Effect of platelet-activating factor on the electrophysiology of the human Fallopian tube: early mediation of embryo-maternal dialogue?

Platelet-activating factor (PAF) is produced by preimplantation embryos and may be involved in the earliest stages of embryo-maternal dialogue. This study explored the potential effects of PAF acting as a signalling agent on human Fallopian tubal epithelial cells grown as a polarized layer in primary culture. The response of the tubal epithelium was assessed in terms of the transepithelial potential difference and short-circuit current (I(scc)), which were recorded using a modified Ussing chamber. Resistance was calculated from the measurements of potential difference and I(scc). PAF (1.9 nmol to 1.9 micromol l(-1)) administered to the apical surface of the cells produced a marked, transient increase in both potential difference and I(scc) in a dose-dependent manner. The mode of action of PAF on the electrophysiological responses of human tubal epithelial cells was investigated. Blockers of Na(+), K(+) and voltage-operated Ca(2+) channels had little effect on PAF action. However, incubation of the epithelial cells in Cl(-)free medium or with a blocker of the Na(+)-K(+)-2Cl(-) cotransporter (Furosemide) reduced the effect of PAF. Blockade of chloride-bicarbonate channels with 4-acetamido-4'-iso-thiocyanostilbene-2.2'-disulphonic acid (SITS) reduced the effect of low doses of PAF only. These results indicate that PAF influences the movement of chloride ions across the tubal epithelial cell and is a candidate molecule for initial embryo-maternal dialogue.     

Intraoperative monitoring with stimulus-evoked electromyography during placement of iliosacral screws. An initial clinical study

Cells of the innate immune system secrete cytokines early in immune responses that guide maturing T helper (Th) cells along appropriate lineages. This study investigates the role of cytokine networks, bridging the innate and acquired immune systems, in the pathogenesis of an organ specific autoimmune disease. Experimental allergic encephalomyelitis (EAE), a demyelinating disease of the central nervous system, is widely used as an animal model for multiple sclerosis. We demonstrate that interleukin (IL)-12 is essential for the generation of the autoreactive Th1 cells that induce EAE, both in the presence and absence of interferon gamma. The disease-promoting effects of IL-12 are antagonized by IL-10 produced by an antigen nonspecific CD4+ T cell which, in turn, is regulated by the endogenous production of IL-12. This unique immunoregulatory circuit appears to play a critical role in controlling Th cell differentiation and provides a mechanism by which microbial triggers of the innate immune system can modulate autoimmune disease.     

Modulation of whole body protein metabolism, during and after exercise, by variation of dietary protein

The aim of this study was to investigate dietary protein-induced changes in whole body leucine turnover and oxidation and in skeletal muscle branched chain 2-oxo acid dehydrogenase (BCOADH) activity, at rest and during exercise. Postabsorptive subjects received a primed constant infusion of L-[1-13C,15N]leucine for 6 h, after previous consumption of a high- (HP; 1.8 g . kg-1 . day-1, n = 8) or a low-protein diet (LP; 0.7 g . kg-1 . day-1, n = 8) for 7 days. The subjects were studied at rest for 2 h, during 2-h exercise at 60% maximum oxygen consumption, then again for 2 h at rest. Exercise induced a doubling of both leucine oxidation from 20 micromol . kg-1 . h-1 and BCOADH percent activation from 7% in all subjects. Leucine oxidation was greater before (+46%) and during (+40%, P < 0.05) the first hour of exercise in subjects consuming the HP rather than the LP diet, but there was no additional change in muscle BCOADH activity. The results suggest that leucine oxidation was increased by previous ingestion of an HP diet, attributable to an increase in leucine availability rather than to a stimulation of the skeletal muscle BCOADH activity.     

Determination of aspirin and salicylic acid in transdermal perfusates

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of aspirin and salicylic acid in transdermal perfusates. The compounds were separated on a C8 Nucleosil column (5 microm, 250x4.6 mm) using a mobile phase containing a mixture of water-acetonitrile-orthophosphoric acid (650:350:2, v/v/v) and a flow-rate of 1 ml/min. The transdermal samples were in phosphate-buffered saline (PBS) and could be injected directly onto the HPLC system. The method was reproducible with inter-day R.S.D. values of no greater than 3.46 and 2.60% for aspirin and salicylic acid, respectively. The method was linear over the concentration range 0.2-5.0 microg/ml and had a limit of detection of 0.05 microg/ml for both compounds. For certain samples, it was necessary to ensure that no transmembrane leakage of the aspirin prodrugs had occurred. In these cases, a gradient was introduced by increasing the acetonitrile content of the mobile phase after the salicylic acid had eluted. The method has been applied to the determination of aspirin and salicylic acid in PBS following in vitro application of the compounds to mouse skin samples.     

Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study

A 16-week, double-blind, placebo controlled, dose titration study was done on 100 normotensive patients age 45 years or older to determine the efficacy and safety of doxazosin, a selective alpha 1-adrenoceptor antagonist, in the treatment of benign prostatic hyperplasia (BPH). Of the 41 efficacy evaluable patients 88% underwent dose titration to a maximum of 8 mg. doxazosin once daily. Maximum and average urinary flow rates increased significantly above baseline with doxazosin (2.9 ml. per second and 1.4 ml. per second, respectively) compared with placebo (0.7 ml. per second and 0.3 ml. per second, respectively). A significant effect on maximum flow rate was noted as early as week 2 of double-blind treatment at the initial efficacy evaluation. Doxazosin was superior to placebo in patient and investigator assessments of total, obstructive and irritative BPH symptoms. The onset of efficacy for total patient-assessed symptoms was significant for doxazosin compared to placebo 4 weeks after the start of the treatment regimen. Statistically significant decreases in mean blood pressure of 4 to 6 mm. Hg were noted with doxazosin compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 44% of patients given doxazosin and 30% of those given placebo. Our results strongly demonstrate that doxazosin is significantly superior to placebo in the treatment of BPH in normotensive patients, with the patient experiencing significant relief early after initiation of therapy.     

Inhibitory effects of Estracyt on R-3327 rat prostatic carcinoma

Estracyt (estramustine phosphate) injected intraperitoneally, 100 mg, per Kg. three days a week for four weeks, retarded growth of the R-3327 tumor in intact rats and in orchiectomized rats given androgen. The growth inhibition was accomplished by reduction of tumor deoxyribonucleic acid concentration and of the activities of acid phosphatase, leucine aminopeptidase, and other hydrolases. Histologic examination revealed cellular necrosis particularly prominent in the orchiectomized, androgen-treated rats. Estracyt did not affect the uptake of 65-Zn in the tumors but markedly reduced the high uptake in the dorsolateral prostate. There was no accumulation of 3H or 14C in the tumors after intravenous administration of 3H, 14C-labeled Estracyt, but the isotope concentrations decreased much in the same way as they decreased in the dorsolateral prostate. The isotopes were retained in the ventral prostate, where their concentrations were approximately twenty times higher than those in the muscle four hours after injection. The results demonstrate the value of the R-3327 tumor in the evaluation of drugs of potential clinical use for the treatment of prostatic cancer. The results also show that Estracyt has an antitumor effect which is not dependent on the antigonadotropic action of the drug.