MHF1–2/CENP-S-X performs distinct roles in centromere metabolism and genetic recombination

Peer reviewedPublisher PD

The endocrine and metabolic factors influencing neuroinflammation and recovery following traumatic brain injury

Background: Traumatic brain injury (TBI) is a major cause of psychological and cognitive disability in young adults in the developed world. The prognosis for these patients is uncertain. Neuroinflammation may be an important underlying mechanism. Growth hormone deficiency (GHD) is a recognised consequence of TBI and may influence recovery. The metabolic syndrome, a state of insulin resistance, may also influence outcome from TBI. Objectives: i) To study the prevalence and consequences of pituitary dysfunction in soldiers who have suffered a blast TBI (bTBI) ii) To investigate the effect of GH deficiency and serum IGF-I levels on recovery from TBI iii)To evaluate a new positron emission tomography (PET) radioligand [18F]GE-180 purported to measure TSPO neuroinflammation in the healthy human brain iv) To quantify neuroinflammation using [18F]GE-180 in patient following TBI and correlate with metabolic factors. Methods: i) Cross-sectional comparative study of 19 soldiers with bTBI vs. 39 civilians with non-blast TBI. Full endocrine testing, neuropsychological testing, diffusion tensor imaging (DTI) ii) Longitudinal study of 39 patients following TBI; IGF-I and GHD testing at baseline, DTI and neuropsychological testing at two study visits designed to be one year apart. Intervention study of 10 patients with GHD pre- and post- 1 year of GH replacement therapy iii) Cross-sectional PET study using [18F]GE-180 in 10 healthy volunteers iv) Longitudinal [18F]GE-180 PET study in 12 patients following TBI: MRI, PET, neuropsychological and metabolic testing at two visits 6 months apart. Results: i) Higher prevalence of pituitary dysfunction in bTBI (31.6%) compared to nbTBI (2.6%), P =0.004 ii) Greater improvement in fractional anisotropy (FA) in patients with a higher IGF-I at baseline, in the splenium of the corpus callosum (SPCC) and in logical memory scores; no effect of GH replacement per se seen on WM recovery or memory, but significant improvement in QoL and depression scores iii) Low brain uptake of [18F]GE-180 in healthy volunteers, two compartmental 4K-fix (2TC) model provided best fit of the data, no effect of TSPO polymorphism seen iv) no significant effect of genotype seen in TBI patients or in outcome measures between patients and controls. Conclusions i) Novel finding of greater prevalence of pituitary dysfunction in patients with bTBI ii) IGF-I, irrespective of the presence of GHD, improves WM recovery in the SPCC and memory iii) GH replacement does not influence cognition or brain structure in this study but did improve quality of life iv) The TSPO ligand [18F]GE-180 appears to be limited by poor brain uptake v) the 2TC-fix model provides the best model fit iv) distribution volumes are low and there appears to be no effect of the TSPO polymorphism on PET outcome measures in patients with TBI and controls.Open Acces

Structural analysis of the starfish SALMFamide neuropeptides S1 and S2: The N-terminal region of S2 facilitates self-association

The neuropeptides S1 (GFNSALMFamide) and S2 (SGPYSFNSGLTFamide), which share sequence similarity, were discovered in the starfish Asterias rubens and are prototypical members of the SALMFamide family of neuropeptides in echinoderms. SALMFamide neuropeptides act as muscle relaxants and both S1 and S2 cause relaxation of cardiac stomach and tube foot preparations in vitro but S2 is an order of magnitude more potent than S1. Here we investigated a structural basis for this difference in potency using spectroscopic techniques. Circular dichroism spectroscopy showed that S1 does not have a defined structure in aqueous solution and this was supported by 2D nuclear magnetic resonance experiments. In contrast, we found that S2 has a well-defined conformation in aqueous solution. However, the conformation of S2 was concentration dependent, with increasing concentration inducing a transition from an unstructured to a structured conformation. Interestingly, this property of S2 was not observed in an N-terminally truncated analogue of S2 (short S2 or SS2; SFNSGLTFamide). Collectively, the data obtained indicate that the N-terminal region of S2 facilitates peptide self-association at high concentrations, which may have relevance to the biosynthesis and/or bioactivity of S2 in vivo

Reducing risks for infant mortality in the Midlands, UK: a qualitative study identifying areas for improvement in the delivery of key public health messages in the perinatal period

© 2022 The Authors. Published by BMC. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1186/s12884-022-05092-1BACKGROUND: The Midlands has amongst the highest rates of neonatal and infant mortality in the UK. A public health parent education and empowerment programme, aimed at reducing key risks associated with this mortality was established and evaluated in the region. This was undertaken in an attempt to identify areas for optimal delivery of the public health messages around reducing risks for neonatal and infant mortality. METHOD: Qualitatively assessment, using the software package Dedoose®, was undertaken. This involved analysis of reflections by the programme trainers, after the delivery of their training sessions to parents, families and carers, between 01 January and 31 December 2021. These were intended to capture insights from the trainers on parent, family, carer and staff perspectives, perceptions/misperceptions around reducing risks for infant mortality. Potential areas for improvement in delivery of the programme were identified from this analysis. RESULTS: A total of 323 programmes, comprising 524 parents, family members and carers were offered the programme. Analysis of 167 reflections around these interactions and those of staff (n = 29) are reported. The programme was positively received across parents, families, carers and staff. Four overall themes were identified: (a) reach and inclusion, (b) knowledge, (c) practical and emotional support and (d) challenges for delivery of the programme. Recommendations for improved delivery of the programme were identified, based on qualitative analysis. CONCLUSION: This novel approach to empowerment and education around neonatal public health messaging is a valuable tool for parents, families, carers and staff in the Midlands. Key practical recommendations for enhancing delivery of these critical public health messages were identified from this qualitative research. These are likely to be of value in other parts of the UK and globally.This project was funded through the Dudley Council and Dudley Public Health Nurture and Resilience Steering Group.Published onlin

Chase-away evolution maintains imperfect mimicry in a brood parasite-host system despite rapid evolution of mimics.

We studied a brood parasite-host system (the cuckoo finch Anomalospiza imberbis and its host, the tawny-flanked prinia Prinia subflava) to test (1) the fundamental hypothesis that deceptive mimics evolve to resemble models, selecting in turn for models to evolve away from mimics ('chase-away evolution') and (2) whether such reciprocal evolution maintains imperfect mimicry over time. Over only 50 years, parasites evolved towards hosts and hosts evolved away from parasites, resulting in no detectible increase in mimetic fidelity. Our results reflect rapid adaptive evolution in wild populations of models and mimics and show that chase-away evolution in models can counteract even rapid evolution of mimics, resulting in the persistence of imperfect mimicry. [Abstract copyright: © 2023. The Author(s).

The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance.

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines

Collinge et al. reply

REPLYING TO C. Feeney et al. Nature 535, 10.1038/nature18602 (2016)

Elevated type-17 cytokines are present in Axial Spondyloarthritis stool

Axial Spondyloarthritis (axSpA) is characterized by type-17 immune-driven joint inflammation, and intestinal inflammation is present in around 70% of patients. In this study, we asked whether axSpA stool contained Th17-associated cytokines and whether this related to systemic Th17 activation. We measured stool cytokine and calprotectin levels by ELISA and found that patients with axSpA have increased stool IL-17A, IL-23, GM-CSF, and calprotectin. We further identified increased levels of circulating IL-17A+ and IL-17F+ T helper cell lymphocytes in patients with axSpA compared to healthy donors. We finally assessed stool metabolites by unbiased nuclear magnetic resonance (NMR) spectroscopy and found that multiple stool amino acids were negatively correlated with stool IL-23 concentrations. These data provide evidence of type-17 immunity in the intestinal lumen, and suggest its association with microbial metabolism in the intestine

Practical Management of the JAK1 Inhibitor Abrocitinib for Atopic Dermatitis in Clinical Practice: Special Safety Considerations

Abrocitinib, an oral, once-daily, Janus kinase (JAK) 1-selective inhibitor, is approved for the treatment of adults and adolescents with moderate-to-severe atopic dermatitis (AD). Abrocitinib has shown rapid and sustained efficacy in phase 3 trials and a consistent, manageable safety profile in long-term studies. Rapid itch relief and skin clearance are more likely to be achieved with a 200-mg daily dose of abrocitinib than with dupilumab. All oral JAK inhibitors are associated with adverse events of special interest and laboratory changes, and initial risk assessment and follow-up monitoring are important. Appropriate selection of patients and adequate monitoring are key for the safe use of JAK inhibitors. Here, we review the practical use of abrocitinib and discuss characteristics of patients who are candidates for abrocitinib therapy. In general, abrocitinib may be used in all appropriate patients with moderate-to-severe AD in need of systemic therapy, provided there are no contraindications, e.g., in patients with active serious systemic infections and those with severe hepatic impairment, as well as pregnant or breastfeeding women. For patients aged ≥ 65 years, current long-time or past long-time smokers, and those with risk factors for venous thromboembolism, major adverse cardiovascular events, or malignancies, a meticulous benefit–risk assessment is recommended, and it is advised to start with the 100-mg dose, when abrocitinib is the selected treatment option