Effect of magnesium therapy on nocturnal leg cramps: a systematic review of randomized controlled trials with meta-analysis using simulations

Background and objective. Nocturnal leg cramps (NLC) are common in primary care and may cause severe pain and sleep disturbance. We systematically reviewed the effectiveness of magnesium in treating NLC and the side-effect profile of magnesium compared to placebo. Methods. We searched Medline, Embase, Cochrane Library, ClinicalTrials.gov, the International Standard Randomised Controlled Trial Number and the International Clinical Trials Registry Platform registries until August 2012. All randomized controlled trials (RCTs) comparing magnesium therapy for NLC in adults with any other comparator were eligible. Two investigators independently selected, extracted data from and rated the risk of bias of relevant studies. To compensate for the heterogeneity in outcome measures, simulations were used to summarize the data. Results. Seven RCTs were included in the review (n = 361), all comparing magnesium to placebo. Three of these trials included only pregnant women. The difference in the median number of leg cramps per week between the placebo and the intervention groups was 0.345 (quantile 2.5%: −0.133, quantile 97.5%: 0.875). This difference was 0.807 (quantile 2.5%: 0.015, quantile 97.5%: 1.207) in the three studies involving only pregnant women and 0.362 (quantile 2.5%: −0.386, quantile 97.5%: 1.148) in the others. Overall gastrointestinal side effects were slightly more common with magnesium therapy than with placebo. The strength of this evidence was weak, mainly due to small study sizes and short follow-up. Conclusions. Magnesium therapy does not appear to be effective in the treatment of NLC in the general population, but may have a small effect in pregnant women. Further research using better designed RCTs is necessar

Rapidly evolving protointrons in Saccharomyces genomes revealed by a hungry spliceosome.

Introns are a prevalent feature of eukaryotic genomes, yet their origins and contributions to genome function and evolution remain mysterious. In budding yeast, repression of the highly transcribed intron-containing ribosomal protein genes (RPGs) globally increases splicing of non-RPG transcripts through reduced competition for the spliceosome. We show that under these "hungry spliceosome" conditions, splicing occurs at more than 150 previously unannotated locations we call protointrons that do not overlap known introns. Protointrons use a less constrained set of splice sites and branchpoints than standard introns, including in one case AT-AC in place of GT-AG. Protointrons are not conserved in all closely related species, suggesting that most are not under positive selection and are fated to disappear. Some are found in non-coding RNAs (e. g. CUTs and SUTs), where they may contribute to the creation of new genes. Others are found across boundaries between noncoding and coding sequences, or within coding sequences, where they offer pathways to the creation of new protein variants, or new regulatory controls for existing genes. We define protointrons as (1) nonconserved intron-like sequences that are (2) infrequently spliced, and importantly (3) are not currently understood to contribute to gene expression or regulation in the way that standard introns function. A very few protointrons in S. cerevisiae challenge this classification by their increased splicing frequency and potential function, consistent with the proposed evolutionary process of "intronization", whereby new standard introns are created. This snapshot of intron evolution highlights the important role of the spliceosome in the expansion of transcribed genomic sequence space, providing a pathway for the rare events that may lead to the birth of new eukaryotic genes and the refinement of existing gene function

Meta-analysis of cell therapy studies in heart failure and acute myocardial infarction

Heart failure (HF) is one of the leading causes of death worldwide and has reached epidemic proportions in most industrialized nations. Despite major improvements in the treatment and management of the disease, the prognosis for patients with HF remains poor with approximately only half of patients surviving for 5 years or longer after diagnosis. The poor prognosis of HF patients is in part because of irreparable damage to cardiac tissue and concomitant maladaptive changes associated with the disease. Cell-based therapies may have the potential to transform the treatment and prognosis of HF through regeneration or repair of damaged cardiac tissue. Accordingly, numerous phase I and II randomized clinical trials have tested the clinical benefits of cell transplant, mostly autologous bone marrow–derived mononuclear cells, in patients with HF, ischemic heart disease, and acute myocardial infarction. Although many of these trials were relatively small, meta-analyses of cell-based therapies have attempted to apply rigorous statistical methodology to assess the potential clinical benefits of the intervention. As a prelude to larger phase III trials, meta-analyses, therefore, remain the obvious means of evaluating the available clinical evidence. Here, we review the different meta-analyses of randomized clinical trials that evaluate the safety and potential beneficial effect of cell therapies in HF and acute myocardial infarction spanning nearly 2 decades since the first pioneering trials were conducted

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma.

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Tumors were pathologically confirmed through review of the first tumor resection (n = 97), local recurrence (n = 35), or distant metastasis (n = 1). A STAT6 immunostain showed nuclear expression in 132 cases. NAB2-STAT6 fusion was detected in 99 of 111 successfully tested tumors (89%) including the single STAT6 immunonegative tumor. Tumors were classified by CNS-G as grade 1 (n = 43), 2 (n = 41), or 3 (n = 49), and by ST-G as SFT (n = 84) or malignant SFT (n = 49). Necrosis was present in 16 cases (12%). On follow-up, 42 patients had at least one subsequent recurrence or metastasis (7 metastasis only, 33 recurrence only, 2 patients had both). Twenty-nine patients died. On univariate analysis, necrosis (p = 0.002), CNS-G (p = 0.01), and ST-G (p = 0.004) were associated with recurrence-free (RFS) but not overall survival (OS). NAB2-STAT6 fusion type was not significantly associated with RFS or OS, but was associated with phenotype. A modified ST-G incorporating necrosis showed higher correlation with RFS (p = 0.0006) and remained significant (p = 0.02) when considering only the primary tumors. From our data, mitotic rate and necrosis appear to stratify this family of tumors most accurately and could be incorporated in a future grading scheme

The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis

Introduction: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis. Methods: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls. Results: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05). Conclusions: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept

Performance of the ESC 0/1-h and 0/3-h Algorithm for the Rapid Identification of Myocardial Infarction Without ST-Elevation in Patients With Diabetes

Patients with diabetes mellitus (DM) have elevated levels of high-sensitivity cardiac troponin (hs-cTn). We investigated the diagnostic performance of the European Society of Cardiology (ESC) algorithms to rule out or rule in acute myocardial infarction (AMI) without ST-elevation in patients with DM.; We prospectively enrolled 3,681 patients with suspected AMI and stratified those by the presence of DM. The ESC 0/1-h and 0/3-h algorithms were used to calculate negative and positive predictive values (NPV, PPV). In addition, alternative cutoffs were calculated and externally validated in 2,895 patients.; In total, 563 patients (15.3%) had DM, and 137 (24.3%) of these had AMI. When the ESC 0/1-h algorithm was used, the NPV was comparable in patients with and without DM (absolute difference [AD] -1.50 [95% CI -5.95, 2.96]). In contrast, the ESC 0/3-h algorithm resulted in a significantly lower NPV in patients with DM (AD -2.27 [95% CI -4.47, -0.07]). The diagnostic performance for rule-in of AMI (PPV) was comparable in both groups: 0/1-h (AD 6.59 [95% CI -19.53, 6.35]) and 0/3-h (AD 1.03 [95% CI -7.63, 9.7]). Alternative cutoffs increased the PPV in both algorithms significantly, while improvements in NPV were only subtle.; Application of the ESC 0/1-h algorithm revealed comparable safety to rule out AMI comparing patients with and without DM, while this was not observed with the ESC 0/3-h algorithm. Although alternative cutoffs might be helpful, patients with DM remain a high-risk population in whom identification of AMI is challenging and who require careful clinical evaluation

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Measurement of the Omega_c Lifetime

We present the measurement of the lifetime of the Omega_c we have performed using three independent data samples from two different decay modes. Using a Sigma- beam of 340 GeV/c we have obtained clean signals for the Omega_c decaying into Xi- K- pi+ pi+ and Omega- pi+ pi- pi+, avoiding topological cuts normally used in charm analysis. The short but measurable lifetime of the Omega_c is demonstrated by a clear enhancement of the signals at short but finite decay lengths. Using a continuous maximum likelihood method we determined the lifetime to be tau(Omega_c) = 55 +13-11(stat) +18-23(syst) fs. This makes the Omega_c the shortest living weakly decaying particle observed so far. The short value of the lifetime confirms the predicted pattern of the charmed baryon lifetimes and demonstrates that the strong interaction plays a vital role in the lifetimes of charmed hadrons.Comment: 15 pages, including 7 figures; gzipped, uuencoded postscrip

Search for the exotic Ξ−−(1860)\Xi^{--}(1860) Resonance in 340GeV/c Σ−\Sigma^--Nucleus Interactions

We report on a high statistics search for the $\Xi^{--}(1860)$ resonance in $\Sigma^-$-nucleus collisions at 340GeV/c. No evidence for this resonance is found in our data sample which contains 676000 $\Xi^-$ candidates above background. For the decay channel $\Xi^{--}(1860) \to \Xi^-\pi^-$ and the kinematic range 0.15$<x_F<$0.9 we find a 3$\sigma$ upper limit for the production cross section of 3.1 and 3.5 $\mu$b per nucleon for reactions with carbon and copper, respectively.Comment: 5 pages, 4 figures, modification of ref. 43 and 4