B cell and/or autoantibody deficiency do not prevent neuropsychiatric disease in murine systemic lupus erythematosus

Background: Neuropsychiatric lupus (NPSLE) can be one of the earliest clinical manifestations in human lupus. However, its mechanisms are not fully understood. In lupus, a compromised blood-brain barrier may allow for the passage of circulating autoantibodies into the brain, where they can induce neuropsychiatric abnormalities including depression-like behavior and cognitive abnormalities. The purpose of this study was to determine the role of B cells and/or autoantibodies in the pathogenesis of murine NPSLE. Methods: We evaluated neuropsychiatric manifestations, brain pathology, and cytokine expression in constitutively (JhD/MRL/lpr) and conditionally (hCD20-DTA/MRL/lpr, inducible by tamoxifen) B cell-depleted mice as compared to MRL/lpr lupus mice. Results: We found that autoantibody levels were negligible (JhD/MRL/lpr) or significantly reduced (hCD20-DTA/MRL/lpr) in the serum and cerebrospinal fluid, respectively. Nevertheless, both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice showed profound depression-like behavior, which was no different from MRL/lpr mice. Cognitive deficits were also observed in both JhD/MRL/lpr and hCD20-DTA/MRL/lpr mice, similar to those exhibited by MRL/lpr mice. Furthermore, although some differences were dependent on the timing of depletion, central features of NPSLE in the MRL/lpr strain including increased blood-brain barrier permeability, brain cell apoptosis, and upregulated cytokine expression persisted in B cell-deficient and B cell-depleted mice. Conclusions: Our study surprisingly found that B cells and/or autoantibodies are not required for key features of neuropsychiatric disease in murine NPSLE

Differential Proteome Analysis of Bone Marrow Mesenchymal Stem Cells from Adolescent Idiopathic Scoliosis Patients

Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. The cause and pathogenesis of scoliosis and the accompanying generalized osteopenia remain unclear despite decades of extensive research. In this study, we utilized two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) to analyze the differential proteome of bone marrow mesenchymal stem cells (BM-MSCs) from AIS patients. In total, 41 significantly altered protein spots were detected, of which 34 spots were identified by MALDI-TOF/TOF analysis and found to represent 25 distinct gene products. Among these proteins, five related to bone growth and development, including pyruvate kinase M2, annexin A2, heat shock 27 kDa protein, γ-actin, and β-actin, were found to be dysregulated and therefore selected for further validation by Western blot analysis. At the protein level, our results supported the previous hypothesis that decreased osteogenic differentiation ability of MSCs is one of the mechanisms leading to osteopenia in AIS. In summary, we analyzed the differential BM-MSCs proteome of AIS patients for the first time, which may help to elucidate the underlying molecular mechanisms of bone loss in AIS and also increase understanding of the etiology and pathogenesis of AIS

Challenges in assessing and managing multi-hazard risks: A European stakeholders perspective

The latest evidence suggests that multi-hazards and their interrelationships (e.g., triggering, compound, and consecutive hazards) are becoming more frequent across Europe, underlying a need for resilience building by moving from single-hazard-focused to multi-hazard risk assessment and management. Although significant advancements were made in our understanding of these events, mainstream practice is still focused on risks due to single hazards (e.g., flooding, earthquakes, droughts), with a limited understanding of the stakeholder needs on the ground. To overcome this limitation, this paper sets out to understand the challenges for moving towards multi-hazard risk management through the perspective of European stakeholders. Based on five workshops across different European pilots (Danube Region, Veneto Region, Scandinavia, North Sea, and Canary Islands) and an expert workshop, we identify five prime challenges: i) governance, ii) knowledge of multi-hazards and multi-risks, iii) existing approaches to disaster risk management, iv) translation of science to policy and practice, and v) lack of data. These challenges are inherently linked and cannot be tackled in isolation with path dependency posing a significant hurdle in transitioning from single- to multi-hazard risk management. Going forward, we identify promising approaches for overcoming some of the challenges, including emerging approaches for multi-hazard characterisation, a common understanding of terminology, and a comprehensive framework for guiding multi-hazard risk assessment and management. We argue for a need to think beyond natural hazards and include other threats in creating a comprehensive overview of multi-hazard risks, as well as promoting thinking of multi-hazard risk reduction in the context of larger development goals

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.In the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.Taken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Invited perspectives: Views of 350 natural hazard community members on key challenges in natural hazards research and the Sustainable Development Goals

In this paper, we present the results of an NHESS (Natural Hazards and Earth System Sciences) 20th anniversary survey, in which 350 natural hazard community members responded to two questions: (Q1) “what are the top three scientific challenges you believe are currently facing our understanding of natural hazards” and (Q2) “what three broad step changes should or could be done by the natural hazard community to address natural hazards in achieving the Sustainable Development Goals”? We have analysed the data quantitatively and qualitatively. According to the 350 respondents, the most significant challenges (Q1) are the following (within brackets % of 350 respondents who identified a given theme): (i) shortcomings in the knowledge of risk and risk components (64 %), (ii) deficiencies of hazard and risk reduction approaches (37 %), (iii) influence of global change, especially climate change (35 %), (iv) integration of social factors (18%), (v) inadequate translation of science to policy and practice (17 %), and (vi) lack of interdisciplinary approaches (6 %). In order for the natural hazard community to support the implementation of the Sustainable Development Goals (Q2), respondents called for (i) enhanced stakeholder engagement, communication and knowledge transfer (39 %), (ii) increased management and reduction of disaster risks (34 %), (iii) enhanced interdisciplinary research and its translation to policy and practice (29 %), (iv) a better understanding of natural hazards (23 %), (v) better data, enhanced access to data and data sharing (9 %), and (vi) increased attention to developing countries (6 %). We note that while the most common knowledge gaps are felt to be around components of knowledge about risk drivers, the step changes that the community felt were necessary related more to issues of wider stakeholder engagement, increased risk management and interdisciplinary working