The future of multiple sclerosis treatments

Introduction. There are not many conditions in which the last few decades have brought such a major change in the landscape of treatments as is the case of multiple sclerosis (MS). A number of disease modifying treatments (DMTs) are presently available for the treatment of the inflammatory phase of this disabling disease; however, the need for treating neurodegeneration and halting the progression of disability is still unmet. Areas covered: In this paper we review the available information on existing and emerging DMTs and we discuss their place within the context of different treatment strategies in MS. Expert Commentary: The future of MS treatments should include the development of new treatment strategies tackling disease progression, together with a better understanding of the side-effects and the best sequential strategy of implementation of available and emerging drugs

Comparative study between wear of uncoated and TiAlN-coated carbide tools in milling of Ti6Al4V

As is recognized widely, tool wear is a major problem in the machining of difficult-to-cut titanium alloys. Therefore, it is of significant interest and importance to understand and determine quantitatively and qualitatively tool wear evolution and the underlying wear mechanisms. The main aim of this paper is to investigate and analyse wear, wear mechanisms and surface and chip generation of uncoated and TiAlN-coated carbide tools in a dry milling of Ti6Al4V alloys. The quantitative flank wear and roughness were measured and recorded. Optical and scanning electron microscopy (SEM) observations of the tool cutting edge, machined surface and chips were conducted. The results show that the TiAlN-coated tool exhibits an approximately 44% longer tool life than the uncoated tool at a cutting distance of 16 m. A more regular progressive abrasion between the flank face of the tool and the workpiece is found to be the underlying wear mechanism. The TiAlN-coated tool generates a smooth machined surface with 31% lower roughness than the uncoated tool. As is expected, both tools generate serrated chips. However, the burnt chips with blue color are noticed for the uncoated tool as the cutting continues further. The results are shown to be consistent with observation of other researchers, and further imply that coated tools with appropriate combinations of cutting parameters would be able to increase the tool life in cutting of titanium alloys

A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury

In preclinical stages of drug development, anticipating potential adverse drug effects such as toxicity is an important issue for both saving resources and preventing public health risks. Current in vitro cytotoxicity tests are restricted by their predictive potential and their ability to provide mechanistic information. This study aimed to develop a metabolomic mass spectrometry-based approach for the detection and classification of drug-induced hepatotoxicity. To this end, the metabolite profiles of human derived hepatic cells (i.e., HepG2) exposed to different well-known hepatotoxic compounds acting through different mechanisms (i.e., oxidative stress, steatosis, phospholipidosis, and controls) were compared by multivariate data analysis, thus allowing us to decipher both common and mechanism-specific altered biochemical pathways. Briefly, oxidative stress damage markers were found in the three mechanisms, mainly showing altered levels of metabolites associated with glutathione and γ-glutamyl cycle. Phospholipidosis was characterized by a decreased lysophospholipids to phospholipids ratio, suggestive of phospholipid degradation inhibition. Whereas, steatosis led to impaired fatty acids β-oxidation and a subsequent increase in triacylglycerides synthesis. The characteristic metabolomic profiles were used to develop a predictive model aimed not only to discriminate between non-toxic and hepatotoxic drugs, but also to propose potential drug toxicity mechanism(s)

Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects

Background: High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects. Methods: This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated. Results: The $AUC_{0-10 hr}$ and $C_{max}$ values increased nonlinearly between 100 mg and 1500 mg. The slope of the $AUC_{0-10 hr}$ vs dose, as well as the $C_{max}$ vs dose, plots are steepest at the lowest thiamine doses. Conclusion: Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process

A comparison of results of empirical studies of supplementary search techniques and recommendations in review methodology handbooks: a methodological review

Background The purpose and contribution of supplementary search methods in systematic reviews is increasingly acknowledged. Numerous studies have demonstrated their potential in identifying studies or study data that would have been missed by bibliographic database searching alone. What is less certain is how supplementary search methods actually work, how they are applied, and the consequent advantages, disadvantages and resource implications of each search method. The aim of this study is to compare current practice in using supplementary search methods with methodological guidance. Methods Four methodological handbooks in informing systematic review practice in the UK were read and audited to establish current methodological guidance. Studies evaluating the use of supplementary search methods were identified by searching five bibliographic databases. Studies were included if they (1) reported practical application of a supplementary search method (descriptive) or (2) examined the utility of a supplementary search method (analytical) or (3) identified/explored factors that impact on the utility of a supplementary method, when applied in practice. Results Thirty-five studies were included in this review in addition to the four methodological handbooks. Studies were published between 1989 and 2016, and dates of publication of the handbooks ranged from 1994 to 2014. Five supplementary search methods were reviewed: contacting study authors, citation chasing, handsearching, searching trial registers and web searching. Conclusions There is reasonable consistency between recommended best practice (handbooks) and current practice (methodological studies) as it relates to the application of supplementary search methods. The methodological studies provide useful information on the effectiveness of the supplementary search methods, often seeking to evaluate aspects of the method to improve effectiveness or efficiency. In this way, the studies advance the understanding of the supplementary search methods. Further research is required, however, so that a rational choice can be made about which supplementary search strategies should be used, and when

Exposure to animals and risk of oligoarticular juvenile idiopathic arthritis: a multicenter case-control study

<p>Abstract</p> <p>Background</p> <p>An inverse association between early contact with microbial compounds and respiratory allergies is well established. The protective effect of infant contact with animals was also shown for inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). We aimed to test the association between animal contact in infancy and oligoarticular juvenile idiopathic arthritis (OA JIA).</p> <p>Methods</p> <p>Parents of children with OA JIA registered at the Hospital for Pediatric Rheumatology in Garmisch-Partenkirchen were asked to complete a questionnaire. Children who underwent strabismus surgery at six referral centers for ophthalmology served as controls. Children age 6 to 18 years born in Germany without malformations were included (238 cases; response 89% and 832 controls; response 86%). Data were analyzed using logistic regression models after adjusting for potential confounders.</p> <p>Results</p> <p>Neither place of living (urban vs. rural area), living on a farm, nor regular farm animal (adjusted odds ratio 0.79; 95% confidence interval 0.42-1.47) or pet contact (0.79; 0.55-1.14) during infancy were clearly related to case status. Allergic rhinitis was inversely related to OA JIA (0.57; 0.34-0.95).</p> <p>Neither place of living (urban vs. rural area), living on a farm, nor regular farm animal (adjusted odds ratio 0.79; 95% confidence interval 0.42-1.47) or pet contact (0.79; 0.55-1.14) during infancy were related to case status. Allergic rhinitis was inversely related to OA JIA (0.57; 0.34-0.95).</p> <p>Conclusions</p> <p>Contact with farm environments in infancy might not be associated with OA JIA. This finding is consistent with previous findings for diabetes mellitus type 1 but contradicts results for IBD and SLE.</p

Target 2035 - an update on private sector contributions

Target 2035, an international federation of biomedical scientists from the public and private sectors, is leveraging ‘open’ principles to develop a pharmacological tool for every human protein. These tools are important reagents for scientists studying human health and disease and will facilitate the development of new medicines. It is therefore not surprising that pharmaceutical companies are joining Target 2035, contributing both knowledge and reagents to study novel proteins. Here, we present a brief progress update on Target 2035 and highlight some of industry's contributions

SPO11-Independent DNA Repair Foci and Their Role in Meiotic Silencing

In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11YF/YF), and blocks its DSB-inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11YF/YFand Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number

Target 2035-update on the quest for a probe for every protein

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome