Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis

Introduction/Aim: Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP). Methods: Patients with PPP in a double-blind, placebo-controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52-week open-label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity-weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies. Results: Sixty-three adults (age, 19-76 years) completed the double-blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity-weighted attack rates from baseline to week 61 (DCP/DCP [n = 25], −1.00 [P < .0001]; placebo/DCP [n = 20], −0.63 [P = .01] and DCP/DCP, −2.25 [P < .0001]; placebo/DCP, −1.69 [P = .01]). Relatively smaller median decreases in weekly attack and severity-weighted attack rates occurred from weeks 9 to 61 among patients receiving DCP continuously (n = 26; −0.14 [P = .1] and −0.24 [P = .09]) than among those switching from placebo to DCP after 9 weeks (n = 16; −1.04 [P = .049] and −2.72 [P = .08]). Common adverse events (AEs) were paresthesia and cognition-related events, which typically first occurred within 1 month of blinded treatment initiation and in rare cases led to treatment discontinuation. Dose reductions were frequently associated with common AE resolution. Discussion: One-year open-label DCP treatment after a 9-week randomized, controlled study confirmed long-term DCP remains safe and effective for chronic use. Tolerability issues (paresthesia, cognition-related AEs) were manageable in most patients

Guidelines on clinical presentation and management of non-dystrophic myotonias

The non‐dystrophic myotonias (NDMs) are rare muscle hyperexcitability disorders caused by gain‐of‐function mutations in the SCN4A gene or loss‐of‐function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography (EMG), and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance (VUS) if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications

Giant regular polyhedra from calixarene carboxylates and uranyl

Self-assembly of large multi-component systems is a common strategy for the bottom-up construction of discrete, well-defined, nanoscopic-sized cages. Icosahedral or pseudospherical viral capsids, built up from hundreds of identical proteins, constitute typical examples of the complexity attained by biological self-assembly. Chemical versions of the so-called 5 Platonic regular or 13 Archimedean semi-regular polyhedra are usually assembled combining molecular platforms with metals with commensurate coordination spheres. Here we report novel, self-assembled cages, using the conical-shaped carboxylic acid derivatives of calix[4]arene and calix[5]arene as ligands, and the uranyl cation UO22+ as a metallic counterpart, which coordinates with three carboxylates at the equatorial plane, giving rise to hexagonal bipyramidal architectures. As a result, octahedral and icosahedral anionic metallocages of nanoscopic dimensions are formed with an unusually small number of components

Transglutaminase 2 facilitates the distant hematogenous metastasis of breast cancer by modulating interleukin-6 in cancer cells

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Introduction Inflammation has been implicated in cancer aggressiveness. As transglutaminase 2 (TG2), which has been associated with inflammatory signaling, has been suggested to play a role in tumor behavior, we propose that TG2 may be an important linker inducing interleukin (IL)-6-mediated cancer-cell aggressiveness, including distant hematogenous metastasis. Methods To investigate the role for TG2 and IL-6, TG2-knocked-down and IL-6-knocked-down cancer cells were generated by using shRNA. Human breast cancer cell xenograft model in highly immunocompromised mice and human advanced breast cancer primary tumor tissue microarrays were used in this study. Results IL-6 production in human breast cancer cells was dependent on their TG2 expression level. In vitro tumor-sphere formation was dependent on TG2 and downstream IL-6 production from cancer cells. Primary tumor growth in the mammary fat pads and distant hematogenous metastasis into the lung was also dependent on TG2 and downstream IL-6 expression levels. The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years. TG2 expression in primary tumor tissue was inversely correlated with recurrence-free survival (P = 0.019) and distant metastasis-free survival (DMFS) (P = 0.006) in patients with advanced breast cancer. Furthermore, by using public datasets that included a total of 684 breast cancer patients, we found that the combined high expression of TG2 and IL-6 was associated with shorter DMFS, compared with the high expression of IL-6 only (P = 0.013). Conclusions We provide evidence that TG2 is an important link in IL-6-mediated tumor aggressiveness, and that TG2 could be an important mediator of distant metastasis, both in a xenograft animal model and in patients with advanced breast cancer

Unpredictability of metabolism—the key role of metabolomics science in combination with next-generation genome sequencing

Next-generation sequencing provides technologies which sequence whole prokaryotic and eukaryotic genomes in days, perform genome-wide association studies, chromatin immunoprecipitation followed by sequencing and RNA sequencing for transcriptome studies. An exponentially growing volume of sequence data can be anticipated, yet functional interpretation does not keep pace with the amount of data produced. In principle, these data contain all the secrets of living systems, the genotype–phenotype relationship. Firstly, it is possible to derive the structure and connectivity of the metabolic network from the genotype of an organism in the form of the stoichiometric matrix N. This is, however, static information. Strategies for genome-scale measurement, modelling and predicting of dynamic metabolic networks need to be applied. Consequently, metabolomics science—the quantitative measurement of metabolism in conjunction with metabolic modelling—is a key discipline for the functional interpretation of whole genomes and especially for testing the numerical predictions of metabolism based on genome-scale metabolic network models. In this context, a systematic equation is derived based on metabolomics covariance data and the genome-scale stoichiometric matrix which describes the genotype–phenotype relationship

A Multi-Center Randomized Trial to Assess the Efficacy of Gatifloxacin versus Ciprofloxacin for the Treatment of Shigellosis in Vietnamese Children

The bacterial genus Shigella is the most common cause of dysentery (diarrhea containing blood and/or mucus) and the disease is common in developing countries with limitations in sanitation. Children are most at risk of infection and frequently require hospitalization and antimicrobial therapy. The WHO currently recommends the fluoroquinolone, ciprofloxacin, for the treatment of childhood Shigella infections. In recent years there has been a sharp increase in the number of organisms that exhibit resistance to nalidixic acid (an antimicrobial related to ciprofloxacin), corresponding with reduced susceptibility to ciprofloxacin. We hypothesized that infections with Shigella strains that demonstrate resistance to nalidixic acid may prevent effective treatment with ciprofloxacin. We performed a randomized controlled trial to compare 3 day ciprofloxacin therapy with 3 days of gatifloxacin, a newer generation fluoroquinolone with greater activity than ciprofloxacin. We measured treatment failure and time to the cessation of individual disease symptoms in 249 children with dysentery treated with gatifloxacin and 245 treated with ciprofloxacin. We could identify no significant differences in treatment failure between the two groups or in time to the cessation of individual symptoms. We conclude that, in Vietnam, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute dysentery

A systematic review of clinical trials of pharmacological interventions for acute ischaemic stroke (1955-2008) that were completed, but not published in full

<p>Abstract</p> <p>Background</p> <p>We assessed the prevalence, and potential impact of, trials of pharmacological agents for acute stroke that were completed but not published in full. Failure to publish trial data is to be deprecated as it sets aside the altruism of participants' consent to be exposed to the risks of experimental interventions, potentially biases the assessment of the effects of therapies, and may lead to premature discontinuation of research into promising treatments.</p> <p>Methods</p> <p>We searched the Cochrane Stroke Group's Specialised Register of Trials in June 2008 for completed trials of pharmacological interventions for acute ischaemic stroke, and searched MEDLINE and EMBASE (January 2007 - March 2009) for references to recent full publications. We assessed trial completion status from trial reports, online trials registers and correspondence with experts.</p> <p>Results</p> <p>We identified 940 trials. Of these, 125 (19.6%, 95% confidence interval 16.5-22.6) were completed but not published in full by the point prevalence date. They included 16,058 participants (16 trials had over 300 participants each) and tested 89 different interventions. Twenty-two trials with a total of 4,251 participants reported the number of deaths. In these trials, 636/4251 (15.0%) died.</p> <p>Conclusions</p> <p>Our data suggest that, at the point prevalence date, a substantial body of evidence that was of relevance both to clinical practice in acute stroke and future research in the field was not published in full. Over 16,000 patients had given informed consent and were exposed to the risks of therapy. Responsibility for non-publication lies with investigators, but pharmaceutical companies, research ethics committees, journals and governments can all encourage the timely publication of trial data.</p