Endothelial modulation of vasoconstrictor responses to endothelin-1 in human placental stem villi small arteries.

1. The aim of this study was to assess the role of endothelial cells in the modulation of vasocontractile responses to endothelin-1 (ET-1) of human placental vasculature. 2. Isolated stem villi small arteries (diameter = 170-250 microns) were obtained from healthy parturients who underwent caesarean surgery during the 39th week of pregnancy for cephalo-pelvic disproportion. Isometric tension was measured in vascular rings mounted in a myograph system and challenged with ET-1 (10(-12) to 10(-6) M). 3. The vasocontractile response to ET-1 was significantly (P < 0.001) increased in endothelial-denuded (active tension = 1156 +/- 214 mN mm-1) as compared with endothelial-preserved vascular rings (active tension = 458 +/- 48 mN mm-1). This difference was significantly (P < 0.05) but only partly abolished by the NO synthase inhibitor N omega-nitro-L-arginine (L-NOARG, 10(-4) M). 4. In endothelial-preserved rings submaximally precontracted with 5-hydroxytryptamine (10(-6) M), ET-1 (10(-12) to 10(-9) M) induced dose-dependent relaxation (maximum relaxation = 70 +/- 7%) at 10(-9) M, which was followed, at higher doses (10(-8) to 10(-6) M), by a contraction. In contrast, no relaxation was seen in endothelial-denuded rings. The relaxation in rings with endothelium was significantly (P < 0.001) reduced by L-NOARG (10(-4) M. Moreover, it was totally abolished by combined pretreatment with L-NOARG (10(-4) M) and the sulphonylurea glibenclamide (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Calciphylaxis – a topical overview

'Calciphylaxis', a calcification syndrome associated with ischaemic cutaneous necrosis, is acquired naturally in humans in disease states. It is a life and limb-threatening complication, usually observed in patients with renal disease and secondary hyperparathyroidism, but known to occur in the absence of renal or parathyroid disease. The reported mortality rate, which ranges from 60-80%, relates to wound infection, sepsis and organ failure. It is a small-vessel vasculopathy, which is estimated to occur in about 4% of haemodialysis patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and eschar may be evident, particularly in the extremities. In addition to the clinical picture, a raised calcium phosphorous product, an elevated parathyroid hormone level, radiographic evidence of vessel and soft-tissue calcification and the finding of mural calcification affecting small arteries and arterioles on histopathology help to confirm the diagnosis of this entity which generally has a poor prognosis. A high index of suspicion and an active multidisciplinary management approach, with rigorous attention to wound care and prevention of sepsis, are vital in the management of these patients. In this overview, we discuss the pathophysiology, clinical features and associations, risk factors, diagnosis and management issues relating to calciphylaxis.     

Combined chemotherapy including rifabutin for rifampicin and isoniazid resistant pulmonary tuberculosis. G.E.T.I.M. (Group for the Study and Treatment of Resistant Mycobacterial Infection).

A prospective multicentre open study has been conducted in France in order to assess the efficacy and tolerability of an antimycobacterial regimen including rifabutin in the treatment of patients with pulmonary tuberculosis due to rifampicin and isoniazid resistant bacilli. Patients were treated with daily rifabutin (450-600 mg), associated with companion drugs to which the organisms remained susceptible; in most cases the regimen included a fluoroquinolone. The duration of treatment was initially scheduled for a minimum period of 12 months after sputum culture conversion. Thirty nine patients were enrolled, 23 of whom were treated for at least 12 months. Culture conversion was obtained at the end of the twelfth month in 14 out of 23 patients. Twenty one out of 39 patients experienced adverse events. These were, however, serious enough to discontinue treatment in only four patients. These results suggest that an antimycobacterial combination including rifabutin might contribute to the treatment of multi-resistant pulmonary tuberculosis.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.      

Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis

Lack of expression of the fragile X mental retardation protein (FMRP) results in mental retardation and macroorchidism, seen as the major pathological symptoms in fragile X patients. FMRP is a cytoplasmic RNA- binding protein which cosediments with the 60S ribosomal subunit. Recently, two proteins homologous to FMRP were discovered: FXR1 and FXR2. These novel proteins interact with FMRP and with each other and they are also associated with the 60S ribosomal subunit. Here, we studied the expression pattern of the three proteins in brain and testis by immunohistochemistry. In adult brain, FMR1, FXR1 and FXR2 proteins are coexpressed in the cytoplasm of specific differentiated neurons only. However, we observed a different expression pattern in fetal brain as well as in adult and fetal testis, suggesting independent functions for the three proteins in those tissues during embryonic development and adult life.