Nuclear targeting of Akt enhances ventricular function and myocyte contractility

Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca2+-ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho-protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart.     

Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies

The objective of this study was to evaluate the effects of steroid anabolic androgenic hormones use on lean mass gain in elderly men through a systematic review with a meta-analysis of randomized controlled studies. We systematically searched PubMed database until 4th October 2013. We included randomized placebo-controlled trials (RCT) that studied testosterone replacement therapy in men over 60 years of age, with total testosterone levels ≤550 ng/dl, observing gains in weight, lean mass tissue and fat mass as outcome. We excluded duplicated studies, studies which mixed men and women, and studies using weak androgens such as dehydroepiandrosterone or androstenedione. The initial search yielded 2681 articles, of which 26 were selected for full text analysis. In the end, 11 studies were included. However, 3 studies were not included in the meta-analysis. Meta-analysis showed that mean weight increased (lean mass), ranging from 1.65 (95 % CI, 1.61–1.69) to 6.20 (95 % CI, 5.22–7.18) kg, although it was heterogeneous (I² = 98 %). Effect estimate was 3.59 [2.38–4.81]. Androgen therapy decreased fat mass; effect estimate was −1.78 [−2.57, −0.99] that analysis had also a high level of heterogeneity (I² = 81 %). The results suggest that testosterone replacement therapy is able to increase muscle mass in elderly men and that is affected by the time that the treatment is carried out and the method of administration of the drug.     

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA-DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well-characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA-DRB1*0801 in both groups of patients compared to population-specific healthy controls (12% versus 4% in the UK patients, P=.00087, OR=3.05; and 18% versus 6% in the Italian patients, P=.021, OR=3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P=.0071, OR=0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P=.042, OR=0.65 in the UK patients; and 10% versus 31%, P=.00092, OR=0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific.     

Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

Background  

Treatment strategies for Retinoblastoma (RB), the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K⁺ channels.     

Platelet-derived growth factors enhance proliferation of human stromal stem cells

Studies on new procedures for bone reconstruction suggest that autologous cells seeded on a resorbable scaffold can improve the treatment of bone defects. It is important to develop culture conditions for ex vivo expansion of stromal stem cells (SSC) that do not compromise their self-renewing and differentiation capability. Bone marrow SSC and platelet gel (PG) obtained by platelet-rich plasma provide an invaluable source for autologous progenitor cells and growth factors for bone reconstruction. In this study the effect of platelet-rich plasma (PRP) released by PG on SSC proliferation and differentiation was investigated. MTT assay was used to investigate the effect of PRP on proliferation: results showed that PRP induced SSC proliferation. The effect was dose dependent and 10% PRP is sufficient to induce a marked cell proliferation. Untreated cells served as controls. Upon treatment with 10% PRP, cells entered logarithmic growth. Removal of PRP restored the characteristic proliferation rate. Because SSC can gradually lose their capability to differentiate along the chondrogenic and osteogenic lineage during subculture in vitro, we tested whether 10% PRP treatment affected SSC ability to mineralize. SSC were first exposed to 10% PRP for five passages, at passage 6 PRP was washed away and plated cells were treated with dexamethasone (DEX). DEX induced a three-fold increase in the number of alkaline phosphatase positive cells and induced mineralization that is consistent with the differentiation of osteochondroprogenitor cells. In conclusion, 10% PRP promotes SSC proliferation; cells expanded with 10% PRP can mineralize the extracellular matrix once PRP is withdrawn.     

Preventative therapy in primary biliary cirrhosis

Because the etiology of PBC is still unknown, therapies remain empirical. Moreover, no contributions on preventative therapy supported by evidence-based medicine have been published to date. However, there are at least two groups of subjects who might benefit from preventative therapy: (1) subjects with normal liver enzymes who are found AMA-positive during autoantibody screening and (2) subjects transplanted for PBC with no histologic or biochemical signs of disease recurrence. The key questions are whether any therapy should be proposed to these subjects, since the natural history of the disease is very long, and what kind of treatment should be prescribed. UDCA is a well-tolerated, definitely "physiologic" treatment, but it is expensive and two recent meta-analyses question its benefit on survival. Current theory considers PBC an autoimmune disease, with a genetic predisposition, possibly triggered by an infectious agent or xenobiotic. If this is so, gene therapies might be the most promising future preventative therapies. For the time being, however, the only practical preventative management is in regards to the complications of PBC, namely osteopenia and portal hypertension.