Rheumatoid arthritis synovial microenvironment induces metabolic and functional adaptations in dendritic cells.

Rheumatoid arthritis (RA) is a chronic autoimmune disease which causes degradation of cartilage and bone. It is well appreciated that the pathogenic hallmark of RA is the mass influx of inflammatory cells into the joint. However, the role that dendritic cells (DC) may play in this inflammatory milieu is still relatively unexplored. Moreover, the contribution this unique synovial microenvironment has on DC maturation is still unknown. Using monocyte-derived DC (MoDC), we established an in-vitro model to recapitulate the synovial microenvironment to explore DC maturation. MoDC treated with conditioned media from ex-vivo synovial tissue biopsy cultures [explant-conditioned media (ECM)] have increased expression of proinflammatory cytokines, chemokines and adhesion molecules. ECM DC have increased expression of CD83 and CC-chemokine receptor (CCR)7 and decreased expression of CCR5 and phagocytic capacity, suggestive of heightened DC maturation. ECM-induced maturation is concomitant with altered cellular bioenergetics, whereby increased expression of glycolytic genes and increased glucose uptake are observed in ECM DC. Collectively, this results in a metabolic shift in DC metabolism in favour of glycolysis. These adaptations are in-part mediated via signal transducer and activator of transcription-3 (STAT-3), as demonstrated by decreased expression of proinflammatory cytokines and glycolytic genes in ECM DC in response to STAT-3 inhibition. Finally, to translate these data to a more in-vivo clinically relevant setting, RNA-seq was performed on RA synovial fluid and peripheral blood. We identified enhanced expression of a number of glycolytic genes in synovial CD1c+ DC compared to CD1c+ DC in circulation. Collectively, our data suggest that the synovial microenvironment in RA contributes to DC maturation and metabolic reprogramming.

Mass and the Dangers of Syncope.

Introduction Syncope is defined as a transient, self-limited loss of consciousness with an inability to maintain postural tone that is followed by spontaneous recovery. We revisit situational syncope focusing on one situation, Mass. Methods We interrogated our electronic syncope database for key terms associated with situational syncope. From the most commonly encountered situation, Mass, we interrogated the results of tilt testing performed to identify evidence of orthostatic hypotension. Results There were 110 cases of situational syncope identified with 56.3% (n=62) taking place at mass. All had tilt table testing performed and 15.4% (n=17) had evidence of orthostatic hypotension. Conclusion The multiple sudden changes in position during mass from sitting to kneeling to standing can precipitate an episode of orthostatic hypotension. Consideration should be given as to whether it is safe for older mass goers to be subjected to such significant orthostatic stress.

Increased T Cell Plasticity With Dysregulation of Follicular Helper T, Peripheral Helper T, and Treg Cell Responses in Children With Juvenile Idiopathic Arthritis and Down Syndrome-Associated Arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common inflammatory arthritis in children; however, an aggressive, erosive arthritis of little-known immunologic mechanism occurs 20 times more frequently in children with Down syndrome. This study was undertaken to characterize T cell and B cell polyreactivity, follicular helper T (Tfh) cell, peripheral helper T (Tph) cell, and Treg cell responses, and synovial inflammation in Down syndrome-associated arthritis (DA). METHODS: Multiparametric flow cytometric analysis and Simplified Presentation of Incredibly Complex Evaluations (SPICE) software were used to examine peripheral blood B cell populations and T cell cytokine responses in patients with DA, JIA, Down syndrome (trisomy 21 [T21]), and in healthy controls. Tfh and Tph cell frequency and origin, in addition to Treg cell frequency, were also evaluated. Synovial inflammation was assessed by immunohistology. RESULTS: Expansion of IgM-only memory B cells was demonstrated in DA compared to JIA (mean ± SEM 22.48 ± 3.278 versus 9.011 ± 1.317; P = 0.005), paralleled by decreased frequency of transitional B cells. T cell responses in DA were characterized by marked functional plasticity, as was evident from the increased frequency of polyfunctional CD8+ Th cells (P < 0.05), CD161+ Th cells (P < 0.05), and CD8- Th cells (P < 0.001), and positivity for tumor necrosis factor, interferon-γ, interleukin-17A, or granulocyte-macrophage colony-stimulating factor, compared to all other groups. Significant expansion of CXCR3+CCR6+ (Th1/Th17) Tfh cells (P = 0.003) and CXCR3+CCR6+ Tph cells (P = 0.01), paralleled by a decrease in CXCR3-CCR6- (Th2) Tfh cells was observed in DA compared to T21. Treg cells were significantly reduced in DA compared to T21 (mean ± SEM 7.111 ± 0.9518 versus 11.96 ± 1.055 versus; P = 0.0028), with a specific reduction in the naive:memory Treg cell ratio. Marked synovial tissue inflammation and increased T cell and B cell infiltrations were demonstrated in DA compared to JIA. CONCLUSION: DA is more common and more aggressive than JIA. It is characterized by increased polyreactive Th, Tfh, and Tph cell responses, reduced Treg cell frequency, and evidence of increased synovial inflammation, all of which are potentially distinct from JIA and T21.

Effect of non-vitamin-K oral anticoagulants on stroke severity compared to warfarin: a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: In addition to lowering stroke risk, warfarin use is also associated with reduced stroke severity in patients with atrial fibrillation and acute ischaemic stroke. It was sought to determine whether the effect of non-vitamin-K oral anticoagulants (NOACs), compared to warfarin, differed by stroke severity. METHODS: Phase III randomized controlled trials with participants who were randomized to receive NOACs or warfarin for stroke prevention in the setting of non-valvular atrial fibrillation were identified. Stroke was classified into two categories, fatal or disabling stroke and non-disabling stroke, and meta-analyses were completed for both outcomes and for comparative case fatality of stroke amongst trials. RESULTS: Five randomized controlled trials met our inclusion criteria. In clinical trials evaluating the NOACs usually prescribed in clinical practice (four trials), acute stroke was reported in 1403 (1.86%) participants, 787 (1.04%) in the NOAC group [386 (0.51%) fatal or disabling, 401 (0.53%) non-disabling] and 616 (0.82%) in the warfarin group [367 (0.49%) fatal or disabling, 249 (0.33%) non-disabling]. On meta-analysis NOACs were significantly superior to warfarin for fatal or disabling stroke (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66-0.89, I2  = 21%) and non-disabling stroke (OR 0.85; 95% CI 0.73-0.98, I2  = 2%). The case fatality of stroke was no different between groups (OR 0.90, 95% CI 0.75-1.13, I2  = 0%), but the point estimate favoured NOACs. CONCLUSION: In phase III trials of NOACs, for prevention of stroke in atrial fibrillation, NOACs are associated with a lower risk of both fatal/disabling and non-disabling stroke compared to warfarin.

Key Service Improvements After the Introduction of an Integrated Orthogeriatric Service.

INTRODUCTION: Models of orthogeriatric care have been shown to improve functional outcomes for patients after hip fractures and can improve compliance with best practice guidelines for hip fracture care. METHODS: We evaluated improvements to key performance indicators in hip fracture care after implementation of a formal orthogeriatric service. Compliance with Irish Hip Fracture standards of care was reviewed, and additional outcomes such as length of stay, access to rehabilitation, and discharge destination were evaluated. RESULTS: Improvements were observed in all of the hip fracture standards of care. Mean length of stay decreased from 19 to 15.5 days (mean difference 3.5 days; P < .05). A higher proportion of patients were admitted to rehabilitation (16.7% vs 7.9%, P < .05), and this happened in a timelier fashion (17.8 vs 24.8 days, P < .05). We found that less patients required convalescence post-hip fracture. DISCUSSION: A standardized approach to integrated post-hip fracture care with orthogeriatrics has improved standards of care for patients. CONCLUSION: Introduction of orthogeriatric services has resulted in meaningful improvements in clinical outcomes for older people with hip fractures.

A review of vitamin D insufficiency and its management: a lack of evidence and consensus persists.

Vitamin D deficiency is the most common nutritional deficiency worldwide, however uncertainty persists regarding the benefits of vitamin D supplementation. Vitamin D is essential for calcium homeostasis, and has been linked to falls and fractures in older people. There are numerous risk factors for vitamin D deficiency, chief among them old age. Studies of vitamin D supplementation have given mixed signals, but over all there is evidence of benefit for those with risk factors for deficiency. International guidelines recommend vitamin D target levels of >25 to >80 nmol/l, best achieved by a daily dose of 800-1000 IU. Large bolus doses should be avoided. There are still unanswered questions regarding vitamin D supplementation and target levels. There is need for well designed and powered trials to achieve consensus.

The pathogenic role of dendritic cells in non-infectious anterior uveitis.

BACKGROUND: Anterior uveitis (AU) is characterised by infiltration of immune cells into the anterior chamber of the eye. Dendritic cells (DC) are professional antigen presenting cells that initiate and promote inflammation. This study aims to characterise DC in AU and to examine the effects of aqueous humor (AqH) on DC maturation and function. METHODS: The frequency and phenotype of AU and healthy control (HC) circulating DC was examined. AU and HC AqH was immunostained and assessed by flow cytometry. The effect of AU and HC AqH on DC activation and maturation was examined and subsequent effects on CD4+ T cell proliferation assessed. RESULTS: AU peripheral blood demonstrated decreased circulating myeloid and plasmacytoid DC. Within AU AqH, three populations of CD45+ cells were significantly enriched compared to HC; DCs (CD11c+ HLA-DR+), neutrophils (CD15+ CD11c+) and T cells (CD4+ and CD8+). A significant increase in IFNγ, IL8 and IL6 was observed in the AU AqH, which was also significantly higher than that of paired serum. AU AqH induced expression of CD40 and CD80 on DC, which resulted in increased T cell proliferation and the production of GM-CSF, IFNγ and TNFα. CONCLUSION: DC are enriched at the site of inflammation in AU. Our data demonstrate an increase in inflammatory mediators in the AU inflamed microenvironment. AU AqH can activate DC, leading to subsequent proliferation and activation of effector T cells. Thus, the AU microenvironment contributes to immune cell responses and intraocular inflammation.

National Alcohol Survey of households in Trinidad and Tobago (NASHTT): Alcohol use in households.

BACKGROUND: To determine the patterns of alcohol use among households in Trinidad and Tobago (T&T) and to estimate the association between alcohol use and negative psychological, social, or physical events experienced by the household. METHODS: A convenience sample of 1837 households across T&T. We identified bivariate correlates of alcohol use, and heavy episodic drinking using chi-square and t-test analyses and used multivariable logistic regression to estimate adjusted associations between household alcohol use and experiences within the past 12 months adjusted for sociodemographic covariates. RESULTS: One thousand five hundred two households had complete data for all variables (82% response rate). Nearly two thirds (64%) of households included alcohol users; 57% of household that consumed alcohol also reported heavy episodic drinking. Households that reported alcohol consumption were significantly more likely to report illnesses within the households, relationship problems, and behavioral and antisocial problems with children. Among households where a member was employed, those who consumed alcohol were nearly twice as likely (OR = 1.98; 95% confidence interval (CI) 1.03, 3.82) to have a household member call in sick to work and 2.9 times as likely (OR = 2.9; CI 1.19, 7.04) to have a household member suffer work related problems compared with households who reported not consuming alcohol. CONCLUSIONS: Approximately two thirds of households in T&T reported using alcohol. These households were more likely to report psychological, physical, and social problems. These findings would support efforts to enforce current policies, laws, and regulations as well as new strategies to reduce the impact of harmful alcohol consumption on households in T&T.

Dysregulated bioenergetics: a key regulator of joint inflammation.

OBJECTIVES: This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation. METHODS: Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO2 mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). RESULTS: DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO2 levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO2 in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions. CONCLUSIONS: Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.

Attitudes to outcomes measured in clinical trials of cardiovascular prevention.

BACKGROUND: Selecting outcome measures in cardiovascular prevention trials should be informed by their importance to selected populations. Major vascular event outcomes are usually prioritized in these trials with considerably less attention paid to cognitive and functional outcomes. AIM: To examine views on importance of outcome measures used in clinical trials. DESIGN: Cross-sectional survey. METHODS: Of 367 individuals approached, 280 (76%) participated: outpatients attending cardiovascular prevention clinics (n = 97), active retirement groups members (n = 75), medical students (n = 108). Participants were asked to rank, in order of importance, outcome measures, which may be included in cardiovascular prevention trials. Results were compared between two groups: <65s (n = 157) and ≥65s (n = 104). RESULTS: When asked what outcomes were most important to measure in cardiovascular prevention trials, respondents reported: death (31.6%) stroke (28.5%), dementia (26.9%), myocardial infarction (MI) (7.9%) and requiring nursing home (NH) care (5.1%). When asked the most relevant outcomes regarding successful ageing respondents reported; maintaining independence (32.4%), avoiding major illness (24.3%), good family life (23.6%), living as long as possible (15.8%), avoiding NH care (3.1%) and contributing to society (0.8%) as most important. When asked what outcome concerned them most about the future, respondents reported: dementia (32.6%), dependence (30.4%), death (12.8%), stroke (12.5%), cancer (6.2%) requiring NH care (4.8%) and MI (0.7%). Maintaining independence was considered most important in younger and older cohorts. CONCLUSION: Cognitive and functional outcomes are important patient-relevant outcomes, sometimes more important than major vascular events. Incorporating these outcomes into trials may encourage patient participation and adherence to preventative regimens.

An accelerator based fusion-product source for development of inertial confinement fusion nuclear diagnostics.

A fusion-product source, utilizing a 150 kV Cockraft-Walton linear accelerator, has been refurbished to provide a reliable nuclear diagnostic development tool to the national inertial confinement fusion (ICF) research program. The accelerator is capable of routinely generating DD reaction rates at approximately 10(7)/s when using a 150 kV, 150 microA deuterium (D) beam onto an erbium (Er) or titanium (Ti) target doped with D, and D(3)He reaction rates at approximately 5 x 10(5)/s when using a using a 120 kV, approximately 100 microA D beam onto a Er or Ti target doped with (3)He. The new accelerator is currently being used in a number of projects related to the national ICF program at the OMEGA Laser Fusion Facility [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)], which includes the wedge range filter charged-particle spectrometry program [F. H. Seguin et al., Rev. Sci Instrum. 75, 3520 (2004)] and the magnetic recoil neutron spectrometer [J. A. Frenje et al., Rev. Sci. Instrum. 72, 854 (2001)].

Psychopathology and economic status in mother-only and mother-father families.

This paper reports evidence on the link between economic resources and psychiatric disorder in female-headed families with children. It has been assumed that a father's absence leads to augmented psychopathology in children and their mother through the disruption of roles, relationships, socialization and development. This study suggests that the absence of father/husband compounds the stress of family separation by diminishing household income, often to the point of poverty.

Managing the discharge crisis following catastrophic illness or injury.

Discharge from the acute care setting frequently represents a serious crisis for the catastrophically ill. Family members and the patient are expected to resume responsibility quickly for ongoing care while simultaneously coping with significant alterations in established role and behavior patterns. The dynamics of this transition are discussed and suggestions for helping the family cope with this crisis are offered.

Therapeutic aspects of discharge planning.

Many aspects of the discharge-planning function have been discussed by social workers, but the therapeutic possibilities inherent in this task have been largely ignored. Examining the social context within which illness, hospitalization, and convalescence or adaptation occur permits recognition of the alternatives for creative intervention. This examination also provides a framework for understanding the intrinsically disruptive nature of discharge from an acute care setting as well as the dangers and possibilities for change.