Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans.

BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.This study was supported by The National Institute for Health Research England (grant number RG65966), and by the Center of Immunodeficiencies Amsterdam (CIDA). JET is supported by an MRC Clinician Scientist Fellowship (MR/L006197/1). AJT is supported by both the Wellcome Trust (104807/Z/14/Z) and by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. EO receives personal fees from CSL Behring and MSD

The metabolic costs of reciprocal supersets vs. traditional resistance exercise in young recreationally active adults

An acute bout of traditional resistance training (TRAD) increases energy expenditure (EE) both during exercise and in the postexercise period. Reciprocal supersets (SUPERs) are a method of resistance training that alternates multiple sets of high-intensity agonist-antagonist muscle groups with limited recovery. The purpose of this study was to compare the energy cost of SUPERs and TRAD both during and in the postexercise period. We hypothesized that SUPERs would produce greater exercise EE relative to the duration of exercise time and greater excess postexercise oxygen consumption (EPOC) than TRAD of matched work. Ten recreationally active, young men each participated in 2 exercise protocols: SUPER, followed 1 week later by TRAD matched within using a 10-repetition maximum load for 6 exercises, 4 sets, and repetitions. Participants were measured for oxygen consumption and blood lactate concentration during exercise and 60 minutes postexercise after each exercise bout. No significant differences were observed in aerobic exercise EE between trials (SUPER 1,009.99 ± 71.42 kJ; TRAD 954.49 ± 83.31 kJ); however, when expressed relative to time, the exercise EE was significantly greater during SUPER (34.70 ± 2.97 kJ·min-1) than TRAD (26.28 ± 2.43 kJ·min-1). Excess postexercise oxygen consumption was significantly greater after SUPER (79.36 ± 7.49 kJ) over TRAD (59.67 ± 8.37 kJ). Average blood lactate measures were significantly greater during SUPER (5.1 ± 0.9 mmol·L-1) than during TRAD (3.8 ± 0.6 mmol·L-1). Reciprocal supersets produced greater exercise kJ·min-1, blood lactate, and EPOC than did TRAD. Incorporating this method of resistance exercise may benefit exercisers attempting to increase EE and have a fixed exercise volume with limited exercise time available

The burden of motorcycle-related neuro-trauma in Ireland and associated helmet usage

Motorcycles represent less than 2% of the licensed vehicles but motorcyclists account for 12% of road deaths in Ireland. The British Road Safety Authority has introduced the Sharp programme, which hopes to save 50 lives in the U.K. each year alone by helping riders to choose the best-fitting and safest helmets. We evaluated the pattern of head injuries sustained by motorcyclists referred to the two neurosurgical centres Beaumont Hospital and Cork University Hospital in Ireland and ascertained if the new SHARP guidelines could be of benefit in reducing the burden of motorcycle related neurotrauma and disability in Ireland. Despite Ireland having mandatory helmet laws almost a quarter of our motorcyclists with traumatic brain injury were unhelmeted. A significant reduction in mortality and morbidity is predicted if all motorcyclists in Ireland were to wear helmets that satisfied the SHARP criteria

Current status of the freshwater Mysidae in The Netherlands, with records of Limnomysis benedeni Czerniavsky, 1882, a Pontocaspian species in Dutch Rhine branches

The freshwater Mysidacea of The Netherlands are presently composed of three species. The indigenous mysid, Neomysis integer (Leach, 1814) has recently been joined by two Pontocaspian species, Limnomysis benedeni Czerniavsky, 1882 and Hemimysis anomala G.O. Sars, 1907. All three species now coexist in the Dutch Rhine. The present paper deals with the first records of L. benedeni in The Netherlands with ecological notes on the three species

Mechanism of interferon stimulated gene induction in HIV-1 infected macrophages

Viruses manipulate the complex interferon and interferon stimulated gene (ISG) system in different ways. We have previously shown that HIV inhibits type I and III interferons in its key target cells but directly stimulates a subset of >20 ISGs in macrophages and dendritic cells many of which are antiviral. Here we examined the mechanism of induction of ISGs and showed this occurred in two phases. The first phase was transient (0-24hpi) induced mainly by extracellular vesicles, and one of its component proteins HSP90α, contained within the HIV inoculum. The second dominant and persistent phase (>48hpi) was induced via newly transcribed HIV RNA and sensed via RIGI, as shown by the reduction in ISG expression after the knock down of the RIGI adaptor, MAVS, by siRNA and the inhibition of both the initiation and elongation of HIV transcription, by shRNA transcriptional silencing. We further defined the induction pathway, showing sequential HIV RNA stimulation via Tat, RIGI, MAVS, IRF1 and IRF7 also identified by siRNA knockdown. IRF1 also plays a key role in the first phase. We also showed that the ISGs, IFITs 1-3 inhibited HIV production, measured as extracellular infectious virus. All induced antiviral ISGs probably lead to restriction of HIV replication in macrophages, contributing to a persistent, non-cytopathic infection while the inhibition of interferon facilitates spread to adjacent cells. Both may influence the size of macrophage HIV reservoirs in vivo. Elucidating the mechanisms of ISG induction may help devise immunotherapeutic strategies to limit the size of these reservoirs. IMPORTANCE HIV, like other viruses, manipulates the antiviral interferon and interferon stimulated gene (ISG) system to facilitate its initial infection and establishment of viral reservoirs. HIV specifically inhibits all type l and lll interferons in its target cells, including, macrophages, dendritic cells and T cells. It also induces a subset of over 20 ISGs of differing composition in each cell target. This occurs in two temporal phases in macrophages. Extracellular vesicles contained within the inoculum induced the first and transient phase of ISGs. Newly transcribed HIV RNA induced the second and dominant ISG phase and here the full induction pathway is defined. Therefore, HIV nucleic acids, which are potent inducers of interferon and ISGs, are initially concealed and antiviral ISGs are not fully induced until replication is well established. Theses antiviral ISGs may contribute to the persistent infection in macrophages and to the establishment of viral reservoirs in vivo.Najla Nasr, Abdullateef A. Alshehri, Thomas K. Wright, Maryam Shahid, Bonnie M. Heiner, Andrew N. Harman, Rachel A. Botting, Karla J. Helbig, Michael R. Beard, Kazuo Suzuki, Anthony D. Kelleher, Paul Hertzog, Anthony L. Cunningha