Neuropsychiatric systemic lupus erythematosus, which often entails cognitive disturbances and memory loss, has become a major complication for lupus patients. Previously, we developed a murine model of neuropsychiatric lupus based on Abs that cross-react with dsDNA and the NMDA receptor (NMDAR). We showed that these murine Abs impair cognition when they access the CNS through a breach in the blood-brain barrier (BBB) triggered by lipopolysaccharide. Because studies show that lupus patients possess anti-NMDAR Abs in their serum and cerebrospinal fluid, we decided to investigate whether these human Abs contribute to cognitive dysfunction. Here, we show that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharide to compromise the BBB integrity. Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. To determine whether anti-NMDAR Abs exist in the brains of systemic lupus erythematosus patients, we eluted IgG from a patient's brain. The IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. We examined four more brains of patients with neuropsychiatric lupus and found that they displayed endogenous IgG colocalizing with anti-NMDAR Abs. Our results indicate that lupus patients have circulating anti-NMDAR Abs capable of causing neuronal damage and memory deficit, if they breach the BBB, and that the Abs exist within patients' brains. Which aspects of neuropsychiatric lupus may be mediated by anti-NMDAR Abs, how often, and in which patients are now important clinical questions.brain-derived antibodies ͉ neuropsychiatric systemic lupus erythematosus ͉ neurotoxic antibodies N europsychiatric lupus has become a prominent problem in patients with systemic lupus erythematosus (SLE) because they live longer due to improved therapy. Neuropsychiatric lupus is a complex set of syndromes, but cognitive impairment, manifested as a memory deficit, represents one of the most common symptoms (1-5). Certainly, multiple pathogenetic mechanisms underlie cognitive dysfunction in neuropsychiatric lupus, including medication, infarction, hypertension, and accelerated atherosclerosis. Because autoAbs clearly contribute to other organ injuries in SLE, we have been interested in their potential contribution to neuropsychiatric lupus. We have demonstrated that a subset of anti-DNA Abs binds a pentapeptide consensus sequence (D/E W E/D Y S/G, or DWEYS for short) present in the NR2A and NR2B subunits of the NMDA receptor (NMDAR) (6-8) but not in NR2C and NR2D. These Abs cross-react with both murine and human NMDAR, and they mediate neuronal death in vitro when added to cultures of fetal brain cells and in vivo when directly injected into a mouse brain (9). Additionally, NMDAR antagonists can protect neurons from Ab-mediated injury, confirming that the Abs function as receptor agonists. FabЈ2 fragments of a monoclonal crossreacti...

Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies (AAbs) and preferentially affecting women of childbearing age. Since the offspring of mothers with SLE exhibit a high frequency of learning disorders1-5, we hypothesized that maternally transferred AAbs that bind DNA and the N-methyl-D-aspartate receptor (NMDAR)6-12 could play a pathogenic role during fetal brain development. Here we describe a maternal SLE murine model wherein pregnant dams harbored DNA-specific, NMDAR-specific AAbs throughout gestation. High titers of these AAbs in maternal circulation led to histological abnormalities in fetal brain and subsequent cognitive impairments in adult offspring. These data support a paradigm in which in utero exposure to neurotoxic AAbs causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.

Objective We sought to evaluate the longitudinal relationship of bone mineral density (BMD) and its change to knee osteoarthritis (OA) progression measured by cartilage outcomes. Methods We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. We obtained bilateral femoral neck BMDs as well as knee MRIs in each subject at baseline and subsequently at 12 and 24 months. We measured change in total cartilage volume, tibial and femoral cartilage thickness by manual cartilage segmentation of two sequential knee MRIs in each subject. Multivariable linear regression models were used to examine the associations of baseline BMD and BMD change with the cartilage outcomes, adjusting for baseline age, gender, BMI, malalignment and vitamin D treatment. We validated model fit and assumptions. Results 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (β=1.25 per 0.1g/cm2, p=0.02) and tibial cartilage thickness (β=0.028, p=0.03). BMD loss of a magnitude greater than least significant change (≤ −4.7%) was associated with 1.02% cartilage volume loss per year (p=0.005), 0.014mm femoral cartilage thickness loss (p=0.04) and 0.021mm tibial cartilage thickness loss per year (p=0.009). There were no significant associations between baseline BMD and any of the cartilage outcomes. Conclusions Longitudinal BMD loss is associated with progressive cartilage loss in knees with OA. Further work to clarify the basis of this relationship could uncover novel therapeutic targets for knee OA.

Myeloperoxidase (MPO) is a pro-inflammatory enzyme abundantly secreted by activated myeloid cells after stroke. We show that when MPO activity is either blocked by the specific inhibitor 4-aminobenzoic acid hydrazide (ABAH) in wildtype (WT) mice or congenitally absent (MPO), there was decreased cell loss, including degenerating neurons and oligodendrocytes, in the ischemic brains compared to vehicle-treated WT mice after stroke. MPO inhibition also reduced the number of activated myeloid cells after ischemia. MPO inhibition increased cytoprotective heat shock protein 70 (Hsp70) by 70% and p-Akt by 60%, while decreased the apoptotic marker p53 level by 62%, compared to vehicle-treated mice after ischemia. Similarly, MPO inhibition increased the number of Hsp70/NeuN cells after stroke by 60%. Notably, MPO inhibition significantly improved neurological outcome compared with the vehicle-treated group after stroke. We further found longer treatment periods resulted in larger reduction of infarct size and greater neurobehavioral improvement from MPO inhibition, even when given days after stroke. Therefore, MPO inhibition with ABAH or MPO deficiency creates a protective environment that decreased inflammatory cell recruitment and increased expression of survival factors to improve functional outcome. MPO inhibition may represent a promising therapeutic target for stroke therapy, possibly even days after stroke has occurred.

Background The incidence of prostate cancer (PC) in Asian countries is increasing for reasons that are not clear. Data describing how PC is diagnosed and treated are fragmented across Asia, with marked intercountry and intracountry differences in outcome and knowledge gaps in clinical diagnostic and treatment practices. To address these knowledge gaps, we have established a PC disease registry with the aim of providing a comprehensive picture of PC diagnosis, prognosis, treatment and outcome, population characteristics, and comorbidities in real-world clinical practice in Asia. Methods This is a multinational, multicenter, longitudinal, and observational registry of PC patients presenting to participating tertiary-care hospitals in eight Asian countries ( www.clinicaltrials.gov NCT02546908. Registry Identifier: NOPRODPCR4001). Approximately 3500-4000 eligible patients with existing or newly diagnosed high-risk localized PC (cohort 1), nonmetastatic biochemically recurrent PC (cohort 2), or metastatic PC (cohort 3) will be consecutively enrolled and followed-up for 5 years. An enrollment cap of 600 patients each will be applied to cohorts 1 and 2. Disease status is collected at enrollment, and outcome variables captured at 3-monthly intervals include diagnostic/staging, treatments including reason for change, laboratory results, comorbidities, and concomitant medications. Treatments and survival outcomes will be captured real time until study end. Patient-reported quality-of-life will be measured every 6 months, and medical resource utilization summarized at study end. Data analysis will include exploratory analyses of potential associations between multiple risk factors and socioeconomic variables with disease progression and evaluation of various treatments for PC including novel therapies on clinical outcome and health-related quality-of-life outcomes. Results 3636 men with PC were enrolled until July 2018; 416 in cohort 1, 399 in cohort 2 and 2821 in cohort 3. Discussion A total of 3636 patients were enrolled until July 2018. The prospective disease registry will provide comprehensive and wide-ranging real-world information on how PC is diagnosed and treated in Asia. Such information can be used to inform policy development for best practice and direct clinical study design evaluating new treatments.

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