Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosis

Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six "healthy" co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8(+) T cells, plasmablasts, and, to a lesser extent, CD4(+) T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (T-RM) cells. The T-RM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded T-RM-like CD8(+) cells

The left frontal cortex supports reserve in aging by enhancing functional network efficiency

Background: Recent evidence from fMRI studies suggests that functional hubs, i.e. highly connected brain regions, are important for mental health. We found recently that global connectivity of a hub in the left frontal cortex (LFC-connectivity) is associated with relatively preserved memory abilities and higher levels of protective factors (education, IQ) in normal aging and Alzheimer’s disease. These results suggest that LFC-connectivity supports reserve capacity alleviating memory decline. An open question is, however, why LFC-connectivity is beneficial and supports memory function in the face of neurodegeneration. We hypothesized that higher LFCconnectivity is associated with enhanced efficiency in connected major networks involved in episodic memory. We further hypothesized that higher LFC-related network efficiency predicts higher memory abilities. Methods: We assessed fMRI during a face-name association learning task in 26 healthy cognitively normal elderly participants. Using beta-series correlation analysis, we computed task-related LFC-connectivity to key memory networks including the default-mode network (DMN) and dorsal attention network (DAN). Network efficiency within the DMN and DAN was estimated by the graph theoretical small-worldness statistic. We applied linear regression analyses in order to test the association between LFC-connectivity to the DMN/DAN and small-worldness of these networks. Mediation analysis was applied to test LFC-connectivity to the DMN and DAN as a mediator of the association between education and higher DMN and DAN smallworldness. Lastly, we tested network small-worldness as a predictor of memory performance. Results: We found that higher LFC-connectivity to the DMN and DAN during successful memory encoding and recognition was associated with higher small-worldness of those networks. Higher task-related LFC-connectivity mediated the association between education and higher small-worldness in the DMN and DAN. Further, higher small-worldness of these networks predicted better performance in the memory task. Conclusions: The current results suggest that higher education-related LFC-connectivity to key memory networks during a memory task is associated with higher network efficiency and thus enhanced reserve of memory abilities in aging

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans

Self-management interventions for adults living with obesity to improve patient-relevant outcomes : An evidence map

To conduct an evidence map on self-management interventions and patient-relevant outcomes for adults living with overweight/obesity. Following Arksey and O'Malley methodology, we searched in five electronical databases including randomized controlled trials (RCTs) on SMIs for overweight/obesity. We used the terms "self-management", "adult" and "obesity" for content. Two independent reviewers assessed eligible references; one reviewer extracted data, a second checked accuracy. We identified 497 RCTs (58% US, 20% Europe) including 99,741 (median 112, range 11-5145) adults living with overweight/obesity. Most research evaluated clinical outcomes (617, 55%) and behaviors adherence (255, 23%). Empowerment skills, quality of life and satisfaction were less targeted (8%, 7%, 0.2%, respectively). The most frequent techniques included sharing information (858, 99%), goal setting (619, 72%) and self-monitoring training (614, 71%), provided face-to-face (386, 45%) or in combination with remote techniques (256, 30%). Emotional management, social support and shared-decision were less frequent (18%, 26%, 4%). Socio-economic status, minorities or health literacy were seldom reported. There is a need of widening the scope of research by focusing on outcomes important to patients, assessing emotional/social/share-decision support, exploring remote techniques and including vulnerable populations

Using a Taxonomy to Systematically Identify and Describe Self-Management Interventions Components in Randomized Trials for COPD

Self-management interventions (SMIs) may improve outcomes in Chronic Obstructive Pulmonary Disease (COPD). However, accurate comparisons of their relative effectiveness are challenging, partly due to a lack of clarity and detail regarding the intervention content being evaluated. This study systematically describes intervention components and characteristics in randomized controlled trials (RCTs) related to COPD self-management using the COMPAR-EU taxonomy as a framework, identifying components that are insufficiently incorporated into the design of the intervention or insufficiently reported. Overall, 235 RCTs published between 2010 and 2018, from a systematic review were coded using the taxonomy, which includes 132 components across four domains: intervention characteristics, expected patient (or caregiver) self-management behaviours, patient relevant outcomes, and target population characteristics. Risk of bias was also assessed. Interventions mainly focused on physical activity (67.4%), and condition-specific behaviours like breathing exercise (63.5%), self-monitoring (50.8%), and medication use (33.9%). Support techniques like education and skills-training, self-monitoring, and goal setting (over 35% of the RCTs) were mostly used for this. Emotional-based techniques, problem-solving, and shared decision-making were less frequently reported (less than 15% of the studies). Numerous SMIs components were insufficiently incorporated into the design of COPD SMIs or insufficiently reported. Characteristics like mode of delivery, intensity, location, and providers involved were often not described. Only 8% of the interventions were tailored to the target population's characteristics. Outcomes that are considered important by patients were hardly taken into account. There is still a lot to improve in both the design and description of SMIs for COPD. Using a framework such as the COMPAR-EU SMI taxonomy may contribute to better reporting and to better informing of replication efforts. In addition, prospective use of the taxonomy for developing and reporting intervention content would further aid in building a cumulative science of effective SMIs in COPD

Depiction of pneumothoraces in a large animal model using x-ray dark-field radiography

The aim of this study was to assess the diagnostic value of x-ray dark-field radiography to detect pneumothoraces in a pig model. Eight pigs were imaged with an experimental grating-based large-animal dark-field scanner before and after induction of a unilateral pneumothorax. Image contrast-to-noise ratios between lung tissue and the air-filled pleural cavity were quantified for transmission and dark-field radiograms. The projected area in the object plane of the inflated lung was measured in dark-field images to quantify the collapse of lung parenchyma due to a pneumothorax. Means and standard deviations for lung sizes and signal intensities from dark-field and transmission images were tested for statistical significance using Student’s two-tailed t-test for paired samples. The contrast-to-noise ratio between the air-filled pleural space of lateral pneumothoraces and lung tissue was significantly higher in the dark-field (3.65 ± 0.9) than in the transmission images (1.13 ± 1.1; p = 0.002). In case of dorsally located pneumothoraces, a significant decrease (−20.5%; p > 0.0001) in the projected area of inflated lung parenchyma was found after a pneumothorax was induced. Therefore, the detection of pneumothoraces in x-ray dark-field radiography was facilitated compared to transmission imaging in a large animal model

Depiction of pneumothoraces in a large animal model using x-ray dark-field radiography

The aim of this study was to assess the diagnostic value of x-ray dark-field radiography to detect pneumothoraces in a pig model. Eight pigs were imaged with an experimental grating-based large-animal dark-field scanner before and after induction of a unilateral pneumothorax. Image contrast-tonoise ratios between lung tissue and the air-filled pleural cavity were quantified for transmission and dark-field radiograms. The projected area in the object plane of the inflated lung was measured in dark-field images to quantify the collapse of lung parenchyma due to a pneumothorax. Means and standard deviations for lung sizes and signal intensities from dark-field and transmission images were tested for statistical significance using Student's two-tailed t-test for paired samples. The contrast-to-noise ratio between the air-filled pleural space of lateral pneumothoraces and lung tissue was significantly higher in the dark-field (3.65 +/- 0.9) than in the transmission images (1.13 +/- 1.1;p = 0.002). In case of dorsally located pneumothoraces, a significant decrease (-20.5%;p > 0.0001) in the projected area of inflated lung parenchyma was found after a pneumothorax was induced. Therefore, the detection of pneumothoraces in x-ray dark-field radiography was facilitated compared to transmission imaging in a large animal model

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Expressionanalysis of immunoproteasomal subunits after stimulation of macrophages, smooth muscle cells and endothelial cells with mediators relevant in atherosclerosis

Atherosklerose wird als eine multifaktoriell bedingte, chronische Inflammation der Gefäßwand verstanden. Das Ubiqutin Proteasom System (UPS) ist nicht nur der Hauptdegradationsweg inrazellulärer Proteine, sondern auch entscheidend beteiligt an der Regulation einer Vielzahl zellulärer Vorgänge. Neben dem konstitutiven 26S Proteasom existiert eine weitere, induzierbare Form des Proteasoms, das Immunoproteasom. Immunoproteasomen zeigen eine hohe Grundexpression in immunologisch relevanten Zellen, während sie in nichtimmunologischen Geweben basal sehr niedrig exprimiert sind, jedoch durch Zytokine induziert werden können. Wichtige, vom UPS beeinflusste Prozesse wie Inflammation, Proliferation, Zellzyklus und Apoptose sind auch von zentraler Bedeutung für die Initiation und Progression der Atherosklerose. Erste experimentelle Daten lassen vermuten, dass das UPS an den pathopyhsiologischen Prozessen der Atherogenese beteiligt ist. Darüber hinaus könnte eine eigenständige Bedeutung, unabhängig vom konstitutiven Proteasom für das Immunoproteasom vermutet werden. In der vorliegenden Arbeit wurden die Grundexpression und die Induzierbarkeit von immunoproteasomalen Untereinheiten in Endothelzellen, Makrophagen und vaskulären glatten Muskelzellen untersucht. Es konnte gezeigt werden, dass in diesen für die Atherosklerose wichtigen Zelltypen Immunoproteasomen neben IFN auch durch TNF-alpha induzierbar sind. Für weitere proinflammatorische Zytokine (IL-1-beta, IL-12, IL-18) sowie oxidativ modifiziertes LDL (oxLDL) konnte keine Beeinflussung der Expression immunoproteasomaler Untereinheiten gezeigt werden. Die vorliegende Arbeit bestätigt IFN und TNF-alpha als potente Regulatoren der immunoproteasomalen Expression und zeigt, dass IL-1-beta, IL-12, IL-18 und oxLDL keinen Einfluss auf die Expression immunoproteasomaler Untereinheiten ausüben.Atherosclerosis is a consequence of oxidative stress and chronic inflammation of the vessel wall. The Ubiquitin Proteasome System (UPS) is not only the main degradation pathway of intracellular proteins but is also important for the regulation of many cellular processes. There are two types of proteasomes: the constitutive 26S type and an inducible type known as the immunoproteasome. Immunoproteasomes show high basic expression in immunologically relevant cells and can be induced by cytokines in non-immunologic tissues. Important processes influenced by the UPS such as inflammation and immunresponse, proliferation, cell cycle and apoptosis are of central importance in the initiation and progression of atherosclerosis. First experimental data suggest that the UPS is involved in pathophysiological processes of atherosclerosis. Furthermore a distinct role of the immunoproteasome, independent of the constitutive proteasome could be suggested. This study examines the basic expression and inducibility of immunoproteasomal subunits in endothelial cells, macrophages and vascular smooth muscle cells. I show that in cell types most relevant to atherosclerosis, immunoproteasomes can be induced not only by IFN but also by TNF-alpha. Other proinflammatory cytokines (IL-1-beta, IL-12, IL-18) as well as oxidatively modified LDL (oxLDL) had no effect on the expression of immunoproteasomal subunits. This study confirms IFN and TNF- alpha as potent regulators of immunoproteasomal expression and shows that IL-1-beta, IL-12, IL-18 and oxLDL have no influence on the expression of immunoproteasomal subunits