The present analysis provides an estimate of the average treatment effects of testosterone therapy in middle-aged men. Our findings are sufficiently strong to justify further interventional studies focused on alternative targets of androgenic treatment carrying more stringent clinical implications, in particular the cardiovascular, metabolic and neurological systems.

Overall, 656 subjects were evaluated: 284 were randomized to T, 284 to placebo (P) and 88 treated in cross-over. The median study length was 3 months (range 1-36 months). Our meta-analysis showed that in men with an average T level at baseline below 12 nmol/l, T treatment moderately improved the number of nocturnal erections, sexual thoughts and motivation, number of successful intercourses, scores of erectile function and overall sexual satisfaction, whereas T had no effect on erectile function in eugonadal men compared to placebo. Heterogeneity was explored by grouping studies according to the characteristics of the study population. A cut-off value of 10 nmol/l for the mean T of the study population failed to predict the effect of treatment, whereas the presence of risk factors for vasculogenic erectile dysfunction (ED), comorbidities and shorter evaluation periods were associated with greater treatment effects in the studies performed in hypogonadal, but not in eugonadal, men. Meta-regression analysis showed that the effects of T on erectile function, but not libido, were inversely related to the mean baseline T concentration. The meta-analysis of available studies indicates that T treatment might be useful for improving vasculogenic ED in selected subjects with low or low-normal T levels. The evidence for a beneficial effect of T treatment on erectile function should be tempered with the caveats that the effect tends to decline over time, is progressively smaller with increasing baseline T levels, and long-term safety data are not available. The present meta-analysis highlights the need, and pitfalls, for large-scale, long-term, randomized controlled trials to formally investigate the efficacy of T replacement in symptomatic middle-aged and elderly men with reduced T levels and ED.

Musculoskeletal aging is a major public health interesting and strain due to the significant demographic modifications in the population, and it is linked to high risk of falls, loss of autonomy in elderly individuals and institutionalization with small health outcomes. Thus, this pathological status is related to high morbidity and health care rates. Bone mass and muscle mass and strength increase during late adolescence and early adulthood but start to reduce noticeably from the fifth decade of life and are closely linked. Bone and muscle tissues were increasingly recognized, as endocrine target organs and endocrine organs themselves, interacting through paracrine and endocrine signals. During growth, bone mineral content closely correlates with muscle mass, and several evidences suggest that osteoporosis and sarcopenia present common pathophysiological factors and show the correlation between low bone mineral density and sarcopenia in both men and women. Then, sarcopenia and osteoporosis, typical features of aging, are often associated with each other and with the frailty syndrome. In particular, sarcopenia and osteoporosis are major contributors to disability and frailty and the common denominators are age-related chronic inflammation, changes in body composition and hormonal imbalance. Frailty syndrome is characterized by a reduced response to stress, triggering the decline of the physiological functioning of the various systems. Frailty syndrome, typical of the older people, is frequently associated with a reduction in the quality of life and mobility. Falls often are the basis of reduced mobility and ability to perform the common functions of daily life and the increase in the number of institutionalizations. Moreover, the reduction of muscle mass, associated with altered muscle composition, fat and fibrous infiltration and alterations in innervations, and the increase in fat mass, have a synergistic effect on the increase in cardiovascular risk. The aim of this review is to analyze the pathophysiological mechanisms underlying the frailty syndrome and its association with sarcopenia and osteoporosis, and investigate possible intervention measures.

Our results indicate that a subpopulation of obese patients has a significant low lumbar BMD than expected for age. Thus, a careful characterisation of skeletal metabolism might be useful in all obese individuals to avoid fragility fractures later in life.

SummaryThe role and function of PE_PGRS proteins of Mycobacterium tuberculosis (Mtb) remains elusive. In this study for the first time, Mtb isogenic mutants missing selected PE_PGRSs were used to investigate their role in the pathogenesis of tuberculosis (TB). We demonstrate that the Mtb DPE_PGRS30 mutant was impaired in its ability to colonize lung tissue and to cause tissue damage, specifically during the chronic steps of infection. Inactivation of PE_PGRS30 resulted in an attenuated phenotype in murine and human macrophages due to the inability of the Mtb mutant to inhibit phagosome-lysosome fusion. Using a series of functional deletion mutants of PE_ PGRS30 to complement Mtb DPE_PGRS30, we show that the unique C-terminal domain of the protein is not required for the full virulence. Interestingly, when Mycobacterium smegmatis recombinant strain expressing PE_PGRS30 was used to infect macrophages or mice in vivo, we observed enhanced cytotoxicity and cell death, and this effect was dependent upon the PGRS domain of the protein.Taken together these results indicate that PE_PGRS30 is necessary for the full virulence of Mtb and sufficient to induce cell death in host cells by the otherwise nonpathogenic species M. smegmatis, clearly demonstrating that PE_PGRS30 is an Mtb virulence factor.

Men with erectile dysfunction (ED) frequently have a disproportionate burden of comorbid vascular disorders including atherosclerotic disease. We investigated whether scheduled tadalafil is better than on-demand (OD) in improving endothelium-dependent vasodilatation of cavernous arteries in men with ED and whether this effect is also exerted on markers of endothelial function. We did an open-label, randomized, crossover study including 20 male outclinic patients aged 18 years or older (mean age 54 years) who had at least a 3-month history of ED of any severity or etiology. Tadalafil (20 mg) on alternate days (ADs) or OD was administered for 4 weeks. Primary end points were variations of basal inflow (peak systolic velocity (PSV)) and flow-mediated dilatation (FMD) of cavernous arteries compared with baseline at penile Duplex ultrasound. Secondary end points were variations of Q13-SIEDY scores regarding morning erections and of markers of endothelial function, that is, vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule, endothelin-1 (ET-1), insulin and C-reactive protein (CRP). PSVs and FMD were higher after AD treatment when compared with OD and baseline, respectively (P ¼ 0.0001), and improvements were maintained from 2 weeks after discontinuation (Po0.005). Patients receiving tadalafil AD experienced a significant improvement of morning erections as compared to AD treatment (Po0.0001); ET1, VCAM and CRP showed a robust decrease after chronic vs OD regimes (Po0.05), with concomitant increase in insulin levels (Po0.05), without any variation in blood pressure and other laboratory parameters. Chronic but not OD tadalafil improves endothelial function with sustained effects from its discontinuation. Chronic treatment also produces a dramatic increase in morning erections, which determines better oxygenation to the penis, thus providing a rationale for vascular rehabilitation.

During the last decades, obesity and osteoporosis have become important global health problems, and the belief that obesity is protective against osteoporosis has recently come into question. In fact, some recent epidemiologic and clinical studies have shown that a high level of fat mass might be a risk factor for osteoporosis and fragility fractures. Several potential mechanisms have been proposed to explain the complex relationship between adipose tissue and bone. Indeed, adipose tissue secretes various molecules, named adipokines, which are thought to have effects on metabolic, skeletal and cardiovascular systems. Moreover, fat tissue is one of the major sources of aromatase, an enzyme that synthesizes estrogens from androgen precursors, hormones that play a pivotal role in the maintenance of skeletal homeostasis, protecting against osteoporosis. Moreover, bone cells express several specific hormone receptors and recent observations have shown that bonederived factors, such as osteocalcin and osteopontin, affect body weight control and glucose homeostasis. Thus, the skeleton is considered an endocrine target organ and an endocrine organ itself, likely influencing other organs as well. Finally, adipocytes and osteoblasts originate from a common progenitor, a pluripotential mesenchymal stem cell, which has an equal propensity for differentiation into adipocytes or osteoblasts (or other lines) under the influence of several cell-derived transcription factors. This review will highlight recent insights into the relationship between fat and bone, evaluating both potential positive and negative influences between adipose and bone tissue. It will also focus on the hypothesis that osteoporosis might be considered the obesity of bone.

The belief that obesity is protective against osteoporosis has recently come into question. The latest epidemiologic and clinical studies have shown that a high level of fat mass might be a risk factor for osteoporosis and fragility fractures. Further, increasing evidence seems to indicate that different components of the metabolic syndrome, ie, hypertension, increased triglycerides, reduced high-density lipoprotein cholesterol, are also potential risk factors for the development of low bone mineral density and osteoporosis. This review considers both the older and more recent data in the literature in order to evaluate further the relationship between fat tissue and bone tissue.