1. Male albino rats were dosed intravenously with either 0.9% saline or cephaloridine in saline at doses of 650, 750 or 950 mg kg-1 d-1 for 7 d. 2. Urine analysis on day 3, after two doses of cephaloridine showed dose-related increases in glucose, total protein, N-acetyl beta-D-glucosaminidase, gamma-glutamyltranspeptidase, alkaline phosphatase and lactate dehydrogenase. 1H-NMR spectroscopy showed corresponding disturbed profiles of products of intermediary metabolism indicative of a disruption of renal function. 3. By day 6, after five doses of cephaloridine, analysis by both 1H-NMR and conventional methods showed that all indices had returned to normal. 1H-NMR was demonstrated to provide useful complementary information to conventional techniques on the time course of the onset of the nephrotoxicity and the recovery phase, and was at least as sensitive as conventional urine analysis.

Continuing education needs assessment in dentistry: the SNAP system.

Needs assessment has become an integral step in planning for continuing education. This article describes a computer-based needs assessment system that has been used successfully in planning continuing dental education in South Carolina. The Statewide Needs Assessment Program (SNAP) provides a general purpose system for collecting and analyzing continuing education needs data for large populations. Needs assessment data from 489 practicing dentists in South Carolina are presented and analyzed.