Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling

Background One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit. Methods To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone. Results We show that muscle of Ercc1(Delta/-) progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.14 mm(3) in untreated mice, cortical bone volume; 0.30 mm(3) in treated progeroid mice vs. 0.22 mm(3) in untreated mice). The onset of neurological abnormalities was delayed (by similar to 5 weeks) and their severity reduced, overall sustaining health without affecting lifespan. Conclusions This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.Peer reviewe

Semantics in active surveillance for men with localized prostate cancer - results of a modified Delphi consensus procedure

Active surveillance (AS) is broadly described as a management option for men with low-risk prostate cancer, but semantic heterogeneity exists in both the literature and in guidelines. To address this issue, a panel of leading prostate cancer specialists in the field of AS participated in a consensus-forming project using a modified Delphi method to reach international consensus on definitions of terms related to this management option. An iterative three-round sequence of online questionnaires designed to address 61 individual items was completed by each panel member. Consensus was considered to be reached if >= 70% of the experts agreed on a definition. To facilitate a common understanding among all experts involved and resolve potential ambiguities, a face-to-face consensus meeting was held between Delphi survey rounds two and three. Convenience sampling was used to construct the panel of experts. In total, 12 experts from Australia, France, Finland, Italy, the Netherlands, Japan, the UK, Canada and the USA participated. By the end of the Delphi process, formal consensus was achieved for 100% (n = 61) of the terms and a glossary was then developed. Agreement between international experts has been reached on relevant terms and subsequent definitions regarding AS for patients with localized prostate cancer. This standard terminology could support multidisciplinary communication, reduce the extent of variations in clinical practice and optimize clinical decision making.Peer reviewe

Psychometric Properties of the Chinese Version of the Perceived Stress Scale in Policewomen

BACKGROUND: The 10-item Perceived Stress Scale (PSS-10) is one of most widely used instruments to measure a global level of perceived stress in a range of clinical and research settings. This study was conducted to examine the psychometric properties of the Simplified Chinese version of the PSS-10 in policewomen. METHODOLOGY: A total of 240 policewomen were recruited in this study. The Simplified Chinese versions of the PSS-10, the Beck Depression Inventory Revised (BDI-II), and the Beck Anxiety Inventory (BAI) were administered to all participants, and 36 of the participants were re-tested two weeks after the initial testing. PRINCIPAL FINDINGS: The overall Cronbach's alpha was 0.86, and the test-retest reliability coefficient was 0.68. Exploratory Factor Analysis (EFA) yielded 2 factors with eigenvalues of 4.76 and 1.48, accounting for 62.41% of variance. Factor 1 consisted of 6 items representing "negative feelings"; whereas Factor 2 consisted of 4 items representing "positive feelings". The item loadings ranged from 0.72 to 0.83. The Confirmatory factor analysis (CFA) indicated a very good fit of this two-factor model to this sample. The PSS-10 significantly correlated with both BDI-II and BAI, indicating an acceptable concurrent validity. CONCLUSIONS: The Simplified Chinese version of the PSS-10 demonstrated adequate psychometric properties for evaluating stress levels. The results support its use among the Chinese population

Molecular, Cellular and Physiological Evidences for the Anorexigenic Actions of Nesfatin-1 in Goldfish

Nesfatin-1 is a recently discovered anorexigen encoded in the precursor peptide, nucleobindin-2 (NUCB2) in mammals. To date, nesfatin-1 has not been described in any non-mammalian species, although some information is available in the sequenced genomes of several species. Our objective was to characterize nesfatin-1 in fish.In the present study, we employed molecular, immunohistochemical, and physiological studies to characterize the structure, distribution, and appetite regulatory effects of nesfatin-1 in a non-mammalian vertebrate. A very high conservation in NUCB2 sequences, especially in the nesfatin-1 region was found in lower vertebrates. Abundant expression of NUCB2 mRNA was detected in several tissues including the brain and liver of goldfish. Nesfatin-1-like immunoreactive cells are present in the feeding regulatory nucleus of the hypothalamus and in the gastrointestinal tract of goldfish. Approximately 6-fold increase in NUCB2 mRNA levels was found in the liver after 7-day food-deprivation, and a similar increase was also found after short-term fasting. This points toward a possible liver specific role for NUCB2 in the control of metabolism during food-deprivation. Meanwhile, ∼2-fold increase at 1 and 3 h post-feeding and an ∼3-fold reduction after a 7-day food-deprivation was observed in NUCB2 mRNA in the goldfish hypothalamus. In vivo, a single intraperitoneal injection of the full-length native (goldfish; gf) nesfatin-1 at a dose of 50 ng/g body weight induced a 23% reduction of food intake one hour post-injection in goldfish. Furthermore, intracerebroventricular injection of gfnesfatin-1 at a dose of 5 ng/g body weight resulted in ∼50% reduction in food intake.Our results provide molecular, anatomical and functional evidences to support potential anorectic and metabolic roles for endogenous nesfatin-1 in goldfish. Collectively, we provide novel information on NUCB2 in non-mammals and an anorexigenic role for nesfatin-1 in goldfish