A 3-month randomized placebocontrolled trial I n men, an association between lower plasma total testosterone (PTT) and insulin resistance has been found in cross-sectional studies (1,2) and in one nested case-control study (3) without any possible conclusion in terms of causality or direction of the relationship. Indeed, to obtain such information, randomized controlled trials are needed. Until now, only one clinical trial has suggested that testosterone therapy improves insulin sensitivity in obese men (4). Crosssectional studies concerning leptin regulation by androgens have provided no definitive conclusions as to whether the negative association between androgens and leptin level is independent (5) or dependent (6). This randomized controlled trial was designed to assess the role of androgens on insulin sensitivity and leptin regulation in healthy adult men.This study was a randomized, double-blind, unicentric, controlled, clinical trial. Three treatments (testosterone, dihydrotestosterone [DHT], and placebo) were compared in parallel groups during a 3-month period. All of the examinations were performed by only two physicians, using a standardized protocol. Blood was drawn between 8:00 A.M. and 9:30 A.M. after an overnight fast to determine fasting plasma glucose, insulin, leptin, sex hormones, lipids, coagulation and fibrinolysis parameters, hepatic enzymes, and prostate-specific antigen (PSA) and blood cell count. Then, a standard 75-g oral glucose tolerance test and a digital rectal examination were performed. In addition, between days 10 and 20, all of the subjects were monitored to measure sex hormones in order to adapt the treatment dose. The study protocol was approved by the Henri Mondor Hospital Ethics Committee. All of the included subjects gave written informed consent.Men with low levels of PTT (confirmed by two measurements) were selected from a large occupation-based population. The inclusion criteria were as follows: 1) either PTT Յ3.4 ng/ml [5th percentile value of PTT distribution in the 1,718 men of the TELECOM Study (7)] from 1985 to 1987 and Ͻ4.0 ng/ml (13th percentile value) from 1992 to 1993 (3) or PTT Ͻ4.0 ng/ml from 1992 to 1993 and Ͻ4.0 ng/ml a few days before inclusion; 2) no history of vascular thrombosis or ischemic heart disease; 3) no treatment by androgens, anti-androgens, and antidiabetic or antithrombotic drugs; 4) normal values of plasma prolactin, estradiol, and thyroxin; 5) no current prostatic disease and a normal PSA value. A total of 18 healthy men with stable low plasma androgens (Table 1) and a range of PTT from 1.4 to 3.7 ng/ml at baseline were included.The 18 selected men were randomly assigned to one of three treatment groups: testosterone, DHT, or placebo. The randomization code was known only to the study manager. Treatment was a gel administered every morning by percutaneous route. The daily dose during the first weeks was 125 mg for the testosterone and 35 mg for the DHT treatment groups. The adaptation of treatment doses between days 10 and 20 aimed at obtain...

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (؎ SD) dose of 0.06 ؎ 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy. (Blood.

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A procoagulant activity was found in the immature cells from patients with acute promyelocytic leukaemia. It was demonstrated that this activity was related to tissue factor. The protein component of tissue factor from brain extract was purified by Nemerson's technique and injected into rabbits to obtain anti-TF antibodies. Similar antibodies were produced against the promyelocyte extract. The anti-brain tissue factor antibodies neutralized the tissue factor activity of promyelocyte extract, and antibodies against immature cells were able to neutralize the tissue factor activity of human brain extract. In immunoprecipitation studies a reaction of partial identity appeared between one component of promyelocyte extract and one component of brain tissue factor. The data demonstrated that the promyelocyte procoagulant is antigenically related to brain tissue factor.

SummaryFour hundred fifty subjects were screened for the 1691 G → A mutation in the factor V gene. Two hundred ninety-seven patients were referred to us for unexplained thrombosis, 133 were family members of these patients and 20 were normal subjects. We studied the relationships between the mutation, resistance to APC and thrombosis. Among the 450 subjects tested, 65 belonging to 42 families were found to have the 1691 G → A mutation in one (n = 61) or both alleles (n = 4). The prevalence of the mutation in the thrombotic patients was 13%. Resistance to APC was tested for in 247 subjects not on anticoagulant treatment (4 homozygous and 44 heterozygous for the mutation, and 199 individuals without the mutation). Incomplete cosegregation of heterozygosity for the 1691 G → A mutation with APC resistance (APC-SR <2.4 or n-APC-SR <0.75) was observed, showing that the functional assay alone is insufficient for a firm diagnosis. In patients carrying the mutation, elevated levels of prothrombin fragment 1+2 and D-dimers pointed to increased thrombin generation in vivo. Clinical manifestations in the heterozygous subjects were very similar to those reported in heterozygous PC or PS deficiencies, but the first thrombotic event occurred later than in PC- or PS-deficient patients. Homozygosity for the factor V gene mutation appears to be a far more benign thrombotic disorder than homozygous PC and PS deficiencies.