Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol

Introduction: Fatigue is a frequent and troublesome manifestation of chronic sarcoidosis. This symptom can be debilitating and difficult to treat, with poor response to the treatment. Symptomatic management with neurostimulants, such as methylphenidate, is a possible treatment option. The use of such treatment strategies is not without precedent and has been trialled in cancer-related fatigue. Their use in sarcoidosis requires further evaluation before it can be recommended for clinical practice. Methods and analysis: The Fatigue and Sarcoidosis—Treatment with Methylphenidate study is a randomised, controlled, parallel-arm and feasibility trial of methylphenidate for the treatment of sarcoidosis-associated fatigue. Patients are eligible if they have a diagnosis of sarcoidosis, significant fatigue (measured using the Fatigue Assessment Scale) and have stable disease. Up to 30 participants will be randomly assigned to either methylphenidate (20 mg two times per day) or identical placebo in a 3:2 ratio for 24 weeks. The primary objective is to collect data determining the feasibility of a future study powered to determine the clinical efficacy of methylphenidate for sarcoidosis-associated fatigue. The trial is presently open and will continue until July 2018. Ethics and dissemination: Ethical approval for the study was granted by the Cambridge Central Research Ethics Committee on 21 June 2016 (reference 16/EE/0087) and was approved and sponsored by the Norfolk and Norwich University Hospital (reference 190280). Clinical Trial Authorisation (EudraCT number 2016-000342-60) from the Medicines and Healthcare products Regulatory Agency (MHRA) was granted on 19 April 2016. Results will be presented at relevant conferences and submitted to appropriate journals following trial closure and analysis

Tendon Immune Regeneration: Insights on the Synergetic Role of Stem and Immune Cells during Tendon Regeneration

Tendon disorders represent a very common pathology in today’s population, and tendinopathies that account 30% of tendon-related injuries, affect yearly millions of people which in turn cause huge socioeconomic and health repercussions worldwide. Inflammation plays a prominent role in the development of tendon pathologies, and advances in understanding the underlying mechanisms during the inflammatory state have provided additional insights into its potential role in tendon dis-orders. Different cell compartments, in combination with secreted immune modulators, have shown to control and modulate the inflammatory response during tendinopathies. Stromal compartment represented by tenocytes has shown to display an important role in orchestrating the inflammatory response during tendon injuries due to the interplay they exhibit with the immune-sensing and infiltrating compartments, which belong to resident and recruited immune cells. The use of stem cells or their derived secretomes within the regenerative medicine field might represent synergic new therapeutical approaches that can be used to tune the reaction of immune cells within the damaged tissues. To this end, promising opportunities are headed to the stimulation of macrophages polarization towards anti-inflammatory phenotype together with the recruitment of stem cells, that possess immunomodulatory properties, able to infiltrate within the damaged tissues and improve tendinopathies resolution. Indeed, the comprehension of the interactions between tenocytes or stem cells with the immune cells might considerably modulate the immune reaction solving hence the inflammatory response and preventing fibrotic tissue formation. The purpose of this review is to compare the roles of distinct cell compartments during tendon homeostasis and injury. Furthermore, the role of immune cells in this field, as well as their interactions with stem cells and tenocytes during tendon regeneration, will be discussed to gain insights into new ways for dealing with tendinopathies

Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis

Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking—but not forced alcohol exposure—reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1658-6) contains supplementary material, which is available to authorized users

Sequences of complete human cytomegalovirus genomes from infected cell cultures and clinical specimens

We have assessed two approaches to sequencing complete human cytomegalovirus (HCMV) genomes (236 kbp) in DNA extracted from infected cell cultures (strains 3157, HAN13, HAN20 and HAN38) or clinical specimens (strains JP and 3301). The first approach involved amplifying genomes from the DNA samples as overlapping PCR products, sequencing these by the Sanger method, acquiring reads from a capillary instrument and assembling these using the Staden programs. The second approach involved generating sequence data from the DNA samples by using an Illumina Genome Analyzer (IGA), processing the filtered reads by reference-independent (de novo) assembly, utilizing the resulting sequence to direct reference-dependent assembly of the same data and finishing by limited PCR sequencing. Both approaches were successful. In particular, the investigation demonstrated the utility of IGA data for efficiently sequencing genomes from clinical samples containing as little as 3 % HCMV DNA. Analysis of the genome sequences obtained showed that each of the strains grown in cell culture was a mutant. Certain of the mutations were shared among strains from independent clinical sources, thus suggesting that they may have arisen in a common ancestor during natural infection. Moreover, one of the strains (JP) sequenced directly from a clinical specimen was mutated in two genes, one of which encodes a proposed immune-evasion function, viral interleukin-10. These observations imply that HCMV mutants exist in human infections

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

The Novel Immunosuppressive Protein Kinase C Inhibitor Sotrastaurin Has No Pro-Viral Effects on the Replication Cycle of Hepatitis B or C Virus

The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients

Effects of PREPARE, a Multi-component, School-Based HIV and Intimate Partner Violence (IPV) Prevention Programme on Adolescent Sexual Risk Behaviour and IPV : Cluster Randomised Controlled Trial

Young South Africans, especially women, are at high risk of HIV. We evaluated the effects of PREPARE, a multi-component, school-based HIV prevention intervention to delay sexual debut, increase condom use and decrease intimate partner violence (IPV) among young adolescents. We conducted a cluster RCT among Grade eights in 42 high schools. The intervention comprised education sessions, a school health service and a school sexual violence prevention programme. Participants completed questionnaires at baseline, 6 and 12 months. Regression was undertaken to provide ORs or coefficients adjusted for clustering. Of 6244 sampled adolescents, 55.3 % participated. At 12 months there were no differences between intervention and control arms in sexual risk behaviours. Participants in the intervention arm were less likely to report IPV victimisation (35.1 vs. 40.9 %; OR 0.77, 95 % CI 0.61-0.99; t(40) = 2.14) suggesting the intervention shaped intimate partnerships into safer ones, potentially lowering the risk for HIV