Plasticity induced by pairing brain stimulation with motor-related states only targets a subset of cortical neurones

Movement-related brain stimulation (MRBS) interventions associate endogenously generated movement-related brain states with external brain stimuli to induce targeted plastic changes in the motor cortex (M1) [[1], [2], [3], [4]]. These studies have emphasised the importance of the timing of stimulation relative to movement onset. However, none has examined whether the effects are specific to the cortical circuits activated by the stimuli. The question arises because previous work has shown that different sets of inputs to corticospinal neurones can be activated using TMS. Stimulation with a posterior-anterior (PA) direction activates a set of neurones that have a shorter latency connection to corticospinal neurones than those activated with an anterior-posterior (AP) current [5]. Previous MRBS studies have paired movement onset with PA pulses [1]. The present work tests whether the after-effects of MRBS are specific to PA-sensitive neurones, or whether those activated by AP pulses are also affected. Here we applied AP or PA TMS pulses applied just prior to the onset of volitional index finger movements in two experiments conducted on separate days in the same group of individuals [3]. Corticospinal excitability changes induced by these interventions were assessed using AP and PA TMS pulses in the effector muscle and in a control muscle

A Single Nucleotide Polymorphism in STK11 Influences Insulin Sensitivity and Metformin Efficacy in Hyperinsulinemic Girls With Androgen Excess

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Predictions of SUSY Masses in the Minimal SUSY GUT

The MSSM distinguishes itself from other GUT's by a successful prediction of many unrelated phenomena with a minimum number of parameters. Among them: a) Unification of the couplings constants; b)Unification of the masses; c) Proton decay; d) Electroweak symmetry breaking. A combined fit of the free parameters in the MSSM to these low energy constraints shows that the MSSM model can satisfy these constraints simultaneously. From the fitted parameters the masses of the as yet unobserved superpartners of the SM particles are predicted. The 2nd order QCD coupling constant is required to be between 0.108 and 0.132. It is shown that a top mass of $174\pm16$ GeV, as suggested recently by the CDF Collaboration, constrains the mixing angle between the Higgs doublets in the MSSM to: 1.2<\tb<5.5 at the 90% C.L.. The most probable value corresponds to \tb = 1.56, which leads to a stop mass below the top mass. In this case the stop production in $p\bar{p}$ collisions would contribute to the top signature. This could be an explanation for the large effective $t\bar{t}$ cross section observed by CDF.Comment: latex + eps fig IEKP-KA/94-0

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

In utero exposure to low doses of environmental pollutants disrupts fetal ovarian development in sheep

Epidemiological studies of the impact of environmental chemicals on reproductive health demonstrate consequences of exposure but establishing causative links requires animal models using ‘real life’ in utero exposures. We aimed to determine whether prolonged, low-dose, exposure of pregnant sheep to a mixture of environmental chemicals affects fetal ovarian development. Exposure of treated ewes (n = 7) to pollutants was maximized by surface application of processed sewage sludge to pasture. Control ewes (n = 10) were reared on pasture treated with inorganic fertilizer. Ovaries and blood were collected from fetuses (n = 15 control and n = 8 treated) on Day 110 of gestation for investigation of fetal endocrinology, ovarian follicle/oocyte numbers and ovarian proteome. Treated fetuses were 14% lighter than controls but fetal ovary weights were unchanged. Prolactin (48% lower) was the only measured hormone significantly affected by treatment. Treatment reduced numbers of growth differentiation factor (GDF9) and induced myeloid leukaemia cell differentiation protein (MCL1) positive oocytes by 25–26% and increased pro-apoptotic BAX by 65% and 42% of protein spots in the treated ovarian proteome were differently expressed compared with controls. Nineteen spots were identified and included proteins involved in gene expression/transcription, protein synthesis, phosphorylation and receptor activity. Fetal exposure to environmental chemicals, via the mother, significantly perturbs fetal ovarian development. If such effects are replicated in humans, premature menopause could be an outcome

Profiling Early Lung Immune Responses in the Mouse Model of Tuberculosis

Tuberculosis (TB) is caused by the intracellular bacteria Mycobacterium tuberculosis, and kills more than 1.5 million people every year worldwide. Immunity to TB is associated with the accumulation of IFNγ-producing T helper cell type 1 (Th1) in the lungs, activation of M.tuberculosis-infected macrophages and control of bacterial growth. However, very little is known regarding the early immune responses that mediate accumulation of activated Th1 cells in the M.tuberculosis-infected lungs. To define the induction of early immune mediators in the M.tuberculosis-infected lung, we performed mRNA profiling studies and characterized immune cells in M.tuberculosis-infected lungs at early stages of infection in the mouse model. Our data show that induction of mRNAs involved in the recognition of pathogens, expression of inflammatory cytokines, activation of APCs and generation of Th1 responses occurs between day 15 and day 21 post infection. The induction of these mRNAs coincides with cellular accumulation of Th1 cells and activation of myeloid cells in M.tuberculosis-infected lungs. Strikingly, we show the induction of mRNAs associated with Gr1+ cells, namely neutrophils and inflammatory monocytes, takes place on day 12 and coincides with cellular accumulation of Gr1+ cells in M.tuberculosis-infected lungs. Interestingly, in vivo depletion of Gr1+ neutrophils between days 10–15 results in decreased accumulation of Th1 cells on day 21 in M.tuberculosis-infected lungs without impacting overall protective outcomes. These data suggest that the recruitment of Gr1+ neutrophils is an early event that leads to production of chemokines that regulate the accumulation of Th1 cells in the M.tuberculosis-infected lungs