Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle.

Testosterone regulates energy metabolism and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. This study investigated the response of skeletal muscle to castration and testosterone replacement in 8-week-old male mice. Using microarray analyses of mRNA levels in gastrocnemius muscle, 91 genes were found to be negatively regulated by testosterone and 68 genes were positively regulated. The mRNA levels of the insulin signalling suppressor molecule Grb10 and the glycogen synthesis inhibitors, protein phosphatase inhibitor-1 and phosphorylase kinase-γ, were negatively regulated by testosterone. The insulin-sensitive glucose and amino acid transporters, Glut3 and SAT2, the lipodystrophy gene, Lpin1 and protein targeting to glycogen were positively regulated. These changes would be expected to increase nutrient availability and sensing within skeletal muscle, increase metabolic rate and carbohydrate utilization and promote glycogen accumulation. The observed positive regulation of atrogin-1 (Fbxo32) by testosterone could be explained by the phosphorylation of Akt and Foxo3a, as determined by Western blotting. Testosterone prevented the castration-induced increase in interleukin-1α, the decrease in interferon-γ and the atrophy of the levator ani muscle, which were all correlated with testosterone-regulated gene expression. These findings identify specific mechanisms by which testosterone may regulate skeletal muscle glucose and protein metabolism.

Safety of gadoversetamide in patients with acute and chronic myocardial infarction.

PURPOSE: To assess the safety data from two large, multicenter, phase 2 trials on the use of gadoversetamide (OptiMARK, Tyco Healthcare/Mallinckrodt, St. Louis, MO) as a contrast agent in delayed hyperenhancement magnetic resonance imaging (DE-MRI) in patients with acute and chronic myocardial infarction (MI). MATERIALS AND METHODS: The study population from both trials comprised 577 patients who were randomly assigned to one of four dose groups (0.05, 0.1, 0.2, or 0.3 mmol/kg) before undergoing DE-MRI. Safety evaluations included physical and electrocardiographic (ECG) examinations. Vital signs, laboratory values, adverse events (AE), and serious adverse events (SAE) were monitored before and after contrast administration. RESULTS: Of the 577 patients who received gadoversetamide, 124 (21.5%) reported a total of 164 AEs; most were mild (139 AEs; 84.8%) or moderate (25 AEs; 15.2%). ECG-related changes were the most frequent AE. Site investigators judged only eight AEs as likely related to gadoversetamide and only two of the eight as clinically relevant. Further evaluation suggested neither AE was related to gadoversetamide. Two SAEs were reported, but none was judged related to gadoversetamide by the site investigators. CONCLUSION: Gadoversetamide is safe for use in patients with acute or chronic MI up to a dose of 0.3 mmol/kg.

Comparison of screening questionnaires for the diagnosis of hypogonadism.

Three questionnaires, the St. Louis University Androgen Deficiency in Aging Male (ADAM), the Aging Male Survey (AMS) and the Massachusetts Male Aging Study (MMAS), have been developed as potential screening tools for hypogonadism in older males. We compared these questionnaires in 148 males aged 23-80 years using bioavailable testosterone as the "biochemical gold standard" for diagnosis of hypogonadism. The sensitivity for the ADAM was 97%, for the AMS 83% and the MMAS 60%. Specificity was 30% for the ADAM, 59% for the MMAS and 39% for AMS. Both bioavailable testosterone and the calculated free testosterone correlated significantly with a number of the individual questions. Total testosterone correlated poorly with most of the questions. In conclusion, the ADAM and AMS may be useful screening tools for hypogonadism across the adult lifespan, but both are relatively nonspecific.

Testosterone, aging and quality of life.

Testosterone levels decline over the lifespan. Many symptoms of hypogonadism are similar to age-related changes in older males. A small number of studies have suggested that some of these symptoms may be reversed by testosterone. Among them, one trial has suggested that decline in bioavailable testosterone may be related to the development of functional decline. Testosterone replacement during rehabilitation may improve functional outcomes and plays an important role in the maintenance of sexual related quality of life. The overall improvement in well-being and/or health-related quality of life in older males needs to be determined with large placebo-controlled trials. This is particularly important in view of the substantial placebo effect on aging symptomatology.

Frailty and the aging male.

Frailty occurs in aging males for a variety of reasons. It is less common in males than females. Diseases which are particularly associated with frailty are diabetes mellitus, atherosclerosis, anemia and chronic obstructive pulmonary disease. Insulin resistance syndrome plays a pathogenetic role in the "fat-frail" syndrome. Sarcopenia occurs predominantly because of hormone deficiency and cytokine excess. Pain and anorexia are also associated with frailty. Stem cell research represents a potential promise for the treatment of frailty.

First national survey on management strategies in non ST-elevation acute ischaemic syndromes in Argentina. Results of the STRATEG-SIA study.

AIMS: To assess the management strategies applied in non-ST elevation acute ischaemic syndromes in Argentina, the factors influencing the choice of treatment, and their relationship to short- and long-term (1 year) patient outcomes. METHODS AND RESULTS: We conducted a 1 month, prospective, population-based survey in 77 hospitals (all over the country). We recruited 492 patients (age 63.9+/-11.7 years, male sex 68.3%, and 59.8% acute ischaemic ECG changes). Subjects were stratified according to the AHCPR classification as: high risk 62.2%, intermediate 25.0% and low 12.8%. At 1 year, the rate of death or myocardial infarction according to risk category and invasive procedures employed were: high risk (angioplasty 5.4% vs coronary artery bypass grafting 12.1% vs medical treatment 17.2%; P=0.001), intermediate risk (angioplasty 5.7% vs coronary artery bypass grafting 12.5% vs medical treatment 4.7%, P=ns), and low risk (angioplasty 10.0% vs coronary artery bypass grafting 15.2% vs medical treatment 1.9%; P<0.001). In the overall population, the 1 year event rate was not significantly different between the invasive and medical treatment groups (11.5% vs 7.2%, P=0.09). CONCLUSIONS: A routine, unselected invasive approach in non-ST elevation acute ischaemic syndromes in Argentina is associated with no apparent improvement of patients' outcome.