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Background: BIBT 986 is a novel potent anticoagulant that dually inhibits Factors Xa and IIa. We hypothesized that BIBT 986 would dose-dependently decrease endotoxin-induced, tissue factor triggered coagulation activation. Hence it was the aim of the study to compare with placebo the anticoagulant activity of three dosages of BIBT 986 on parameters of coagulation, platelet activation and inflammation and to examine the safety of BIBT 986 in this setting. Methods: This study was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants were randomised to receive bolus primed continuous infusions of one of the three doses of BIBT 986 or placebo. All of them received a bolus infusion of 2ng/kg body weight lipopolysaccharide (LPS). Results: BIBT dose-dependently increased anti-Xa activity, activated partial thromboplastin time (APTT), ecarin clotting time (ECT), thrombin time (TT) and the international normalisation ratio (INR). Importantly, BIBT 986 dose-dependently blocked the LPS-induced coagulation as assessed by the in vivo markers of thrombin generation and action: BIBT 986 doses that prolonged APTT by 25% were already effective. The BIBT dose that prolonged APTT by 100%, completely suppressed the increase in prothrombin fragment (F1+2), thrombin-antithrombin complexes (TAT) and D-dimer. BIBT 986 had no influence on activation markers of inflammation, fibrinolysis, endothelial or platelet activation. Conclusion: Infusion of BIBT 986 was safe and well tolerated. BIBT 986 specifically and dose-dependently blocked LPS-induced, tissue factor trigger coagulation. When compared to different anticoagulants tested previously in this standardized model, BIBT 986 was more effective in suppressing thrombin generation (F1+2 levels) than standard doses of danaparoid, dalteparin or lepirudin. BIBT 986 represents the first drug of a new class of dual FXa and FIIa inhibitors, and displays high potency.

To establish the incidence of neuronal ceroid-lipofuscinoses (NCL) in Italy, we sent a questionnaire to all Neuropediatric and Child Neuropsychiatric Departments (answer rate 15/34 = 44%). Diagnoses were accepted only when based on firm clinical and/or electron microscopic criteria. We collected 58 cases born between 1966-1991 (2 infantile NCL, 37 late infantile NCL, and 19 juvenile NCL). The incidence was calculated only on patients born between 1974-1984. In this period, the incidence of overall NCL in the Italian population was calculated to be 0.56 per 100,000 live births (0.36 for late infantile NCL, and 0.20 for juvenile NCL). Our data show that infantile NCL is very rare in Italy, and that late infantile seems to be the most frequent form of NCL.

The relationship between HPRT deficiency and the devastating neurologic dysfunction in Lesch-Nyhan syndrome is still unknown. Different metabolic alterations have been found, mainly in the erythrocytes, which could suggest involvement of different metabolic pathways; one of the described alterations is the high NAD level reported in patients with partial or total HPRT deficiency.1 Whether NAD increase can contribute to the clinical features is not known, but due to the peculiar role played by this coenzyme, it is reasonable that its alteration may be reflected on various metabolic aspects. In order to understand the mechanisms causing NAD raised concentrations, we have looked for possible increase in the stability, which was demonstrated not to be altered in patient erythrocytes.2 Possible alterations of NAD synthesis were thus hypothesized and “in vitro” incorporation of NAD precursors by intact erythrocytes was studied, demonstrating altered regulation in patients with partial or total deficiency.3 In the present study we have assayed the enzyme activities of the so-called deamidated pathway, starting from nicotinic acid, i.e. nicotinate phosphoribosyl transferase (NAPRT), nicotinate mononucleotide adenylyltransferase (NAMN-AT) and NAD synthetase (NADs), in order to ascertain the involvement of the committed enzymes leading to NAD synthesis. The possible effect of endogenous compounds and the heat resistance of the enzyme activities in crude lysates has also been examined in controls and patients.

SummaryThrombin is a coagulation protease that activates platelets, endothelial cells, leukocytes and mesenchymal cells. Thrombin signaling is mediated at least in part by protease-activated receptors (PARs). As little is known about the in vivoregulation of PAR1, this study aimed to characterize the effects of systemic thrombin formation during human endotoxemia on the regulation of PAR1 and the associated responsiveness of human platelets to thrombin receptor activating peptide (TRAP). Endotoxin (2 ng/kg) was infused into 40 healthy men to study the regulation of PAR1 in systemic human inflammation. The SPAN12 antibody was used to determine the in vivoregulation of PAR1. To measure whether modulation of the PAR1 receptor may be associated with altered platelet reactivity, whole blood was stimulated with TRAP ex vivo. Thrombin generation was determined by prothrombin (F1+2) fragment. F1+2levels increased almost 9-fold from 0.5±0.1 nmol/L to 4.5±1.9 nmol/L at 4 h (p

The aim of the present study is to investigate further the ultrastructural skin patterns in five cases of late infantile ceroid-lipofuscinosis: two of these were classic forms, the others were variants. Ultrastructural examinations of skin biopsies revealed the presence of characteristic cytosomes; typical lipofuscin, consisting of osmiophilic granular materials, curvilinear bodies, and fingerprint bodies. Different ultrastructural profiles were found simultaneously in each case, without a significant prevalence of any specific one, and were often associated with lipid droplets. These inclusions were found in several epidermal and dermal cells. A different degree of involvement of the myelinated sheaths in the five cases was observed. This difference could be genetically determined or perhaps related to different stages of the disease. The findings demonstrate the involvement of clinically unaffected skin and confirm the relevance of electron microscopic studies in diagnosing these disorders. In fact, recognition of typical ultrastructural changes is a valuable diagnostic tool that can be used in supplementing clinical and electrophysiological examinations, especially when the metabolic error is unknown and no diagnostic biochemical assay is available.