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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. Keywords: Asia, Overall survival, Prostate cancer, Quality of life, Registry

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.

Objective To evaluate the longitudinal relationship between bone mineral density (BMD) and BMD changes and the progression of knee osteoarthritis (OA), as measured by cartilage outcomes. Methods We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. Bilateral femoral neck BMD values as well as knee magnetic resonance imaging (MRI) scans in each subject were obtained at baseline and subsequently at 12 months and 24 months. The change in total cartilage volume and tibial and femoral cartilage thickness was measured by manual cartilage segmentation of 2 sequential knee MRI scans 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, sex, body mass index, malalignment, and vitamin D treatment. Model fit and assumptions were validated. Results A total of 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (β = 1.25 per 0.1 gm/cm2, P = 0.02) and loss of tibial cartilage thickness (β = 0.028, P = 0.03). BMD loss of a magnitude greater than the least significant change (

Pediatric multiple sclerosis (MS) is a chronic inflammatory neurologic disease that is challenging to diagnose and treat. Although there are many clinical parallels between pediatric-onset MS and adult-onset MS, there is also accumulating evidence of distinguishing clinical features that may, in part, arise from development-specific, neuroimmune processes governing MS pathogenesis in children. Here the authors describe the clinical features, diagnosis, and treatment of pediatric MS, with a particular focus on describing clinical features and highlighting new developments that promise a better understanding of pediatric MS pathogenesis. An important task that lies ahead for pediatric neurologists is better understanding the early gene-environment interaction that precipitates the first demyelinating event in pediatric MS. This area is of particular importance for understanding the MS etiology and the natural history of pediatric MS. Such understanding should in turn inform new developments in diagnostic tools, long-term therapies, and much-needed biomarkers. Such biomarkers are not only valuable for defining the disease onset, but also for monitoring both the treatment response and a disease evolution that spans multiple decades in children with MS.

Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by autoantibodies and preferentially affecting women of childbearing age. Because the offspring of mothers with SLE show a high frequency of learning disorders, we hypothesized that maternally transferred autoantibodies that bind DNA and the N-methyl-D-aspartate receptor (NMDAR) could have a pathogenic role during fetal brain development. Here we describe a maternal SLE mouse model wherein pregnant dams harbored DNA-specific, NMDAR-specific autoantibodies throughout gestation. High titers of these autoantibodies 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 autoantibodies causes abnormal brain development with long-term consequences. This paradigm may apply to multiple congenital neuropsychiatric disorders.

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.

INTRODUCTION: We reviewed our experience with the use of gabapentin to treat symptoms of overactive bladder (OAB) and nocturia in patients who have failed conventional anticholinergic therapy. METHODS: Thirty-one patients referred to us with refractory (OAB) and/or nocturia were treated with oral gabapentin. All the patients had tried or remained on antimuscarinic drugs during treatment. Twenty-four of 31 complained of bothersome symptoms during day and night and the other seven had primary complaints of nocturia. Initial gabapentin doses ranged from 100-300 mg at bedtime. Dose was slowly titrated up to 3,000 mg based on patients' symptomatology and tolerability. RESULTS:The mean age was 51 years old (range 27-78). There were 13 men and 18 women. The median steady state dose chosen by the patient after initial titration was 600 mg/day. Fourteen of 31 patients reported subjective improvement of their frequency and 8 have been on the medication for over 12 months with persistent efficacy. For the 14 improved patients, mean frequency/24 hours decreased from 14.1 ± 2.2 to10.0 + 2.1. Three patients with primary nocturia reported improvement from a mean of 4.0 ± 1.3 to 1.0 ± 0.3 episodes/night. Six patients stopped taking the drug within one month due to side effects mostly described as drowsiness or lethargy. CONCLUSION: Fourteen of 31 patients with refractory (OAB) and nocturia improved with oral gabapentin. Gabapentin was generally well tolerated and can be considered in selective patients when conventional modalities have failed.

Specification and validation of a real-time system are often based on making simplistic predictions and assumptions about relevant behavior of the external environment and the controlled device interacting with it. However, in many cases, real-time systems physically interact with other external objects in a complex manner in a dynamically changing world and thus, their form (e.g. physical properties such as shape, mass, material, and configuration) can play a critical role in producing a correct specification and obtaining realistic simulation output. We present ASADAL/PROTO, a specification and simulation tool for real-time systems, that takes form into account in addition to the function and behavior handled by ASADAL/SIM, its predecessor. Simulation of the control system specification runs in conjunction with the environmental simulation, and the resulting interactive behavior of the controlled system is observed visually for analysis. Our vision is to incrementally model, simulate and analyze all three views (behavior, function, and form) of real-time system specification for its increased level of confidence at early prototyping stage.

To evaluate the longitudinal relationship between bone mineral density (BMD) and BMD changes and the progression of knee osteoarthritis (OA), as measured by cartilage outcomes.We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. Bilateral femoral neck BMD values as well as knee magnetic resonance imaging (MRI) scans in each subject were obtained at baseline and subsequently at 12 months and 24 months. The change in total cartilage volume and tibial and femoral cartilage thickness was measured by manual cartilage segmentation of 2 sequential knee MRI scans 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, sex, body mass index, malalignment, and vitamin D treatment. Model fit and assumptions were validated.A total of 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (β = 1.25 per 0.1 gm/cm(2) , P = 0.02) and loss of tibial cartilage thickness (β = 0.028, P = 0.03). BMD loss of a magnitude greater than the least significant change (-4.7%) was associated with 1.02% cartilage volume loss per year (P = 0.005), 0.014 mm femoral cartilage thickness loss (P = 0.04), and 0.021 mm tibial cartilage thickness loss per year (P = 0.009). There were no significant associations between baseline BMD and any of the cartilage outcomes.Longitudinal BMD loss is associated with progressive cartilage loss in knees with OA. Further work to clarify the basis of this relationship could reveal novel therapeutic targets for knee OA.

Caveolae are organelles abundant in the plasma membrane of many specialized cells including endothelial cells (ECs), epithelial cells, and adipocytes, and in these cells, caveolin-1 (Cav-1) is the major coat protein essential for the formation of caveolae. To identify proteins that require Cav-1 for stable incorporation into membrane raft domains, a quantitative proteomics analysis using isobaric tagging for relative and absolute quantification was performed on rafts isolated from wild-type and Cav-1-deficient mice. In three independent experiments, 117 proteins were consistently identified in membrane rafts with the largest differences in the levels of Cav-2 and in the caveola regulatory proteins Cavin-1 and Cavin-2. Because the lung is highly enriched in ECs, we validated and characterized the role of the newly described protein Cavin-1 in several cardiovascular tissues and in ECs. Cavin-1 was highly expressed in ECs lining blood vessels and in cultured ECs. Knockdown of Cavin-1 reduced the levels of Cav-1 and -2 and weakly influenced the formation of high molecular weight oligomers containing Cav-1 and -2. Cavin-1 silencing enhanced basal nitric oxide release from ECs but blocked proangiogenic phenotypes such as EC proliferation, migration, and morphogenesis in vitro. Thus, these data support an important role of Cavin-1 as a regulator of caveola function in ECs.

Most real-time embedded control software feature complex interactions with asynchronous inputs and environment objects, and a meaningful simulation of a real-time control software specification requires realistic simulation of its environment. Two problems that need to be addressed in the simulation of a target software system and its environment: First, integration and simulation of the specifications of a target software system and its artificial environment are often performed too late in the lifecycle to provide any significant value. Second, real world objects in the environment usually have spatial characteristics ( form ) such as shape, motion, etc. that must be specified for simulation, and there is no method to express these spatial characteristics at various levels of abstraction that are adequate for the required simulation fidelity.To address these problems, we have developed a method that supports incremental specification and simulation of both the target software system and its environmental objects. The method includes: (1) a specification method for behavior, function, and form integrated objects; (2) form specification primitives that abstract common spatial characteristics of real world objects, their typical spatial relations, and spatial interactions; and (3) a methodology that refines, verifies, and validates behavior, function, and form specification of both the real-time embedded control software and its environment in a systematic and incremental manner. The proposed specification, verification, and validation method has been applied to a robot control system example to demonstrate its effectiveness and usefulness.

Retinoid X receptors (RXRs) are nuclear receptors for retinoids that play a critical role in the regulation of growth and differentiation in normal and tumor cells. Deregulation of RXR expression has been reported in non-small cell lung cancer (NSCLC); however, the mechanism underlying the impaired expression of RXRs in lung cancer is not known. Aberrant methylation of promoter CpG islands is known to be a major mechanism for inactivation of tumor suppressor genes. We investigated the methylation status of the RXR genes in 139 surgically-resected NSCLCs and correlated the results with the clinicopathologic characteristics of the patients. Methylation in the tumors was detected at RXRα (5.7%), RXRβ (4.3%), and RXRγ (23.7%). RT-PCR analysis showed that RXRγ methylation correlates with mRNA expression. Methylation of the RXRγ gene was not significantly associated with the prognosis of patients; however, when the patients are categorized by smoking status, the effect of RXRγ methylation on prognosis was significantly different between never- and ever-smokers (P = 0.003 [test for homogeneity]); specifically, RXRγ methylation was associated with a significantly worse survival in never-smokers, whereas it exhibited a better survival outcome in ever-smokers, although not statistically significant. This finding suggests that methylation-associated down-regulation of the RXRγ gene may play a differential role in the carcinogenesis of NSCLCs according to smoking status, but further studies are needed to confirm this. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4935.