Beta-receptor sensitivity in autonomic failure.

We examined the cardiovascular, plasma norepinephrine (NE), and plasma renin (PRA) responses to isoproterenol infusion in patients with autonomic failure and in normal subjects. Slopes of the blood pressure response/dose relationships were more negative in patients with multiple system atrophy and pure autonomic failure (PAF) than in normal subjects, consistent with impaired baroreflex modulation. A shift to the left in patients with PAF suggests beta-adrenergic receptor supersensitivity. In normal subjects, the increase in plasma NE and PRA was proportional to the log of the plasma isoproterenol level. Isoproterenol infusion did not increase plasma NE or PRA in either patient group despite a reduction in mean blood pressure. Reflexive cardiovascular and renal mechanisms appear to play a role in eliciting the plasma NE and PRA responses to isoproterenol infusion in normal subjects.     

Antihypercholesterolemic studies with sterols: beta-sitosterol and stigmasterol.

Stigmasterol, which differs from beta-sitosterol by unsaturation at C22, was tested for antihypercholesterolemic activity under an experimental protocol that gave the results expected with beta-sitosterol and cholestyramine. In terms of serum cholesterol, stigmasterol had a barely significant antihypercholesterolemic effect while exhibiting no obvious effect on the heart or liver. It was concluded that saturation of the side chain, at least at C22, is important in conferring antihypercholesterolemic activity on a sterol.     

Reduced Ia-afferent-mediated Hoffman reflex in streptozotocin-induced diabetic rats

Familial amyloidotic polyneuropathy (FAP) is a late-onset inherited disease characterized by the deposition of amyloid fibrils. FAP is associated with mutations on the transthyretin (TTR) gene. A monoclonal antibody, MAb 39-44, reacting with high molecular weight aggregates of TTR but not with tetrameric TTR has recently been generated and characterized. This antibody recognizes a cryptic epitope that is expressed in isolated recombinant amyloidogenic mutants and in ex vivo amyloid. In the present work we show that this amyloid-specific antibody specifically recognizes in a direct enzyme-linked immunoassay (ELISA) plasma TTR from carriers of various mutations associated with FAP, both in asymptomatic individuals and in patients. In contrast, it does not react with plasma TTR from healthy individuals or that from carriers of nonpathogenic mutations. Using the ELISA developed in this study we identified three different TTR mutations in Portuguese patients with neuropathy of unknown cause, later shown to have amyloid tissue deposition. This antibody recognizes conformations that express cryptic epitopes shared by amyloidogenic TTR variants associated with FAP, not present among nonpathogenic TTR molecules. This antibody will contribute to further identify and characterize intermediates of the amyloidogenic cascade. In addition, it will also be useful for screening amyloidogenic TTR mutations in patients with neuropathy of unknown cause, prior to precise molecular diagnosis using protein and/or DNA analysis.     

Buccal absorption of ergotamine

The rate of disappearance of ergotamine from the mouth after buccal administration has been studied in seven subjects. Allowance has been made for non-absorptive losses of the drug due to experimental technique. The absorption of ergotamine across the buccal mucosa appears to be a passive process, pH-dependent but independent of ergotamine concentration or the simultaneous presence of caffeine. Because of the low solubility of ergotamine at the pH of saliva, it is unlikely that therapeutically useful amounts of the drug would have absorbed across the buccal mucosa even after the drug had been in the mouth for five minutes.     

Percutaneous dilation of benign biliary strictures

Percutaneous balloon dilation of benign biliary strictures was successful in 15 of 18 patients in whom the procedure was attempted. Successful dilation was achieved in nine of 11 patients who had biliary enteric strictures, with follow-up of 22-55 months (mean, 35.4 months) after catheter removal in seven patients. Five of six strictures in the biliary tree that developed after surgery were successfully dilated, with long-term follow-up available in two patients (58 and 42 months). A patient with an inflammatory common bile duct stricture that was successfully dilated was followed up for 18 months. Percutaneous dilation of biliary tract strictures is a promising technique with good long-term results and may be the initial treatment of choice in biliary stricture management.