Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pituitary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double blind trial

Hyperresponsiveness of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system, is presumably due to diminished corticosteroid receptor function. It probably influences the immune response, but its clinical significance is not clear. Similar HPA dysregulation occurs in depression and is reversible with successful antidepressant treatment. We conducted a double blind, placebo-controlled trial to evaluate the neuroendocrine effect of cotreatment with the antidepressant moclobemide as an adjunct to oral corticosteroids in MS. Twenty-one patients with definite relapsing-remitting MS (11 females, aged 33.9 +/- 2.0 yr; Expanded Disability Status Scale score of neurological impairment, 2.0--6.5) in acute relapse were treated with placebo (n = 13) or 300 mg moclobemide (reversible monoamine oxidase A inhibitor; n = 8) for 75 days. All received oral fluocortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined dexamethasone-CRH test and clinically on days 1, 30, and 75. At baseline, the HPA axis was mildly activated, comparably for treatment groups [area under the curve for cortisol (AUC-Cort), 213.8 +/- 76.8 arbitrary units in the moclobemide group vs. 225.8 +/- 65.1 in the steroid alone group; mean +/- SEM]. In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 +/- 14.1. Moclobemide cotreatment resulted in normalization of the HPA axis response, whereas the HPA system hyperresponse was maintained with steroids alone (AUC-Cort on day 30, 85.9 +/- 22.8 vs.177.1 +/- 68.5; on day 75, 111.0 +/- 46.0 vs. 199.2 +/- 64.6). The change in Expanded Disability Status Scale was comparable for both groups. Although corticosteroids alone had no effect on the HPA response using the dexamethasone-CRH test, treatment with moclobemide combined with corticosteroids favors normalization of the HPA response in relapsing-remitting MS.     

Neuroplasticity in Corticolimbic Brain Regions in Patients After Anterior Cruciate Ligament Reconstruction

ContextFear has been cited as the primary barrier to return to sport (RTS) by athletes after anterior cruciate ligament reconstruction (ACLR). Understanding the neural factors that contribute to fear after ACLR may help us to identify interventions for this population.ObjectiveTo characterize the underlying neural substrate of injury-related fear in patients after ACLR versus healthy matched control individuals during a picture imagination task (PIT) consisting of sport-specific images and images of activities of daily living (ADL).DesignCase-control study.SettingResearch laboratory.Patients or Other ParticipantsA total of 24 right-hand–dominant participants (12 with left-sided ACLR and 12 control individuals) were enrolled. Participants underwent full-brain functional magnetic resonance imaging.Main Outcome Measure(s)Functional data were acquired using blood oxygen level–dependent (BOLD) echoplanar imaging. Independent t tests were conducted to identify between-groups differences in BOLD signal changes during all images of the PIT. Paired t tests were computed to examine differences in BOLD signal change between sport-specific and ADL images in the ACLR group.ResultsIncreased activation in the inferior parietal lobule and the mediodorsal thalamus was observed during PIT in the ACLR group. An inability to suppress the default mode network in the ACLR group was noted. The ACLR group exhibited increased activation in the cerebellum and inferior occipital regions during the sport-specific images versus the ADL images, but no other regions of interest demonstrated differences.ConclusionAfter ACLR, patients may be more predisposed to fear, anxiety, and pain during sport-specific activities and ADLs. Psychosocial interventions may be warranted after ACLR to reduce injury-related fear and mitigate potentially maladaptive neuroplasticity.     

Mentoring in Clinical‐Translational Research: A Study of Participants in Master's Degree Programs

Research projects in translational science are increasingly complex and require interdisciplinary collaborations. In the context of training translational researchers, this suggests that multiple mentors may be needed in different content areas. This study explored mentoring structure as it relates to perceived mentoring effectiveness and other characteristics of master''s‐level trainees in clinical‐translational research training programs. A cross‐sectional online survey of recent graduates of clinical research master''s program was conducted. Of 73 surveys distributed, 56.2% (n = 41) complete responses were analyzed. Trainees were overwhelmingly positive about participation in their master''s programs and the impact it had on their professional development. Overall the majority (≥75%) of trainees perceived they had effective mentoring in terms of developing skills needed for conducting clinical‐translational research. Fewer trainees perceived effective mentoring in career development and work‐life balance. In all 15 areas of mentoring effectiveness assessed, higher rates of perceived mentor effectiveness was seen among trainees with ≥2 mentors compared to those with solo mentoring (SM). In addition, trainees with ≥2 mentors perceived having effective mentoring in more mentoring aspects (median: 14.0; IQR: 12.0–15.0) than trainees with SM (median: 10.5; IQR: 8.0–14.5). Results from this survey suggest having ≥2 mentors may be beneficial in fulfilling trainee expectations for mentoring in clinical‐translational training.     

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.     

Lipotoxicity,neuroinflammation, glial cells and oestrogenic compounds

The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis, and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as oestradiol not only have beneficial effects on brain tissue, but also exert some adverse effects on peripheral tissues, including the ovary and breast. For this reason, some studies have evaluated the protective effect of oestrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro‐survival factors and cell signalling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by oestrogens.