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1 The therapeutic use of the antifungal drug amphotericin B (AmB) is limited due to severe side eects like glomerular vasoconstriction and risk of renal failure during AmB administration. As nitric oxide (NO) has substantial functions in renal autoregulation, we have determined the eects of AmB on endothelial constitutive NO synthase (ecNOS) expression and activity in human and rat endothelial cell cultures.2 AmB used at concentrations of 0.6 to 1.25 mg ml 71 led to increases in ecNOS mRNA and protein expression as well as NO production. This was the result of an increased ecNOS mRNA half-life. In contrast, incubation of cells with higher albeit subtoxic concentrations of AmB (2.5 ± 5.0 mg ml 71) resulted in a decrease or respectively in completely abolished ecNOS mRNA and protein expression with a strongly reduced or inhibited ecNOS activity, due to a decrease of ecNOS mRNA half-life. None of the AmB concentrations aected promoter activity as found with a reporter gene construct stably transfected into ECV304 cells. 3 Thus, our experiments show a concentration-dependent biphasic eect of AmB on expression and activity of ecNOS, an eect best explained by AmB in¯uencing ecNOS mRNA stability. In view of the known renal accumulation of this drug the results reported here could help to elucidate its renal toxicity.

Two patients with acute disseminated encephalomyelitis after repeated injection of extracts from several diVerent plants are described. There was no evidence of prior infection or vaccination. Both patients recovered rapidly after treatment with methylprednisolone. Acute disseminated encephalomyelitis should be considered a rare complication of parenteral therapy with herbal extracts. (J Neurol Neurosurg Psychiatry 2000;69:516-518)

Type I (insulin-dependent) diabetes is an immune-mediated disease [1,2] characterised by early leucocyte accumulation around and then infiltration of pancreatic islets [3], concomitant with a progressive destruction of insulin-producing beta cells [4]. The mechanisms leading to the accumulation of circulating leucocytes at the sites of pancreatic islets are poorly characterised. Prior to this accumulation, circulating mononuclear cells must extravasate, a process dependent on leucocyte interaction with the local endothelium [5,6].It has been postulated that malfunction of the vascular endothelium represents an early pathological Diabetologia (1999) 42: 457±464 A regulatory defect of constitutive no-synthase in islet endothelial cells correlates with probability of disease manifestation in BBdp rats Abstract Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is characterised by leucocyte infiltration of pancreatic islets and a progressive destruction of insulin-producing beta cells. As endothelial nitric oxide production is known to regulate adhesion molecule expression and leucocyte permeation, we examined the activity and expression of the constitutive nitric oxide synthase (ecNOS) of islet endothelial cells from prediabetic BBdp rats. Methods. Cultures of aortic endothelial cells and islet capillary endothelial cells were established from young normoglycaemic BBdp rats, Wistar rats and diabetes-resistant BBdr rats, all matched for age. Nitrite and citrulline production was measured in all culture supernatants as indicators for ecNOS activities. Expression of ecNOS mRNA was assessed by reverse transcription-polymerase chain reaction.Results. In contrast to those of the aorta, the Wistar rat islet derived endothelial cells exhibited a strong positive correlation of ecNOS activity with the culture medium glucose concentration but none of the BB rat-derived islet endothelial cells showed a similar glucose-responsiveness. Furthermore, at physiological as well as at increased glucose concentrations islet endothelia from all BBdp rats exhibited a considerable decrease in ecNOS activity by a factor of 3 to 6, indicating a specific dysfunction which is also found for the inducible nitric oxide synthase activity after cytokine challenge but effects were less (2.5 to 3 times) dramatic. In contrast, aorta endothelia from all rats exhibited identical ecNOS activities and no glucose responsiveness. We also found a correlation between ecNOS activities and ecNOS-mRNA expression and can exclude the involvement of the inducible isoform. Conclusion/interpretation. A reproducible and highly significant dysfunction of islet ecNOS expression and activity in young normoglycaemic BBdp rats, which strongly correlates with the probability for disease manifestation is shown. [Diabetologia (1999) 42: 457±464]