Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-gamma in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-gamma production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56 bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-gamma. Blockade of IL-10 +/- TGF-beta restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-gamma, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-gamma persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-beta blockade

Physical function in UK adults with osteogenesis imperfecta: a cross-sectional analysis of the RUDY study

© 2020, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: We describe the physical function in adults with osteogenesis imperfecta (OI) and explored clinical and non-clinical factors related to its impairment. Our data showed that physical dysfunction is a common feature of adults with OI, varying by OI severity, and mediated by the presence and quality of pain and fatigue symptoms. Introduction: There is a paucity of data describing physical function in adults with osteogenesis imperfecta (OI). We investigated the effects of OI and its severity on physical function and explored the relationship between physical function and number of fractures and symptomatology. Methods: Adults with OI of different types were recruited from the RUDY study, an ongoing UK-based prospective cohort study. Participants completed demographic and clinical questions and questionnaires. These assessed physical function (SF-36), mobility (EQ-5D-5L and NEADL), fatigue (FACIT-F), and pain (SF-MQ-2). Scores were compared using parametric or non-parametric statistical analyses, whereas correlations between outcomes were examined using univariate and multivariate regression analysis. Results: Seventy-eight adults with OI aged 43.5 ± 14.5 years were enrolled (type I, 32; type III, 11; type IV, 10; unknown type, 26). Physical function (PCS, SF-36) was significantly lower in all participants than normative values (p < 0.001) and in type III than type I (p = 0.008). Mobility was significantly different across the types (EQ-5D-EL, p = 0.007; NEADL, p < 0.001), with type III having more severe problems, followed by types IV, unknown, and I. Physical function was associated with OI type (r = 0.26; p = 0.021), presence and quality of pain (r = − 0.57; p < 0.0001), and fatigue (r = − 0.51; p < 0.0001). Multivariate analysis revealed that physical function correlated independently with age, OI type, fatigue, and non-neuropathic pain. Conclusions: Individuals with OI display a marked deterioration in physical function during adulthood. This impairment varies in severity according to the OI phenotype and is associated with the presence of non-neuropathic pain and fatigue

Development and validation of a clinical prediction model for patient-reported pain and function after primary total knee replacement surgery

To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery

A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

Objective To create a prognostic tool to quantify the 5-year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease. Methods We reviewed CV outcomes during the long-term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort. Results Seventy-four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11–1.90), diastolic hypertension (OR 1.97, 95% CI 0.98–3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20–0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80). Conclusion Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83751/1/20433_ftp.pd

Pregnant women with bronchial asthma benefit from progressive muscle relaxation: A randomized, prospective, controlled trial

Background: Asthma is a serious medical problem in pregnancy and is often associated with stress, anger and poor quality of life. The aim of this study was to determine the efficacy of progressive muscle relaxation (PMR) on change in blood pressure, lung parameters, heart rate, anger and health-related quality of life in pregnant women with bronchial asthma. Methods: We treated a sample of 64 pregnant women with bronchial asthma from the local population in an 8-week randomized, prospective, controlled trial. Thirty-two were selected for PMR, and 32 received a placebo intervention. The systolic blood pressure, forced expiratory volume in the first second, peak expiratory flow and heart rate were tested, and the State-Trait Anger Expression Inventory and Health Survey (SF-36) were employed. Results: According to the intend-to-treat principle, a significant reduction in systolic blood pressure and a significant increase in both forced expiratory volume in the first second and peak expiratory flow were observed after PMR. The heart rate showed a significant increase in the coefficient of variation, root mean square of successive differences and high frequency ranges, in addition to a significant reduction in low and middle frequency ranges. A significant reduction on three of five State-Trait Anger Expression Inventory scales, and a significant increase on seven of eight SF-36 scales were observed. Conclusions: PMR appears to be an effective method to improve blood pressure, lung parameters and heart rate, and to decrease anger levels, thus enhancing health-related quality of life in pregnant women with bronchial asthma. Copyright (c) 2006 S. Karger AG, Basel

Rare musculoskeletal diseases in adults: a research priority setting partnership with the James Lind Alliance

Background Osteogenesis imperfecta, fibrous dysplasia/McCune-Albright syndrome and X-linked hypophosphatemia are three rare musculoskeletal diseases characterised by bone deformities, frequent fractures and pain. Little high-quality research exists on appropriate treatment and long-term management of these conditions in adults. This is further worsened by limited research funding in rare diseases and a general mismatch between the existing research priorities and those of the patients. This partnership adopted the James Lind Alliance approach to identify the top 10 research priorities for rare musculoskeletal diseases in adults through joint patient, carer and healthcare professional collaboration. Results The initial survey for question collection recruited 198 respondents, submitting a total of 988 questions. 77% of the respondents were patients with a rare musculoskeletal disease. Following out-of-scope question exclusion, repeating query grouping and scientific literature check for answers, 39 questions on treatment and long-term management remained. In the second public survey, 220 respondents, of whom 85% were patients with a rare musculoskeletal disease, their carers, relatives or friends, prioritised these uncertainties, which allowed selection of the top 25. In the last stage, patients, carers and healthcare professionals gathered for a priority setting workshop to reach a consensus on the final top 10 research priorities. These focus on the uncertainties surrounding appropriate treatment and holistic long-term disease management, highlighting several aspects indirect to abnormal bone metabolism, such as extra-skeletal symptoms, psychological care of both patients and their families and disease course through ageing. Conclusions This James Lind Alliance priority setting partnership is the first to investigate rare bone diseases. The priorities identified here were developed jointly by patients, carers and healthcare professionals. We encourage researchers, funding bodies and other stakeholders to use these priorities in guiding future research for those affected by rare musculoskeletal disorders

Maternal Dietary Supplementation with Oligofructose-Enriched Inulin in Gestating/Lactating Rats Preserves Maternal Bone and Improves Bone Microarchitecture in Their Offspring

This study received financial support from Abbott Nutrition, a commercial company, and coauthors PBV, MM, JMLP and RR are employees of Abbott Nutrition. There are two patents related with the data presented (EP 2502507 A1 and EP 2745706 A1).Some of these results were presented in the 7th World Congress of DOHaD (2011) and in the World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Disease (WCO-IOF-ESCEO) (2014).Nutrition during pregnancy and lactation could exert a key role not only on maternal bone, but also could influence the skeletal development of the offspring. This study was performed in rats to assess the relationship between maternal dietary intake of prebiotic oligofructose-enriched inulin and its role in bone turnover during gestation and lactation, as well as its effect on offspring peak bone mass/architecture during early adulthood. Rat dams were fed either with standard rodent diet (CC group), calcium-fortified diet (Ca group), or prebiotic oligofructose-enriched inulin supplemented diet (Pre group), during the second half of gestation and lactation. Bone mineral density (BMD) and content (BMC), as well as micro-structure of dams and offspring at different stages were analysed. Dams in the Pre group had significantly higher trabecular thickness (Tb.Th), trabecular bone volume fraction (BV/TV) and smaller specific bone surface (BS/BV) of the tibia in comparison with CC dams. The Pre group offspring during early adulthood had an increase of the lumbar vertebra BMD when compared with offspring of CC and Ca groups. The Pre group offspring also showed significant increase versus CC in cancellous and cortical structural parameters of the lumbar vertebra 4 such as Tb.Th, cortical BMD and decreased BS/BV. The results indicate that oligofructose-enriched inulin supplementation can be considered as a plausible nutritional option for protecting against maternal bone loss during gestation and lactation preventing bone fragility and for optimizing peak bone mass and architecture of the offspring in order to increase bone strength.This study was funded by Abbott Nutrition R&D, and co-authors PBV, MM, JMLP and RR receive salary from Abbott Nutrition

Differential contributions of peripheral and central mechanisms to pain in a rodent model of osteoarthritis

The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1mg) or saline, and weight bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic)+capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314+capsaicin signfcantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and refex excitability measured using electromyography. DAMGO (3ng) had a signifcantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints