Transthyretin (TTR) is a plasma homotetrameric protein implicated in fatal systemic amyloidoses. TTR tetramer dissociation precedes pathological TTR aggregation. Native state stabilizers are promising drugs to treat TTR amyloidoses. Here we repurpose tolcapone, an FDA-approved molecule for Parkinson's disease, as a potent TTR aggregation inhibitor. Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity. Crystal structures of tolcapone bound to wild-type TTR and to the V122I cardiomyopathy-associated variant show that it docks better into the TTR T4 pocket than tafamidis, so far the only drug on the market to treat TTR amyloidoses. These data indicate that tolcapone, already in clinical trials for familial amyloid polyneuropathy, is a strong candidate for therapeutic intervention in these diseases, including those affecting the central nervous system, for which no small-molecule therapy exists.

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Although some authors have reported clinical features of autonomic dysfunction in patients with malignant disease only a few systematic studies have been carried out. We have investigated the autonomic function of 48 patients with carcinoma or lymphoma by testing their cardiovascular reflexes, and compared their results with those of 62 healthy volunteers. Our patients showed a smaller increase in heart rate and a greater fall in blood pressure on standing up, as well as a smaller rise in blood pressure in response to contralateral handgrip. The study group showed a higher percentage of established sympathetic lesion (54.2% vs 27.4%, p: 0.008) and of atypical pattern of global autonomic function impairment (50% vs 24.2%, p: 0.03) than the control group. Our data suggest that patients with malignant disease suffer from a definite autonomic dysfunction.

An ischemic stroke (IS) group including 386 patients under 50 years old is analysed taking into account different etiological subgroups and comparing risk factors against a control group of 100 people. The series points out the presence of 66.1% patients included in the inconclusive-atherothrombosis group, of which 22.7% had defined criteria of atheromatosis, while 11.6% were diagnosed of lacunar infarct. 13.5% of cases were considered as cardiac origin embolisms, and 14.1% were affected of mitral valve prolapse. The migraine group includes 4.9% of the patients while 17.6% belong to the miscellaneous group. The comparison of each of these groups with the control group showed significant differences for family history of stroke, personal history of peripheral arteriopathy, tobacco, arterial hypertension and previous IS.

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